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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Selonsertib, GS-4997, GS-4977


Selonsertib.png

GS-4997, GS-4977, Selonsertib

Selonsertib; 1448428-04-3; GS-4997; UNII-NS3988A2TC; NS3988A2TC; 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]benzamide

  • 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-[6-[4-(1-methylethyl)-4H-1,2,4-triazol-3-yl]-2-pyridinyl]benzamide
  • 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}benzamide
Molecular Formula: C24H24FN7O
Molecular Weight: 445.502 g/mol
      • NMR  https://file.medchemexpress.com/batch_PDF/HY-18938/Selonsertib-HNMR-25028-MedChemExpress.pdf

str1

Selonsertib is an orally bioavailable inhibitor of apoptosis signal-regulating kinase 1 (ASK1; IC50 = 3.2 nM), which is involved in a variety of conditions, including fibrosis, oxidative stress, and inflammation, among others.1 A formulation containing selonsertib showed antifibrotic activity in a Phase II clinical trial. Clinical trials are ongoing for other conditions, including severe alcoholic hepatitis and nonalcoholic steatohepatitis.

Synonyms
  • GS-4997
  • GS-4977
  • Originator Gilead Sciences
  • Class Benzamides; Cardiovascular therapies; Imidazoles; Pyridines; Triazoles
  • Mechanism of Action MAP kinase kinase kinase 5 inhibitors

Highest Development Phases

  • Phase III Non-alcoholic steatohepatitis
  • Phase II Alcoholic hepatitis; Diabetic nephropathies; Non-alcoholic fatty liver disease; Pulmonary arterial hypertension

Most Recent Events

  • 13 Apr 2018 Efficacy data from a phase II trial in Non-alcoholic fatty liver disease presented at the The International Liver Congress™ 2018 of the European Association for the Study of the Liver (EASL-2018)
  • 13 Apr 2018 Gilead completes enrolment in the STELLAR 3 phase III trial for Non-alcoholic steatohepatitis in US, Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, South Korea, Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, Turkey, and United Kingdom (NCT03053050)
  • 13 Apr 2018 Gilead completes enrolment in the STELLAR 4 phase III trial for Non-alcoholic steatohepatitis in the US, Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, South Korea, Mexico, New Zealand, Poland, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, and United Kingdom ( NCT03053063)

Apoptosis signal -regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (“MAP3K”) family that activates the c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase (Ichijo, H., Nishida, E., e, K., Dijke, P. T., Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94).

ASK1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-a, FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., Naguro, I., Runchel, C, and Ichijo, H. (2009) Cell Comm. Signal. 7: 1-10; Takeda, K., Noguchi, T., Naguro, I., and Ichijo, H. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27; Nagai, H., Noguchi, T., Takeda, K., and Ichijo, I. (2007) J. Biochem. Mol. Biol. 40: 1-6).

Phosphorylation of ASK1 protein can lead to apoptosis or other cellular responses depending on the cell type. ASK1 activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory,

autoimmune, and metabolic disorders. In addition, ASK1 has been implicated in mediating organ damage following ischemia and reperfasion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al, (2003) Life Sci 74-37-43; Terada et al. (2007) BBRC 364: 1043-49).

ROS are reported be associated with increases of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. (Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 201 1 Mar;7(3): 176- 184; Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001 Dec 13; 414(6865):813-820; Mimura I, Nangaku M. The suffocating kidney:

tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 2010 Nov; 6(1 1):667- 678).

Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS. (Hung KY, et al. N- acetylcysteine-mediated antioxidation prevents hyperglycemia-induced apoptosis and collagen synthesis in rat mesangial cells. Am J Nephrol 2009;29(3): 192-202).

Tubulointerstitial fibrosis in the kidney is a strong predictor of progression to renal failure in patients with chronic kidney diseases (Schainuck LI, et al. Structural-functional correlations in renal disease. Part II: The correlations. Hum Pathol 1970; 1 : 631-641.).

Unilateral ureteral obstruction (UUO) in rats is a widely used model of tubulointerstitial fibrosis. UUO causes tubulointerstital inflammation, increased expression of transforming growth factor beta (TGF-β), and accumulation of myofibroblasts, which secrete matrix proteins such as collagen and fibronectin. The UUO model can be used to test for a drug’s potential to treat chronic kidney disease by inhibiting renal fibrosis (Chevalier et al., Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy, Kidney International (2009) 75, 1 145-1152.

Thus, therapeutic agents that function as inhibitors of ASK1 signaling have the potential to remedy or improve the lives of patients in need of treatment for diseases or conditions such as neurodegenerative, cardiovascular, inflammatory, autoimmune, and metabolic disorders. In particular, ASK1 inhibitors have the potential to treat cardio-renal diseases, including kidney disease, diabetic kidney disease, chronic kidney disease, fibrotic diseases (including lung and kidney fibrosis), respiratory diseases (including chronic obstructive pulmonary disease (COPD) and acute lung injury), acute and chronic liver diseases.

U.S. Publication No. 2007/0276050 describes methods for identifying AS 1 inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal.

WO2009027283 discloses triazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases.

U.S. Patent Publication No. 2001/00095410A1, published January 13, 201 1, discloses compounds useful as ASK-1 inhibitors. U.S. Patent Publication No. 2001/00095410A1 relates to compounds of Formula (I):

Figure imgf000004_0001
SYN
WO  2016106384

PRODUCT PATENT

WO 2013112741

https://patents.google.com/patent/WO2013112741A1/en

InventorGregory Notte Original AssigneeGilead Sciences, Inc. Priority date 2012-01-27

SCHEME 1

Figure imgf000013_0001

SCHEME 2

 Figure imgf000015_0001

COUPLING

Figure imgf000014_0001Figure imgf000015_0003

GIVES

Figure imgf000015_0002

The name of the compound of the present invention as generated using ChemBioDraw Ultra 11.

Figure imgf000012_0001
is 5-(4-cyclopropyl- 1 H-imidazol- 1 -yl)-N-(6-(4-isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)-2- fluoro-4-methylbenzamide also known as 5-((4-cyclopropyl-lH-imdazol-l-yl)-2-fluoro-N-(6-(4- isopropyl-4H- 1 ,2,4-triazole-3 -yl)pyridine-2-yl)-4-methylbenzamide.

One method of preparing compounds of formula (I) is shown in Reaction Schemes 1 and 2 below.

Scheme 1

Figure imgf000013_0001

Preparation of Compound A

To a solution of methyl 6-aminopicolinate (432 g, 2.84 mol) in MeOH (5 L) was added NH2NH2.H2O (284 g, 5.68 mol, 2.0 eq.). The reaction mixture was heated under reflux for 3 hr and then cooled to room temperature. The precipitate formed in the mixture was collected by filtration, washed with EA (2 L><2) and then dried in vacuo to give compound A (405 g, 94% yield) as white solid.

Preparation of compound B

A mixture of compound A (405 g, 2.66 mol) in dimethylformamide-dimethylacetal (DMF-DMA) (3.54 L) was heated under reflux for 18 hr, cooled to room temperature and then concentrated under reduced pressure. The residue was taken up in EA (700 mL) and heated at 50°C for 20 min. After being cooled to room temperature, the solid was collected by filtration and dried in vacuo to give compound B (572 g, 82% yield) as white solid.

Preparation of C

To a solution of compound B (572 g, 2.18 mol) in a mixture of CH3CN-AcOH (3.6 L, 4:1) was added propan-2-amine (646 g, 5.0 eq.). The resulting mixture was heated under reflux for 24 hr and then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in water (2.8 L) and 1 N aqueous NaOH was added to a pH of 8.0 H. The precipitate was collected by filtration and the filtrate was extracted with EA (500 mLx3). The combined organic layers were dried over anhydrous Na2S04, and then concentrated to a volume of 150 mL. To this mixture at 0°C was slowly added PE (400 mL) and the resulting suspension was filtered. The combined solid was re-crystallized from EA-PE to give compound C (253 g, 57% yield) as off-white solid.

1H- MR (400 MHz, CDC13): δ 8.24 (s, 1 H), 7.52 (m, 2 H), 6.51 (dd, J = 1.6, 7.2 Hz, 1 H), 5.55 (m, 1 H), 4.46 (bs, 2 H), 1.45 (d, J = 6.8 Hz, 6 H). MS (ESI+) m/z: 204 (M+l)+.

Compound C is a key intermediate for the synthesis of the compound of formula (I). Thus, an object of the present invention is also the provision of the intermediate compound C,

Figure imgf000014_0001

its salts or protected forms thereof, for the preparation of the compound of formula (I). An example of a salt of the compound C is the HC1 addition salt. An example of a protected form of compound C is the carbamate compound such as obtained with Cbz-Cl. Protective groups, their preparation and uses are taught in Peter G.M. Wuts and Theodora W. Greene, Protective Groups in Organic Chemistry, 2nd edition, 1991, Wiley and Sons, Publishers. Scheme 2

Preparation of the Compound of formula (I) continued:

Figure imgf000015_0001
Figure imgf000015_0002

Formula (I)

Compound 6 is a key intermediate for the synthesis of the compound of formula (I). Thus an object of the present invention is also the provision of intermediate compound 6,

Figure imgf000015_0003

6

salts or protected forms thereof, for the preparation of the compound of formula (I). An example of a salt of the compound 6 is the HC1 addition salt. An example of a protected form of the compound 6 is an ester (e.g. methyl, ethyl or benzyl esters) or the carbamate compound such as obtained with Cbz-Cl. Protective groups, their preparations and uses are taught in Peter G.M. Wuts and Theodora W. Greene, Protective Groups in Organic Chemistry, 2nd edition, 1991, Wiley and Sons, Publishers. Step 1 – Preparation of 5-amino-2-fluoro-4-methylbenzonitrile – Compound (2)

The starting 5-bromo-4-fluoro-2-methylaniline (1) (20g, 98 mmol) was dissolved in anhydrous 1-methylpyrrolidinone (100 mL), and copper (I) cyanide (17.6g, 196 mmol) was added. The reaction was heated to 180°C for 3 hours, cooled to room temperature, and water (300 mL) and concentrated ammonium hydroxide (300 mL) added. The mixture was stirred for 30 minutes and extracted with EA (3 x 200 mL). The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oily residue was washed with hexanes (2 x 100 mL), and the solid dissolved in dichloromethane and loaded onto a silica gel column. Eluting with 0 to 25% EA in hexanes gradient provided 5-amino-2-fluoro- 4-methylbenzonitrile (10.06g, 67.1 mmol). LC/MS (m/z:151 M+1).

Step 2 – Preparation of 5-(2-cvclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile – Compound (3)

5-Amino-2-fluoro-4-methylbenzonitrile (12g, 80mmol) was dissolved in anhydrous N,N- dimethylformamide (160 mL) under nitrogen, and potassium carbonate (13.27g, 96 mmol) and potassium iodide (14.61g , 88mmol) were added as solids with stirring. The reaction was stirred for 5 minutes at room temperature and then bromomethyl cyclopropylketone (20.24 mL, 180 mmol) was added. The reaction mixture was heated to 60°C for 3 hours, and then the solvents removed under reduced pressure. The residue was dissolved in EA (400 mL) and washed with 400 mL of water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The residue was re-dissolved in a minimum amount of EA, and hexanes were added to bring the solution to 3: 1 hexanes: EA by volume. The product precipitated out of solution and was collected by filtration to provide 5-(2-cyclopropyl-2- oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19g, 61.2 mmol). LC/MS (m/z : 233, M+1)

Step 3 – Preparation of 5-(4-cvclopropyl-2-mercapto-lH-imidazol-l -yl)-2-fluoro-4- methylbenzonitrile – Compound (4)

5-(2-Cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19g, 61.2mmol) was dissolved in glacial acetic acid (300 mL). Potassium thiocyanate (11.9g, 122.4mmol) was added as a solid with stirring. The reaction mixture was heated to 110°C for 4 hours at which time the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (200 mL) and washed with 200 mL water. The aqueous extract was extracted with (2 x 200 mL) additional dichloromethane, the organic extracts combined and dried over magnesium sulfate. The solvent was removed under reduced pressure and the oily residue was re-dissolved in EA (50 mL) and 150 mL hexanes was added. A dark layer formed and a stir bar was added to the flask. Vigorous stirring caused the product to precipitate as a peach colored solid. The product was collected by filtration, to yield 5-(4-cyclopropyl-2-mercapto-lH- imidazol-l-yl)-2-fluoro-4-methylbenzonitrile, (14.26g, 52.23 mmol). Anal. LC/MS (m/z : 274, M+1)

Step 4 – Preparation of 5-(4-cyclopropyl-lH-imidazol -yl)-2-fluoro-4-methylbenzonitrile – Compound (5)

In a 500 mL three neck round bottom flask was placed acetic acid (96 mL), water (19 mL) and hydrogen peroxide (30%, 7.47 mL, 65.88 mmol). The mixture was heated to 45°C with stirring under nitrogen while monitoring the internal temperature. 5-(4-Cyclopropyl-2- mercapto-lH-imidazol-l-yl)-2-fluoro-4-methylbenzonitrile (6.00g, 21.96 mmol) was then added as a solid in small portions over 30 minutes while maintaining an internal temperature below 55°C. When addition of the thioimidazole was complete the reaction was stirred for 30 minutes at a temperature of 45 C, and then cooled to room temperature, and a solution of 20% wt/wt sodium sulfite in water (6 mL) was slowly added. The mixture was stirred for 30 minutes and solvents were removed under reduced pressure. The residue was suspended in 250 mL of water and 4N aqueous ammonium hydroxide was added to bring the pH to ~10. The mixture was extracted with dichloromethane (3 x 200ml), the organics combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL EA, and 80 mL of hexanes were added with stirring. The solvents were decanted off and an oily residue was left behind. This process was repeated and the product, 5-(4-cyclopropyl-lH- imidazol-l-yl)-2-fluoro-4-methylbenzonitrile was obtained as a viscous oil (5.14 g, 21.33 mmol) Anal. LC/MS (m/z: 242, M+1)

Step 5 – Preparation of 5-(4-cvclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (6)

5-(4-Cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methylbenzonitrile (1 1.21g, 46.50mmol) was placed in a round bottom flask fitted with a reflux condenser, and suspended in 38% hydrochloric acid (200 mL). The mixture was heated to 100°C for 4.5 hours, and then cooled to room temperature. Solvent was removed under reduced pressure to give a pink solid, to which was added 100ml of EA. The solid product was collected by filtration and washed with 3 xlOO mL EA. To the solid product was added 100 mL 10% methanol in dichloromethane, the mixture stirred, and the filtrate collected. This was repeated with 2 more 100ml portions of 10% methanol in dichloromethane. The filtrates were combined and solvent was removed under reduced pressure, to provide crude 5-(4-cyclopropyl-lH-imidazol-l -yl)-2-fluoro-4- methylbenzoic acid hydrochloride. No further purification was carried out (1 1.13g, 37.54mmol). Anal. LC/MS (m/z: 261 , M+1)

Step 6 – Preparation of 5-(4-cvclopropyl- 1 H-imidazol- 1 -yl)-2-fluoro-N-(6-(4-isopropyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide – formula (I)

5-(4-Cyclopropyl- 1 H-imidazol- 1 -yl)-2-fluoro-4-methylbenzoic acid hydrochloride (1.5g,

5.07mmol) was suspended in anhydrous 1 ,2-dichlorom ethane (25 mL) at room temperature. Oxalyl chloride (0.575ml, 6.59mmol) was added with stirring under nitrogen, followed by N,N- dimethylformamide (0.044ml, 0.507mmol). The ; mixture was stirred for 4 hr at room temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in 25 mL anhydrous dichloromethane. 6-(4-isopropyl-4H-l ,2,4-triazol-3-yl)pyridin-2- amine (1.13g, 5.58mmol) (compound C) and 4-dimethylaminopyridine (0.62g, 5.07 mmol) were rapidly added with stirring under nitrogen. The reaction was stirred for 2 hours at room temperature and aqueous saturated NaHC03 (15 mL) was added. The mixture was stirred for 10 minutes, and the layers were separated, and the aqueous layer was washed 1 x 20 mL dichloromethane. The combined organics were dried (MgS04), filtered and concentrated. The residue was dissolved in a minimum amount of CH3CN and water was slowly added until solids precipitated from the mixture. The solid was collected by filtration and dried to give 5-(4- cyclopropyl-lH-imidazol-l -yl)-2-fluoro-N-(6-(4-isopropyl-4H-l ,2,4-triazol-3-yl)pyridin-2-yl)- 4-methylbenzamide in -96% purity (1.28g, 2.88 mmol). Anal. LC/MS (m/z: 446, M+1). The material was further purified by RP-HPLC (reverse phase HPLC) to obtain an analytically pure sample as the HC1 salt.

Figure imgf000018_0001

C24H24FN7O-HCI. 446.2 (M+1). 1H-NMR (DMSO): δ 1 1.12 (s, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.07 (t, J = 8.4 Hz, 1 H), 7.95 (d, J = 6.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J = 10.4 Hz, 1H), 5.72 (sept, J = 6.8 Hz, 1H), 2.29 (s, 3H), 2.00-2.05 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.01-1.06 (m, 2H), 0.85-0.89 (m, 2H).

PATENT

US 9067933

US 20150342943

WO 2016187393

WO 2016025474

WO 2016112305

WO 2017205684

WO 2017210526

WO 2018013936

PAPER

Bioorganic & Medicinal Chemistry Letters (2018), 28(3), 400-404

https://www.sciencedirect.com/science/article/pii/S0960894X17311861?via%3Dihub

https://ars.els-cdn.com/content/image/1-s2.0-S0960894X17311861-mmc1.pdf

PAPER

ACS Medicinal Chemistry Letters (2017), 8(3), 316-320

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00481

https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00481/suppl_file/ml6b00481_si_001.pdf

Abstract Image

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

PATENT

FORM I TO IX POLYMORPHS

WO 2016105453

https://patents.google.com/patent/WO2016105453A1/zh-CN

Compound I is known to exhibit ASK1 inhibitory activity and is described in, for example, U.S. Patent No. 8,742,126, which is hereby incorporated by reference in its entirety. Compound I has the formula:

Compound I

Compound I can be synthesized according to the methods described in U.S. Patent No. 8,742,126 or U.S. Provisional Application No. 62/096,391, U.S. Provisional Application No. 62/269,064 and PCT Application PCT/US2015/067511 (filed on even date herewith and titled “Processes for Preparing ASK1 Inhibitors”), all of which are incorporated by reference in their entirety.

The present disclosure provides forms of Compound I and salts, co-crystals, hydrates, and solvates thereof. Also described herein are processes for making the forms of Compound I, pharmaceutical compositions comprising crystalline forms of Compound I and methods for using such forms and pharmaceutical compositions in the treatment of diseases mediated by ASK1 disregulation.

Thus, one embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form I) characterized by an X-ray powder diffractogram comprising the following peaks: 16.7, 21.3, and 22.8 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Kct radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form II) characterized by an X-ray powder diffractogram comprising the following peaks: 11.2, 16.6, and 17.4 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form III) characterized by an X-ray powder diffractogram comprising the following peaks: 5.1, 10.2, and 25.3 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κ radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormIV) characterized by an X-ray powder diffractogram comprising the following peaks: 7.2, 12.6, and 19.3 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormV) characterized by an X-ray powder diffractogram comprising the following peaks: 9.7, 13.3, and 16.4 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVI) characterized by an X-ray powder diffractogram comprising the following peaks: 8.8, 23.2, and 23.5 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVII) characterized by an X-ray powder diffractogram comprising the following peaks: 8.2, 14.2, and 22.9 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVIII) characterized by an X-ray powder diffractogram comprising the following peaks: 8.4, 19.3, and 24.3 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyI-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormIX) characterized by an X-ray powder diffractogram comprising the following peaks: 6.9, 14.3, 23.7, and 24.8 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is amorphous 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide.

Some embodiments provided herein relate to crystalline forms of salts or co-crystals of Compound I.

The compound, 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (also known as 5-((4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazole-3-yl)pyridine-2-yl)-4-methylbenzamide)) designated herein as Compound I, has the formula:

Compound I exhibits an EC50 value of about 2 nanomolar in an ASK1 293 cell-based assay. The experimental protocol for this assay is known in the art and is described in U.S. Patent No. 8,742,126, which is hereby incorporated by reference in its entirety.

The present disclosure relates to various crystalline forms of Compound I, and processes for making the crystalline forms. Compound I also provides forms further described herein as “Compound I Form I,” “Compound I Form II,” “Compound I Form III,” “Compound I Form TV,” “Compound I Form V,” “Compound I Form VI,” “Compound I Form VII,” “Compound I Form VIII,” “Compound I Form IX,” and “amorphous Compound I.” In some embodiments, such forms of Compound I may be a solvate or a hydrate.

Additional crystalline forms of Compound I are also further described herein. In some embodiments, crystalline forms of Compound I may include salts or co-crystals of Compound I. Salts or co-crystals of Compound I may have the following formula:

 X

PATENT

WO 2016106384

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016106384&recNum=31&docAn=US2015067511&queryString=EN_ALL:nmr%20AND%20PA:(gilead%20sciences)&maxRec=1065

As described generally above, the disclosure provides in some embodiments processes for making a compound of formula (A).

Scheme 1 represents an exemplary synthesis of a compound of formula (A) and can be carried out according to the embodiments described herein. It is contemplated that the exemplary synthesis shown in Scheme 1 may be particularly advantageous. For example, the synthesis employs less toxic starting materials (i.e., using Compound (H) in place of its corresponding analog having bromide at the tosylate position), avoids toxic reagents (i.e., CuCN), and employs less toxic solvents (i.e., using dichloromethane instead of dichloroethane), including at the final step of the synthesis. The synthesis also can utilize milder reaction conditions (i.e., avoids high temperatures needed for cyanation, etc.), can avoid the use of heavy metals, and can require less purification steps (e.g. avoid column chromatography). The particular reaction conditions and reagents employed in Scheme 1 are discussed below.

Scheme 1


Compound (B)

Scheme 2

Compound (A)

Scheme 3

Compound (E) Compound (A)

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of compounds described herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers. Unless otherwise noted, the starting materials for the following reactions may be obtained from commercial sources.

Example 1: Synthesis of Compound (A)

Compound (C)


MeCN Toluene, /Pr2EtN

Compound (J) Compound (H)

ompound F

(COCI)2, DMF 

Compound (D-a)

Compound (B) J Compound (A) Hydroxytosylation of Compound (J) to form Compound (H)

Compound (J) Compound (H)

Koser’s reagent, PhI(OH)OTs, (1.0 eq.) and acetonitrile (5 vols) are charged to a flask. Cyclopropylmethyl ketone (Compound (J), 1.2 eq.) is charged and the mixture is heated to about 70 °C to about 75 °C. Once the reaction is complete, the contents are cooled and concentrated. The residue is diluted in dichloromethane (about 2.5 vols) and washed with water (2 x about 1 to 2 volumes). The organic phase is concentrated to approximately 1.5 vols and the product is triturated with hexanes (about 1.5 to 2 vols) and concentrated to remove dichloromethane and the distilled volume is replaced with hexanes. The slurry is agitated for about two hours, filtered and washed with hexanes. The solids are dried under vacuum at about 40 °C to afford Compound (H). 1H MR (400 MHz, DMSO-d6): δ 7.82 (d, 2H, J= 8.0 Hz), 7.49 (d, 2H, J= 8.0 Hz), 4.98 (s, 2H), 2.42 (s, 3H), 2.02-2.08 (m, 1H), 0.95-0.91 (m, 2H), 0.89-0.82 (m, 2H). 13C MR (100 MHz, DMSO-de): 202.39, 145.60, 132.76, 130.57, 128.12, 72.98, 21.52, 17.41, 11.39.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Koser’s reagent, alternative reagents may include, but are not limited to, (diacetoxyiodo)benzene organosulfonic acid, (diacetoxyiodo)benzene and p-toluenesulfonic acid, iodosylbenzene/p-toluenesulfonic acid, m-chloroperbenzoic acid/p-toluenesulfonic acid, poly(4-hydroxy tosyloxyiodo)styrenes, N-methyl-O-tosylhydroxylamine, Dess-Martin periodinane/p-toluenesulfonic acid, HlCVp-toluenesulfonic acid, and o-iodoxybenzoic acid/p-toluenesulfonic acid. Various solvents, such as toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and chloroform, may be employed. The reaction may take place at temperatures that range from about 20 °C to about 100 °C.

Alkylation of Compound (H) with Compound (I) to form Compound (G)

Co

To a mixture of Compound (I) (1.0 equiv) and Compound (H) (1.1 equiv) in toluene (5 vols) is charged iPr2 Et (2.1 equiv). The mixture is heated to about 90 to about 100 °C and aged for about less than 10 hours. Upon completion, the mixture is cooled and diluted with water (about 5 to about 6 vols). The biphasic mixture is separated and the organic solution is washed sequentially with aq. H4C1 (about 27 wt%, about 2 to about 3 vols), aq. NaHC03 (about 9 wt%, about 2 to about 3 vols), and aq. NaCl (about 15 wt%, about 1 vols). The organic solution is dried over Na2S04, filtered, and washed with toluene (about 2 to about 3 vols). The solution is concentrated under vacuum at about 45 °C and the residue is crystallized by the addition of hexane at about 20 °C to about 25 °C and at about 10 °C to about 15 °C. The slurry is filtered, washed with cooled isopropanol (about 1 vol) and dried under vacuum at about 37 °C to about 43 °C to afford Compound (G). 1H NMR(400 MHz, DMSO-d6): δ 7.05 (d, 1H, J= 12.0 Hz), 6.51 (d, lH, J= 8.0 Hz), 5.27 (t, 1H, J= 4.0 Hz), 4.17 (d, 2H, J= 4.0 Hz), 2.21-2.14 (m, 1H), 2.10 (s, 3H), 0.96-0.86 (m, 4H). 13NMR (100 MHz, DMSO-d6): 208.17, 151.63, 149.32, 143.99, 143.97, 123.81, 123.74, 118.13, 117.90, 112.87, 105.09, 104.88, 53.72, 18.33, 17.43, 17.42, 10.85.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organic bases (e.g., DBU and DMAP), alkali metal bases (e.g., NaH), hexamethyldisilazane bases (e.g, sodium, potassium and lithium hexamethyldisilazide), carbonate bases (e.g., Cs2C03, Na2C03), and potassium tert-butoxide. Various solvents, such as THF, MTBE, 2-MeTHF, acetonitrile, dioxane, benzene, DMF, DMAc, NMP, may be employed. The reaction may take place at temperatures that range from about -78 °C to about 100 °C.

Formylation of Compound (G) to form Compound (F)

Acetic anhydride (4 equiv) is added to aqueous formic acid (about 3 to about 4 vols) at about 0 °C to about 5 °C and the mixture is agitated. Compound (G) (1.0 equiv) in DCM (about 3 vols) is charged. The reaction is aged at about 0 to about 5 °C until it is deemed complete. Upon reaction completion, water (about 4 vols) is charged and the mixture is adjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH with the content temperature maintained between about 0 °C to about 15 °C. The biphasic mixture is separated and the aqueous solution is extracted with dichloromethane (about 6 vols). The organic solution is washed with saturated aqueous NaCl (about 4 vols), dried over Na2S04, and filtered. Compound (F) is carried forward to the next step as a solution in dichloromethane without further purification. 1H MR (400 MHz, DMSO-de): δ (mixture of amide rotamers) 8.17 (s, 1H), 8.14 (s, 1H), 7.61 (d, 1H, J= 8.0 Hz), 7.45 (d, 1H, J= 8.0 Hz), 7.42 (d, 1H, J= 12.0 Hz), 7.33 (d, 1H, J= 12.0 Hz), 4.87 (s, 2H), 4.68 (s, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 2.12-2.03 (m, 1H), 0.98-0.85 (m, 4H). 13C MR (100 MHz, DMSO-de): 206.68 (204.85), 163.71 (163.22), 158.95 (158.69), 156.51 (156.35), 139.09 (139.02), 138.61 (138.53), 137.58 (137.55), 133.35 (133.34), 132.45, 119.02 (118.79), 118.58 (118.36), 105.35 (105.03), 104.77 (104.55), 58.68, 55.40, 17.84 (17.77).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of acetic anhydride and formic acid, acetic acid monoanhydride with carbonic acid or trifluoroacetic anhydride with formic acid may be used. Various solvents, such as chloroform, acetonitrile, isopropyl acetate, or THF, may be employed. The reaction may take place at temperatures that range from about -10 °C to about 40 °C.

Imidazole Cyclization to Form Compound (E)

To a solution of Compound (F) (1.0 equiv) in DCM is charged acetic acid (about 5 vols). The solution is concentrated under vacuum at about 35 °C to remove the bulk of DCM and ammonium acetate (3.9 equiv) is added. The mixture is heated to about 110 °C to about 115 °C and agitated until the reaction is deemed complete. The reaction is cooled, diluted with water (about 10 vols) and iPrOAc (about 6 vols). The mixture is adjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH. The biphasic mixture is separated. Sodium chloride (about 0.3 wt equiv wrt Compound (F)) is charged to the aqueous layer and the aqueous layer is extracted with iPrOAc (about 2 vols). The organic solution is washed with water (about 5 vols) and aq. NaCl (about 10 wt%, about 4 to about 5 vols). The solution is concentrated under vacuum and solvent exchanged to about 2-3 vols Ν,Ν-di methyl acetamide (DMAc). Water (about 5 to about 6 vols) is charged to afford Compound (E) as a slurry. The slurry is filtered and washed sequentially with DMAc/water, water, and hexanes. The resulting solids are dried under vacuum at about 55 °C to afford Compound (E). 1H NMR (400 MHz, DMSO-d6): δ 7.68 (d, 1H, J= 4.0 Hz), 7.64 (d, 1H, J= 1.0 Hz), 7.46 (d, 1H, J= 12.0 Hz), 7.12 (d, 1H, J= 1.0 Hz), 2.12 (s, 3H), 1.85-1.79 (m, 1H), 0.81-0.76 (m, 2H), 0.70-0.66 (2H). 13NMR (100 MHz, DMSO-d6): 159.11, 156.67, 156.67, 143.94, 137.36, 136.19, 136.11, 134.44, 134.41, 131.21, 131.20, 119.05, 118.82, 116.21, 105.56, 105.34, 17.72, 17.71, 9.26, 7.44.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of ammonium acetate, alternative sources of ammonia may be used, including but not limited to ammonium formate and ammonium hydroxide. Various solvents, such as toluene, benzene, and isopropanol, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 120 °C.

Carboxylation o Compound (E) to form Compound (D)

Compound (E) then 15 10 25 c Compound (D)

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooled to about -10 to about 0 °C and a solution of iPrMgCl (2.0 M in THF, 1.2 equiv) was charged slowly to maintain the internal temperature below about 5 °C. The mixture was stirred for about 1 hour at about -5 to about 5 °C after which C02 was bubbled slowly into the mixture (exothermic). The addition is continued until the exotherm subsides and the internal temperature typically increases to about 15 to about 25 °C after the addition. Upon reaction completion, the mixture is concentrated under vacuum to approximately 3 vols and water (about 6 to about 7 vols) is added, followed by about 1 vol 6M HC1. MTBE (about 10 vols) is added and the biphasic mixture is separated. A solution of 6 M HC1 is added slowly to the aqueous layer to adjust the pH (initially at > 10) to approximately 4.8. The mixture is seeded with Compound (D) (if necessary), which was formed according to the procedure outlined above, and the resultant slurry is cooled slowly to about 0 °C to about 5 °C and aged. The slurry is filtered, washed with water (about 4 vols), isopropanol (about 4 vols), followed by n-heptane (about 6 vols). The solids are dried under vacuum at about 40 °C to afford Compound (D). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13NMR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organolithium bases (e.g., MeLi, «-BuLi, t-BuLi, and sec- uLi) and Grignard bases (e.g., MeMgCl, «-BuMgCl, and PhMgCl). Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et20, may be employed. The reaction may initially take place at temperatures that range from about -20 °C to about 40 °C and then continue at temperature that range from about -10 °C to about 50 °C.

Conversion o Compound (D) to form Compound (D-a)

Compound (D) Compound (D-a)

To a mixture of Compound (D) (1.0 equiv) in methanol (about 4 vols) at about 15 °C to about 25 °C is charged concentrated HC1 (1.1 equiv relative to Compound (D)). The mixture is aged until most of the Compound (D) is dissolved, seeded with Compound (D-a) (0.005 equiv), which was formed according to the procedure outlined above, and MTBE (about 3 vols relative to the amount of seed) is charged slowly. The slurry is aged, filtered, and rinsed with MTBE (5 vols) and the solids are dried under vacuum at about 40 °C to afford Compound (D-a). 1H MR (400 MHz, DMSO-de): δ 9.34 (s, 1H), 8.00 (d, 1H, J= 8.0 Hz), 7.76 (d, 1H, J= 2.0 Hz), 7.54 (d, 1H, J= 12.0 Hz), 2.25 (s, 3H), 2.08-2.01 (m, 1H), 1.05-1.00 (m, 2H), 0.92-0.88 (m, 2H). 13C MR QOO MHz, DMSO-d6): 164.08, 164.05, 162.73, 160.14, 142.11, 142.01, 137.11, 135.91, 131.14, 131.11, 130.73, 120.19, 119.96, 118.78, 118.39, 118.27, 17.71, 8.24, 6.13.

Carboxylation o Compound (E) to form Compound (D) Hydrate

Compound (E) then 15 10 25 °c Compound (D) Hydrate

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooled to about -10 to about 0 °C and a solution of iPrMgCl (2.0 M in THF, 1.2 equiv) was charged slowly to maintain the internal temperature below about 5 °C. The mixture was stirred for about 1 hour at about -5 to about 5 °C after which C02 was bubbled slowly into the mixture (exothermic). The addition is continued until the exotherm subsides and the internal temperature typically increases to about 15 to about 25 °C after the addition. Upon reaction completion, the mixture is concentrated under vacuum to approximately 3 vols and water (about 6 to about 7 vols) is added, followed by about 1 vol 6 M HC1. MTBE (about 10 vols) is added and the biphasic mixture is separated. A solution of 6 M HC1 is added slowly to the aqueous layer to adjust the pH (initially at > 10) to approximately 4.8. The mixture is seeded with Compound (D) (if necessary), which was formed according to the procedure outlined above, and the resultant slurry is cooled slowly to about 0 °C to about 5 °C and aged. The slurry is filtered and washed with water (about 4 vols). The solids are dried under vacuum at about 40 °C to afford Compound (D) hydrate. 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13NMR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organolithium bases (e.g., MeLi, «-BuLi, t-BuLi, and sec- uLi) and Grignard bases (e.g., MeMgCl, «-BuMgCl, and PhMgCl). Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et20, may be employed. The reaction may initially take place at temperatures that range from about -20 °C to about 40 °C and then continue at temperature that range from about -10 °C to about 50 °C.

Acid Chloride Formation Using Compound (D-a) to Form Compound (B)

Compound (B)

To a mixture of Compound (D-a) (1.0 equiv), DCM (about 10 vols) and DMF (0.1 equiv), a solution of oxalyl chloride (about 1.7 equiv) was slowly charged to maintain the internal temperature below about 30 °C. The mixture was stirred for about 1 hour at about 20 °C after which time the mixture is distilled to about about 4 vols total volume. DCM (about 5 vols) is repeatedly charged and the mixture distilled to about 4 vols total volume. DCM is then charged to bring the total volume to about 12 vols of Compound (B). The solution is carried forward to the next step without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (D-a), compound (D) may be used. Additionally, in lieu of oxalyl chloride and DMF, thionyl chloride, PC15, and PCI3 may be used. Various

solvents, such as MeCN, THF, and MTBE, may be employed. In some embodiments, additives may be used, including but not limited to trimhetylsilyl chloride, water, HC1, or tetrabutyl ammonium chloride. The reaction may take place at temperatures that range from about -20 °C to about 40 °C.

Acid Chloride Formation Using Compound (D) Hydrate to Form Compound (B)

To a mixture of Compound (D) hydrate (1.0 equiv), DCM (about 10 vols) and DMF (0.1 equiv), a solution of oxalyl chloride (1.2 equiv) was slowly charged to maintain the internal temperature below about 30 °C. The mixture was stirred for about 1 hour at about 20 °C after which time the mixture is distilled to about about 4 vols total volume. DCM (about 5 vols) is repeatedly charged and the mixture distilled to about 4 vols total volume. DCM is then charged to bring the total volume to about 12 vols of Compound (B). The solution is carried forward to the next step without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (D) hydrate, compound (D) may be used.

Additionally, in lieu of oxalyl chloride and DMF, thionyl chloride, PC15, and PCI3 may be used. Various solvents, such as MeCN, THF, and MTBE, may be employed. In some embodiments, additives may be used, including but not limited to trimhetylsilyl chloride, water, HC1, or tetrabutyl ammonium chloride. The reaction may take place at temperatures that range from about -20 °C to about 40 °C.

mide Bond Formation to form Compound (A)

Compound (C) 15 to 25 °C Compound (A)

Compound (C) was synthesized as described in U.S. Patent No. 8,742, 126, which is hereby incorporated by reference in its entirety.

To a solution of Compound (B) (about 1 equiv in about 12 vols DCM) was charged diisopropylethyl amine (1.0 equiv) followed by Compound (C) (1.05 equiv). Upon reaction completion, 5% aqueous sodium hydroxide (about 5 vols) is added and the layers of the biphasic mixture are separated. A solution of 10% aqueous citric acid (about 2 vols) is charged to the organic layer and the layers of the biphasic mixture are separated. Water (about 5 vols) is charged to the organic layer and the layers of the biphasic mixture are separated. The organic solution is filtered, and the solution is solvent swapped to about 15% DCM in EtOH under vacumm at about 45 °C. The mixture is seeded with about 0.001 equiv of Compound (A), which was synthesized as described by U.S. Patent No. 8,742,126, and the resultant slurry is aged at about 45 °C. An additional 2-3 vols solvent is distilled in vacuo and then heptane (about 10 vols) is charged slowly and the slurry is aged, cooled to about 20 °C, filtered and washed with 1 :2 EtOH:heptane (about 3 vols). The solids are dried under vacuum at about 40 °C to afford Compound (A). Characterization data for Compound (A) matches that disclosed in U.S. Patent No. 8,742,126.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases may be used, including but not limited to Et3N, pyridine, and DMAP. Various solvents, such as 2-MeTHF, toluene, MTBE, and chloroform, may be employed. The reaction may take place at temperatures that range from about 0 °C to about 40 °C.

In lieu of Compound (B), Compound (D) or activated esters thereof may be employed.

Coupling reagents may also be employed; non-limiting examples of such reagents include

propane phosphonic acid anhydride (T3P®), Ι, -carbonyldiimidazole, EDC/HOBt or other imide coupling reagents, isobutylchloroformate (to generate an isobutyl ester), and pivoyl chloride (to generate a pivalate ester).

Example 2: Alternative Synthesis of Compound (D)


ompound (K) Compound (L)

Compound (D)

Coupling of Compound (K) and Compound (L-a) to provide Compound (D)

Compound (K) Compound (L-a) Compound (D)

Compound 2-1 Compound 2-2

Compound (L-a) (1.0 eq), Compound (K) (1.5 eq), potassium phosphate (5.0 eq), copper

(I) oxide (0.05 eq), and 8-hydroxyquinoline, Compound 2-2 (0.2 eq) were combined with degassed DMSO (about 6 vols). The reaction mixture was heated to about 95 °C to about 105 °C and stirred for about 22 h. Upon reaction completion, the mixture was cooled to ambient temperature and diluted with water (about 6 vols) and isopropyl acetate (about 5 vols). The aqueous layer was washed with isopropyl acetate (about 5 vols), and the pH was adjusted to about 6 by the addition of 8 M HC1. The solution was seeded with about about 0.003 equiv of Compound (D) seed, which was synthesized as described in U.S. Patent No. 8,742, 126, and the pH was further adjusted to pH about 4.8. The resultant slurry was cooled to about 0 °C for about 2 h, filtered, and washed with cold dilute HC1 (pH about 4.8, about 2 vols) and cold isopropyl alcohol (about 2 vols) to provide Compound (D). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d,

1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases may be used, including but not limited to carbonate bases (such as CS2CO3, K2C03, and Na2C03). In lieu of Cu20, alternative catalysts may be used, such as CuOAc, Cul, CuBr, and [(CuOTf)2-benzene complex]. Non-limiting examples of alternative ligands include phenanthroline ligands (such as 4,7-dimethoxy-l, 10-phenanthroline (Compound 2-1) and 1,10-phenanthroline), aminoarenethiols (such as 2-((dimethylamino)methyl)benzenethiol), oxime-phospine oxides, phosphoramidites, 2-aminopyrimidine diols (such as 2-aminopyrimidine-4,6-diol), and oxime-phosphine oxides (such as 2-hydroxybenzaldehyde oxime). In some embodiments, additives may be used, including but not limited to polyethyleneglycol and/or water, Et4NHC03, and cetryltrimethylammonium bromide.

In lieu of Compound (L-a), alternative starting material can be used, including but not limited to 5-bromo-2-fluoro-4-methylbenzoic acid, 2-fluoro-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzoic acid, and 2-fluoro-4-methyl-5-(tosyloxy)benzoic acid. Additionally, in lieu of the free base of Compound (K), various salts of Compound (K) may be used, such as the besylate salt.

Various solvents may be used, including but not limited to DMF, DMAc, DMSO, butyronitrile, xylenes, EtCN, dioxane, and toluene. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Coupling of Compound (L-b) with Compound (K) to provide Compound (D)

Compound (L-b) Compound (K) Compound (D)

Compound (L-b) (1 equiv), Compound (K) (1.2 equiv), and Cu(OAc)2 (1 equiv) was added methanol (about 20 vols) followed by pyridine (2.2 equiv). The mixture was then stirred at about 23 °C for about 16 h, then at about 45 °C for about 4 h.The reaction mixture was diluted with methanol (about 60 vols), filtered though a pad of celite and concentrated in vacuo to afford Compound (D) . 1H MR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (L-b), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid may be used. In lieu of Compound (K), the besylate salt of Compound (K) may be used.

Various copper reagents can be employed, such as Cu(OTf)2, Cu20, and CuBr.

Alternative bases include but are not limited to triethylamine and N,N-diisopropylethylamine. Various solvents, such as DCM and DMF, may be employed. The reaction may take place at temperatures that range from about 23 °C to about 100 °C and under an atmosphere of oxygen or nitrogen.

Example 3: Alternative Synthesis of Compound (C)

C


Compound (C)

Coupling of Compound (O) with Compound (N-a) to form Compound (M)

Compound (O) Compound (N-a)

Compound (M)

To a mixture of Compound (O) (1.0 equiv), Compound (N-a) (1.6 equiv), PdCl2(PPh3)2 (65 mol%), Cs2C03 (2.0 equiv), and Cul (4.7 mol%) was charged dioxane (10 mL). The mixture

was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 10 vols), washed with water (about 10 vols) and the layers of the biphasic mixture were separated. The organic layer was dried over MgS04 and concentrated in vacuo. The crude residue was purified by silica gel chromatography to afford Compound (M). 1H NMR (400

MHz, DMSO-de): δ 8.95 (s, 1H), 8.16-8.04 (m, 2H), 7.67 (d, 1H, J= 8.4 Hz), 5.34 (sep, 1H, J = 6.6 Hz), 1.50 (d, 6H, 6.6 Hz). 13NMR (100 MHz, DMSO-d6): 149.90, 149.58, 148.36, 144.11, 141.62, 125.27, 122.92, 48.91, 23.42.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp, Pd(OAc)2/PPh3, Pd(OAc)2/dppe, Pd2dba3/dppf. Various bases may be used, such as a carbonate base (e.g. K2C03 or Na2C03). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, and NMP, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Conversion of Compound (M) to form Compound (C)

Compound (M) Compound (C)

To a mixture of Compound (M) (1.0 equiv), Pd(OAc)2 (2.0 mol%), rac-BINAP (3.0 mol%), and Cs2C03 (1.4 equiv), was charged dioxane (about 9 vols) followed by benzophenone imine (2.0 equiv). The mixture was degassed, sealed and then heated to about 75 °C to about 85 °C under nitrogen. After a period of about 20 hours, the mixture was cooled to ambient temperature, and HC1 (6 M, about 8 vols) was charged until the pH of the reaction mixture was about 1 to about 2. The solution was maintained at ambient temperature for about 15 minutes, then NaOH (30 wt.%, about 1 to about 2 vols) was charged until the pH of the reaction mixture was about 8-9. The reaction mixture was concentrated in vacuo, slurried in MeOH (about 22 vols), and filtered to remove gross solids, which were washed with MeOH (2 x about 3 vols). The resulting solution was concentrated in vacuo, adsorbed onto celite and purified by silica gel chromatography to provide compound (C). LRMS [M+H]+: 204.08.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp, Pd(OAc)2/PPh3, Pd(OAc)2/dppe, Pd2dba3/dppf,

Pd2dba3/CyJohnPhos, Pd2dba3/P(t-Bu)3. Various ammonia sources may be used such as

LiHMDS or ammonium hydroxide. Various carbonate bases (e.g. K2C03 or Na2C03) or phosphate bases such as K3P04 may be used. Various solvents, such as THF, DMAc, DMSO, and NMP, may be employed. The reaction may take place at temperatures that range from about 75 °C to about 150 °C and pressures ranging from about 15 to about 50 psig.

Example 4: Alternative Synthesis of Compound (C)

Co 
mpound (O)

Compound (C)

Coupling of Compound (O) with Compound (P-a) to form Compound (C)

C


)

To a mixture of Compound (O) (1.0 equiv), Compound (P-a) (1.0 equiv), PdCl2(PPh3)2 (10 mol%), Cs2C03 (2.0 equiv), and Cul (4.7 mol%) was charged dioxane (about 20 vols). The mixture was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 to about 40 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 40 vols) and the organic layer was washed with water (about 40 vols) The layers of the biphasic mixture were separated and the aqueous phase was extracted with

EtOAc (about 40 vols). The combined organic phases were concentrated in vacuo. To the residue was charged IPA (about 20 vols), and the resulting suspension was stirred at about 40 °C to about 50 °C for about 1 h and then stirred at ambient temperature for about 16 h. The suspension was cooled to about 5 °C, filtered and washed with cold IPA (about 4 vols). The resulting solids were dried at about 40 °C to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, J= 8.0 Hz), 1.42 (d, 6H, J= 8.0 Hz). 13NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp; Pd(OAc)2/PPh3; Pd(OAc)2/dppe; Pd2dba3/dppf, Pd(OAc) 2/(m-tolyl)3P, Pd(OAc)2/JohnPhos; PdCl2dppf, Pd(OAc)2/(o-tolyl)3P; PdCl2(AmPhos)2; Pd(OAc) 2/(cyclohexanlyl)3P. Various bases may be used, such as a carbonate base (e.g. K2C03 or Na2C03). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, and NMP, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Coupling of Compound (O) with Compound (P-b) to form Compound (C)

Co


)

A solution of Compound (O) (1.0 equiv) in THF (about 20 vols) was degassed with nitrogen. The solution was cooled to about -55 °C to about -70 °C and a solution of n-BuLi (1.6 M solution in hexane, 1.0 equiv) was added over about 15 to about 20 minutes. The suspension was stirred for about 15 to about 25 minutes at about -55 °C to about -60 °C, followed by the slow addition of ZnCl2 (0.5 M solution in THF, 1 equiv). The suspension was stirred for about 30 minutes and warmed to ambient temperature. To a separate flask was charged Compound (P-b) (1.0 equiv) and Pd(PPh3)4 (231 mg, 4.4 mol%) in dioxane (about 20 vols). The mixture was degassed and transferred to the flask containing the organozinc intermediate. The mixture was sealed and heated to about 115 °C to about 125 °C for about 15 hours then cooled to ambient temperatureThe reaction mixture was concentrated in vacuo at ambient temperature and triturated with MTBE (about 10 mL) to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, 7= 8.0 Hz), 1.42 (d, 6H, 7= 8.0 Hz). 13NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, for the metallation, in lieu of n-BuLi, other organolithium reagents (such as t-BuLi, MeLi, and s-BuLi) or Grignard reagents (such as iPrMgCl and PhMgCl) may be used. In lieu of 1 equivalent of ZnCl2, 0.5 equivalent of ZnCl2 or ZnCl2 with LiCl, ZnBr2, or Znl2 can be used. Alternative solvents to THF can include 2-MeTHF, MTBE, or Et20, and this reaction may take place at temperatures that range from about -78 °C to about -40 °C.

Additionally, during the coupling reaction, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as Pd(PPh3)4.

Various solvents, such as NMP, THF, butyronitrile, and toluene, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 140 °C.

Example 5: Alternative Synthesis for Compound (D) 

Compound (E) Compound (Q) Compound (D)

Carboalkoxylation to form Compound (Q)

CO (1 atm)

Compound (E)

Compound (Q)

To a reaction flask was added 1-butanol (7 volumes). Compound (E) (1 equiv) was added followed by K2C03 (1.5 equiv) and Pd(dppf)Cl2 (0.02 equiv) and the reaction was placed under a CO atmostphere. The reaction mixture was heated at about 90 °C until reaction completion. The reaction contents were cooled to ambient temperature, the reaction mixture was filtered through a pad of Celite to remove solids, and then rinsed forward with EtOAc. The mother liquor was washed with water and brine, and dried over Na2S04, filtered, and concentrated to afford Compound (Q). Purification by flash chromatography afforded Compound (Q): 1H MR (400 MHz, CDC13) δ 7.77 (d, J = 6.7 Hz, 1H), 7.39 (s, 1H), 7.08 (d, J= 10.8 Hz, 1H), 6.74 (s, 1H), 4.31 (t, J= 6.6 Hz, 2H), 2.20 (s, 3H), 1.87 (m, 1H), 1.73 (tt, J= 6.7, 6.6 Hz, 3H), 1.43 (tq, J= 7.3, 7.4 Hz), 0.94 (t, J= 7.4 Hz, 3H), 0.88 (m, 2H), 0.79 (m, 2H); Exact mass for Ci8H22N202F [M+H], 317.2. Found [M+H], 317.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be used. Non-limiting examples include other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as

PdCl2(dppf) or Pd(OAc)2 with PPh3, xantphos, tBu3P-HBF4, dppe, dppb, dpcb, tBu-dppf, and (Ad)2P(nBu). Alternative bases can be used, such as other carbonate bases (such as Cs2C03, and Na2C03), NaOAc, KOAc, or organic bases such as TMEDA, Et3N, and iPr2NEt. Various solvents may be employed, such as 1-butanol with other co-solvents (e.g. DMF). The reaction may take place at temperatures that range from about 70 °C to about 115 °C and at CO pressures of about 5 to about 50 psig.

Hydrolysis of Compound (Q) to Compound (D)

Compound (Q) Compound (D)

To a reaction flask was added Compound (Q) (1.0 equiv) and MeOH (7 volumes). A 25% NaOH solution (5 equiv) was then added dropwise. Consumption of Compound (D) was observed after about 1.5 hours at which point the pH of the solution was carefully adjusted to about 1 by the addition of 6 N HC1. Methanol was removed under vacuum to afford a solid which was isolated by filtration. The crude product was first triturated in THF and then filtered. This solid was then triturated in CH2Cl2/MeOH (9: 1) and filtered. Concentration of the mother liquor afforded Compound (D). 1H MR (400 MHz, CD3OD) δ 8.87 (s, 1H), 7.94 (d, J = 6.6 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J= 1 1.5 Hz, lH), 2.21 (s, 3H), 1.96 (m, 1H), 1.04 (m, 2H), 0.81 (m, 2H); LRMS: Calculated mass for C14H14N2O2F [M+H], 261.1. Found [M+H], 261.

Alternative reagents and reaction conditions to those disclosed above may also be employed.

For example, an alternative hydroxide base, including but not limited to KOH, LiOH, and CsOH, may be used in lieu of NaOH. Various solvents may be employed, such as THF, EtOH, and 2-propanol. The reaction may take place at temperatures that range from about 0 °C to about 50 °C.

Example 6: Alternative Synthesis of Compound (A)

Com ound C

(A)

Compound (E) (1 equiv.), Compound (C) (1 equiv.), DMF (about 16 vols), Et3N (1.5 equiv.), Pd(OAc)2 (0.02 equiv.), and Ad2P(«-Bu) (0.04 equiv.) were combined and the contents were purged with N2 followed by CO and then pressurized with CO (20 psi). The reaction mixture was heated to about 95 °C to about 105 °C. After about 24 hours, the reaction was allowed to cool to about 20 °C to about 30 °C to afford Compound (A).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be used. Non-limiting examples include other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as

PdCl2(PPh3)2, PdCl2(A-Phos)2 or Pd(OAc)2 with PPh3. Alternative bases can be used, including but not limited to other organic bases (such as iPr2NEt and TMEDA) and inorganic bases (such as NaOAc, KOAc, Na2C03, and Cs2C03). Various solvents, NMP, dioxane, and toluene, may be employed. The reaction may take place at temperatures that range from about 90 °C to about 120 °C and at CO pressures of about 20 psig to about 60 psig.

Example 7: Alternative Synthesis of Compound (A)

Compound (A)

Compound (D) (1.0 equiv), Compound (C) (1.05 equiv), 4-(dimethylamino)pyridine (1.0 equiv), ethyl acetate (about 4 V) and diisopropylethylamine (1.2 equiv) were combined and the resulting slurry was charged T3P® as a 50 wt% solution in ethyl acetate (2.0 equiv) over about 3 min at about 20 °C. During the addition, a small exotherm was observed. The mixture was stirred at about 20 °C for about 24 h. After reaction completion, 0.5 M aqueous hydrochloric acid (about 5 vols was added, and the mixture was stirred for about 15 min. Stirring was then stopped, and the phases were allowed to separate. Then, the aqueous phase was reintroduced to the reactor. The pH of the aqueous solution was then adjusted to about 7 with a 5 wt% solution of aqueous sodium hydroxide (about 12 vols). The resulting slurry was stirred for about 12 h at about 20 °C and then filtered, and the reactor was rinsed forward with water (about 3 vols). The filter cake was washed with isopropanol (2 vols), and the resulting solids were dried under vacuum at about 45 °C to provide Compound (A).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of T3P®, other coupling reagents may be used, including but not limited to Ι, Γ-carbonyldiimidazole, isobutyl chloroformate, pivoyl chloride, EDC-HCl/HOBt, thionyl chloride, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Alternative bases may be used, including but not limited organic amines (such as trialkyl amine bases (for example, triethylamine), N-methyl morpholine, and the like) and carbonates (such as lithium carbonates, sodium carbonates, cesium carbonates, and the like). Various solvents, such as DCM, THF, DMF, ethyl acetate, MTBE, toluene, MP, DMAc, acetonitrile, dichloroethane,

2-MeTHF, and cyclopentyl methyl ether, may be employed. The reaction may take place at temperatures that range from about -10 °C to about 60 °C or from about 0 °C to about 30 °C.

Example 8: Alternative Synthesis of Compound (C)

Compound (8-b)

The mixture of Compound (8-a) and Compound (8-b) is dissolved in about 10 volumes of process water. The solution is heated to about 80 °C, and the solution is allowed to age for about 6 hours. Upon reaction completion, the solution is cooled to about 60 °C. The reaction mixture is seeded with 0.001 equiv of Compound (C), which was obtained by suitable means, and cooled to about 0 °C. Compound (C) is filtered from the cold aqueous solution to yield the product.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, instead of the mixture of Compuond (8-a) and (8-b), the reaction may be carried out with Compound (8-a) or Compound (8-b). Additionally, other organic acids may be used, including but not limited to acetic acid and trifluoroacetic acid. Various solvents, such as toluene, dimethylacetamide, MP, and 2-MeTHF, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 100 °C.

rnative Synthesis of Compound (C)

Compound (9-c)

Compound (C) may be synthesized as described in U.S. Patent No. 8,742, 126, which is hereby incorporated by reference in its entirety. Additionally, when starting with Compound (9-a), it was found that Compound (C) may be formed through two additional intermediates, Compound (9-b) and Compound (9-c). LRMS for Compound (9-b): Calculated mass, C14H14N2O2F [M+H], 235.1; Found [M+H], 235.9. LRMS for Compound (9-c): Calculated mass, C14H14N2O2F [M+H], 207.1; Found [M+H], 208.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of acetic acid, other organic acids may be used, including but not limited to trifluoroacetic acid. Various solvents, such as toluene, dimethylacetamide, NMP, 2-MeTHF, acetic acid, and water, may be employed. The reaction may take place at

temperatures that range from about 80 °C to about 110 °C or about 100 °C.

Example 10: Alternative Synthesis of Compou

Compound (10-a) Compound (C)

Compound (10-a) (1 equiv), toluene (about 20 vols), N-isopropylformamide (3.00 equiv), isopropylamine (3.00 equiv) and trifluoroacetic acid (2.50 equiv) were sequentially

combined. The vial was sealed and heated to about 100 °C. After about 22 h, the vial was cooled to room temperature and the contents were analyzed by HPLC. Compound (C) was observed by HPLC.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, other organic acids may be used, including but not limited to acetic acid. Various solvents, such as dimethylacetamide, MP, and acetic acid, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 100 °C.

Example 11: Alternative Synthesis of Compound (C)

Compound (10-a) Compound (11 -b) Compound (C)

Compound (10-a) (1.0 equiv), toluene (about 12 volumes), 79 wt% 

dimethylformimidamide (3.0 equiv), isopropylamine (3.0 equiv) and trifluoroacetic acid 2.5 equiv) were combined and heated to about 100 °C. After about 22 h, the reaction mixture was cooled to room temperature. The mixture was seeded with Compound (C), which was obtained by suitable means, and cooled to about 0 °C. After about 30 min, the heterogeneous mixture was filtered and the vial was rinsed forward with toluene (about 25 vols). The solid was collected and dried under vacuum at about 40 °C to provide Compound (C).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, organic acids may be used, including but not limited to acetic acid. Various solvents, such as acetic acid, dimethylacetamide, and NMP, may be employed.

Alternative organic amines may also be added. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 90 °C to about 100 °C.

Example 12: Alternative Synthesis of Compound (C)

Compound (10-a) Compound (C)

A suitable reactor fitted with a reflux condenser was charged with acyl hydrazide (1 equiv), toluene (6 volumes), isopropylamine (7.20 equiv) andN.N-dimethylformamide dipropyl acetal (2.70 equiv). To the resulting slurry was charged acetic acid (1.50 equiv) over about 2 min at about 20 °C. During the addition, an exotherm was observed. The mixture was heated to about 95 °C for about 20 h. After reaction completion, the mixture was concentrated under vacuum at about 80 °C. The mixture was diluted with water (10 volumes), and the resulting biphasic solution was concentrated under vacuum at about 80 °C. Water was added (3 volumes), and the solution is heated to about 85 °C. The resulting solution was cooled to about 60 °C and seeded with Compound (C), which was obtained by suitable means. The resulting slurry was aged for about 30 min and then cooled to about 20 °C over about 1 h and aged for about 15 h. The resulting slurry was cooled to about 5 °C and aged for about 3 h. The cold slurry is filtered and the reactor is rinsed forward with cold water (15 mL). The resulting solids were dried under vacuum at about 40 °C to give Compound (C).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative formamide reagents may be used, such as dimethyl formamide diethyl acetal, dimethyl formamide diisopropyl acetal, dimethyl formamide disec-butyl acetal, dimethyl formamide diisobutyl acetal, and the like. Other organic acids may be used, including but not limited to trifluoroacetic acid, chloroacetic acid, and methanesulfonic acid. Various solvents, such as acetic acid, dimethylacetamide, 2-MeTHF, NMP, isobutyl acetate, isobu

Phase 2 Data for Selonsertib in Nonalcoholic Steatohepatitis (NASH) Presented at The Liver Meeting® 2016

— Results Demonstrate Improvement in Fibrosis Stage among NASH Patients with Moderate to Severe Fibrosis —

BOSTON–(BUSINESS WIRE)–Nov. 14, 2016– Gilead Sciences (Nasdaq:GILD) today announced detailed results from an open-label Phase 2 trial evaluating the investigational apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997) alone or in combination with the monoclonal antibody simtuzumab (SIM) in patients with nonalcoholic steatohepatitis (NASH) and moderate to severe liver fibrosis (fibrosis stages F2 or F3). The data demonstrate regression in fibrosis that was, in parallel, associated with reductions in other measures of liver injury in patients treated with selonsertib for 24 weeks. These data were presented in a late-breaking abstract session at The Liver Meeting® 2016 in Boston (#LB-3).

Patients receiving selonsertib demonstrated improvements in several measures of liver disease severity, including fibrosis stage, progression to cirrhosis, liver stiffness (measured by magnetic resonance elastography, MRE) and liver fat content (measured by magnetic resonance imaging (MRI)-proton density fat fraction, PDFF). Data for these efficacy endpoints are summarized in the table below. As no differences were observed between combination and monotherapy, results are presented for selonsertib (18 mg and 6 mg) with/without SIM and for SIM alone. Additionally, patients with fibrosis improvement demonstrated reductions in hepatic collagen content, liver biochemistry (e.g., serum ALT) and the apoptosis marker, cytokeratin-18, supporting the biological activity of selonsertib.

Endpoint (Week 24) Selonsertib

18 mg ± SIM

Selonsertib 
6 mg ± SIM

SIM
Fibrosis Improvement ≥1 Stage from Baseline* 43% (n=13/30) 30% (n=8/27) 20% (n=2/10)
Progression to Cirrhosis 3% (n=1/30) 7% (n=2/27) 20% (n=2/10)
≥15% Reduction in Liver Stiffness by MRE 20% (n=5/25) 32% (n=7/22) 0% (n=0/7)
≥30% Reduction in Liver Fat by MRI-PDFF 26% (n=8/31) 13% (n=3/24) 10% (n=1/10)

*Fibrosis staged according to the NASH Clinical Research Network (CRN) classification by a central pathologist blinded to treatment group.

Selonsertib demonstrated no dose-related increases in treatment-emergent adverse events or serious adverse events. Headache, nausea and sinusitis were the most common adverse events in patients receiving selonsertib.

“Currently, no approved treatments exists for NASH, and patients with advanced fibrosis would potentially benefit from new options to halt and/or reverse the progression of their disease,” said Rohit Loomba, MD, MHSc, lead study author and Director, NAFLD Research Center, Director of Hepatology, Professor of Medicine, Vice Chief, Division of Gastroenterology, University of California San Diego School of Medicine. “After only 24 weeks of therapy, selonsertib exhibited promising anti-fibrotic activity in this study, which was the first known multi-center NASH clinical trial to use centrally-assessed MRE, MRI-PDFF, in addition to liver biopsy as endpoints. Based on these data, selonsertib represents an important investigational drug candidate for further clinical trials in patients with NASH and significant fibrosis.”

Other Gilead NASH data being presented at The Liver Meeting include results from Phase 1 studies evaluating the investigational selective, non-steroidal Farnesoid X receptor (FXR) agonist GS-9674. Data from a Phase 1 study demonstrated the biological activity and safety profile of GS-9674 in healthy volunteers and support the evaluation of this compound in patients with NASH and cholestatic liver disorders (#1077 and #1140). Phase 2 studies with GS-9674 are ongoing in patients with NASH, primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Additionally, preclinical data for the combination of selonsertib and GS-9674 in a rodent model of advanced fibrosis suggested that the combination of selonsertib and GS-9674 resulted in greater anti-fibrotic activity than either agent alone (#1588). These preclinical data support clinical evaluation of combination approaches with selonsertib and GS-9674 in patients with NASH and advanced fibrosis.

Selonsertib, GS-9674 and simtuzumab have not been determined to be safe or efficacious.

About Selonsertib and the Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

This Phase 2, randomized, open-label trial evaluated the safety, tolerability and efficacy of selonsertib alone or in combination with SIM in 72 patients with NASH and fibrosis stages F2 (n=25) or F3 (n=47). Eligible patients were randomized (2:2:1:1:1) to receive selonsertib 6 mg (n=20), selonsertib 18 mg (n=22), selonsertib 6 mg plus SIM 125 mg (n=10), selonsertib 18 mg plus SIM 125 mg (n=10) or SIM 125 mg alone (n=10) for 24 weeks. Selonsertib was administered orally once daily and SIM was administered via weekly subcutaneous injection.

About Gilead’s Clinical Programs in NASH

Gilead is advancing a pipeline of novel investigational therapies for the treatment of NASH with advanced fibrosis. Gilead is currently planning or conducting Phase 2 and Phase 3 clinical trials evaluating single-agent and combination therapy approaches against multiple core pathways associated with NASH – metabolic dysfunction, inflammation and fibrosis. Compounds in development include the ASK1 inhibitor, selonsertib; the FXR agonist, GS-9674; and an inhibitor of acetyl-coA carboxylase (ACC), GS-0976, currently being evaluated in a Phase 2 study in patients with NASH.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

 

Patent ID

Patent Title

Submitted Date

Granted Date

US2016166556 METHODS OF TREATING PULMONARY HYPERTENSION
2015-08-11
2016-06-16
US2015342943 METHODS OF TREATING LIVER DISEASE
2015-05-29
2015-12-03
US9771328 Processes for preparing ASK1 inhibitors
2017-01-23
2017-09-26
US9586933 Processes for preparing ASK1 inhibitors
2015-12-22
2016-08-25
US8742126 Apoptosis signal-regulating kinase inhibitor
2013-01-24
2014-06-03
Patent ID

Patent Title

Submitted Date

Granted Date

US9643956 SOLID FORMS OF AN ASK1 INHIBITOR
2015-12-22
2016-09-29
US9750730 APOPTOSIS SIGNAL-REGULATING KINASE INHIBITOR
2016-04-27
2016-08-18
US2017273952 METHODS OF TREATING LIVER DISEASE
2015-09-22
US9333197 APOPTOSIS SIGNAL-REGULATING KINASE INHIBITOR
2014-04-16
2014-08-14
US8552196 Apoptosis signal-regulating kinase inhibitors
2012-09-13
2013-10-08

/////////Selonsertib,  GS-4997, PHASE 3, GILEAD, GS-4997, GS-4977

CC1=C(C=C(C(=C1)F)C(=O)NC2=CC=CC(=N2)C3=NN=CN3C(C)C)N4C=C(N=C4)C5CC5

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Voxilaprevir, فوكسيلابريفير , 伏西瑞韦 , Воксилапревир


Voxilaprevir.svgUNII-0570F37359.pngChemSpider 2D Image | voxilaprevir | C40H52F4N6O9S

Figure imgf000410_0002

Voxilaprevir

  • Molecular FormulaC40H52F4N6O9S
  • Average mass868.934 Da
 1535212-07-7 cas
(1R,18R,20R,24S,27S,28S)-N-[(1R,2R)-2-(Difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-28-ethyl-13,13-difluoro-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,2  ;3,26-tetraazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3(12),4,6,8,10-pentaene-27-carboxamide
Cyclopropanecarboxamide, N-[[[(1R,2R)-2-[5,5-difluoro-5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl]cyclopropyl]oxy]carbonyl]-3-methyl-L-valyl-(3S,4R)-3-ethyl-4-hydroxy-L-prolyl-1-amino-2-(difluoromethyl)-N-[(1-methylcyclopropyl)sulfonyl]-, cyclic (1→2)-ether, (1R,2R)-
(laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)– 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide
(laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)- 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide

8H-7,10-Methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide, N-[(1R,2R)-2-(difluoromethyl)-1-[[[(1-methylcyclopropyl)sulfonyl]amino]carbonyl]cyclopropyl]-5-(1 ,1-dimethylethyl)-9-ethyl-18,18-difluoro-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-3,6-dioxo-, (1aR,5S,8S,9S,10R,22aR)-

GS-9857
UNII:0570F37359
Воксилапревир [Russian] [INN]
فوكسيلابريفير [Arabic] [INN]
伏西瑞韦 [Chinese] [INN]

Voxilaprevir is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with sofosbuvirand velpatasvir. The combination has the trade name Vosevi and has received a positive opinion from the European Committee for Medicinal Products for Human Use in June 2017.[1]

In July 18, 2017, Vosevi was approved by Food and drug administration.[2]

The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-1 12). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, MP., Clin. Liver Dis., 201 1 , 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 201 1 , 66, 1573-1686; Brody, H., Nature Outlook, 201 1 , 474, S1 -S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1 -20;

Maradpour, D., et al., Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al., Hepatology, 1996, 24, 1351 -4;

Domingo, et al., Gene 1985, 40, 1 -8; Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1 -6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1 , 2, 3, and so on).

HCV is distributed worldwide with genotypes 1 , 2, and 3 predominate within the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China). Genotype 4 is largely found in the Middle East, Egypt and central Africa while genotype 5 and 6 are found predominantly in South Africa and South East Asia respectively (Simmonds, P. et al. J Virol. 84: 4597-4610, 2010).

The combination of ribavirin, a nucleoside analog, and interferon-alpha (a) (IFN), is utilized for the treatment of multiple genotypes of chronic HCV infections in humans. However, the variable clinical response observed within patients and the toxicity of this regimen have limited its usefulness. Addition of a HCV protease inhibitor (telaprevir or boceprevir) to the ribavirin and IFN regimen improves 12-week post-treatment virological response (SVR12) rates

substantially. However, the regimen is currently only approved for genotype 1 patients and toxicity and other side effects remain.

The use of directing acting antivirals to treat multiple genotypes of HCV infection has proven challenging due to the variable activity of antivirals against the different genotypes. HCV protease inhibitors frequently have compromised in vitro activity against HCV genotypes 2 and 3 compared to genotype 1 (See, e.g., Table 1 of Summa, V. et al., Antimicrobial Agents and Chemotherapy, 2012, 56, 4161 -4167; Gottwein, J. et al, Gastroenterology, 201 1 , 141 , 1067-1079).

Correspondingly, clinical efficacy has also proven highly variable across HCV genotypes. For example, therapies that are highly effective against HCV genotype 1 and 2 may have limited or no clinical efficacy against genotype 3.

(Moreno, C. et al., Poster 895, 61 st AASLD Meeting, Boston, MA, USA, Oct. 29 – Nov. 2, 2010; Graham, F., et al, Gastroenterology, 201 1 , 141 , 881 -889; Foster, G.R. et al., EASL 45th Annual Meeting, April 14-18, 2010, Vienna, Austria.) In some cases, antiviral agents have good clinical efficacy against genotype 1 , but lower and more variable against genotypes 2 and 3. (Reiser, M. et al.,

Hepatology, 2005, 41 ,832-835.) To overcome the reduced efficacy in genotype 3 patients, substantially higher doses of antiviral agents may be required to achieve substantial viral load reductions (Fraser, IP et al., Abstract #48, HEP DART 201 1 , Koloa, HI, December 201 1 .)

Antiviral agents that are less susceptible to viral resistance are also needed. For example, resistance mutations at positions 155 and 168 in the HCV protease frequently cause a substantial decrease in antiviral efficacy of HCV protease inhibitors (Mani, N. Ann Forum Collab HIV Res., 2012, 14, 1 -8;

Romano, KP et al, PNAS, 2010, 107, 20986-20991 ; Lenz O, Antimicrobial agents and chemotherapy, 2010, 54,1878-1887.)

In view of the limitations of current HCV therapy, there is a need to develop more effective anti-HCV therapies. It would also be useful to provide therapies that are effective against multiple HCV genotypes and subtypes.

Image result

Kyla BjornsonEda CanalesJeromy J. CottellKapil Kumar KARKIAshley Anne KatanaDarryl KatoTetsuya KobayashiJohn O. LinkRuben MartinezBarton W. PhillipsHyung-Jung PyunMichael SangiAdam James SCHRIERDustin SiegelJames G. TAYLORChinh Viet TranMartin Teresa Alejandra TrejoRandall W. VivianZheng-Yu YangJeff ZablockiSheila Zipfel
Applicant Gilead Sciences, Inc.

Kyla Ramey (Bjornson)

Kyla Ramey (Bjornson)

Senior CTM Associate at Gilead Sciences

……………………………………………………………………………….str1

PATENT

WO 2014008285

https://www.google.com/patents/WO2014008285A1?cl=en

26. A compound of Formula IVf:
Figure imgf000410_0002

RELATIVE SIMILAR EXAMPLE WITHOUT DIFLUORO GROUPS, BUT NOT SAME COMPD

Example 1. Preparation of (1 aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N- [(1 R,2R)-2-(difluoromethyl)-1 -{[(1 – methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo- 1 ,1 a,3,4,5,6,9,10,18,19,20,21 ,22,22a-tetradecahydro-8H-7,10- methanocyclopropa[18,19][1 ,10,3,6]dioxadiazacyclononadecino[1 1 ,12- b]quinoxaline-8-carboxamide.

Figure imgf000182_0001
Figure imgf000183_0001

Step 1 . Preparation of 1-1 : A mixture containing Intermediate B4 (2.03 g, 6.44 mmol), Intermediate E1 (1 .6 g, 5.85 mmol), and cesium carbonate (3.15 g, 9.66 mmol) in MeCN (40 mL) was stirred vigorously at rt under an atmosphere of Ar for 16 h. The reaction was then filtered through a pad of Celite and the filtrate concentrated in vacuo. The crude material was purified by silica gel

chromatography to provide 1-1 as a white solid (2.5 g). LCMS-ESI+ (m/z): [M- Boc+2H]+ calcd for C2oH27CIN3O4: 408.9; found: 408.6.

Step 2. Preparation of 1-2: To a solution 1 -1 (2.5 g, 4.92 mmol) in dioxane

(10 mL) was added hydrochloric acid in dioxane (4 M, 25 mL, 98.4 mmol) and the reaction stirred at rt for 5 h. The crude reaction was concentrated in vacuo to give 1-2 as a white solid (2.49 g) that was used in subsequently without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C2oH26CIN3O4: 407.9; found: 407.9.

Step 3. Preparation of 1-3: To a DMF (35 mL) solution of 1-2 (2.49 g, 5.61 mmol), Intermediate D1 (1 .75 mg, 6.17 mmol) and DIPEA (3.9 mL, 22.44 mmol) was added COMU (3.12 g, 7.29 mmol) and the reaction was stirred at rt for 3 h. The reaction was quenched with 5% aqueous citric acid solution and extracted with EtOAc, washed subsequently with brine, dried over anhydrous MgSO , filtered and concentrated to produce 1 -3 as an orange foam (2.31 g) that was used without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C35H49CIN4O7: 673.3; found: 673.7.

Step 4. Preparation of 1-4: To a solution of 1-3 (2.31 g, 3.43 mmol), TEA (0.72 mL, 5.15 mmol) and potassium vinyltrifluoroborate (0.69 mg, 5.15 mmol) in EtOH (35 mL) was added PdCI2(dppf) (0.25 g, 0.34 mmol, Frontier Scientific). The reaction was sparged with Argon for 15 min and heated to 80 °C for 2 h. The reaction was adsorbed directly onto silica gel and purified using silica gel chromatography to give 1 -4 as a yellow oil (1 .95 g). LCMS-ESI+ (m/z): [M+H]+ calcd for C37H53N4O7: 665.4; found: 665.3.

Step 5. Preparation of 1 -5: To a solution of 1 -4 (1 .95 g, 2.93 mmol) in

DCE (585 ml_) was added Zhan 1 B catalyst (0.215 g, 0.29 mmol, Strem) and the reaction was sparged with Ar for 15 min. The reaction was heated to 80 °C for 1 .5 h, allowed to cool to rt and concentrated. The crude product was purified by silica gel chromatography to produce 1 -5 as a yellow oil (1 .47 g; LCMS-ESI+ (m/z): [M+H]+ calcd for C35H49N4O7: 637.4; found: 637.3).

Step 6. Preparation of 1 -6: A solution of 1 -5 (0.97 g, 1 .52 mmol) in EtOH (15 ml_) was treated with Pd/C (10 wt % Pd, 0.162 g). The atmosphere was replaced with hydrogen and stirred at rt for 2 h. The reaction was filtered through Celite, the pad washed with EtOAc and concentrated to give 1 -6 as a brown foamy solid (0.803 g) that was used subsequently without further purification. LCMS-ESr (m/z): [M+H]+ calcd for C35H5i N4O7: 639.4; found: 639.3.

Step 7. Preparation of 1 -7: To a solution of 1 -6 (0.803 g, 1 .26 mmol) in DCM (10 ml_) was added TFA (5 ml_) and stirred at rt for 3 h. An additional 2 ml_ TFA was added and the reaction stirred for another 1 .5 h. The reaction was concentrated to a brown oil that was taken up in EtOAc (35 ml_). The organic solution was washed with water. After separation of the layers, sat. aqueous NaHCO3 was added with stirring until the aqueous layer reached a pH ~ 7-8. The layers were separated again and the aqueous extracted with EtOAc twice. The combined organics were washed with 1 M aqueous citric acid, brine, dried over anhydrous MgSO4, filtered and concentrated to produce 1 -6 as a brown foamy solid (0.719 g) that was used subsequently without further purification. LCMS-ESr (m/z): [M+H]+ calcd for C3i H43N4O7: 583.3; found: 583.4 .

Step 8. Preparation of Example 1 : To a solution of 1 -7 (0.200 g, 0.343 mmol), Intermediate A10 (0.157 g, 0.515 mmol), DMAP (0.063 g, 0.51 mmol) and DIPEA (0.3 ml_, 1 .72 mmol) in DMF (3 ml_) was added HATU (0.235 g, 0.617 mmol) and the reaction was stirred at rt o/n. The reaction was diluted with MeCN and purified directly by reverse phase HPLC (Gemini, 30-100% MeCN/H2O + 0.1 % TFA) and lyophilized to give Example 1 (1 18.6 mg) as a solid TFA salt. Analytic HPLC RetTime: 8.63 min. LCMS-ESI+ (m/z): [M+H]+ calcd for

C40H55F2N6O9S: 833.4; found: 833.5. 1H NMR (400 MHz, CD3OD) δ 9.19 (s, 1 H); 7.80 (d, J = 8.8 Hz, 1 H); 7.23 (dd, J = 8.8, 2.4 Hz, 1 H); 7.15 (d, J = 2.4 Hz, 1 H); 5.89 (d, J = 3.6 Hz, 1 H); 5.83 (td, JH-F = 55.6 Hz, J = 6.4 Hz, 1 H); 4.56 (d, J = 7.2 Hz, 1 H); 4.40 (s, 1 H) 4.38 (ap d, J = 7.2 Hz, 1 H); 4.16 (dd, J = 12, 4 Hz, 1 H); 3.93 (s, 3H); 3.75 (dt, J = 7.2, 4 Hz, 1 H); 3.00-2.91 (m, 1 H); 2.81 (td, J = 12, 4.4 Hz, 1 H); 2.63-2.54 (m, 1 H); 2.01 (br s, 2H); 1 .88-1 .64 (m, 3H); 1 .66-1 .33 (m, 1 1 H) 1 .52 (s, 3H); 1 .24 (t, J = 7.2 Hz, 3H); 1 .10 (s, 9H); 1 .02-0.96 (m, 2H); 0.96- 0.88 (m, 2H); 0.78-0.68 (m, 1 H); 0.55-0.46 (m, 1 H).

PATENT

US 20150175625

PATENT

US 20150175626

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C6BE27513351D0F12E95BC8C04756872.wapp1nA?docId=WO2015100145&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, MP., Clin. Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474, S1-S7; Gordon, C. P., et al, J. Med. Chem. 2005, 48, 1-20; Maradpour, D., et al, Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al, Science 1998, 282, 103-7; Fukimoto, et al, Hepatology, 1996, 24, 1351-4; Domingo, et al, Gene 1985, 40, 1-8; Martell, et al, J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1-6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1, 2, 3, and so on).

HCV is distributed worldwide with genotypes 1, 2, and 3 predominate within the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China). Genotype 4 is largely found in the Middle East, Egypt and central Africa while genotype 5 and 6 are found predominantly in South Africa and South East Asia respectively (Simmonds, P. et al. J Virol. 84: [0006] There remains a need to develop effective treatments for HCV infections. Suitable compounds for the treatment of HCV infections are disclosed in U.S. Publication No. 2014-0017198, titled “Inhibitors of Hepatitis C Virus” filed on July 2, 2013 including the compound of formula I:

Example 1. Synthesis of (laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)- 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide (I) by route I

[0195] Compound of formula I was synthesized via route I as shown below:

Synthesis of intermediates for compound of formula I SEE PATENT

US  20150175626

str1

References

Patent ID Patent Title Submitted Date Granted Date
US2014343008 HEPATITIS C TREATMENT 2014-01-30 2014-11-20
US2014212491 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS 2014-01-30 2014-07-31
US2014017198 INHIBITORS OF HEPATITIS C VIRUS 2013-07-02 2014-01-16
US2015064253 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS 2014-01-30 2015-03-05
US2015150897 METHODS OF TREATING HEPATITIS C VIRUS INFECTION IN SUBJECTS WITH CIRRHOSIS 2014-12-01 2015-06-04
US2015175625 CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND 2014-12-18 2015-06-25
US2015175626 SYNTHESIS OF AN ANTIVIRAL COMPOUND 2014-12-18 2015-06-25
US2015175646 SOLID FORMS OF AN ANTIVIRAL COMPOUND 2014-12-08 2015-06-25
US2015175655 INHIBITORS OF HEPATITIS C VIRUS 2013-07-02 2015-06-25
US2015361087 ANTIVIRAL COMPOUNDS 2015-06-09 2015-12-17
Patent ID Patent Title Submitted Date Granted Date
US2016120892 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS 2015-09-28 2016-05-05
US2016130300 INHIBITORS OF HEPATITIS C VIRUS 2016-01-15 2016-05-12
Voxilaprevir
Voxilaprevir.svg
Clinical data
Trade names Vosevi (combination with sofosbuvir and velpatasvir)
Identifiers
CAS Number
PubChemCID
ChemSpider
UNII
Chemical and physical data
Formula C40H52F4N6O9S
Molar mass 868.94 g·mol−1

FDA approves Vosevi for Hepatitis C

07/18/2017
The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis.

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. Vosevi is a fixed-dose, combination tablet containing two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir. Vosevi is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and develop complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Vosevi was evaluated in two Phase 3 clinical trials that enrolled approximately 750 adults without cirrhosis or with mild cirrhosis.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5 or 6 all received Vosevi.

The second trial compared 12 weeks of Vosevi with the previously approved drugs sofosbuvir and velpatasvir in adults with genotypes 1, 2 or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

Results of both trials demonstrated that 96-97 percent of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history.

The most common adverse reactions in patients taking Vosevi were headache, fatigue, diarrhea and nausea.

Vosevi is contraindicated in patients taking the drug rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Vosevi.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted approval of Vosevi to Gilead Sciences Inc

//////////Voxilaprevir, فوكسيلابريفير ,  伏西瑞韦 , Воксилапревир , fda 2017, GS 9857, gilead, 1535212-07-7

CCC1C2CN(C1C(=O)NC3(CC3C(F)F)C(=O)NS(=O)(=O)C4(CC4)C)C(=O)C(NC(=O)OC5CC5CCCCC(C6=NC7=C(C=C(C=C7)OC)N=C6O2)(F)F)C(C)(C)C
CC1(CC1)S(=O)(=O)NC(=O)[C@]2(C[C@H]2C(F)F)NC(=O)[C@@H]7[C@H](CC)[C@@H]3CN7C(=O)[C@@H](NC(=O)O[C@@H]6C[C@H]6CCCCC(F)(F)c4nc5ccc(OC)cc5nc4O3)C(C)(C)C

FIRSOCOSTAT, ND 630, GS-0976, NDI-010976


str1

ndi molecul
str1
FIRSOCOSTAT, ND 630, NDI 010976,  ND-630, NDI-010976
CAS: 1434635-54-7UNII: XE10NJQ95M

PHASE 2, Non-alcoholic steatohepatitis, GILEAD

1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid
2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid
2-[1-[(2R)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid
CAS 1434635-54-7
Thieno[2,3-d]pyrimidine-3(2H)-acetic acid, 1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-
Molecular Formula: C28H31N3O8S
Molecular Weight: 569.62604 g/mol
Company Nimbus Therapeutics LLC
Description Small molecule allosteric inhibitor of acetyl-coenzyme A carboxylase alpha (ACACA; ACC1) and acetyl-coenzyme A carboxylase beta (ACACB; ACC2)
Molecular Target Acetyl-Coenzyme A carboxylase alpha (ACACA) (ACC1) ; Acetyl-Coenzyme A carboxylase beta (ACACB) (ACC2)
Mechanism of Action Acetyl-coenzyme A carboxylase alpha (ACACA) (ACC1) inhibitor; Acetyl-coenzyme A carboxylase beta (ACACB) (ACC2) inhibitor
Therapeutic Modality Small molecule
Preclinical Diabetes mellitus; Hepatocellular carcinoma; Metabolic syndrome; Non-alcoholic steatohepatitis; Non-small cell lung cancer
CHEMBL3407547.png

1,4-Dihydro-1-((2R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-alpha,alpha,5-trimethyl-6-(2-oxazolyl)-2,4-dioxothieno(2,3-d)pyrimidine-3(2H)-acetic acid

In April 2016, Gilead Sciences and Nimbus Therapeutics, LLC announced that the companies have signed a definitive agreement under which Gilead will acquire Nimbus Apollo, Inc., a wholly-owned subsidiary of Nimbus Therapeutics, and its Acetyl-CoA Carboxylase (ACC) inhibitor program. Nimbus Therapeutics will receive an upfront payment of $400 million, with the potential to receive an additional $800 million in development-related milestones over time.

The Nimbus Apollo program includes the lead candidate NDI-010976, an ACC inhibitor, and other preclinical ACC inhibitors for the treatment of non-alcoholic steatohepatitis (NASH), and for the potential treatment of hepatocellular carcinoma (HCC) and other diseases.

In May 2016, Nimbus Therapeutics announced the recent closing of Gileads acquisition of Nimbus Apollo. The acquisitions completion triggered a $400 million upfront payment to Nimbus from Gilead.

In January 2016, fast track designation was assigned in the U.S. for this indication. In May 2016, Gilead Sciences acquired Nimbus Apollo from Nimbus Therapeutics, including its acetyl-CoA carboxylase (ACC) inhibitor program.

Gilead Sciences following the acquisition of Nimbus Apollo , is developing firsocostat , the lead from a program of acetyl-CoA carboxylase (ACC)-targeting compounds, for treating fatty liver disease including non-alcoholic steatohepatitis.

Acetyl CoA carboxylase 1/2 allosteric inhibitors – Nimbus

Therapeutics

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting, San Francisco, CA, USA

Nimbus compounds targeting liver disease in rat models

Data were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND-630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively, EC50 values in HepG2 serum free and 10% serum of 9 and 66 nM, respectively, and 2-fold C2C12 fatty acid oxidation (FAOxn) stimulation at 200 nM. Rat FASyn (synthase), malonyl-CoA (liver) and malonyl-COA (muscle) respective ED50 values were 0.14 mg/kg po, 0.8 and 3 mg/kg. The rat respiratory quotient (RQ) MED was 3 mg/kg po. ADME data showed low multispecies intrinsic clearance (human, mouse, rat, dog, monkey). NDI-010976 was eliminated predominantly as the parent drug. Additionally, P450 inhibition was > 50 microM. In liver and muscle, NDI-010976 modulated key metabolic parameters including a dose-dependent reduction in the formation of the enzymatic product of acetyl coA carboxyloase malonyl coA; the ED50 value was lower in muscle. The drug also decreased FASyn dose dependently and increased fatty acid oxidation in the liver (EC50 = 0.14 mg/kg). In 28-day HS DIO rats, NDI-010976 favorably modulated key plasma and liver lipids, including decreasing liver free fatty acid, plasma triglycerides and plasma cholesterol; this effect was also seen in 37-day ZDF rats

 PATENT

http://www.google.com/patents/WO2013071169A1?cl=en

Example 76: Synthesis of 2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid (1-181).

Synthesis of compound 76.1. Into a 250-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed oxan-4-ol (86 g, 842.05 mmol, 2.01 equiv) and FeCl3 (10 g). This was followed by the addition of 57.2 (63 g, 419.51 mmol, 1.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 500 mL of H20. The resulting solution was extracted with 3×1000 mL of ethyl acetate and the organic layers combined. The resulting solution was extracted with 3×300 mL of sodium chloride (sat.) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 22 g (21%) of 76.1 as a white solid.

Synthesis of compound 76.2. The enantiomers of 76.1 (22g) were resolved by chiral preparative HPLC under the following conditions (Gilson Gx 281): Column: Venusil Chiral OD-

H, 21.1 *25 cm, 5 μιη; mobile phase: hexanes (0.2% TEA) and ethanol (0.2% TEA) (hold at 10% ethanol (0.2%TEA) for 13 min); detector: UV 220/254 nm. 11.4 g (52%) of 76.2 were obtained as a white solid.

Synthesis of compound 76.3. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 70.1 (12 g, 20.49 mmol, 1.00 equiv), tetrahydrofuran (200 mL), 76.2 (6.2 g, 24.57 mmol, 1.20 equiv) and DIAD (6.5 g, 32.18 mmol, 1.57 equiv). This was followed by the addition of a solution of triphenylphosphane (8.4 g, 32.03 mmol, 1.56 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at 0 °C in 60 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 17 g (crude) of 76.3 as a white solid.

Synthesis of compound 76.4. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 76.3 (17 g, crude), toluene (300 mL), Pd(PPh3)4 (1.7 g, 1.47 mmol, 0.07 equiv) and 2-(tributylstannyl)-l,3-oxazole (8.6 g, 24.02 mmol, 1.16 equiv). The resulting solution was stirred overnight at 110 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). Purification afforded 6 g of 76.4 as a white solid.

Synthesis of compound 1-181. Into a 250-mL 3-necked round-bottom flask, was placed 76.4 (6 g, 7.43 mmol, 1.00 equiv), tetrahydrofuran (100 mL), TBAF (2.3 g, 8.80 mmol,

I .18 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50: 1). This resulted in 3.4 g (80%) of Compound 1-181 as a white solid.

Purification: MS (ES): m/z 570 (M+H)+, 592 (M+Na)+.

1H NMR (300 MHz, DMSO- d6): δ 1.22-1.36 (m, 2H), 1.62 (m, 8H), 2.75 (s, 3H), 3.20-3.39 (m, 3H), 3.48-3.58 (m, 2H), 3.80 (s, 3H), 3.85-4.20 (m, 2H), 5.30 (m, 1H), 7.03 (m, 2H), 7.33-7.50 (m, 3H), 8.2 (s, 1H).

Figure imgf000193_0001

ndi molecul

Preparation of ND-630.1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid, ND-630, was prepared as described (49)…….http://www.pnas.org/content/113/13/E1796.full.pdf
Harriman GC, Masse CE, Harwood HJ, Jr, Baht S, Greenwood JR (2013) Acetyl-CoA
carboxylase inhibitors and uses thereof. US patent publication US 2013/0123231.
CLIPS

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting,  San Francisco, CA, USA

Conference: 66th Annual Meeting of the American Association for the Study of Liver Diseases Conference Start Date: 13-Nov-2015

…candidates for minimizing IR injury in liver transplantation.Nimbus compounds targeting liver disease in rat modelsData were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively…

REFERENCES

November 13-17 2015
The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting  San Francisco, CA, USA ,
WO-2014182943

WO-2014182951 

WO-2014182945

WO-2014182950 

Patent ID Date Patent Title
US2015203510 2015-07-23 ACC INHIBITORS AND USES THEREOF
US2013123231 2013-05-16 ACC INHIBITORS AND USES THEREOF

 

WO2017151816 ,

CN 107629069

CN 107629069

CN 107151251

WO 2013071169

WO 2016112305

PATENT

WO-2018161022

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018161022&tab=PCTDESCRIPTION&maxRec=1000

Solid forms, including a salts (such as choline, diethylamine, NN-dibenzylethylenediamine, ethanolamine) or co-crystal, of firsocostat and compositions comprising them are claimed, which exhibits Acetyl-CoA carboxylase inhibitory activity and useful for treating ACC mediated diseases such as metabolic disorders, neurological disorders, and infectious diseases. Also claimed are process for preparing firsocostat and intermediates useful for preparing them are claimed.

The present disclosure provides forms of Compound I or a compound of formula (I) having the formula:

Compound I may be referred to by formula (I):

(I)

or its chemical name of (R)-2-(l-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-l,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid. U.S. Patent No. 8,969,557 discloses that Compound I exhibits ACC inhibitory activity. In the present disclosure, compounds may be presented in the form of chemical structures or names.

Scheme 1 represents an exemplary synthesis of a compound of formula (F) and may be carried out according to the embodiments described herein.

Scheme 1

(E) (F)

Scheme 2

(E-1 ) (I)

Scheme 3

Step (g)

Scheme 4

scheme 5

Example 1 : Synthesis of Compound B-2

B-2

[0401] Compound A-2 was combined with Compound G-1 (about 1 equivalents (“equiv”)) with K2CO3 (about 2.3 equiv) in dimethylacetamide. The mixture was stirred at room temperature. The resulting mixture was then diluted with ethyl acetate and washed with water and brine. The organic layer was separated and concentrated to dryness, and the resulting product was purified by column chromatography (eluent: 0 to about 28% ethyl acetate:

heptanes). The resulting product was Compound B-2. ¾ NMR (300 MHz, CDCh): δ 7.92 (d, J

= 8.4 Hz, 1H), 7.57 (m, 1H), 7.06 (m, 2H), 5.20 (s, 2H), 4.00 (s, 3H), 2.42 (s, 3H), 1.77 (s, 6H), 1.44 (s, 9H).

Example 2: Synthesis of a compound of formula (C)

(B) (C)

[0402] Compound of formula (B) or Compound B (which may be prepared as described in Example 1) and a (S,S)-Ruthenium catalyst, such as a Ruthenium catalyst as described herein, or a suitable antipode of the Ruthenium catalyst, are combined in the presence of potassium tert-butoxide (“KO^-Bu”) and isopropanol and refluxed to yield a compound of formula (C) or Compound C. Compound C is isolated and purified by methods described herein.

Example 3: Synthesis of Compound D-1

C-1 D-1

[0403] To Compound C-1 in dichloromethane is added 4-bromotetrahydro-2H-pyran. Upon addition of an organic base, the reaction mixture is stirred ovemight to yield a compound of formula D-1 or Compound D-1. Compound D-1 is isolated and purified by the methods described herein.

Example 4: S

D-1 E-2

[0404] Oxazole in THF is cooled to between about -80 °C and about -60 °C. Then, ft-butyllithium in hexanes is added while maintaining the temperature of the reaction below about -60 °C. The mixture is stirred at this temperature for 90 minutes. Zinc (II) chloride is added, maintaining the temperature of the mixture below about -60 °C, and the mixture is stirred at that temperature for about one hour before warming to about 10-20 °C. Compound D-1 is added to the reactor followed by tetrakis(triphenylphosphine)palladium(0) (“Pd(PPh3)4”), and the temperature is adjusted to between about 55-65 °C. The mixture is stirred at that temperature for about 12 hours to yield Compound E-2. Compound E-2 is isolated and purified by the methods described herein.

Example 5: Synthesis of Compound I

[0405] A sulfuric acid solution was prepared by addition of concentrated sulfuric acid (47 g,

4.7 w/w Compound E-2) to water (12 g, 1.2 v/w Compound E-2) followed by a water (15 g, 1.5 v/w Compound E-2) rinse forward. 2-Propanol (37 g, 4.7 v/w Compound E-2) was slowly charged to a reactor containing sulfuric acid solution at about 9 °C while maintaining the reaction contents at no more than about 40 °C, and the solution was cooled to about 5 °C .

Compound E-2 (10 g, 1.0 equiv) was charged to the solution, followed by a 2-propanol rinse forward (2 g, 0.25 v/w E-2). The contents were cooled to about 7 °C and stirred for a minimum of about 21 hours. The contents were slowly added into water, and the slurry was agitated for about 30 minutes. The slurry was filtered, and the filter cake was washed and dried under vacuum for about 4 hours. The crude wet cake was charged back to the reactor, followed by additions of ethyl acetate (40 g, 4.4 v/w Compound E-2) and water (100 g, 10 v/w Compound E-2). The slurry was adjusted to pH at about 8-9 with an about 20 wt% sodium hydroxide solution at about 22 °C, and then agitated for about 30 minutes at about 22 °C. The solution was allowed to settle. The top organic layer was collected and the bottom aqueous layer was washed with ethyl acetate (40 g, 4.4 v/w Compound E-2) at about 22 °C for about 30 minutes. The solution was allowed to settle, and the top organic layer was removed. 2-Methyltetrahydrofuran (86 g, 10 v/w Compound E-2) was then added, was adjusted to pH at about 4-5 with an about 4 N HCl solution at about 22 °C. The solution was agitated for about 30 minutes at about 22 °C and then allowed to settle. The bottom aqueous layer was extracted with 2-methyltetrahydrofuran (52 g, 6 v/w Compound E-2) at about 22 °C for about 30 minutes. After the solution was allowed to settle, the bottom aqueous layer was removed. The organic layers were combined and distilled under vacuum (jacket at about < 45 °C) to about 4V pot volume. Ethanol (55.4 g, 7 v/w

Compound E-2) was added and the reaction as distilled (repeated twice). Ethanol was again added (23.7 g,3 v/w Compound E-2), followed by water (30 g, 3 v/w Compound E-2). The reaction was heated to about 75 °C and then cooled over about 4 hours to about 50 °C, then to about 0 °C over about 5 hours. The reaction was then aged and filtered, and the solid was washed with a precooled mixture of ethanol (9.5 g, 1.2 v/w Compound E-2) and water (6 g, 0.6 v/w Compound E-2). The resulting product was washed to afford Compound of formula (I). ¾ NMR (400 MHz, CDCh): δ 7.70 (s, 1H), 7.57 (dd, J= 1.6 Hz, J= 7.6 Hz, 1H), 7.29 (td, J= 1.6 Hz, J = 8.0 Hz, 1H), 7.23 (d, J= 0.4 Hz, 1H), 7.02 (t, J= 7.6 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 5.39 (dd, J= 5.6 Hz, J= 8.0 Hz, 1H), 4.17-4.14 (m, 1H), 4.04 (br, 1H), 3.86 (s, 3H), 3.78-3.67 (m, 2H), 3.46-3.40 (m, 1H), 3.37-3.32 (m, 2H), 2.85 (s, 3H), 1.87 (s, 3H), 1.83 (s, 3H), 1.75-1.72 (m, 2H), 1.59-1.51 (m, 1H), 1.48-1.39 (m, 1H).

Example 6: Synthesis of Compound J-l

Step (a): Formation of Compound P-l

[0406] 2-Methoxyphenylmagnesium bromide (1 M in THF, 1.0 equiv.) was added to a solution of diethyl oxalate (1.1 equiv.) in THF (250 mL) at about -20 °C over approximately 20 min. After aging for about 45 min at about -20 °C, the resulting slurry was quenched with saturated NH4CI (250 mL) and was diluted with water (200 mL). This mixture was extracted with EtO Ac (400 mL), and the organic phase was washed with brine (200 mL). The organic phase was concentrated and the solvent was exchanged to THF. The resulting THF solution was used in the next step as is. ¾ NMR (400 MHz, CDCh): δ 7.90 (m, 1H), 7.61 (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.01 (d, J= 8.4 Hz 1H), 4.41 (q, J= 7.1 Hz, 2H), 3.88 (s, 3H), 1.41 (t, J= 7.1 Hz, 3H).

Alternate Preparation Compound P-l:

[0407] Anisole (1.0 equiv.) in THF (15 mL) was cooled to about -20 °C, and 2.5 M n-BuLi/hexane (1.1 equiv.) was added. The mixture was allowed to warm to about 0 °C and aged for about 2 hours, then warmed to room temperature overnight. The solution was then added to a solution of diethyl oxalate (4.0 equiv.) in THF (10 mL) at about -20 °C. The mixture was allowed to warm to about room temperature and aged for approximately 2 hours, then cooled to about 0 °C and quenched via addition of saturated NH4CI (30 mL). This mixture was extracted with EtOAc, and the organic phase was washed with brine and dried over MgSCk

Concentration afforded Compound P-1.

Alternate Preparation Compound P-1:

[0408] 2-Bromoanisole (1.0 equiv.) in THF (63 mL) was cooled to about -65 °C and 2.5M ft-BuLi/hexanes (1.0 equiv) was added. After aging for approximately 1 h, diethyl oxalate (4.0 equiv.) was charged, and the reaction mixture was allowed to warm to about room temperature. After approximately 1 h at about room temperature, the reaction mixture was cooled to about 0 °C, quenched by addition of saturated NH4CI (50 mL), and diluted with EtOAc. The aqueous phase was separated and was extracted with EtOAc. The combined organic phases were washed with brine and dried over MgS04. Concentration under high vacuum afforded a product that was passed through a plug of silica gel to afford Compound P-1.

Step (b): Hydrolysis of Compound P-1 and salt conversion to Compound O-l:

P-1 0-1

[0409] The resulting solution of ketoester, compound P-1, in THF (about 1.0 equiv.) was cooled over an ice bath and 2N NaOH (1.36 equiv.) was added. The reaction was agitated at about 0 °C and after reaction completion, the reaction was then acidified by addition of 6N HC1 (57 mL) to about pH<l and extracted with EtOAc (500 mL). The organic phase was washed with brine (200 mL). The organic phase was concentrated and then solvent exchanged to EtOAc. The resulting solution was cooled to about 0 °C and solid KOlBu (1.0 equiv.). The slurry was agitated for approximately 4 h and the solids were filtered, rinsed with EtOAc, and dried overnight at about 60 °C under vacuum to afford Compound O-l . ¾ NMR (400 MHz, DMSO-d6): 5 7.61 (d, J= 7.6 Hz, 1H), 7.49 – 7.41 (m, 1H), 7.04 (d, J= 8.4 Hz 1H), 6.96 (t, J = 7.4 Hz, 1H), 3.73 (s, 3H).

Step (c): Reduction of Compound O-l to Compound N-1:

0-1 N-1

[0410] To triethylamine (3.6 equiv.) precooled to about 0 °C, was added formic acid (9.0 equiv.) over about 30 min while maintaining a temperature less than about 30 °C. Solid RuCl (i?,i?)-Ts-DENEB catalyst (0.07 mol%) followed by ketoacid potassium salt (1.0 equiv.) were then charged to the mixture of triethylarnine/forrnic acid. The resulting slurry was warmed to about 50 °C and was stirred under nitrogen until the reaction was complete. The reaction was cooled over an ice bath and quenched by the addition of water (76 mL) followed by 10N NaOH (128 mL) to pH>13. Water (30 mL) and iPrAc (130 mL) were added and the organic layer was separated, and the aqueous phase was extracted with iPrAc (2 χ 130 mL). The aqueous phase was cooled and was acidified with concentrated HC1. This was extracted with iPrAc several times and the combined organic extract was concentrated and solvent exchanged to toluene, filtered hot, and then cooled to about 30 °C over approximately 2 h, aged for approximately 1 h, then filtered to afford solids that were then slurry-rinsed with toluene (50 mL) at room temperature and filtered. The wet cake was dried to afford Compound N-1. ¾ NMR (400 MHz, CDCh): δ 7.44 (d, J = 7.6 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.06 (t, J = 7.6 Hz 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.41 (s, 1H), 3.94 (s, 3H).

Step (d): Spiroketalization to afford Compound L-1:

N-1 L-1

[0411] Compound N-1 (1.0 equiv.), tetrahydropyran-4-one (compound M, 1.1 equiv.), and MTBE (30 mL) were sequentially charged and cooled to about 0 °C. Boron trifluoride THF complex (1.4 equiv.) was added over about 10 mins. After reaction completion, the reaction was slowly quenched with a pre-mixed solution of sodium bicarbonate (3.66 g) and water (40 mL). The solution was warmed to about 20 °C and diluted with toluene (40 mL) and stirred until dissolved. Agitation was stopped and the aqueous layer removed. The organic layer was washed with water (20 mL) and removed. The organic layer was collected and reactor rinsed forward with toluene (4 mL) to yield Compound L-1. ¾ NMR (400 MHz, CDCh): δ 7.42 – 7.38 (m, 1H), 7.32 (dd, J = 7.5, 1.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.52 (s, 1H), 3.97 – 3.79 (m, 7H), 2.18 – 1.97 (m, 4H).

Step (e): Reduction of Compound L-1 to Compound K-l :

L-1 K-1

[0412] A stock solution of spiroketal, compound L-1, in MeTHF/MTBE (1.0 equiv.) was charged to a reactor. The solution was then distilled to about 4 volumes. MeTHF (187 mL) was charged, and distilled down to about 5 volumes. The solution was cooled to about 20 °C. DCM (90 mL) was charged and the solution was cooled to about 10 °C and tert-butyl magnesium chloride (2 M in diethyl ether) (5.0 equiv.) was added over approximately 45 mins. Following addition, the contents were cooled to about 7 °C and aged overnight at about 10 °C, then to about 0 °C. A premixed solution of HC1 (45 mL) and water (126 mL) was then slowly added. The aqueous bottom layer was drained and the aqueous layer extracted with MeTHF (93 mL). The combined organic layers were washed with water (37 mL) and the remaining organic layer was distilled down to about 4 volumes. Isopropyl acetate (181 mL) was charged and the solution reduced to about 5 volumes. The reaction was cooled to about 72 °C and heptanes (58 mL) was charged and the solution was held for about 1 hour before cooling to about 0 °C over approximately 5 hours. The slurry was agitated at about 0 °C for >12 h and then filtered, rinsed with an isopropyl acetate (9 mL) and heptanes (18 mL) mixture, followed by water (54 mL). The solids were dried to yield compound K-l. ¾ NMR (400 MHz, CDCh): δ 8.49 (br. s, 1 H), 7.42 – 7.29 (m, 2H), 6.98 (t, J= 7.4 Hz, 1H), 6.92 (d, 8.3 Hz, 1H), 5.43 (s, 1H), 3.96 (dt, J = 11.5, 4.3 Hz, 1H), 3.89 (dt, J = 11.5, 4.3 Hz, 1H), 3.85 (s, 3H), 3.67 – 3.58 (m, 1H), 3.47 – 3.30 (m, 2H), 2.03 – 1.93 (m, 1H), 1.84 – 1.75 (m, 1H), 1.75 – 1.56 (m, 2H).

Step (f): Reduction of Com ound K-l to Compound J-1:

J-1

K-1

[0413] A solution of acid, compound K-l (1.0 equiv.), in THF (90 mL) was cooled to about 0 °C and NaBH4 (1.2 equiv.) was added followed by BF3 THF complex (1.5 equiv.). The solution was warmed to about 20 °C and agitated until the reaction was deemed complete. Upon completion, MeOH (24 mL) was added to the reaction mixture after adjusting the temperature to about 5 °C, and was stirred until the gas evolution ceased. EtOAc (102 mL) was charged followed by saturated NLUClaq solution (87 mL). The agitation was stopped and the aqueous layer was removed. The organic layer was distilled down to about 3 volumes under vacuum, and then heptane (46 mL) was charged. The resulting mixture was cooled to about 0 °C and agitated at this temperature for approximately 4 h before being filtered and rinsed with heptane (3 mL). The resulting solids were dried to yield compound J-1. ¾ NMR (400 MHz, CDCh): δ 7.42 (d, J = 7.2 Hz, 1H), 7.27 (m, 1H), 6.98 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 8.4, 2.8 Hz, 1H), 3.93 (m, 2H), 3.82 (s, 3H), 3.67 (m, 1H), 3.55 – 3.46 (m, 2H), 3.41 – 3.32 (m, 2H), 2.27 (d, J = 8.0 Hz, 1H), 2.01 (m, 1H), 1.80 – 1.70 (m, 1H), 1.65 (m, 2H).

Step (g): Alternate Direct Reduction of Compound L-1 to Compound J-1:

L-1 J-1

[0414] To a solution of ketal, compound L-1 (1 equiv.), in diglyme (0.7 mL) was added NaBH4 (3.6 equiv.) followed by BF3 THF complex (4.5 equiv.). Reaction mixture was agitated for about 18 hours and was quenched by dropwise addition of MeOH (1 mL) followed by saturated Ν¾(¾ solution (1 mL). EtOAc (2 mL) was added, shaken well and the aqueous layer was removed. Organic solvent was removed under reduced pressure to obtain the crude compound J-1.

Example 7: Alternate Synthesis to Compound N-1

Step (a): Addition of hydrogen cyanide to ortho-anisaldehyde, compound U-1, to form compound T-1

[0415] To an Eppendorf tube was added ort/ro-anisaldehyde, compound U-1 (1.0 equiv), followed by 0.4 M sodium acetate buffer pH 5 (0.25 mL) and fert-butyl methyl ether (0.75 mL). The mixture was shaken using a thermomixer at about 30 °C and about 1200 rpm to ensure

complete dissolution of the aldehyde. Once this was complete acetone cyanohydrin (1.15 equiv) is added to the reaction mixture followed by hydroxynitrilase enzyme (2 mg). The Eppendorf tube was shaken in a thermomixer at about 30 °C and about 1200 rpm overnight. The Eppendorf tube was then heated to about 60 °C at about 1400 rpm for about 15 mins in order to denature the enzyme before being cooled to about 30 °C. The Eppendorf tube was then centrifuged at about 13,400 rpm for about 15 mins in order to pellet the denatured enzyme from the organic layer. The organic layer was removed and concentrated to dryness to give crude compound T-l . ¾ NMR (400 MHz, CDCh): δ 7.45 – 7.39 (m, 2H), 7.04 – 6.96 (m, 2H), 5.63 (s 1H), 3.94 (s, 3H), 3.75 (br, 1H).

Step (b): Hydrolysis of c

T-1 N-1

[0416] Before starting the reaction the following stock solutions were prepared: A solution of the crude cyanohydrin (compound T-l) in DMSO (about 100 mg/mL); a solution of 50 mM potassium phosphate (pH 7) containing 2 mM dithiothreitol (DTT); and 1 mM ethylenediamine tetraacetic acid (EDTA). To an Eppendorf tube was added nitrilase enzyme (4 mg) followed by 1.1 mL of the reaction buffer solution and 0.05 mL of the solution containing the crude cyanohydrin (about 10 mg). The Eppendorf tube was shaken in a thermomixer at about 30 °C and about 1200 rpm overnight. The Eppendorf tube was then heated to about 60 °C at about 1400 rpm for about 15 mins in order to denature the enzyme before being cooled to about 30 °C once more. The Eppendorf tube was centrifuged at about 13,400 rpm for about 15 mins in order to pellet the denatured enzyme and then separate it from the supernatant. The supernatant was either sampled directly for reverse phase UPLC or extracted with DCM for normal phase HPLC. In the case of DCM extraction, after separating the layers the organic layer was concentrated to dryness before the appropriate diluent was added for normal phase HPLC. UPLC analysis showed a peak with retention time identical to a reference standard of compound N-1.

Example 8: Alternate S nthesis to Compound N-1

P-1 V-1 N-1

Step (a): Reduction of Compound P-1 to form 2 ‘-methoxy-ethyl mandelate, Compound V-1:

P-1 V-1

[0417] The following stock solutions were made prior to the start of the reaction: a solution of starting material in DMSO (about 100 mg/ mL), NADP+ or NAD+ in 0.1M phosphate buffer (as appropriate) (2 mg/mL), glucose dehydrogenase in 0.1 M phosphate buffer (4 mg/mL), and glucose in 0.1 M phosphate buffer (20 mg/mL). To an Eppendorf tube is charged the ketoreductase enzyme (2 mg) followed by 0.25 mL of buffer solution containing NAD(P)+, 0.25 mL of buffer solution containing glucose dehydrogenase (GDH) and 0.5 mL of buffer solution containing glucose. Finally, 0.05 mL of the stock solution containing the starting material, compound P-1 in DMSO is added. The Eppendorf tube was then shaken in a thermomixer at about 30 °C and about 1200 rpm overnight. The Eppendorf tube was then heated to about 60 °C at about 1400 rpm for about 15 mins in order to denature the enzymes before being cooled to about 30 °C. The Eppendorf tube was then centrifuged at about 13,400 rpm for about 15 mins in order to pellet the denatured enzyme and the supernatant removed. This was either sampled directly for reverse phase UPLC or extracted with DCM for normal phase HPLC. In the case of DCM extraction after separating the layers the organic layer was concentrated to dryness before the appropriate diluent was added for normal phase HPLC. UPLC analysis showed a peak with retention time identical to a reference standard of the product material.

Step (b) Hydrolysis of 2 ‘-methoxy-ethyl mandelate, compound V-1, to provide compound N-1:

V-1 N-1

[0418] A solution of 2′ -methoxy-ethyl mandelate (1.0 equiv.) in EtOH (30 mL) was cooled to about 0 °C and 1.25 M NaOH (30 mL) was slowly added. Upon reaction completion, the reaction was adjusted to about pH 1 with 1M HC1 (40 mL). The mixture was extracted three times with ethyl acetate (30 mL) and the combined organics were washed with a brine solution (25 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvent removed under vacuum to provide the product. NMR data reported as above.

CLIP

https://cen.acs.org/articles/94/i39/silent-liver-disease-epidemic.html

A structure Nimbus's ACC inhibitor ND-630.

Patent ID

Title

Submitted Date

Granted Date

US8969557 ACC INHIBITORS AND USES THEREOF
2012-11-09
2013-05-16
US2017267690 SOLID FORMS OF A THIENOPYRIMIDINEDIONE ACC INHIBITOR AND METHODS FOR PRODUCTION THEREOF
2017-03-01
US2016297834 ACC INHIBITORS AND USES THEREOF
2016-03-11
US9453026 ACC INHIBITORS AND USES THEREOF
2015-01-23
2015-07-23

/////// ND 630, NDI 010976,  ND-630, NDI-010976, NIMBUS, GILEAD, 1434635-54-7, PHASE 2

FIRSOCOSTAT,  ND 630, GS-0976, NDI-010976, FAST TRACK, CS-6509

COc1ccccc1[C@H](CN2C(=O)N(C(=O)c3c(C)c(sc23)c4occn4)C(C)(C)C(=O)O)OC5CCOCC5

O=C(O)C(C)(C)N4C(=O)c1c(C)c(sc1N(C[C@H](OC2CCOCC2)c3ccccc3OC)C4=O)c5ncco5

GS 9883, Bictegravir an HIV-1 integrase inhibitor


UNII-8GB79LOJ07.png

GS 9883, bictegravir

CAS 1611493-60-7

PHASE 3

HIV-1 integrase inhibitor

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

2,5-Methanopyrido(1′,2′:4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-

2,5-Methanopyrido(1′,2′:4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

(2 ,5S,13aI )-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluoroheoctahydro-2,5-methanopyrido[ 1 ‘,2’:4,5]pyrazino[2, 1 -b][ 1 ,3]oxazepine- 10-carboxamide

MF  C21H18F3N3O5,

 MW 449.37993 g/mol

 UNII-8GB79LOJ07; 8GB79LOJ07

 

2D chemical structure of 1611493-60-7

BICTEGRAVIR

 

  • 16 Nov 2015 Phase-III clinical trials in HIV-1 infections (Combination therapy, Treatment-naive) in USA (PO) (Gilead Pipeline, November 2015)
  • 01 Jul 2015 Gilead Sciences completes a phase I trial in HIV-1 infections in USA and New Zealand (NCT02400307)
  • 01 Apr 2015 Phase-I clinical trials in HIV-1 infections (In volunteers) in New Zealand (PO) (NCT02400307)

UPDATE       Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide); Gilead; For the treatment of HIV-1 infection in adults, Approved February 2018

Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV and that minimize PXR activation when co-administered with other drugs.

Certain polycyclic carbamoylpyridone compounds have been found to have antiviral activity, as disclosed in PCT/US2013/076367. Accordingly, there is a need for synthetic routes for such compounds.

 

SYNTHESIS

WO 2014100323

PATENTS

WO2014100323

xample 42

Preparation of Compound 42

(2 ,5S,13aI )-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorohe

octahydro-2,5-methanopyrido[ 1 ‘,2’:4,5]pyrazino[2, 1 -b][ 1 ,3]oxazepine- 10-carboxamide


42

Step 1

l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l ,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesuffhnic acid (0.195 mL, 3 mmol) and placed in a 75 deg C bath. The reaction mixture was stirred for 7 h, cooled and stored at -10 °C for 3 days and reheated to 75 °C for an additional 2 h. This material was cooled and carried on crude to the next step.

Step 2

Crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (lR,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol) and heated to 85 °C. After 2 h, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HQ (50 mL) was added, and the clear yellow solution was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a light orange solid. Recrystallization from dichloimethane:hexanes afforded the desired intermediate 42 A: LC S-ESI (m/z): [M+H]+ calculated for Ci5Hi7N206: 321.1 1 ; found: 321.3.

Step 3

Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethyiammo)- V,A/-dimethyi(3H-[l ,2,3]triazolo[4,5-&]pyridm~3-yiox.y)methammimum hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LfJMS-ESlT (m/z): [M+H calculated for (\ ,l l.,, i \\:0< : 464.14; found: 464.2.

Step 4

To the crude reaction mixture of the previous step was added MgBr2

(0.258 g, 1.40 mmol). The reaction mixture was stirred at 50 °C for 10 minutes, acidified with 10% aqueous HC1, and extract twice with dichloromethane. The combined organic phases were dried over MgS04, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN H2O with 0.1 % TFA modifier) to afford compound 42: 1H~ M (400 MHz, DMSO-</6) δ 12.43 (s, 1H), 10.34 (t, J = 5.7 Hz, IH), 8.42 (s, 1H), 7.19 (t, J = 8.7 Hz, 2H), 5.43 (dd, ./’ 9.5, 4.1 Hz, I H), 5.08 (s, i l l ). 4.66 (dd, ./ 12.9, 4.0 Hz, IH), 4.59 (s, 1 1 1 ). 4.56 4.45 (m, 2H), 4.01 (dd, J = 12.7, 9.7 Hz, IH), 1.93 (s, 4H), 1.83 (d, J —— 12.0 Hz, I H),

1.56 (dt, J = 12.0, 3.4 Hz, I H). LCMS-ESI+ (m/z): [M+H]+ calculated for { · Ί ί ] ΝΓ :Χ.¾ϋ : 450.13; found: 450.2.

PATENT

WO2015177537

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015177537&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

WO2015196116

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196116&redirectedID=true

PATENT

WO2015196137

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196137&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

http://www.google.com/patents/US20140221356

Example 42 Preparation of Compound 42 (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

  • 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL, 3 mmol) and placed in a 75 deg C. bath. The reaction mixture was stirred for 7 h, cooled and stored at −10° C. for 3 days and reheated to 75° C. for an additional 2 h. This material was cooled and carried on crude to the next step.

Step 2

  • Crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (1R,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol) and heated to 85° C. After 2 h, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HCl (50 mL) was added, and the clear yellow solution was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a light orange solid. Recrystallization from dichlormethane:hexanes afforded the desired intermediate 42A: LCMS-ESI+ (m/z): [M+H]+ calculated for C15H17N2O6: 321.11; found: 321.3.

Step 3

  • Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LCMS-ESI+ (m/z): [M+H]+ calculated for C22H21F3N3O5: 464.14; found: 464.2.

Step 4

  • To the crude reaction mixture of the previous step was added MgBr2 (0.258 g, 1.40 mmol). The reaction mixture was stirred at 50° C. for 10 minutes, acidified with 10% aqueous HCl, and extract twice with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN/H2O with 0.1% TFA modifier) to afford compound 42: 1H-NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.34 (t, J=5.7 Hz, 1H), 8.42 (s, 1H), 7.19 (t, J=8.7 Hz, 2H), 5.43 (dd, J=9.5, 4.1 Hz, 1H), 5.08 (s, 1H), 4.66 (dd, J=12.9, 4.0 Hz, 1H), 4.59 (s, 1H), 4.56-4.45 (m, 2H), 4.01 (dd, J=12.7, 9.7 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J=12.0 Hz, 1H), 1.56 (dt, J=12.0, 3.4 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calculated for C21H19F3N3O5: 450.13; found: 450.2.

 

 

PATENT

WO-2015195656

 

General Scheme I:

General Scheme II:

General Scheme II

General Scheme III:

General Scheme III

General Scheme IV:

G-1

 

General Scheme V:

II

 

EXAMPLES

In order for this invention to be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating embodiments, and are not to be construed as limiting the scope of this disclosure in any way. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art.

In one embodiment, a multi-step synthetic method for preparing a compound of Formula I is provided, as set forth below. In certain embodiments, each of the individual steps of the Schemes set forth below is provided. Examples and any combination of two or more successive steps of the below Examples are provided.

A. Acylation and amidation of Meldrum ‘s acid to form C-la:

[0520] In a reaction vessel, Meldrum’s acid (101 g, 1.0 equivalent) and 4-dimethylaminopyridine (1.8 g, 0.2 equivalents) were combined with acetonitrile (300 mL). The resulting solution was treated with methoxyacetic acid (6.2 mL, 1.2 equivalents). Triethylamine (19.4 mL, 2.0 equivalents) was added slowly to the resulting solution, followed by pivaloyl chloride (9.4 mL, 1.1 equivalents). The reaction was then heated to about 45 to about 50 °C and aged until consumption of Meldrum’s acid was deemed complete.

A separate reaction vessel was charged with acetonitrile (50 mL) and J-la (13.4 g, 1.2 equivalents). The resulting solution was treated with trifluoroacetic acid (8.0 mL, 1.5 equivalents), and then this acidic solution was added to the acylation reaction in progress at about 45 to about 50 °C.

The reaction was allowed to age for at least 18 hours at about 45 to about 50 °C, after which time the solvent was removed under reduced pressure. The crude residue was dissolved in ethyl acetate (150 mL), and the organic layer was washed with water. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, and the combined bicarbonate washes were back extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified twice via silica gel chromatography to yield C-la.

lH NMR (400 MHz, CDC13): δ 7.12 (br, 1H), 6.66 (app t, J= 8.1 Hz, 2H), 4.50 (app d, J= 5.7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). 13C NMR (100 MHz, CDC13): δ 203.96, 164.90, 162.37 (ddd, J= 250.0, 15.7, 15.7 Hz), 161.71 (ddd, J = 250.3, 14.9, 10.9 Hz), 110.05 (ddd, J= 19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J= 3.5 Hz). LCMS, Calculated: 275.23, Found: 275.97 (M).

I l l

B. Alkylation of C-la to form E-la:

A solution of C-la (248 mg, 1.0 equivalent) and 2-methyl tetrahydrofuran (1.3 niL) was treated with N,N-dimethylformamide dimethylacetal (0.1 mL, 1.1 equivalent) and stirred at room temperature overnight (~14 hours). The reaction was treated with aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalents), and was allowed to age for about 2 hours, and then was quenched via the addition of 2 Ν HC1

(1.5 mL).

The reaction was diluted via the addition of ethyl acetate, and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography to yield E-la.

1H NMR (400 MHz, CDC13): δ 10.85 (s, 1H), 9.86 (s, 1H), 8.02 (d, J= 13.1 Hz, 1H), 6.65 (dd, J= 8.7, 7.7 Hz, 2H), 4.53 (d, J= 3.9 Hz, 2H), 4.40 (t, J= 5.1 Hz, 1H), 4.18 (s, 2H), 3.42 (s, 6H), 3.39 (m, 2H), 3.37 (s, 3H). 13C MR (100 MHz, CDC13): δ 193.30, 169.15, 162.10 (ddd, J= 248.9, 15.5, 15.5 Hz), 161.7 (ddd, J =

250.0, 14.9, 1 1.1 Hz), 161.66, 1 11.08 (ddd J= 19.9, 19.9, 4.7 Hz) 103.12, 100.29 (ddd, J= 28.1, 17.7, 2.3 Hz), 76.30, 58.83, 54.98, 53.53, 51.57, 29.89 (t, J= 3.3 Hz). LCMS, Calculated: 390.36, Found: 390.92 (M).

c. Cyclization of E-la to form F-la:

E-1a F-1a

] E-la (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5 equivalents) and methanol (1.5 mL) were combined and cooled to about 0 to about 5 °C. Sodium methoxide (0.2 mL, 30% solution in methanol, 1.75 equivalents) was introduced to the reaction slowly while keeping the internal temperature of the reaction below about 10 °C throughout the addition. After the addition was completed the reaction was heated to about 40 to about 50 °C for at least 18 hours.

After this time had elapsed, the reaction was diluted with 2 N HC1 (1.5 mL) and ethyl acetate (2 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and solvent was removed under reduced pressure. The resulting crude oil was purified via silica gel chromatography to afford F-la.

lR NMR (400 MHz, CDC13): δ 10.28 (t, J= 5.5 Hz, 1H), 8.38 (s, 1H), 6.66 – 6.53 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H), 4.43 (t, J= 4.7 Hz, 1H), 4.00 (d, J= 4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). 13C NMR (100 MHz, CDC13): δ 173.08, 163.81, 162.17, 162.14 (ddd, J= 249.2, 15.6, 15.6 Hz), 161.72 (ddd, J= 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 1 10.53 (ddd, J= 19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15 (M+H).

D. Alkylation and cyclization of C-la to form F-la:

1 . DMFDMA

C-1a NaOMe, MeOH, 40 °C F-1a

To a reaction vessel were added C-la (245 mg, 1.0 equivalent) and N,N-dimethylformamide dimethylacetal (0.5 mL, 4.3 equivalent). The reaction mixture was agitated for approximately 30 minutes. The reaction was then treated with 2-methyl tetrahydrofuran (2.0 mL) and aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalent). The reaction was allowed to age for several hours and then solvent was removed under reduced pressure.

The resulting material was dissolved in methanol and dimethyl oxalate was added (0.3 g, 2.5 equivalents). The reaction mixture was cooled to about 0 to about 5 °C, and then sodium methoxide (0.4 mL, 30% solution in methanol, 1.75 equivalents) was introduced to the reaction slowly. After the addition was completed the reaction was heated to about 40 to about 50 °C.

After this time had elapsed, the reaction was cooled to room temperature and quenched via the addition of 2 Ν HC1 (1.5 mL). The reaction was then diluted with ethyl acetate, and the resulting phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography to yield F-la.

lR NMR (400 MHz, CDC13): δ 10.28 (t, J= 5.5 Hz, 1H), 8.38 (s, 1H), 6.66 – 6.53 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H), 4.43 (t, J= 4.7 Hz, 1H), 4.00 (d, J= 4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). 13C NMR (100 MHz, CDC13): δ 173.08, 163.81, 162.17, 162.14 (ddd, J= 249.2, 15.6, 15.6 Hz), 161.72 (ddd, J= 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 1 10.53 (ddd, J= 19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15 (M+H).

E. Condensation of F-la with N-la to form G-la:

K2C03, MeCN, 75 °C

To a reaction vessel were added F-la (202 mg, 1.0 equivalent) and acetonitrile (1.4 mL). The resulting solution was treated with glacial acetic acid (0.2 mL, 6.0 equivalents) and methane sulfonic acid (0.01 mL, 0.3 equivalents). The reaction was then heated to about 70 to about 75 °C.

After 3 hours, a solid mixture of N-la (0.128g, 1.5 equivalents) and potassium carbonate (0.2 g, 2.7 equivalents) was introduced to the reaction at about 70 to about 75 °C. After the addition was completed, the reaction was allowed to progress for at least about 1 hour.

After this time had elapsed, water (1.4 mL) and dichloromethane (1.4 mL) were introduced to the reaction. The phases were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, then were filtered and concentrated under reduced pressure. The resulting crude material was purified via silica gel chromatography to obtain G-la.

lR NMR (400 MHz, CDC13): δ 10.23 (t, J= 5.5 Hz, 1H), 8.39 (s, 1H), 6.60 (t, J= 8.1 Hz, 2H), 5.29 (dd, J= 9.5, 3.7 Hz, 2H), 4.57 (d, J= 5.4 Hz, 3H), 4.33 (dd, J = 12.8, 3.8 Hz, 1H), 4.02 – 3.87 (m, 1H), 3.94 (s, 3H), 2.06 – 1.88 (m, 4H), 1.78 (dd, J = 17.2, 7.5 Hz, 1H), 1.55 – 1.46 (m, 1H). 13C MR (100 MHz, CDC13): δ 174.53, 163.75, 162.33 (dd, J= 249.4, 15.7, 15.7 Hz), 161.86 (ddd, J= 250.4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44, 129.75, 1 18.88, 1 10.58 (ddd, J= 19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS, Calculated: 463.14, Found: 464.15 (M+H).

Γ. Deprotection of G-la to form a compound of Formula la:

G-la (14 g) was suspended in acetonitrile (150 mL) and dichloromethane (150 mL). MgBr2 (12 g) was added. The reaction was heated to 40 to 50 °C for approximately 10 min before being cooled to room temperature. The reaction was poured into 0.5M HC1 (140 mL) and the layers separated. The organic layer was washed with water (70 mL), and the organic layer was then concentrated. The crude product was purified by silica gel chromatography (100% dichloromethane up to 6% ethanol/dichloromethane) to afford la.

 

REFERENCES

Patent Submitted Granted
POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE [US2014221356] 2013-12-19 2014-08-07
US9216996 Dec 19, 2013 Dec 22, 2015 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections

see full gravir series at…………..http://medcheminternational.blogspot.in/p/ravir-series.html

//////////

C1CC2CC1N3C(O2)CN4C=C(C(=O)C(=C4C3=O)O)C(=O)NCC5=C(C=C(C=C5F)F)F

OR

c1c(cc(c(c1F)CNC(=O)c2cn3c(c(c2=O)O)C(=O)N4[C@H]5CC[C@H](C5)O[C@@H]4C3)F)F

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BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA

WO2018005328) DEUTERATED BICTEGRAVIR 

CONCERT PHARMACEUTICALS, INC.

TUNG, Roger, D.; (US)

How A Kidney Drug Almost Torpedoed Concert Pharma’s IPO

Concert CEO Roger Tung

Novel deuterated forms of bictegravir is claimed.  Gilead Sciences is developing the integrase inhibitor bictegravir as an oral tablet for the treatment of HIV-1 infection.

This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11b is independently hydrogen or deuterium; provided that if each Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, and Y11 is hydrogen, then Y11b is deuterium.

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Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Exemplary Synthesis

[72] Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.

[73] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

[74] A convenient method for synthesizing compounds of Formula I is depicted in the Schemes below.

 [75] A generic scheme for the synthesis of compounds of Formula I is shown in Scheme 1 above. In a manner analogous to the procedure described in Wang, H. et al. Org. Lett.2015, 17, 564-567, aldol condensation of compound 1 with appropriately deuterated compound 2 affords enamine 3. Enamine 3 is then reacted with primary amine 4 to afford enamine 5, which then undergoes cyclization with dimethyl oxalate followed by ester hydrolysis to provide carboxylic acid 7.

[76] In a manner analogous to the procedure described in US 9,216,996, acetal deprotection of carboxylic acid 7 followed by cyclization with appropriately deuterated aminocyclopentanol 9 provides carboxylic acid intermediate 10. Amide coupling with appropriately deuterated benzylamine 11 followed by deprotection of the methyl ether ultimately affords a compound of Formula I in eight overall steps from compound 1.

[77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11bpositions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and/or Y11b.

[78] Appropriately deuterated intermediates 2a and 2b, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.

S h 2 S th i f C d 2 d 2b

[79] Synthesis of compound 2a (wherein Y3=H) by acetal formation of N,N-dimethylformamide (DMF) with dimethylsulfate has been described in Mesnard, D. et. al. J. Organomet. Chem.1989, 373, 1-10. Replacing DMF with N,N-dimethylformamide-d1 (98-99 atom % D; commercially available from Cambridge Isotope Laboratories) in this reaction would thereby provide compound 2b (wherein Y3=D).

[80] Use of appropriately deuterated reagents allows deuterium incorporation at the Y3 position of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at Y3.

[81] Appropriately deuterated intermediates 4a-4d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.

[82] As described in Malik, M. S. et. al. Org. Prep. Proc. Int.1991, 26, 764-766, acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl2 in methanol. As described in CN 103739506, reaction of 14a with aqueous ammonia and then sodium hydroxide provides primary amine 4a (wherein Y9=Y10a=Y10b=H). Replacing acetaldehyde with acetaldehyde-d1, acetaldehyde-2,2,2-d3, or acetaldehyde-d4 (all commercially available from CDN Isotopes with 98-99 atom % D) in the sequence then provides access to compounds 4b (Y9=D, Y10a=Y10b=H), 4c (Y9=H,

Y10a=Y10b=D) and 4d (Y9=Y10a=Y10b=D) respectively (Schemes 3b-d).

[83] Use of appropriately deuterated reagents allows deuterium incorporation at the Y9, Y10a, and Y10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y9, Y10a, and/or Y10b.

[84] Appropriately deuterated intermediates 9a-9d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.

 [85] Following the procedures described by Gurjar, M. et. al. Heterocycles, 2009, 77, 909-925, meso-diacetate 16a is prepared in 2 steps from cyclopentadiene. Desymmetrization of 16a is then achieved enzymatically by treatment with Lipase as described in Specklin, S. et. al. Tet. Lett.201455, 6987-6991, providing 17a which is subsequently converted to aminocyclopentanol 9a (wherein Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b=Y8=H) via a 3 step sequence as reported in WO 2015195656.

[86] As depicted in Scheme 4b, aminocyclopentanol 9b (Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b= Y8=D) is obtained through an analogous synthetic sequence using cyclopentadiene-d6 and performing the penultimate hydrogenation with D2 in place of H2. Cyclopentadiene-d6 is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.

[87] Alternatively, as shown in Scheme 4c, the meso-diol obtained in Scheme 4a is oxidized to the diketone following the procedure reported by Rasmusson, G.H. et. al. Org. Syn.1962, 42, 36-38. Subsequent mono-reduction with sodium borodeuteride and CeCl3 then affords the D1-alcohol in analogy to the method described in WO 2001044254 for the all-protio analog using sodium borohydride. Reduction of the remaining ketone using similar conditions provides the meso-D2-diol in analogy to the method reported in Specklin, S. et. al. Tet. Lett.2014, 55, 6987-6991 for the all protio analog using sodium borohydride. The meso-D2-diol is then converted to 9c (Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=H, Y6=Y8=D) following the same procedures outlined in Scheme 4a.

[88] Likewise, the meso-diol obtained in Scheme 4b may be converted to 9d

(Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=D, Y6=Y8=H) in an analogous manner as depicted in Scheme 4d. The use of deuterated solvents such as D2O or MeOD may be considered to reduce the risk of D to H exchange for ketone containing intermediates.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and Y8 positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and/or Y8.

[90] Appropriately deuterated intermediates 11a-11d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5 below.

Scheme 5. Synthesis of Benzylamines 11a-11d

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FDA Approves Tybost (cobicistat) for use in the treatment of HIV-1 Infection


 

Cobicistat, GS-9350

1004316-88-4

40 H 53 N 7 O 5 S 2

N-[1(R)-Benzyl-4(R)-[2(S)-[3-(2-isopropylthiazol-4-ylmethyl)-3-methyl]ureido]-4-(4-morpholinyl)butyramido]-5-phenylpentyl]carbamic acid thiazol-5-ylmethyl ester

(1,3-thiazol-5-yl) methyl (5S, 8R, 11R) -8,11-dibenzyl-2-methyl-5-[2 – (morpholin-4-yl) ethyl] -1 – [2 – (propan-2-yl) -1,3-thiazol-4-yl] -3,6-dioxo-2 ,4,7,12-tetraazatridecan-13-oate

cytochrome P450 3A4 (CYP3A4) inhibitor

Gilead Sciences, Inc.

FDA Approves Tybost (cobicistat) for use in the treatment of HIV-1 Infection
September 24, 2014 — The U.S. Food and Drug Administration (FDA) has approved Tybost (cobicistat), a CYP3A inhibitor used in combination with atazanavir or darunavir for the treatment of human immunodeficiency virus type 1 (HIV-1) infection

Cobicistat is a pharmacokinetic enhancer that works by inhibiting the enzyme (CYP3A) that metabolizes atazanavir and darunavir. It increases the systemic exposure of these drugs and prolongs their effect. Cobicistat is also one of the ingredients in the combination HIV drug Stribild, which was approved by the FDA in August, 2012.

Tybost comes in 150 mg tablets and is administered once daily in combination with the protease inhibitors atazanavir (Reyataz), or darunavir (Prezista).

Because Tybost inhibits CYP3A, other medications metabolized by CYP3A may result in increased plasma concentrations and potentially severe side effects, which may be life-threatening or even fatal. Extra care should be exercised by healthcare professionals to ensure than other medications are reviewed and their concentrations monitored, especially when initiating new medicines or changing doses.

The approval of Tybost was based on the following clinical trials:
•The data to support the use of atazanavir and Tybost were from a phase 2 and 3 trial in treatment-naïve adults comparing atazanavir/cobicistat 300/150 mg and atazanavir/ritonavir 300/100 mg once daily each in combination with Truvada. The atazanavir/cobicistat based regimen was non-inferior to the atazanavir/ritonavir based regimen.
•The data to support the use of cobicistat with darunavir is from a multiple dose trial in healthy subjects comparing the relative bioavailability of darunavir/cobicistat 800/150 mg to darunavir/ritonavir 800/100 mg.


The most common adverse drug reactions observed with Tybost (in combination with atazanavir) in clinical trials were jaundice, ocular icterus, and nausea.

Tybost is a product of Gilead Sciences, Foster City, CA.

Cobicistat (formerly GS-9350) is a licensed drug for use in the treatment of infection with the human immunodeficiency virus (HIV).

Like ritonavir (Norvir), cobicistat is of interest not for its anti-HIV properties, but rather its ability to inhibit liver enzymes that metabolize other medications used to treat HIV, notablyelvitegravir, an HIV integrase inhibitor currently under investigation itself. By combining cobicistat with elvitegravir, higher concentrations of elvitgravir are achieved in the body with lower dosing, theoretically enhancing elvitgravir’s viral suppression while diminishing its adverse side-effects. In contrast with ritonavir, the only currently approved booster, cobicistat has no anti-HIV activity of its own.[1]

Cobicistat, a cytochrome P450 CYP3A4 inhibitor, was approved in the E.U. in 2013 as a pharmacokinetic enhancer of the HIV-1 protease inhibitors atazanavir and darunavir in adults. First launch took place in 2014 in United Kingdom. In 2012, Gilead filed a New Drug Application in the U.S. for the same indication. In April 2013, the FDA issued a Complete Response Letter from the FDA. In 2014 the FDA accepted Gilead’s resubmission.

Cobicistat is a component of the four-drug, fixed-dose combination HIV treatmentelvitegravir/cobicistat/emtricitabine/tenofovir (known as the “Quad Pill” or Stribild).[1][2] The Quad Pill/Stribild was approved by the FDA in August 2012 for use in the United States and is owned by Gilead Sciences.
Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the importantCYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavirdarunavir and tenofovir alafenamide fumarate.[3]

The drug candidate acts as a pharmaco-enhancer to boost exposure of HIV protease inhibitors. In 2011, cobicistat was licensed to Japan Tobacco by Gilead for development and commercialization in Japan as a stand-alone product for the treatment of HIV infection. In 2012, orphan drug designation was assigned in Japan for the pharmacokinetic enhancement of anti-HIV agent.

Oxidative metabolism by cytochrome P450 enzymes is one of the primary mechanisms of drug metabolism.. It can be difficult to maintain therapeutically effective blood plasma levels of drugs which are rapidly metabolized by cytochrome P450 enzymes. Accordingly, the blood plasma levels of drugs which are susceptible to cytochrome P450 enzyme degradation can be maintained or enhanced by co-administration of cytochrome P450 inhibitors, thereby improving the pharmacokinetics of the drug.

While certain drugs are known to inhibit cytochrome P450 enzymes, more and/or improved inhibitors for cytochrome P450 monooxygenase are desirable. Particularly, it would be desirable to have cytochrome P450 monooxygenase inhibitors which do not have appreciable biological activity other than cytochrome P450 inhibition. Such inhibitors can be useful for minimizing undesirable biological activity, e.g., side effects. In addition, it would be desirable to have P450 monooxygenase inhibitors that lack significant or have a reduced level of protease inhibitor activity. Such inhibitors could be useful for enhancing the effectiveness of antiretroviral drugs, while minimizing the possibility of eliciting viral resistance, especially against protease inhibitors.

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Cobicistat (GS-9350): A potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer
ACS Med Chem Lett 2010, 1(5): 209

http://pubs.acs.org/doi/abs/10.1021/ml1000257

http://pubs.acs.org/doi/suppl/10.1021/ml1000257/suppl_file/ml1000257_si_001.pdf

Abstract Image

Cobicistat (3, GS-9350) is a newly discovered, potent, and selective inhibitor of human cytochrome P450 3A (CYP3A) enzymes. In contrast to ritonavir, 3 is devoid of anti-HIV activity and is thus more suitable for use in boosting anti-HIV drugs without risking selection of potential drug-resistant HIV variants. Compound 3 shows reduced liability for drug interactions and may have potential improvements in tolerability over ritonavir. In addition, 3 has high aqueous solubility and can be readily coformulated with other agents.

1-Benzyl-4-{2-[3-(2-isopropyl-thiazol-4-ylmethyl)-3-methyl-ureido]-4-morpholin-4-yl-butyrylamino}-5-phenyl-pentyl)-carbamic acid thiazol-5-ylmethyl ester (GS-9350)
HPLC (Chiral CelROD-H, Chiral Technologies Inc;heptane/iPrOH = 70/30).
1H NMR (CD3OD)
δ8.98 (1 H, s), 7.82 (1 H, s), 7.25-7.05
(11 H, m), 5.25-5.10 (2 H, m), 4.60-4.50 (2 H, m), 4.21-4.03 (2 H, m), 3.82-3.72 (1
H, m), 3.65-3.65 (4 H, m), 3.35-3.25 (1 H, m), 2.98 (3 H, s), 2.8-2.6 (4 H, m), 2.4-2.2
(6 H, m), 1.95-1.8 (1 H, m), 1.8-1.6 (1 H, m), 1.6-1.4 (4 H, m), 1.42-1.32 (6 H, m).
MS (ESI) m/z: 776.2 (M+H)+.
HRMS calc. for C40H53N7O5S2: 775.355, found: 775.353.

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http://www.google.com/patents/CN103694196A?cl=en

 CN 103694196

oxidative metabolism by cytochrome P450 enzymes is one of the main mechanisms of drug metabolism, generally by administration of cytochrome P450 inhibitors to maintain or increase the degradation of cytochrome P450 enzymes are sensitive to the drug plasma levels, in order to improve the pharmacokinetics of drugs dynamics, can be used to enhance the effectiveness of anti-retroviral drugs. For example W02008010921 discloses compounds of formula I as a cytochrome P450 monooxygenase specific compounds (Cobicistat):

 

Figure CN103694196AD00051

  W02008010921 discloses the synthesis of compounds of formula I with a variety of, as one of the methods of the following routes

Shows:

 

Figure CN103694196AD00061

The reagents used in the method is expensive, and more difficult to remove by-products, long reaction time, high cost, is not conducive to industrial

Production.

W02010115000 on these routes has been improved:

 

Figure CN103694196AD00062

The first step in the route used for the ring-opening reaction reagent trimethylsilyl iodide, trimethylsilyl iodide expensive. W02010115000 reports this step and the subsequent ring-opening reaction of morpholine substitution reaction yield of two steps is not high, only 71%, so that only iodotrimethylsilane a high cost of raw material is not suitable for industrial production.

 

Figure CN103694196AC00023

 

Figure CN103694196AC00031

Figure CN103694196AC00041

Preparation of compounds of formula I

Example [0126] Implementation

[0127] I1-a (20g) was dissolved in dichloromethane, was added 50% K0H (5.5g) solution, control the internal temperature does not exceed 25 ° C, TLC analysis ΙΙ-a disappears. Was cooled to O ~ 10 ° C, was added (2R, 5R) -5 – amino-1 ,6 – diphenyl-2 – hexyl-carbamic acid 5 – methyl-thiazole ester hydrochloride (14.8g), stirred for I ~ 2 h, 1 – hydroxybenzotriazole triazole (5.5g), stirred for I h, 1 – ethyl – (3 – dimethylaminopropyl) carbodiimide hydrochloride (15g), and incubated for 5 ~ 10 hours, TLC analysis of the starting material disappeared, the reaction was completed. The reaction was quenched with aqueous acetic acid, methylene chloride layer was separated, washed with saturated aqueous NaHCO3, washed with water, dried and concentrated. By HPLC purity of 99.1%. Adding ethanol, the ethanol was evaporated to give the product compound of part I of a solution in ethanol. Molar yield 88%, LC-MS: M +1 = 777.1 [0128] All publications mentioned in the present invention are incorporated by reference as if each reference was individually incorporated by reference, as cited in the present application. It should also be understood that, after reading the foregoing teachings of the present invention, those skilled in the art that various modifications of the present invention or modifications, and these equivalents falling as defined by the appended claims scope of claims of the present application.

 

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US 2014088304

http://www.google.com/patents/US20140088304

International Patent Application Publication Number WO 2008/010921 and International Patent Application Publication Number WO 2008/103949 disclose certain compounds that are reported to be useful to modify the pharmacokinetics of a co-administered drug, e.g. by inhibiting cytochrome P450 monooxygenase. One specific compound identified therein is a compound of the following formula I:

There is currently a need for improved synthetic methods and intermediates that can be used to prepare the compound of formula I and its salts

Schemes 1-4 below.

Preparation of a Compound of Formula IV

Scheme V.

 

Example 14Preparation of Compound I

To the solution of L-thiazole morpholine ethyl ester oxalate salt XIVa (35.6 kg) in water (66.0 kg) was charged dichloromethane (264 kg), followed by a slow addition of 15 wt % KHCO3 solution (184.8 kg). The resulting mixture was agitated for about 1 hour. The layers were separated and the organic layer was washed with water (132 kg). The organic layer was concentrated under vacuum to dryness. Water (26.5 kg) was charged and the content temperature was adjusted to about 10° C., followed by slow addition of 45% KOH solution (9.8 kg) while maintaining the content temperature at less than or equal to 20° C. The mixture was agitated at less than or equal to 20° C. until the reaction was judged complete by HPLC. The reaction mixture was concentrated under vacuum to dryness and co-evaporated five times with dichloromethane (132 kg each time) under reduced pressure to dryness. Co-evaporation with dichloromethane (132 kg) was continued until the water content was <4% by Karl Fischer titration. Additional dichloromethane (264 kg) was charged and the content temperature was adjusted to −18° C. to −20° C., followed by addition of monocarbamate.HCl salt IXa (26.4 kg). The resulting mixture was agitated at −18° C. to −20° C. for about 1 hour. HOBt (11.4 kg) was charged and the reaction mixture was again agitated at −18° C. to −20° C. for about 1 hour. A pre-cooled solution (−20° C.) of EDC.HCl (21.4 kg) in dichloromethane (396 kg) was added to the reaction mixture while the content temperature was maintained at less than or equal to −20° C. The reaction mixture was agitated at −18° C. to −20° C. until the reaction was judged complete. The content temperature was adjusted to about 3° C. and the reaction mixture quenched with a 10 wt % aqueous citric acid solution (290 kg). The layers were separated and the organic layer was washed once with 15 wt % potassium bicarbonate solution (467 kg) and water (132 kg). The organic layer was concentrated under reduced pressure and then co-evaporated with absolute ethanol.

The product I was isolated as the stock solution in ethanol (35.0 kg product, 76.1% yield).

1H NMR (dDMSO) δ□ 9.05 (s, 1H), 7.85 (s, 1H), 7.52 (d, 1H), 7.25-7.02 (m, 12H), 6.60 (d, 1H), 5.16 (s, 2H), 4.45 (s, 2H), 4.12-4.05 (m, 1H), 3.97-3.85 (m, 1H), 3.68-3.59 (m, 1H), 3.57-3.45 (m, 4H), 3.22 (septets, 1H), 2.88 (s, 3H), 2.70-2.55 (m, 4H), 2.35-2.10 (m, 6H), 1.75 (m, 1H), 1.62 (m, 1H), 1.50-1.30 (m, 4H), 1.32 (d, 6H).

13C NMR (CD3OD) δ 180.54, 174., 160.1, 157.7, 156.9, 153.8, 143.8, 140.1, 140.0, 136.0, 130.53, 130.49, 129.4, 127.4, 127.3, 115.5, 67.7, 58.8, 56.9, 55.9, 54.9, 53.9, 51.6, 49.8, 42.7, 42.0, 35.4, 34.5, 32.4, 32.1, 29.1, 23.7.

Example 13Preparation of L-Thiazole Morpholine Ethyl Ester Oxalate Salt XIVa

To a solution of (L)-thiazole amino lactone XII (33.4 kg) in dichloromethane (89.5 kg) was charged dichloromethane (150 kg) and absolute ethanol (33.4 kg). The content temperature was then adjusted to about 10° C., followed by slow addition of TMSI (78.8 kg) while the content temperature was maintained at less than or equal to 22° C. and agitated until the reaction was judged complete. The content temperature was adjusted to about 10° C., followed by a slow addition of morpholine (49.1 kg) while the content temperature was maintained at less than or equal to 22° C. Once complete, the reaction mixture was filtered to remove morpholine.HI salt and the filter cake was rinsed with two portions of dichloromethane (33.4 kg). The filtrate was washed twice with water (100 kg). The organic layer was concentrated under vacuum to dryness. Acetone (100 kg) was then charged to the concentrate and the solution was concentrated under reduced pressure to dryness. Acetone (233.8 kg) was charged to the concentrate, followed by a slow addition of the solution of oxalic acid (10 kg) in acetone (100 kg). The resulting slurry was refluxed for about 1 hour before cooling down to about 3° C. for isolation. The product XIVa was filtered and rinsed with acetone (66.8 kg) and dried under vacuum at 40° C. to afford a white to off-white solid (40 kg, 71% yield). 1H NMR (CDCl3) δ □7.00 (s, 1H), 6.35 (broad s, 1H), 4.60-4.40 (m, 3H), 4.19 (quartets, 2H), 4.00-3.90 (m, 4H), 3.35-3.10 (m, 7H), 3.00 (s, 3H), 2.40-2.30 (m, 1H), 2.15-2.05 (m, 1H), 1.38 (d, 6H), 1.25 (triplets, 3H).

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W02008010921

http://www.google.co.in/patents/WO2008010921A2?cl=en

Preparation of Example A

Scheme 1

Example A Compound 2

To a solution of Compound 1 (ritonavir) (1.8 g, 2.5 mmol) in 1,2- dichloroethane (15 mL) was added l,l’-thiocarbonyldiimidazole (890 mg, 5.0 mmol). The mixture was heated at 75 SC for 6 hours and cooled to 25 SC. Evaporation under reduced pressure gave a white solid. Purification by flash column chromatography (stationary phase: silica gel; eluent: EtOAc) gave Compound 2 (1.6 g). m/z: 831.1 (M+H)+. Example A

To the refluxing solution of tributyltin hydride (0.78 mL, 2.9 mmol) in toluene (130 mL) was added a solution of Compound 2 (1.6 g, 1.9 mmol) and 2,2′- azobisisobutyronitrile (31 mg, 0.19 mmol) in toluene (30 mL) over 30 minutes. The mixture was heated at 1152C for 6 hours and cooled to 25 BC. Toluene was removed under reduced pressure. Purification by flash column chromatography (stationary phase: silica gel; eluent: hexane/EtOAc = 1/10) gave Example A (560 mg). m/z: 705.2 (M+H)+. 1H-NMR (CDCl3) δ 8.79 (1 H, s), 7.82 (1 H, s), 7.26-7.05 (10 H, m), 6.98 (1 H, s), 6.28 (1 H, m), 6.03 (1 H, m), 5.27 (1 H7 m), 5.23 (2 H, s), 4.45-4.22 (2 H, m), 4.17 (1 H, m), 3.98 (1 H, m), 3.75 (1 H, m), 3.25 (1 H7 m), 2.91 (3 H, s), 2.67 (4 H, m), 2.36 (1 H, m), 1.6-1.2 (10 H, m), 0.85 (6 H, m).

 

EP1183026A2 * 25 May 2000 6 Mar 2002 Abbott Laboratories Improved pharmaceutical formulations
US20060199851 * 2 Mar 2006 7 Sep 2006 Kempf Dale J Novel compounds that are useful for improving pharmacokinetics

 

Thiazol-5-ylmethyl N-[1-benzyl-4-[[2-[[(2-isopropylthiazol-4-yl)methyl-methyl-carbamoyl]amino]-4-morpholino-butanoyl]amino]-5-phenyl-pentyl]carbamate
Clinical data
Legal status
fda approved sept 2014
Identifiers
CAS number 1004316-88-4 Yes
ATC code V03AX03
PubChem CID 25151504
ChemSpider 25084912 Yes
UNII LW2E03M5PG Yes
Chemical data
Formula C40H53N7O5S2 
Mol. mass 776.023 g/mol
US7939553 * Jul 6, 2007 May 10, 2011 Gilead Sciences, Inc. co-administered drug (as HIV protease inhibiting compound, an HIV (non)nucleoside/nucleotide inhibitor of reverse transcriptase, capsid polymerization inhibitor, interferon, ribavirin analog) by inhibiting cytochrome P450 monooxygenase; ureido- or amido-amine derivatives; side effect reduction
       Highleyman, L.

Elvitegravir “Quad” Single-tablet Regimen Shows Continued HIV Suppression at 48 Weeks

  1.  R Elion, J Gathe, B Rashbaum, and others. The Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF; Quad) Maintains a High Rate of Virologic Suppression, and Cobicistat (COBI) is an Effective Pharmacoenhancer Through 48 Weeks. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12–15, 2010.
  2. Lepist, E. -I.; Phan, T. K.; Roy, A.; Tong, L.; MacLennan, K.; Murray, B.; Ray, A. S. (2012). “Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340, in Vitro”Antimicrobial Agents and Chemotherapy 56 (10): 5409–5413. doi:10.1128/AAC.01089-12PMC 3457391PMID 22850510.
  3. Patent No

    all US

    Expiry
    5814639 Sep 29, 2015
    5814639*PED Mar 29, 2016
    5914331 Jul 2, 2017
    5914331*PED Jan 2, 2018
    5922695 Jul 25, 2017
    5922695*PED Jan 25, 2018
    5935946 Jul 25, 2017
    5935946*PED Jan 25, 2018
    5977089 Jul 25, 2017
    5977089*PED Jan 25, 2018
    6043230 Jul 25, 2017
    6043230*PED Jan 25, 2018
    6642245 Nov 4, 2020
    6642245*PED May 4, 2021
    6703396 Mar 9, 2021
    6703396*PED Sep 9, 2021
    7176220 Nov 20, 2023
    7635704 Oct 26, 2026
    8148374 Sep 3, 2029

EU OK’s Gilead’s rare blood cancers drug


EU OK's Gilead's rare blood cancers drug

SEPT 21 , 2014

Patients with the incurable blood cancers chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL) have gained access to a new treatment option in Europe with the approval of Gilead’s Zydelig (idelalisib).

For CLL, the drug can now be used alongside Rituxan (rituximab) in patients who have received at least one prior therapy, and it has also been green lighted for first-line use in those carrying a 17p deletion or TP53 mutation who are unsuitable for chemo-immunotherapy.

SEE

SYNTHESIS AT

https://newdrugapprovals.org/2014/01/14/idelalisib-us-fda-accepts-nda-for-gileads-idelalisib-for-the-treatment-of-refractory-indolent-non-hodgkins-lymphoma/

Tecadenoson…………Atrial Fibrillation


Tecadenoson

 

Tecadenoson
CAS : 204512-90-3
N-[(3R)-Tetrahydro-3-furanyl]adenosine
(2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[(3R)-oxolan-3-yl]amino]purin-9-yl]oxolane-3,4-diol
 
Manufacturers’ Codes: CVT-510
UNII-GZ1X96601Z; AC1L4KMO;
Molecular Formula: C14H19N5O5
Molecular Weight: 337.33
Percent Composition: C 49.85%, H 5.68%, N 20.76%, O 23.71%
Therap-Cat: Antiarrhythmic.
 
Tecadenoson is a novel selective A1 adenosine receptor agonist that is currently being evaluated for the conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. It is being developed by CV Therapeutics, Inc.
 
Tecadenoson is an adenosine A1 agonist which had been in phase II clinical evaluation by Gilead Sciences for treatment of atrial fibrillation. The company was also conducting phase III clinical trials for the treatment of paroxysmal supraventricular tachycardia (PSVT); however, no recent developments have been reported for these indications.
Due to the fact that tecadenoson selectively stimulates the A1 receptor and slows electrical impulses in the heart’s conduction system without significantly stimulating the A2 receptor, the intravenous administration of CVT-510 may hold potential for rapid intervention in the control of atrial arrhythmias without lowering blood pressure.
 
 
 
 
 
 
 
 
The reaction of 3-tetrahydrofuroic acid (I) with diphenyl phosphoryl azide (DPPA) in refluxing dioxane gave the intermediate isocyanate (II), which was treated with benzyl alcohol (III) to yield carbamate (IV). Subsequent hydrogenolysis in the presence of Pd/C afforded racemic amine (V), which was resolved by treatment with S-(+)-10-camphorsulfonyl chloride (VI) in pyridine, followed by column chromatography and recrystallization from acetone of the resulting sulfonamide (VII). Then, hydrolysis in HCl-AcOH provided the S-amine (VIII). Condensation of amine (VIII) with 6-chloropurine riboside (IX) in the presence of triethylamine in refluxing MeOH furnished the title compound.
 
 
EP 0920438; EP 0992510; JP 2000501426; US 5789416; WO 9808855
……………………………
 
 
 
 
 
 
 
 
………………………….
 

CVT-510 (tecadenoson) has chemical structure (8 :

Figure imgf000011_0002
 
 
…………………………………….
 
Compound I can be prepared through reaction of the corresponding primary amino compound, R1NH2, through heating with commercially available 6-chloroadenosine in the appropriate solvent (e.g. n-butanol, dimethylformamide, and ethanol). The primary amino compound, R1NH2, is either commercially available or can be prepared as previously described (International Patent Application WO 98/08855).
 
Figure US06576619-20030610-C00008
 
 ……………………………
 
 
 

EXAMPLE 1

The compounds of this invention may be prepared by conventional methods of organic chemistry. The reaction sequence outlined below, is a general method, useful for the preparation of compounds of this invention.

According to this method, oxacycloalkyl carboxylic acid is heated in a mixture of dioxane, diphenylphosphoryazide and triethylamine for 1 hour. To this mixture is added benzyl alcohol and the reaction is further heated over night to give intermediate compound 1. Compound 1 is dissolved in methanol. Next, concentrated HC1, Pd/C is added and the mixture is placed under hydrogen at 1 atm. The mixture is stirred overnight at room temperature and filtered. The residue is recrystallized to give intermediate compound 2. 6-chloropurine riboside is combined and the mixture is compound 2 dissolved in methanol and treated with triethylamine. The reaction is heated to 80° C for 30 hours. Isolation and purification leads to Compound 3.

EXAMPLE 2

Compounds of this invention prepared according to the method of Example 1 were tested in two functional models specific for adenosine A, receptor agonist function. The first was the A , receptor mediated inhibition of isoproterenol stimulated cAMP accumulation in DDT cells. The EC50 of each derivative is shown in Table I. Also shown in Table I is the ability of each derivative to stimulate cAMP production in PC 12 cells, a function of agonist stimulation of adenosine A2 receptors. The ratio of the relative potency of each compound in stimulating either an A, receptor or an A2 receptor effect is termed the selectivity of each compound for the A, receptor. As can be seen in Table I, each derivative is relatively selective as an A, receptor agonist. The use of measuring cAMP metabolism as an assay for adenosine A , receptor function has been previously described (Scammells, P., Baker, S., Belardinelli, L., and Olsson, R. , 1994, Substituted 1 ,3-dipropylxanthines as irreversible antagonists of A, adenosine receptors. J. Med. Chem 37: 2794-2712, 1994).

Table I

Compound R EC50 (nM) ECS, (nM) A,/A2 A-/A, DDT cells PC 12 cells

I 4-arninopyran 12 970 0.012 80.0

II (±)-3-aminotetrahydrofuran 13 1400 0.0093 107.6

III (R)-3-aminotetrahydrofuran 1.08 448 0.0024 414

IV ( 1 )-caprolactam 161 181 0.889 1.12

V (S)-3-aminotetrahydrofuran 3.40 7680 0.00044 2258

Compounds were also tested in a whole organ model of A, receptor activation with respect to atrial and AV nodal function. In this model, guinea pig hearts are isolated and perfused with saline containing compound while atrial rate and AV nodal conduction time are assessed by electrographic measurement of atrial cycle length and AV intervals, as detailed in Belardinelli, L, Lu, J. Dennis, D. Martens, J, and Shryock J. (1994); The cardiac effects of a novel A,-adenosine receptor agonist in guinea pig isolated heart. J. Pharm. Exp. Therap. 271:1371-1382 (1994). As shown in Figure 1, each derivative was effective in slowing the atrial rate and prolonging the AV nodal conduction time of spontaneously beating hearts in a concentration-dependent manner, demonstrating efficacy as adenosine A, receptor agonists in the intact heart.

EXAMPLE 3

Preparation ofN-benzyloxycarbonyl-4-aminopyran.

A mixture of 4-pyranylcarboxylic acid (2.28 gm, 20 mmol), diphenylphosphorylazide (4.31 ml, 20 mmol), triethylamine (2.78 ml, 20 mmol) in dioxane (40 ml) was heated in a 100° C oil bath under dry nitrogen for 1 hour. Benzyl alcohol (2.7 ml, 26 mmol) was added, and heating was continued at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice with EtOAc. The extracts were washed with water, sodium bicarbonate, brine and then dried over MgSO4, and concentrated to an oil which solidified upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 1.85 g of a white solid (40%).

Preparation of 4-aminopyran.

N-benzyloxycarbonyl-4-aminopyran (1.85 gm, 7.87 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C ( 10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of eelite and concentrated. The residue was co-evaporated twice with MeOH/EtOAc and recrystallized from MeOH/EtOAc to afford 980 mg (91 %) of white needles (mp 228-230° C).

Preparation of 6-(4-aminopyran)-purine riboside. A mixture of 6-chloropurine riboside (0.318 gm, 1. 1 mmol), 4-aminopyran-HCl

(0.220 mg,

1.6 mmol) and triethylamine (0.385 ml, 2.5 mmol) in methanol (10 ml) was heated to 80° C for 30 hours. The mixture was cooled, concentrated and the residue chromatographed (90: 10: 1, CH2 Cl2/MeOH/PrNH2). The appropriate fractions were collected and recliromatographed using a chromatotron

(2 mm plate, 90: 10: 1, CH2 Cl2/MeOH/PrNH2) to give an off white foam (0.37 gm, 95%).

EXAMPLE 4

Preparation of N-benzyloxycarbonyl-3-aminotetrahydrofuran. A mixture of 3-tetrahydrofuroic acid (3.5 gm, 30 mmol), diphenylphosphorylazide (6.82 ml, 32 mmol), triethylamine (5 ml, 36 mmol) in dioxane (35 ml) was stirred at RT for 20 min then heated in a 100° C oil bath under dry nitrogen for 2 hours. Benzyl alcohol (4.7 ml, 45 mmol) was added, and continued heating at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice using EtOAc. The extracts were washed with water, sodium bicarbonate, brine dried over MgSO4, and then concentrated to an oil which solidifies upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 3.4 g of an oil (51

%).

Preparation of 3-aminotetrahydrofuran.

N-benzyloxycarbonyl-3-aminotetrahydrofuran (3.4 gm, 15 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C (10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of celite and concentrated. The residue was co-evaporated two times with MeOH/EtOAc and recrystallized from MeOH/EtOAc to give 1.9 g of a yellow solid.

Preparation of 6-(3-aminotetrahydrofuranyl)purine riboside. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran

(0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluting with 90/10/1 (CH2Cl2/MeOH/PrNH2), the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1 , CH2CL2/MeOH/P.NH2). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128-130° C).

EXAMPLE 5

Resolution of 3-arninotetrahydrofuran hydrochloride

A mixture of 3-aminotetrahydrofuran hydrochloride (0.5 gm, 4 mmol) and

(S)-(+)-10-camphorsulfonyl chloride (1.1 gm, 4.4 mmol) in pyridine (10 ml) was stirred for 4 hours at room temperature and then concentrated. The residue was dissolved in EtOAc and washed with 0.5N HC1, sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated to give 1. 17 g of a brown oil (97%) which was chromatographed on silica gel (25% to 70% EtOAc/Hex). The white solid obtained was repeatedly recrystallized from acetone and the crystals and supernatant pooled until an enhancement of greater than 90% by 1H NMR was acheived.

Preparation of 3-(S)-aminotetrahydrofuran hydrochloride.

The sulfonamide (170 mg, 0.56 mmol) was dissolved in cone. HCl/AcOH (2 mL each), stirred for 20 hours at room temperature, washed three times with CH2C12 (10 ml) and concentrated to dryness to give 75 mg (qaunt ) of a white solid

 

Preparation of 6-(3-(S)-aminotetrahydrofuranyl)puπne riboside.

A mixture of 6-chloropurιne riboside (30 mg, 0.10 mmol),

3-(S)-amιnotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol

(0.5 ml) was heated to 80° C for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (CH2Cl /MeOH) to give 8 mg (24%) of a white solid.

Chemical structure for tecadenoson
Literature References:
Selective adenosine A1-receptor agonist. Prepn: R. T. Lum et al., WO 9808855; eidem, US 5789416 (both 1998 to CV Therapeutics).
Clinical effect on AV nodal conduction: B. B. Lerman et al., J. Cardiovasc. Pharmacol. Ther. 6, 237 (2001).
Clinical evaluation in paroxysmal supraventricular tachycardia: E. N. Prystowsky et al., J. Am. Coll. Cardiol. 42, 1098 (2003); K. A. Ellenbogen et al., Circulation 111, 3202 (2005).
Review of pharmacology and clinical experience: A. Zaza, Curr. Opin. Invest. Drugs 3, 96-100 (2002); J. W. Cheung, B. B. Lerman, Cardiovasc. Drug Rev. 21, 277-292 (2003).
US7144871 * 19 Feb 2003 5 Dec 2006 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
US7696181 * 24 Aug 2006 13 Apr 2010 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
 
 
 
Keywords: Antiarrhythmic,  Adenosine Receptor Agonist, Tecadenoson, CVT-510, CV Therapeutics

Gilead’s HCV drug Sovaldi gets Europe OK


Gilead's HCV drug Sovaldi gets Europe OK

Gilead Sciences’ closely-watched hepatitis C drug Sovaldi has been given the green light in Europe.

The European Commission has granted marketing authorisation for Sovaldi (sofosbuvir) 400mg tablets

which, as part of HCV combination therapy with peg-interferon and ribavirin, offers cure rates of around 90% in previously-untreated adults. However, most significant is that the once-daily nucleotide analogue polymerase inhibitor is the first all-oral treatment option for up to 24 weeks for patients unsuitable for interferon.

Read more at: http://www.pharmatimes.com/Article/14-01-20/Gilead_s_HCV_drug_Sovaldi_gets_Europe_OK.aspx#ixzz2qwHI3iJi

SYNTHESIS

  1. sofosbuvir » All About Drugs

    ALL ABOUT DRUGS BY DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER HELPING  US Approves Breakthrough Hepatitis C Drug,Sofosbuvir.

US Approves Breakthrough Hepatitis C Drug, Sofosbuvir » All About Drugs


SOFOSBUVIR

DO NOT FORGET TO CLICK

US Approves Breakthrough Hepatitis C Drug, Sofosbuvir » All About Drugs

AND ALSO

DO NOT FORGET TO CLICK

SEE………………….http://orgspectroscopyint.blogspot.in/2015/02/sofosbuvir-visited.html

READ ABOUT SYNTHESIS BY CLICKING ABOVE LINK


Sofosbuvir

Sovaldi

M.Wt: 529.45

Formula: C22H29FN3O9P

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

A prodrug of 2′-deoxy-2′-alpha-F-2′-beta-C-methyluridine 5′-monophosphate.
GS-7977, PSI-7977

  • GS 7977
  • GS-7977
  • PSI 7977
  • PSI-7977
  • Sofosbuvir
  • Sovaldi
  • UNII-WJ6CA3ZU8B

CAS Registry Number :1190307 -88-0

http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf

Indications: Chronic hepatitis C (HCV GT1, GT2, GT3, GT4)
Mechanism: nucleoside NS5B polymerase inhibitor
approved Time: December 6, 2013
,U.S. Patent Number: 7964580,8415322,8334270,7429572;, patent validity: March 26, 2029 (U.S. Patent No.: 7,964,580 and 8,334,270), April 3, 2025 (U.S. Patent No.: 7,429,572 and 8,415,322)

US patent number 7964580, US patent number 8415322, US patent number 8334270,US patent number 7429572 Patent Expiration Date: March 26, 2029 for US patent number 7964580 and 8334270 (2028 in EU); April 3, 2025 for US patent number 7429572 and 8415322

Sales value (estimated): $ 1.9 billion (2014), 6600000000 USD (2016)

Drug Companies: Gilead Sciences, Inc. (Gilead Sciences)

WASHINGTON, Dec. 6, 2013 (AP) — Federal health officials have approved a highly anticipated hepatitis C drug from Gilead Sciences Inc. that is expected to offer a faster, more palatable cure to millions of people infected with the liver-destroying virus.

The Food and Drug Administration said Friday it approved the pill Sovaldi in combination with older drugs to treat the main forms of hepatitis C that affect U.S. patients.

Current treatments for hepatitis C can take up to a year of therapy and involve weekly injections of a drug that causes flu-like side effects. That approach only cures about three out of four patients. Sovaldi is a daily pill that in clinical trials cured roughly 90 percent of patients in just 12 weeks, when combined with the older drug cocktail.http://www.pharmalive.com/us-approves-breakthrough-hepatitis-c-drug

  • The end of October 2013 saw a nod from the FDA given to Gilead’s New Drug Application for Sofosbuvir, a much needed treatment for hepatitis C.
  • As a nucleotide analogue, Sofosbuvir is designed as a once daily treatment.
  • There are roughly 170 million cases of hepatitis C around the world.
  • A report in the Journal of the American Medical Association on August 28, 2013 revealed that the Sofosbuvir and Ribavirin combination treatment effectively cured many patients with the Hepatitis C Virus.
  • The Sofosbuvir and Ribavirin drug combination was void of interferon-based treatments, which  many patients are resistant too.
  • More than 3 million Americans have chronic Hepatitis C Virus, and 22 percent of these patients are African American.

Sofosbuvir (brand names Sovaldi and Virunon) is a drug used for hepatitis C virus (HCV) infection, with a high cure rate.[1][2] It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.[3]

Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic Hepatitis C.[4]

In 2013, the FDA approved sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4.[4] Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, compared to 24 weeks for treatment of genotype 3. The label furhter states that sofosbuvir in combination with ribavirin may be considered for patients infected with genotype 1 who are interferon-ineligible.[5] Sofosbuvir will cost $84,000 for 12 weeks of treatment and $168,000 for the 24 weeks, which some patient advocates have criticized as unaffordable.

Interferon-free therapy for treatment of hepatitis C eliminates the substantial side-effects associated with use of interferon. Up to half of hepatitis C patients cannot tolerate the use of interferon.[6]

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate.[7] Sofosbuvir is anucleotide analog inhibitor of the hepatitis C virus (HCV) polymerase.[8] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

The New Drug Application for Sofosbuvir was submitted on April 8, 2013 and received the FDA’s Breakthrough Therapy Designation, which grants priority review status to drug candidates that may offer major treatment advantages over existing options.[9]

On 6th December 2013, the U.S. Food and Drug Administration approved sofosbuvir for the treatment of chronic hepatitis C.[10]

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[11][12] It has shown clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[13]

Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.[14][15]

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[16] Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3.[17] This represents a substantial pricing increase from previous treatments consisting of interferon and ribavirin, which cost between $15,000 and $20,000.[18] The price is also significantly higher than that of Johnson & Johnson‘s recently approved drug simeprevir (Olysio), which costs $50,000 and also treats chronic hepatitis C.[18] The high cost of the drug has resulted in a push back from insurance companies and the like, includingExpress Scripts, which has threatened to substitute lower priced competitors, even if those therapies come with a more unfriendly dosing schedule.[18] Other treatments that have recently entered the market have not matched the efficacy of sofosbuvir, however, allowing Gilead to set a higher price until additional competition enters the market.[18] Patient advocates such as Doctors Without Borders have complained about the price, which is particularly difficult for underdeveloped countries to afford.[19]

ChemSpider 2D Image | Sofosbuvir | C22H29FN3O9P

sofosbuvir

  1.  News: United States to approve potent oral drugs for hepatitis C, Sara Reardon, Nature, 30 October 2013
  2.  Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA (October 2010). “Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus”. J. Med. Chem. 53 (19): 7202–18.doi:10.1021/jm100863xPMID 20845908.
  3.  “PSI-7977”. Gilead Sciences.
  4. Tucker M (December 6, 2013). “FDA Approves ‘Game Changer’ Hepatitis C Drug Sofosbuvir”. Medscape.
  5.  “U.S. Food and Drug Administration Approves Gilead’s Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C – See more at: http://www.gilead.com/news/press-releases/2013/12/us-food-and-drug-administration-approves-gileads-sovaldi-sofosbuvir-for-the-treatment-of-chronic-hepatitis-c#sthash.T9uTbSWK.dpuf”. Gilead. December 6, 2013.
  6.  “Sofosbuvir is safer than interferon for hepatitis C patients, say scientists”. News Medical. April 25, 2013.
  7.  Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA (November 2010). “Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977”J. Biol. Chem. 285 (45): 34337–47.doi:10.1074/jbc.M110.161802PMC 2966047PMID 20801890.
  8.  Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
  9.  “FDA Advisory Committee Supports Approval of Gilead’s Sofosbuvir for Chronic Hepatitis C Infection”Drugs.com. October 25, 2013.
  10.  “FDA approves Sovaldi for chronic hepatitis C”FDA New Release. U.S. Food and Drug Administration. 2013-12-06.
  11.  Murphy T (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”.Bloomberg Businessweek.
  12.  Asselah T (January 2014). “Sofosbuvir for the treatment of hepatitis C virus”. Expert Opin Pharmacother 15 (1): 121–30. doi:10.1517/14656566.2014.857656PMID 24289735.
  13.  “AASLD 2012: Sofosbuvir and daclatasvir dual regimen cures most people with HCV genotypes 1, 2, or 3”News. European Liver Patients Association. 2012-11-21.
  14.  AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
  15.  Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (January 2013). “Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C”.N. Engl. J. Med. 368 (1): 34–44. doi:10.1056/NEJMoa1208953PMID 23281974.
  16.  CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
  17.  Campbell T (December 11, 2013). “Gilead’s Sofosbuvir Gets New Name, Price, Headaches”. The Motley Fool.
  18.  Cohen, J. (2013). “Advocates Protest the Cost of a Hepatitis C Cure”. Science 342 (6164): 1302–1303. doi:10.1126/science.342.6164.1302PMID 24337268edit

The chemical structure

Chemical Structure of Sovaldi_Sofosbuvir_Hepatatis C-Gilead

GS-7977, (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin^l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, available from Gilead Sciences, Inc., is described and claimed in U.S. Patent No. 7,964,580. (See also US 2010/0016251, US 2010/0298257, US 201 1/0251 152 and US 2012/0107278.) GS-7977 has the structure:

Figure imgf000013_0001

GS-7977 can be crystalline or amorphous. Examples of preparing crystalline and amorphous forms of GS-7977 are disclosed in US 2010/0298257 (US 12/783,680) and US 201 1/0251 152 (US 13/076,552),

Chemical Synthesis of Sofosbuvir_Sovaldi_GS-7977_PSI-7977_Hepatitis C_Gilead

Commerically available isopropylidine protected D-glyceraldehyde was reacted with (carbethoxyethylidene)triphenylmethylphosphorane gave the chiral pentenoate ester YP-1. Permanganate dihydroxylation of YP-1 in acetone gave the D-isomer diol YP-2. The cyclic sulfate YP-3 was obtained by first making the cyclic sulfite with thionyl chloride and then oxidizing to cyclic sulfate with sodium hypochlorite. Fluorination of YP-3 with triethylamine-trihydrofluoride(TEA-3HF) in the presence of triethylamine, followed by the hydrolysis of sulfate ester in the presence of concentrated HCl provided diol YP-4 which was benzoylated to give ribonolactone YP-5. Reduction of YP-5 with Red-Al followed by chlorination with sulfuryl chloride in the presence of catalytic amount of tetrabutylammonium bromide yielded YP-6. The conversion of YP-6 to benzoyl protected 2′-deoxyl-2′-alpha-F-2′-Beta-C-methylcytidine (YP-7) was achieved by using O-trimethyl silyl-N4-benzoylcytosine and stannic chloride. Preparation of the uridine nucleoside YP-8 was accomplished by first heating benzoyl cytidine YP-7 in acetic acid then treating with methoanolic ammonia to provide YP-8 in 78% yield.

The phosphoramidating reagent YP-9 was obtained by first reacting phenyldichlorophosphate with L-Alanine isopropyl ester hydrochloride and then with pentafluorophenol. Isolation of single Sp diastereomer YP-9 was achieved via crystallization-induced dynamic resolution in the presence of 20% MTBE/hexane at room temperature.

The uridine nucleoside YP-8 was treated with tert-butylmagnesium chloride in dry THF, followed by pentafluorophenyl Sp diastereomer YP-9 to furnish the Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate (Sovaldi, sofosbuvir, GS-7977, PSI-7977)。

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US 7429572

US  8415322

US 7964580

US 8334270B

WO 2006012440

WO 2011123668

US8334270

/US20080139802

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In US 20050009737 published Jan. 13, 2005, J. Clark discloses fluoro-nucleoside derivatives that inhibit Hepatitis C Virus (HCV) NS5B polymerase. In particular, 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-faran-2-yl)-1H-pyrimidin-2-one (18) was a particularly potent inhibitor of HCV polymerase as well as the polymerase of other Flaviviridae.

Figure US20080139802A1-20080612-C00002

In WO2006/012440 published Feb. 2, 2006, P. Wang et al disclose processes for the preparation of 18. Introduction of the cytosine is carried out utilizing the Vorbruggen protocol. In US 20060122146 published Jun. 8, 2006, B.-K. Chun et al. disclose and improved procedures for the preparation of the 2-methyl-2-fluoro-lactone 10. In the latter disclosure the nucleobase is glycosylated by reacting with ribofuranosyl acetate which is prepared by reduction of 10 with LiAlH(O-tert-Bu)followed by acetylaton of the intermediate lactol which was treated with an O-trimethylsilyl N4-benzoylcytosine in the presence of SnClto afford the O,O,N-tribenzoylated nucleoside.

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http://www.google.nl/patents/US20080139802

The present process as described in SCHEME A and the following examples contain numerous improvements which have resulted in higher yields of the desired nucleoside. The asymmetric hydroxylation of 22 was discovered to be best carried out with sodium permanganate in the presence of ethylene glycol, sodium bicarbonate in acetone which afforded the diol in 60-64% on pilot plant scale. The sodium permanganate procedure avoids introduction of osmium into the process stream. Further more the stereospecific hydroxylation can be accomplished without using an expensive chiral ligand. The requisite olefin is prepared from (1S,2S)-1,2-bis-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethane-1,2-diol (20) (C. R. Schmid and J. D. Bryant, Org. Syn. 1995 72:6-13) by oxidative cleavage of the diol and treating the resulting aldehyde with 2-(triphenyl-λ5-phosphanylidene)-propionic acid ethyl ester to afford 22.

Figure US20080139802A1-20080612-C00005

(i) NaIO4, NaHCO3, DCM; (ii) MeC(═PPh3)CO2Et; (iii) acetone-NaMnO(aq), ethylene glycol, NaHCO3, −10 to 0° C.; aq. NaHSO(quench); (iv) i-PrOAc, MeCN, TEA, SOCl2; (v) i-PrOAc, MeCN, NaOCl; (vi) TEA-3HF, TEA; (vii) HCl (aq)-BaCl2-aq; (viii) (PhCO)2O, DMAP, MeCN, (ix) RED-AL/TFE (1:1), DCM; (x) SO2Cl2-TBAB, DCM; (xi) 32, SnCl4-PhCl; (xii) MeOH-MeONa

EXAMPLE 3 (2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (24)

Figure US20080139802A1-20080612-C00008

A suspension of 22 (10 kg, CAS Reg. No. 81997-76-4), ethylene glycol (11.6 kg), solid NaHCO(11.8 kg) and acetone (150 L) is cooled to ca.-15° C. A solution of 36% aqueous NaMnO(19.5 kg) is charged slowly (over 4 h) to the suspension maintaining reaction temperature at or below −10° C. After stirring for 0.5 h at −10° C., an aliquot of the reaction mixture (ca. 5 mL) is quenched with 25% aqueous sodium bisulfite (ca. 15 mL). A portion of resulting slurry is filtered and submitted for GC analysis to check the progress of the reaction. When the reaction is complete, the reaction mixture is quenched by slow addition (over 40 min) of cooled (ca. 0° C.) 25% aqueous NaHSO(60 L). The temperature of the reaction mixture is allowed to reach 4° C. during the quench. CELITE® (ca. 2.5 kg) is then slurried in acetone (8 kg) and added to the dark brown reaction mixture. The resulting slurry is aged at RT to obtain light tan slurry. The slurry is filtered, and the filter cake is washed with acetone (3×39 kg). The combined filtrate is concentrated by vacuum distillation (vacuum approximately 24 inches of Hg; max pot temperature is 32° C.) to remove the acetone. The aqueous concentrate is extracted with EtOAc (3×27 kg), and the combined organic extracts were washed with water (25 L). The organic phase is then concentrated by atmospheric distillation and EtOAc is replaced with toluene. The volume of the batch is adjusted to ca. 20 L. Heptane (62 kg) is added and the batch cooled to ca. 27° C. to initiate crystallization. The batch is then cooled to −10° C. After aging overnight at −10° C., the product is filtered, washed with 10% toluene in heptane and dried at 50° C. under vacuum to afford 6.91 kg (59.5%) of 24 (CARN 81997-76-4) as a white crystalline solid.

EXAMPLE 4 (3R,4R,5R)-3-Fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-dihydro-furan-2-one (10)

Figure US20080139802A1-20080612-C00009

steps 1 & 2—A dry, clean vessel was charged with 24 (6.0 kg), isopropyl acetate (28.0 kg), MeCN (3.8 kg) and TEA (5.4 kg). The mixture was cooled to 5-10° C., and thionyl chloride (3.2 kg) was added slowly while cooling the solution to maintain the temperature below 20° C. The mixture was stirred until no starting material was left (GC analysis). The reaction was typically complete within 30 min after addition is complete. To the mixture was added water (9 kg) and after stirring, the mixture was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a mixture of water (8 kg) and saturated NaHCO(4 kg) solution. To the remaining organic phase containing 36 was added MeCN (2.5 kg) and solid NaHCO(3.1 kg). The resulting slurry was cooled to ca. 10° C. Bleach (NaOCl solution, 6.89 wt % aqueous solution, 52.4 kg, 2 eq.) was added slowly while cooling to maintain temperature below 25° C. The mixture was aged with stirring over 90-120 min at 20-25° C., until the reaction was complete (GC analysis). After completion of the reaction, the mixture was cooled to ca. 10° C. and then quenched with aqueous Na2SOsolution (15.1% w/w, 21 kg) while cooling to maintain temperature below 20° C. The quenched reaction mixture was filtered through a cartridge filter to remove inorganic solids. The filtrate was allowed to settle, and phases are separated and the aqueous phase is discarded. The organic layer was washed first with a mixture of water (11 kg) and saturated NaHCOsolution (4.7 kg), then with of saturated NaHCOsolution (5.1 kg). DIPEA (220 mL) was added to the organic phase and the resulting solution was filtered through CELITE® (bag filter) into a clean drum. The reactor was rinsed with isopropyl acetate (7 kg) and the rinse is transferred to the drum. The organic phase was then concentrated under vacuum (25-28 inches of Hg) while maintaining reactor jacket temperature at 45-50° C. to afford 26 as an oil (˜10 L). Additional DIPEA (280 mL) was added and the vacuum distillation was continued (jacket temperature 50-55° C.) until no more distillate was collected. (batch volume ca. 7 L).

step 3—To the concentrated oil from step 2 containing 26 was added TEA (2.34 kg) and TEA-trihydrofluoride (1.63 kg). The mixture was heated to 85° C. for 2 h. The batch was sampled to monitor the progress of the reaction by GC. After the reaction was complete conc. HCl (2.35 kg) was added to the mixture and the resulting mixture heated to ca. 90° C. (small amount of distillate collected). The reaction mixture was stirred at ca. 90° C. for 30 min and then saturated aqueous BaCl2solution (18.8 kg) was added. The resulting suspension was stirred at about 90° C. for 4 h. The resulting mixture was then azeotropically dried under a vacuum (9-10 inches of Hg) by adding slowly n-propanol (119 kg) while distilling off the azeotropic mixture (internal batch temperature ca. 85-90° C.). To the residual suspension was added toluene (33 kg) and vacuum distillation was continued to distill off residual n-propanol (and traces of water) to a minimum volume to afford 28.

step 4—To the residue from step 3 containing 28 was added MeCN (35 kg) and ca. 15 L was distilled out under atmospheric pressure. The reaction mixture was cooled to ca. 10° C. and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 40° C. The batch was aged at ca. 20° C. and the progress of the benzoylation is monitored by HPLC. After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE® pad (using a nutsche filter) to remove inorganic salts. The solid cake was washed with EtOAc (38 kg). The combined filtrate and washes were washed successively with water (38 kg), saturated NaHCOsolution (40 kg) and saturated brine (44 kg). The organic phase was polish-filtered (through a cartridge filter) and concentrated under modest vacuum to minimum volume. IPA (77 kg) was added to the concentrate and ca. 25 L of distillate was collected under modest vacuum allowing the internal batch temperature to reach ca. 75° C. at the end of the distillation. The remaining solution was then cooled to ca. 5° C. over 5 h and optionally aged overnight. The precipitate was filtered and washed with of cold (ca. 5° C.) IPA (24 kg). The product was dried under vacuum at 60-70° C. to afford 6.63 kg (70.7% theory of 10 which was 98.2% pure by HPLC.

EXAMPLE 1 Benzoic acid 3-benzoyloxy-5-(4-benzoylamino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl ester (14)

Figure US20080139802A1-20080612-C00006

Trifluoroethanol (4.08 kg) is added slowly to a cold solution (−15° C.) of RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at or below −10° C. After warming up to RT (ca. 20° C.), the modified RED-AL reagent mixture (30.1 kg out of the 37.6 kg prepared) is added slowly to a pre-cooled solution (−15° C.) of fluorolactone dibenzoate 10 (10 kg) in DCM (94.7 kg) while maintaining reaction temperature at or below −10° C. After reduction of the lactone (monitored by in-process HPLC), a catalytic amount of tetrabutylammonium bromide (90 g) is added to the reaction mixture. Sulfiiryl chloride (11.86 kg) is then added while maintaining reaction temperature at or below 0° C. The reaction mixture is then heated to 40° C. until formation of the chloride is complete (ca. 4 h) or warmed to RT (20-25° C.) and stirred over night (ca. 16 h). The reaction mixture is cooled to about 0° C., and water (100 L) is added cautiously while maintaining reaction temperature at or below 15° C. The reaction mixture is then stirred at RT for ca. 1 h to ensure hydrolytic decomposition of excess sulfuryl chloride and the phases are separated. The organic layer is washed with a dilute solution of citric acid (prepared by dissolving 15.5 kg of citric acid in 85 L of water) and then with dilute KOH solution (prepared by dissolving 15 kg of 50% KOH in 100 L of water). The organic phase is then concentrated and solvents are replaced with chlorobenzene (2×150 kg) via atmospheric replacement distillation. The resulting solution containing 30 is dried azeotropically.

A suspension of N-benzoyl cytosine (8.85 kg), ammonium sulfate (0.07 kg) and hexamethyldisilazane (6.6 kg) in chlorobenzene (52.4 kg) is heated to reflux (ca. 135° C.) and stirred (ca. 1 h) until the mixture becomes a clear solution. The reaction mixture is then concentrated in vacuo to obtain 32 as a syrupy liquid. The anhydrous solution of 30 in chlorobenzene (as prepared) and stannic chloride (28.2 kg) is added to this concentrate. The reaction mixture is maintained at about 70° C. until the desired coupling reaction is complete (ca. 10 h) as determined by in-process HPLC. Upon completion, the reaction mixture is cooled to RT and diluted with DCM (121 kg). This solution is added to a suspension of solid NaHCO(47 kg) and CELITE® (9.4 kg) in DCM (100.6 kg). The resulting slurry is cooled to 10-15° C., and water (8.4 kg) is added slowly to quench the reaction mixture. The resulting suspension is very slowly (caution: gas evolution) heated to reflux (ca. 45° C.) and maintained for about 30 min. The slurry is then cooled to ca. 15° C. and filtered. The filter cake is repeatedly reslurried in DCM (4×100 L) and filtered. The combined filtrate is concentrated under atmospheric pressure (the distillate collected in the process is used for reslurrying the filter cake) until the batch temperature rises to about 90° C. and then allowed to cool slowly to about −5° C. The resulting slurry is aged for at least 2 h at −5° C. The precipitated product is filtered and washed with IPA (30 kg+20 kg), and oven-dried in vacuo at about 70° C. to afford 8.8 kg (57.3%) of 1-(2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-β-D-ribofuranosyl)-N-4-benzoylcytosine (14, CAS Reg No. 817204-32-3) which was 99.3% pure.

EXAMPLE 2 4-Amino-1-(3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (18)

Figure US20080139802A1-20080612-C00007

A slurry of 14 (14.7 kg) in MeOH (92.6 kg) is treated with catalytic amounts of methanolic sodium methoxide (0.275 kg). The reaction mixture is heated to ca. 50° C. and aged (ca. 1 h) until the hydrolysis is complete. The reaction mixture is quenched by addition of isobutyric acid (0.115 kg). The resulting solution is concentrated under moderate vacuum and then residual solvents are replaced with IPA (80 kg). The batch is distilled to a volume of ca. 50 L. The resulting slurry is heated to ca. 80° C. and then cooled slowly to ca. 5° C. and aged (ca. 2 h). The precipitated product is isolated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70° C. in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure.

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https://www.google.com/patents/US8334270

EXAMPLE 4 Preparation of 2′-deoxy-2′-fluoro-2′-C-methyluridine

2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1.0 g, 1 eq) (Clark, J., et al., J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10 ml of anhydrous pyridine and concentrated to dryness in vacuo. The resulting syrup was dissolved in 20 ml of anhydrous pyridine under nitrogen and cooled to 0° C. with stirring. The brown solution was treated with benzoyl chloride (1.63 g, 3 eq) dropwise over 10 min. The ice bath was removed and stirring continued for 1.5 h whereby thin-layer chromatography (TLC) showed no remaining starting material. The mixture was quenched by addition of water (0.5 ml) and concentrated to dryness. The residue was dissolved in 50 mL of dichloromethane (DCM) and washed with saturated NaHCOaqueous solution and H2O. The organic phase was dried over NaSOand filtered, concentrated to dryness to give N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, Yield: 91%).

N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After cooling and standing at room temperature (15° C.), most of the product precipitated and then was filtered through a sintered funnel. White precipitate was washed with water and co-evaporated with toluene to give a white solid. The filtrate was concentrated and co-evaporated with toluene to give additional product which was washed with water to give a white solid. Combining the two batches of white solid gave 1.50 g of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (Yield: 91%).

To a solution of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60%).

Example numbers 13-54 and 56-66 are prepared using similar procedures described for examples 5-8. The example number, compound identification, and NMR/MS details are shown below:

entry 25
Figure US08334270-20121218-C00063
entry 251H NMR (DMSO-d6) δ 1.13-1.28 (m, 12H), 3.74-3.81 (m, 2H), 3.95-4.08 (m, 1H), 4.20-4.45 (m, 2H), 4.83-4.87 (m, 1H), 5.52-5.58 (m, 1H),5.84-6.15 (m, 3H), 7.17-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57(m, 1H), 11.50 (s. 1H); MS, m/e 530.2 (M + 1)+

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Synthesis of diastereomerically pure nucleotide phosphoramidates.

Ross BS, Reddy PG, Zhang HR, Rachakonda S, Sofia MJ.

J Org Chem. 2011 Oct 21;76(20):8311-9. doi: 10.1021/jo201492m. Epub 2011 Sep 26.

The HCV NS5B nucleoside and non-nucleoside inhibitors.

Membreno FE, Lawitz EJ.

Clin Liver Dis. 2011 Aug;15(3):611-26. doi: 10.1016/j.cld.2011.05.003. Review.

Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.

Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA.

J Med Chem. 2010 Oct 14;53(19):7202-18. doi: 10.1021/jm100863x.

Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977.

Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA.

J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26.

Michael J. Sofia,Donghui Bao, Wonsuk Chang, Jinfa Du, Dhanapalan Nagarathnam, Suguna Rachakonda, P. Ganapati Reddy, Bruce S. Ross, Peiyuan Wang, Hai-Ren Zhang, Shalini Bansal, Christine Espiritu, Meg Keilman, Angela M. Lam, Holly M. Micolochick Steuer, Congrong Niu, Michael J. Otto, and Phillip A. Furman; Discovery of a β-D-2-Deoxy-2-a-fluoro-2-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus; J. Med. Chem. 2010, 53, 7202–7218; Pharmasset, Inc.

Bruce S. Ross, P. Ganapati Reddy , Hai-Ren Zhang , Suguna Rachakonda , and Michael J. Sofia; Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates; J. Org. Chem., 2011, 76 (20), pp 8311–8319; Pharmasset, Inc.

Peiyuan Wang, Byoung-Kwon Chun, Suguna Rachakonda, Jinfa Du, Noshena Khan, Junxing Shi, Wojciech Stec, Darryl Cleary, Bruce S. Ross and Michael J. Sofia; An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase; J. Org. Chem., 2009, 74 (17), pp 6819–6824;Pharmasset, Inc.

Jeremy L. Clark, Laurent Hollecker, J. Christian Mason, Lieven J. Stuyver, Phillip M. Tharnish, Stefania Lostia, Tamara R. McBrayer, Raymond F. Schinazi, Kyoichi A. Watanabe, Michael J. Otto, Phillip A. Furman, Wojciech J. Stec, Steven E. Patterson, and Krzysztof W. Pankiewicz; Design, Synthesis, and Antiviral Activity of 2‘-Deoxy-2‘-fluoro-2‘-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication; J. Med. Chem., 2005, 48 (17), pp 5504–5508; Pharmasset, Inc

SOVALDI is the brand name for sofosbuvir, a nucleotide analog inhibitor of HCV NS5B polymerase.

The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:

SOVALDI™ (sofosbuvir) Structural Formula Illustration

Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2-7.7 at 37 oC and is slightly soluble in water.

SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

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J. Med. Chem. 2005, 48, 5504.
WO2008045419A1
CN201180017181

 

(WO2015139602) Sofosbuvir New Patent

(WO2015139602) 2′-SUBSTITUTED-2,2′-DEHYDRATED URIDINE OR 2′-SUBSTITUTED-2,2′-DEHYDRATED CYTIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF
ZHANG, Rongxia
A further object of the present invention to provide a method for preparing a compound of formula I.
The present invention provides a process for preparing a compound I 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-cytidine using the following formula or 2′-deoxy-2′-substituted 2′-2′-substituted nitrile or uridine 2′-deoxy-2′-substituted-2′-carbonitrile The method of cytidine compound,
2′-deoxy-2′-fluoro-2′-methyl-uridine (IIIa) is the preparation of anti-hepatitis C drugs Sofosbuvir key intermediate.
Sofosbuvir developed by Gilead Science Company, FDA on December 6, 2013 Sofosbuvir formally approved for the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is first used to treat certain types of HCV infection without the use of interferon effective and safe drugs. Clinical trials have shown, sofosbuvir can achieve very high proportion of sustained virologic response (clinical cure). More revolutionary breakthrough that, sofosbuvir without joint peginterferon α situation is still very significant effect, such as sofosbuvir ribavirin genotype 2 and genotype 3 patients with previously untreated chronic hepatitis C continued virological response rate of 100%. Sofosbuvir is a prodrug is metabolized in vivo to 2′-deoxy-2′-fluoro-2′-methyl-uridine-5′-monophosphate.
Currently reported 2′-deoxy-2′-fluoro-2′-methyl uridine synthetic methods are as follows:

In the literature (Journal of Medicinal Chemistry, 2005,48,5504) in order cytidine as a raw material, first selectively protected 3 ‘, 5′-hydroxyl group, and then oxidizing the 2′-hydroxyl to a carbonyl group, and the reaction of methyllithium get the 2’-hydroxyl compound, and then removing the protective group, use benzoyl protected 3 ‘, 5’-hydroxyl group, and then reacted with DAST fluorinated compound, followed by hydrolysis and aminolysis reaction products, such as the following Reaction Scheme. The method of route length, the need to use expensive silicon ether protecting group molecule relatively poor economy; conducting methylation time will generate a non-methyl enantiomer beta bits.

In Patent (WO2005003147, WO2006031725A2, US20040158059) using 2′-fluoro-2′-methyl – ribose derivative with N- benzoyl cytosine for docking the reaction, then after the hydrolysis, aminolysis reaction to obtain the final product, As shown in the following reaction scheme. Raw material of the process is not readily available, synthetic steps cumbersome, expensive; the reaction product obtained contained docking base for the alpha position isomers, need purification removed to form waste.
SUMMARY OF THE INVENTION
The present inventors have designed and synthesized a compound of formula I as shown, the compound may be a fluorinated or nitrile reaction of 2′-deoxy-2′-fluoro-2′-get-substituted uridine or 2 under appropriate conditions’ – 2′-deoxy-2′-fluoro-2′-deoxy-2′-substituted cytidine or nitrile uridine or 2′-substituted-2′-deoxy-2′-substituted-2′-cytidine nitrile compound; or a compound of formula I or a nitrile group by fluoro reaction, followed by deprotection reaction to give 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro–2 ‘- cytidine or 2′-substituted-2′-deoxy-2′-nitrile-substituted uridine or 2′-deoxy-2′-substituted-2′-cytidine compound nitrile group; or a compound of formula I through the opening cyclization reaction, and then through the group of fluoro or nitrile, and finally deprotection reaction to give 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-2’-substituted Cellular glycoside or 2 ‘substituted-2′-deoxy-2′-carbonitrile 2′-deoxy-uridine or 2′-substituted-2’-cytidine compound nitrile group; or a compound of formula I through a ring-opening reaction, and then 2 ‘- hydroxyl forming a leaving group, and then after a nitrile group or a fluorinated reaction, the final deprotection reaction of 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′- cytidine or 2′-fluoro-2′-substituted-2′-deoxy-2′-nitrile-substituted uridine or 2′-deoxy-2′-substituted-2’-cytidine nitrile compound.
It is therefore an object of the present invention is to provide a compound of the general formula I prepared 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-2′-substituted cytidine or 2′-substituted-2′-deoxy-2′-carbonitrile uridine or 2′-deoxy-2′-substituted-2′-carbonitrile The method of cytidine compound.
Example 1:
The 2′-C- methyl uridine (18.4g, 0.07mol), N, N’- carbonyldiimidazole (216.2g, 0.10mol), sodium bicarbonate (8.4g, 0.10mol) was suspended N, N- two dimethylformamide (50ml), the temperature was raised to 130 ℃, reaction for 4 hours, cooled and filtered to remove inorganic salts, the filtrate was added ethyl acetate (200ml), analyze the material at room temperature, suction filtered, washed with ethyl acetate cooled to, drying to give a yellow solid (19.9g, yield: 83%).
Ia: 1 H NMR (300 MHz, CD 3 OD): [delta] 7.80 (d, 1H, J = 7.5 Hz), 6.05 (d, 1H, J = 7.5 Hz), 5.91 (s, 1H), 4.34 (d, 1H, J = 4.8Hz), 4.07 (m, 1H), 3.56 (m, 2H), 1.63 (s, 3H); ESI-MS m / z (M + 1) 241.
Example 2:
The compound of Example 1 Ia (0.24g, 1mmol)) was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure, the residue was added acetone, beating, and filtered to give solid (0.18g, yield: 70%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 3:
Compound Ib (0.45g, 1mmol) was dissolved in a mixture of dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2), dried over anhydrous dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the residue was subjected to column chromatography to give the product (0.36g, yield: 78%).
IIa: 1 H NMR (400 MHz, CDCl 3 and DMSO-d 6 ): [delta] 7.99 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 7.34 ~ 7.61 (m, 7H ), 6.10 (brs, 1H), 5.64 (brs, 1H), 5.42 (d, J = 8.0Hz, 1H), 4.53-4.68 (m, 3H), 1.40 (d, J = 22.8Hz, 3H); ESI -MS m / z (M + 1) 469.
Example 4:
The compound of Example 3 IIa (0.47g, 1mmol) dissolved in 10% methanol solution of ammonia and stirred overnight, the solvent was removed under reduced pressure, and the residue was slurried in ethyl acetate, filtered to give a white solid (0.2g, yield : 77%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 5:
Compound IVa (0.57g, 1mmol) was dissolved in dichloroethane (20ml) was added trifluoromethanesulfonic acid trimethylsilyl ester (1ml), was heated for 12 hours, cooled, and the reaction solution was concentrated dryness, added two dichloromethane (100ml) was dissolved, washed successively with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give an oil which was purified by column chromatography to give a white solid (0.3g, yield : 67%).
Ib: 1 H NMR (300 MHz, CDCl 3 ): δ7.96-8.10 (m, 6H), 7.41-7.65 (m, 9H), 7.32 (d, 1H, J = 5.4 Hz), 6.09 (d, 1H, J = 5.4Hz), 5.79 (m, 2H), 4.67 (m, 1H), 4.48 (m, 2H), 1.81 (s, 3H); ESI-MS m / z (M-1) 447.
Example 6:
N The compound of Example 1 Ia (1.3g, 5.4mmol) dissolved in dry, N- dimethylformamide (10ml) was added p-toluenesulfonic acid monohydrate (1.12g, 5.9mmol) and 3,4- dihydropyran (1.28ml, 14.04mmol), The reaction was stirred for 5 hours at room temperature, water was added and the methylene chloride solution was separated, the organic layer was concentrated and purified by silica gel chromatography to give the product 1.3g.
Ic: 1 H NMR (300 MHz, CDCl 3 ): [delta] 7.29 (m, 1H), 6.08 (m, 1H), 5.61 (m, 1H), 4.33-4.72 (m, 4H), 3.37-3.90 (m, 6H), 1.43-1.82 (m, 12H), 1.25 (s, 3H); ESI-MS m / z (M + 1) 427.
Example 7:
The solvent was removed, the residue was purified compound of Example 6 Ic (0.43g, 1mmol) was dissolved in 70% HF in pyridine was heated to 100 ~ 120 ℃, stirred for 5 hours, cooled, reduced pressure was purified through silica gel column to give a solid ( 0.18g, yield: 72%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 8:
The compound of Example 6 Ic (50mg, 0.122mmol) was dissolved in methanol (1ml) was added 1N sodium hydroxide solution (0.2ml), stirred at room temperature overnight, water was added and the methylene chloride solution was separated, the organic layer was concentrated after purified by column chromatography to give the product (45mg, yield: 87%).
VA: 1 H NMR (300 MHz, CDCl 3 ): [delta] 7.89 (d, 1H, J = 4.5Hz), 6.01 (s, 1H), 5.95 (d, 1H, J = 4.5Hz), 5.65 (m, 2H ), 4.73 (m, 3H), 4.59 (m, 1H), 3.52-4.30 (m, 4H), 1.56-1.80 (m, 12H), 1.32 (s, 3H); ESI-MS m / z (M + 35) 461.
Example 9:
The mixture of Example 8 Compound Va (0.43g, 1mmol) was dissolved in dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2) and washed , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound IIb. Compound IIb is dissolved in methanol (10ml) was added p-toluenesulfonic acid (200mg), stirred for 6 hours at room temperature, the methanol was removed under reduced pressure, silica gel column chromatography to give the product IIIa (180mg, yield: 75%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 10:
The 2′-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added N, N’- carbonyldiimidazole (0.194g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), was heated to 130 ℃, stirred for 4 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled, The solvent was removed under reduced pressure, the residue was added to acetone and filtered to obtain a solid IIIa (0.12g, yield: 60%).
Example 11:
The 2′-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate ( 55mg, 0.66mmol), was heated to 150 ℃, stirred for 6 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure The residue was added to acetone and filtered to obtain a solid IIIa (0.13g, yield: 65%).
Example 12:
Under nitrogen, the compound of Example 9 Example Va (4.26g, 10mmol) was dissolved in dry tetrahydrofuran (100ml) was added triethylamine (6g, 60mmol), cooled to -78 ℃, was added trifluoromethanesulfonic anhydride (4.23g , 15mmol), stirred for 1 hour, the reaction system was added saturated ammonium chloride solution, extracted three times with methylene chloride, organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product Vb ( 4g, yield: 72%). ESI-MS m / z (M-1) 557.
Compound Vb (4g) was dissolved in dry tetrahydrofuran, was added tetrabutylammonium fluoride (1.87g, 7.1mmol), warmed to reflux, cooled to room temperature after heating for 1 hour, water was added to the reaction system, and extracted with methylene chloride three times, the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product IIb (2.7g, yield: 88%). ESI-MS m / z (M-1) 427.
Compound IIb (2.7g) was dissolved in methanol (20ml) was added 3M hydrochloric acid (10ml), 50 ℃ stirred for 8 hours, and concentrated to give a solid, was added acetonitrile, beating, and filtered to give the product IIIa (1g, yield: 61%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.








 UPDATE DEC2015………….
File:Sofosbuvir structure.svg

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

Step (a):

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ8.25 & 7.94 (1: 1);

1 HNMR (CDCl 3 , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

13 C NMR (CDCl 3 , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ3.54ppm;

13 C NMR (CDCl 3 , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

1 HNMR (CDCl 3 , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(4) nucleophile as NaN 3 , phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN 3 (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N 3 ).

1 HNMR (CDCl 3 , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

31 PNMR- (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

1 HNMR (CDCl 3 , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

(2) X is N 3

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

File:Sofosbuvir structure.svg


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European Commission Approves Gilead’s VitektaTM, an Integrase Inhibitor for the Treatment of HIV-1 Infection


Elvitegravir

697761-98-1 CAS

FOSTER CITY, Calif.–(BUSINESS WIRE)–Nov. 18, 2013– Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorization for VitektaTM (elvitegravir 85 mg and 150 mg) tablets, an integrase inhibitor for the treatment of HIV-1 infection in adults without known mutations associated with resistance to elvitegravir. Vitekta is indicated for use as part of HIV treatment regimens that include a ritonavir-boosted protease inhibitor.http://www.pharmalive.com/eu-oks-gileads-vitekta Vitekta interferes with HIV replication by blocking the virus from integrating into the genetic material of human cells. In clinical trials, Vitekta was effective in suppressing HIV among patients with drug-resistant strains of HIV.http://www.pharmalive.com/eu-oks-gileads-vitekta

Elvitegravir (EVG, formerly GS-9137) is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed[1] by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.[2][3][4] The drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.[5]

According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor.[6]

 Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS).  After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS.  The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART).  Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs.  Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists).

  1.  Gilead Press Release Phase III Clinical Trial of Elvitegravir July 22, 2008
  2.  Gilead Press Release Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor March 22, 2008
  3.  Shimura K, Kodama E, Sakagami Y, et al. (2007). “Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137)”J Virol 82 (2): 764. doi:10.1128/JVI.01534-07PMC 2224569PMID 17977962.
  4.  Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”. Eur. J. Med. Res. 12 (9): 483–95. PMID 17933730.
  5.  Sax, P. E.; Dejesus, E.; Mills, A.; Zolopa, A.; Cohen, C.; Wohl, D.; Gallant, J. E.; Liu, H. C.; Zhong, L.; Yale, K.; White, K.; Kearney, B. P.; Szwarcberg, J.; Quirk, E.; Cheng, A. K.; Gs-Us-236-0102 Study, T. (2012). “Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks”.The Lancet 379 (9835): 2439–2448. doi:10.1016/S0140-6736(12)60917-9PMID 22748591edit
  6.  Thaczuk, Derek and Carter, Michael. ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents Aidsmap.com. 19 Sept. 2007.

 

 The life cycle of HIV-1.  1. HIV-1 gp120 binds to CD4 and co-receptor CCR5/CXCR4 on target cell; 2. HIV-1 gp41 mediates fusion with target cell; 3. Nucleocapsid containing viral genome and enzymes enters cells; 4. Viral genome and enzymes are released; 5. Viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming RNA-DNA hybrids; 6. RNA template is degraded by ribonuclease H followed by the synthesis of HIV dsDNA; 7. Viral dsDNA is transported into the nucleus and integrated into the host chromosomal DNA by the viral integrase enzyme; 8. Transcription of proviral DNA into genomic ssRNA and mRNAs formation after processing; 9. Viral RNA is exported to cytoplasm; 10. Synthesis of viral precursor proteins under the catalysis of host-cell ribosomes; 11. Viral protease cleaves the precursors into viral proteins; 12. HIV ssRNA and proteins assemble under host cell membrane, into which gp120 and gp41 are inserted; 13. Membrane of host-cell buds out, forming the viral envelope; 14. Matured viral particle is released

Elvitegravir, also known as GS 9137 or JTK 303, is an investigational new drug and a novel oral integrase inhibitor that is being evaluated for the treatment of HIV-1 infection. After HIVs genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIVs DNA inside the cell’s DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. Elvitegravir has the chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1 -hydroxy -methyl-2- methylpropyl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and has the following structural formula:

Figure imgf000002_0001

WO 2000040561 , WO 2000040563 and WO 2001098275 disclose 4-oxo-1 , 4-dihydro-3- quinoline which is useful as antiviral agents. WO2004046115 provides certain 4- oxoquinoline compounds that are useful as HIV Integrase inhibitors.

US 7176220 patent discloses elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and their method of treatment. The chemistry involved in the above said patent is depicted below in the Scheme A. Scheme-A

Toluene, DIPEA

SOCl2 ,COCl (S)-(+)-Valinol

Toluene

Figure imgf000003_0001

,4-Difluoro-5-iodo- benzoic acid

Figure imgf000003_0003
Figure imgf000003_0002

THF

dichlorobis(triphenylphosphine)

palladium argon stream,

Figure imgf000003_0004

Elvitegravir Form ] Elvitegravir (residue) US 7635704 patent discloses certain specific crystalline forms of elvitegravir. The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound. Further, process for the preparation of elvitegravir also disclosed and is depicted below in the Scheme B. The given processes involve the isolation of the intermediates at almost all the stages.

Scheme B

2,

Figure imgf000004_0001

Zn THF,

CK Br THF CU “ZnBr dιchlorobis(trιphenylphos

phine)palladium

Figure imgf000004_0002

Elvitegravir WO 2007102499 discloses a compound which is useful as an intermediate for the synthesis of an anti-HIV agent having an integrase-inhibiting activity; a process for production of the compound; and a process for production of an anti-HIV agent using the intermediate.

WO 2009036161 also discloses synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

The said processes are tedious in making and the purity of the final compound is affected because of the number of steps, their isolation, purification etc., thus, there is a need for new synthetic methods for producing elvitegravir which process is cost effective, easy to practice, increase the yield and purity of the final compound, or that eliminate the use of toxic or costly reagents.

US Patent No 7176220 discloses Elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and ■ their method of treatment. US Patent No 7635704 discloses Elvitegravir Form II, Form III and processes for their preparation. The process for the preparation of Form Il disclosed in the said patent is mainly by three methods – a) dissolution of Elvitegravir followed by seeding with Form II, b) recrystallisation of Elvitegravir, and c) anti-solvent method.

The process for the preparation of Form III in the said patent is mainly by three methods – a) dissolution of Form Il in isobutyl acetate by heating followed by cooling the reaction mass, b) dissolution of Form Il in isobutyl acetate by heating followed by seeding with Form III, and c) dissolving Form Il in 2-propanol followed by seeding with Form III.

Amorphous materials are becoming more prevalent in the pharmaceutical industry. In order to overcome the solubility and potential bioavailability issues, amorphous solid forms are becoming front-runners. Of special importance is the distinction between amorphous and crystalline forms, as they have differing implications on drug substance stability, as well as drug product stability and efficacy.

An estimated 50% of all drug molecules used in medicinal therapy are administered as salts. A drug substance often has certain suboptimal physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic drug molecule with a counter- ion to create a salt version of the drug. The process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug. Salt forms of drugs have a large effect on the drugs’ quality, safety, and performance. The properties of salt-forming species significantly affect the pharmaceutical properties of a drug and can greatly benefit chemists and formulators in various facets of drug discovery and development.

Figure imgf000020_0003

chemical synthesis from a carboxylic acid 1 starts after conversion to the acid chloride iodide NIS 2 , and with three condensation 4 . 4 and the amino alcohol 5 addition-elimination reaction occurs 6 , 6 off under alkaline conditions with TBS protected hydroxy get the ring 7 , 7 and zinc reagent 8 Negishi coupling occurs to get 9 , the last 9 hydrolysis and methoxylated

Egypt for Raltegravir (Elvitegravir) -2012 August of anti-AIDS drugs approved by the FDA

Elvitegravir dimer impurity, WO2011004389A2

Isolation of 1-[(2S)-1-({3-carboxy-6-(3-chloro-2-fluorobenzyl)-1 -[(2S)-I- hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl}oxy)-3- methylbutan-2-yl 6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (elvitegravir dimer impurity, 13)

After isolation of the elvitegravir from the mixture of ethyl acetate-hexane, solvent from the filtrate was removed under reduced pressure. The resultant residue purified by column chromatography using a mixture of ethyl acetate-hexane (gradient, 20-80% EtOAc in hexane) as an eluent. Upon concentration of the required fractions, a thick solid was obtained which was further purified on slurry washing with ethyl acetate to get pure elvitegravir dimer impurity (13). The 1H-NMR, 13C-NMR and mass spectral data complies with proposed structure.

Figure imgf000041_0001

1H-NMR (DMSO-Cf6, 300 MHz, ppm) – δ 0.79 (m, d=6.3 Hz, 6H, 20 & 2O’)\ 1.18 & 1.20 (d, J=6.3 Hz & J=6.2 Hz, 6H, 21 & 21′)1, 2.42-2.49 (m, 2H, 19 & 19′), 3.81-3.89 (m, 3H, T & 17’Ha), 3.94-4.01 (m, 1 H, 17’Hb), 4.01 (s, 3H, 23), 4.11 (s, 2H, 7), 4.83-4.85 (m, 3H, 17 & 18′), 5.22 (t, J=4.7 Hz, 1H, OH), 5.41-5.44 (m, 1 H, 18), 6.73-6.78 (t, J=7.1 Hz, 1 H, 11)1‘ 2, 6.92-6.98 (t, J=8.0 Hz, 1H, 3′) 12, 7.12-7.22 (m, 2H, 1 & 3), 7.34-7.39 (m, 1H, 2′),

7.45-7.48 (m, 1 H, 2), 7.49, 7.56 (s, 2H, 15 & 15′), 7.99, 8.02 (s, 2H, 9 & 9′), 8.89, 9.01 (s, 2H, 13 & 13′), 15.30, 15.33 (s, 2H, COOH’ & COOH”).

13C-NMR (DMSO-Cf6, 75 MHz, ppm)- δ 18.87, 19.03 (2OC, 20’C), 19.11 , 19.24 (21 C, 21 ‘C), 27.94 (7’C), 28.40 (7C), 28.91 , 30.08 (19C, 19’C), 56.80(23C), 60.11 (171C), 63.59 (18C), 66.52 (18’C), 68.53 (17C), 97.86, 98.97 (15, 15′), 107.43, 108.16 (12C, 12’C),

118.77, 119.38 (1OC, 10’C), 119.57 (d, J=17.6 Hz, 41C), 119.61 (d, J=17.9 Hz, 4C),

124.88 (d, J=4.3 Hz, 31C), 125.18 (d, J=4.2 Hz, 3C), 126.59, 126.96 (9C1 9’C), 127.14 (8’C), 127.62 (d, J=15.9 Hz, 61C), 127.73 (8C), 127.99 (d, J=15.2 Hz, 6C), 128.66 (2’C),

128.84 (11C), 128.84 (2C), 130.03 (d, J=3.4 Hz, 1C), 142.14, 142.44 (14C, 14’C), 144.37, 145.56 (13C, 131C), 155.24 (d, J=245.1 Hz, 5’C)1 155.61 (d, J=245.1 Hz, 5C),

160.17 (16’C), 162.04 (16C), 166.00, 166.14 (22C, 22’C), 176.17, 176.22 (11C, 111C).

DIP MS: m/z (%)- 863 [M+H]+, 885 [M+Na]+.

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