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ORGANIC SPECTROSCOPY

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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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ELAGOLIX


Elagolix.svgChemSpider 2D Image | Elagolix | C32H30F5N3O5Elagolix.png

ELAGOLIX

  • Molecular FormulaC32H30F5N3O5
  • Average mass631.590 Da
NBI56418, ABT 620
UNII:5B2546MB5Z
4-({(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phenylethyl}amino)butanoic acid
834153-87-6 FREE ACID
SODIUM SALT  832720-36-2
Acide 4-({(1R)-2-[5-(2-fluoro-3-méthoxyphényl)-3-[2-fluoro-6-(trifluorométhyl)benzyl]-4-méthyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phényléthyl}amino)butanoïque
Butanoic acid, 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-

GNRH antagonist, Endometriosis

Endometriosis PREREGISTERED

Phase III Uterine leiomyoma

WO2001055119A2,

Inventors Yun-Fei ZhuChen ChenFabio C. TucciZhiqiang GuoTimothy D. GrossMartin RowbottomR. Scott Struthers,
Applicant Neurocrine Biosciences, Inc.

WO 2005007165 PDT PATENT

Image result for Neurocrine Biosciences, Inc.

Inventors Zhiqiang GuoYongsheng ChenDongpei WuChen ChenWarren WadeWesley J. DwightCharles Q. HuangFabio C. Tucci
Applicant Neurocrine Biosciences, Inc.
  • Originator Icahn School of Medicine at Mount Sinai
  • Developer AbbVie; Neurocrine Biosciences
  • Class Antineoplastics; Fluorinated hydrocarbons; Pyrimidines; Small molecules
  • Mechanism of Action LHRH receptor antagonists
  • Highest Development Phases
  • Preregistration Endometriosis
  • Phase III Uterine leiomyoma
  • Discontinued Benign prostatic hyperplasia; Prostate cancer
  • Most Recent Events
  • 23 Nov 2017 AbbVie plans a phase III trial for Endometriosis (Monotherapy, Combination therapy) in USA in November 2017 (NCT03343067)
  • 01 Nov 2017 Updated efficacy and adverse events data from two phase III extension trials in Endometriosis released by AbbVie
  • 27 Oct 2017 Elagolix receives priority review status for Endometriosis in USA

 

SYN

Elagolix is a specific highly potent non-peptide, orally active antagonist of the GnRH receptor. This compound inhibits pituitary luteinizing hormone (LH) secretion directly, potentially preventing the several week delay and flare associated with peptide agonist therapy.

Image result for Neurocrine Biosciences, Inc.

In 2010, elagolix sodium was licensed to Abbott by Neurocrine Biosciences for worldwide development and commercialization for the treatment of endometriosis. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie.

AbbVie , following its spin-out from Abbott in January 2013, under license from Neurocrine , is developing elagolix, the lead from a series of non-peptide gonadotropin-releasing hormone antagonists, for treating hormone-dependent diseases, primarily endometriosis and uterine fibroids.

Elagolix sodium is an oral gonadotropin releasing hormone (GnRH) antagonist in development at Neurocrine Biosciences and Abbvie (previously Abbott). In 2017, Abbvie submitted a New Drug Application (NDA) in the U.S. for the management of endometriosis with associated pain. The candidate is being evaluated in phase III trials for the treatment of uterine fibroids.

Elagolix (INNUSAN) (former developmental code names NBI-56418ABT-620) is a highly potent, selective, orally-active, short-duration, non-peptide antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (KD = 54 pM) which is under development for clinical use by Neurocrine Biosciences and AbbVie.[2][3] As of 2017, it is in pre-registration for the treatment of endometriosis and phase III clinical trials for the treatment of uterine leiomyoma.[1][4] The drug was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia, but development for these indications was ultimately not pursued.[4] Elagolix is the first of a new class of GnRH inhibitors that have been denoted as “second-generation”, due to their non-peptide nature and oral bioavailability.[1]

Because of the relatively short elimination half-life of elagolix, the actions of gonadotropin-releasing hormone (GnRH) are not fully blocked throughout the day.[1][5] For this reason, gonadotropin and sex hormone levels are only partially suppressed, and the degree of suppression can be dose-dependently adjusted as desired.[1][5] In addition, if elagolix is discontinued, its effects are rapidly reversible.[1][5] Due to the suppression of estrogen levels by elagolix being incomplete, effects on bone mineral density are minimal, which is in contrast to first-generation GnRH inhibitors.[6][7] Moreover, the incidence and severity of menopausal side effects such as hot flashes are also reduced relative to first-generation GnRH inhibitors.[1][5]

Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl] -4-methyl-2,6-dioxopyrimidin- 1 -yl] -1 -phenylethyl] amino] butanoate as below.

The US patent number 7056927 B2 discloses, elagolix sodium salt as a white solid and process for its preparation in Example-1; Step-IH.

The US patent number 8765948 B2 discloses a process for preparation of amorphous elagolix sodium by spray drying method and solid dispersion of amorphous elagolix sodium with a polymer.

The US patent number 7056927 B2 discloses a process for preparation of elagolix sodium salt in Example -1 as given in below scheme -I.

Scheme -I

The US patent number 8765948 B2 describes a process for preparation of elagolix sodium in example- 1 and 4 as given below scheme-II:

(1c) (1e) (4a)

Scheme-II

Further, the US patent number 8765948 B2 discloses an alternate process for the preparation of compound of formula (le) as mentioned below scheme-Ill.

Scheme -III

PATENT

WO2001055119A2 * Jan 25, 2001 Aug 2, 2001 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

PATENT

WO 2005007165

https://encrypted.google.com/patents/WO2005007165A1?cl=en

EXAMPLE 1

3-[2(R)-{HYD OXYCARBONYLPROPYL-AMINθ} -2-PHENYLETHYL]-5-(2-FLUORO-3- METHOXYPHENYL)-l-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL- PYRIMIDINE-2,4(lH,3H)-DIONE

Figure imgf000027_0001

Step IA: Preparation of 2-fluoro-6-(trifluoromethyl)benzylamine la To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of TΗF was added 1 M BΗ3:TΗF slowly at 60 °C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (C\) m/z 194.0 (MH+).

Step IB: Preparation of N-|2-fluoro-6-(trifluoromethyl)benzyl|urea lb To 2-fluoro-6-(trifluoromethyl)benzylamine la (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HC1 (cone, 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave lb as a white solid (46.2 g, 0J96 mmol). MS (CI) m/z 237.0 (MH+).

Step 1C: Preparation of l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methylpyrimidine-2.4(lH.3H)-dione lc Nal (43.9 g, 293 mmol) was added to N-[2-fluoro-6- (trifluoromethyl)benzyl]urea lb (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give lc as a white solid (48.5 g, 16 mmol). 1H ΝMR (CDC13) δ 2.15 (s, 3Η), 5.37 (s, 2H), 5.60 (s, 1H), 7.23-7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).

Step ID: Preparation of 5-bromo-l -[2-fluoro-6-(trifluoromethyl)benzyl|-6- methylpyrimidine-2.4(lH.3H)-dione Id Bromine (16.5 mL, 0.32 mmol) was added to l-[2-fluoro-6-

(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(lHJH)-dione lc (48.5 g, 0J6 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat. ΝaΗCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of Id (0J56 mol) total. Η NMR (CDC13) δ 2.4 (s, 3H), 5.48 (s, 2H), 7.25-7.58 (m, 3H), 8.61 (s, 1H); MS (CI) m/z 380.9 (MH+). 5-Bromo-l-[2, 6-difluorobenzyl]-6-methylpyrimidine-2,4(lHJH)-dione ld.l was made using the same procedure.

Step IE: Preparation of 5-bromo-l -r2-fluoro-6-(trifluoromethyl)benzyll-6- methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyll-pyrimidine-2.4(lHJH)-dione le To 5-bromo- 1 -[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- 2,4(lHJH)-dione Id (15 g, 39.4 mmol) in 225 mL of TΗF were added N-t-Boc-D- phenylglycinol (11.7 g, 49.2 mmol) and triphenylphosphine (15.5 g, 59J mmol), followed by addition of di-tert-butyl azodicarboxylate (13.6 g, 59J mmol). The resulting yellow solution was stirred overnight. The volatiles were evaporated and the residue was purified by silica gel with 3:7 EtOAc Ηexane to give le as a white solid (23.6 g, 39.4 mmol). MS (CI) m/z 500.0 (MΗ+-Boc).

Step IF: Preparation of 3-[2(R)-amino-2-phenylethyll-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyll-6-methyl-pyrimidine- 2.4(lH.3H)-dione If To 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)- tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione le (15 g, 25 mmol) in 30 mL/90 mL of Η2O/dioxane in a pressure tube were added 2-fluoro-3- methoxyphenylboronic acid (4.25 g, 25 mmol) and sodium carbonate (15.75 g, 150 mmol). N2 gas was bubbled through for 10 min.

Tetrakis(triphenylphosphine)palladium (2.9 g, 2.5 mmol) was added, the tube was sealed and the resulting mixture was heated with stirring at 90 °C overnight. After cooling to ambient temperature, the precipitate was removed by filtration. The volatiles were removed by evaporation and the residue was partitioned between EtOAc/sat. NaHCO3. The organic solvent was evaporated and the residue was chromatographed with 2:3 EtOAc/Hexane to give 13.4 g (20.8 mmol, 83 %) yellow solid. This yellow solid (6.9 g, 10.7 mmol) was dissolved in 20 mL/20 mL CH2C12/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave If as a yellow oil (4.3 g, 7.9 mmol, 74%). Η NMR (CDC13) δ 2.03 (s, 3H), 3.72-4.59 (m, 6H), 5.32-5.61 (m, 2H), 6.74-7.56 (m, 11H); MS (CI) m/z 546.0 (MH+). 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2,6- difluorobenzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione lf.l was made using the same procedure described in this example.

Step 1G: Preparation of 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyll-5-

(2-fluoro-3 -methoxyphenyl)- 1 -[2-fluoro-6-(trifluoromethyl)benzyl|-6-methyl- pyrimidine-2,4(lHJH)-dione lg To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione If (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4- bromobutyrate (4 mL, 28.2 mmol) and Ηunig’s base (1.6 mL, 9.4 mmol). After reflux at 95 °C overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10: 1 EtOAc/Ηexane/Et3N to give lg as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).

Step 1H: Preparation of 3-[2(R)- {hydroxycarbonylpropyl-amino} -2-phenylethyl]- 5-(2-fluoro-3-methoxyphenyl)-l- 2-fluoro-6-(trifluoromethyl)benzyl1-6-methyl- pyrimidine-2,4(lHJH)-dione 1-1 Compound 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione lg (2.6 g, 4.0 mmol) was dissolved in 30 mL/30 mL of TΗF/water. Solid NaOΗ (1.6 g, 40 mmol) was added and the resulting mixture was heated at 50 °C overnight. The mixture was cooled to ambient temperature and the volatiles were evaporated. Citric acid was added to the aqueous solution until pΗ = 3. Extraction with EtOAc followed by evaporation of solvent gave 1.96 g of a white gel. The gel was passed through a Dowex MSC-1 macroporous strong cation-exchange column to convert to sodium salt. Lyopholization gave white solid 1-1 as the sodium salt (1.58 g, 2.47 mmol). Η NMR (CD3OD) δ 1.69-1.77 (m, 2H), 2.09 (s, 3H), 2.09-2.19 (t, J = 7.35 Hz, 2H), 2.49-2.53 (t, J = 735 H, 2H), 3.88 (s, 3H), 4.15-4.32 (m, 3H), 5.36-5.52 (m, 2H), 6.60-7.63 (m, 1 IH); HPLC-MS (CI) m/z 632.2 (MH+), tR = 26.45, (method 5)

PATENT

WO 2017221144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017221144&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for the preparation of elagolix sodium and its polymorph forms and intermediates is claimed. Represents first filing from Dr. Reddy’s Laboratories Limited and the inventors on this API.

n a seventh aspect, the present invention provides a process for preparation of compound of formula (VII)

(VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like,

comprising;

a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above

b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula

(VII)

(VI) (VII)

The reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.

The seventh aspect of the present invention is depicted below scheme-IV.

Scheme-IV

The eighth aspect of the present invention is depicted below scheme-IV.

R=alkyl

Scheme-IV

Example 11: Preparation of ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (Ilia; R is ethyl)

R-(-)-2-phenylglycinol (10 g), DMAP (0.17 g) were added in THF (80 ml) at room temperature under nitrogen atmosphere. Triethylamine (30.48 ml) was added to the reaction mixture and stirred for five minutes. Ethyl-4-bromo butyrate (15.64 ml) was added and the reaction mixture heated to 80°C then stirred for 16 hours. Water (20 volumes) followed by ethyl acetate (200 ml) were added to separate the aqueous and organic layer. The organic layer was washed with IN HC1 (100 ml) followed by neutralize the resulting aqueous layer with saturated sodium carbonate solution then extract with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate then evaporated below 50°C under reduced pressure to obtain the title compound. Yield: 14.50 g. Purity: 94.75% (by HPLC). ¾ NMR (400 MHz, DMSO-d6): δ 7.17-7.30 (m, 5H), 4.83 (m, 1H), 3.99 (q, 2H), 3.58 (dd, 1H, J = 8.8, 4.4 Hz), 3.88 (m, 1H ), 3.27 (m, 1H), 2.38 (m, 1H), 2.26 (m, 3H), 2.10 (s, 1H), 1.61 (m, 2H), 1.12 (t, 3H); m/z: 252 (MH )

Example 12: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l-phenylethyl) amino)butanoate (III; R is ethyl)

Ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (14 g) was added to THF (140 ml) at room temperature. The reaction mixture was cooled to 0-5 °C. Triethylamine (16.9 mL) was added to the reaction mixture followed by Di-tert-butyl dicarbonate (13.37 g) was added to reaction mixture at 0-5 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (300 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with sodium chloride then died over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound as a pale yellow syrup. Yield: 9.5 g. Purity: 95.42% (by HPLC). ¾ NMR (400 MHz, CDC13): δ 7.24-7.34 (m, 5H), 5.08 (m, 1H), 4.09 (m, 4H), 3.10 (m, 2H), 3.00 (s, 1H), 2.21(m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.23 (t, 3H). m/z: 352.20 (MH )

Example 13: Preparation of ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl)

Ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l -phenyl ethyl) amino)butanoate (III; R is ethyl) (1.0 g), 5-bromo-l-(2-fluoro-6-trifluoromethyl)benzyl-6-methylpyrimidine-2,4 (1H, 3H)-dione (II) (1.08 g), Triphenyl phosphine (1.49 g) were added to THF (30 mL) at room temperature under nitrogen atmosphere. DIAD (1.11 mL) was added to the reaction mixture and stirred for 16 hours at room temperature. Water (60 volume) was added to the reaction mixture followed by ethylacetate (60 mL) was added then the layers were separated. The organic layer was dried over sodium sulfate and evaporated below 50°C under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound. Yield (1.3 g). Purity: 68.87% (by HPLC); l NMR (DMSO-d6) δ 1.15-2.0 (11H), 2.43-2.48 (4H), 3.9 (2H), 4.71-4.8 (5H), 5.3 -5.4 (3H), 7.28-7.3 (8H), 8.4 (2H); m/z: 616 (M-BOC)+

Example 14: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl)

Ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl) (0.9 g), 2-fluoro-3-methoxy phenyl boronic acid (V) (0.214 g) and sodium carbonate (0.797 g) were added to the mixture of 1,4-dioxane (9 mL) and water (3.06 mL) at room temperature under nitrogen atmosphere. Argon gas was bubbled through for 30 minutes. Tetrakis (triphenylphosphine)palladium (0.145 g) was added to the reaction mixture at room temperature then heated to 90-95 °C and stirred for 5 hours. The reaction mixture cooled to room temperature and filtered through celite bed then the filtrate washed with ethylacetate (9 mL) and water (36 mL) was added and stirred for 30 minutes at room temperature. Ethylacetate (36 mL) was added and the separated organic layer washed with brine and dried over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with 20-25% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 0.5 g; Purity: 75.1% (by HPLC); m/z: 660 (M-BOC)+.

Example 15: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VII; R is ethyl)

Ethyl(R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoro methyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl) (0.4 g) was added to dichloromethane (4 mL) at room temperature. The reaction mixture was cooled to 0-5 °C then trifluoroacetic acid (2 mL) was added and stirred for five hours at 0-5 °C. Saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture followed by dichloromethane (40 mL) was added. The organic layer was washed with brine then dried over sodium sulfate and evaporated at 35°C to obtain the crude compound. The crude compound purified by silica gel (60/120 mesh) with 30-35% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 160 mg; Purity: 88.6% (by HPLC). ‘H NMR (400 MHz, DMSO-d6): δ 7.64 (m, 1H), 7.54 (m, 2H), 7.15-7.27 (m, 6H), 6.85 (m, 2H), 5.31 (s, 2H), 3.99 (m, 3H), 3.87 (m, 2H), 3.83 (s, 3H), 2.30-2.16 (m, 4H), 2.10 (s, 3H), 1.50 (m, 2H), 1.10 (t, 3H). m/z: 660 (MH )

PAPER

Discovery of sodium R-(+)-4-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl-)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-1-phenylethamino)butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2008, 51(23): 7478

Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

Department of Medicinal Chemistry, Department of Endocrinology, and Department of Preclinical Development, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130
J. Med. Chem.200851 (23), pp 7478–7485
DOI: 10.1021/jm8006454

* To whom correspondence should be addressed. Phone: 1-858-617-7600. Fax: 1-858-617-7925. E-mail: cchen@neurocrine.comsstruthers@neurocrine.com., †

Department of Medicinal Chemistry., ‡ Department of Endocrinology., § Department of Preclinical Development.

Abstract

Abstract Image

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

NA SALT

(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric Acid Sodium Salt

sodium salt as a white solid (1.58 g, 2.47 mmol, 62%). HPLC purity: 100% (220 and 254 nm). 1H NMR (CD3OD): 1.72 (m, 2H), 2.08 (s, 3H), 2.16 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 4.24 (m, 3H), 5.40 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 9.0 Hz, 1H), 6.62 and 6.78 (m, 1H), 7.12 (m, 2H), 7.34 (m, 5H), 7.41 (m, 1H), 7.56 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H). MS: 632 (M − Na + 2H+). Anal. (C32H29F5N3O5Na·0.75H2O): C, H, N, Na.

PATENT

CN 105218389

PATENT

WO2014143669A1

“Elagolix” refers to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2- fluoro-6 rifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l- phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof. Elagolix is an orally active, non-peptide GnRH antagonist and is unlike other GnRH agonists and injectable (peptide) GnRH antagonists. Elagolix produces a dose dependent suppression of pituitary and ovarian hormones in women. Methods of making Elagolix and a pharmaceutically acceptable salt thereof are described in WO 2005/007165, the contents of which are herein incorporated by reference.

References

  1. Jump up to:a b c d e f g Ezzati, Mohammad; Carr, Bruce R (2015). “Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain”. Women’s Health11(1): 19–28. doi:10.2217/whe.14.68ISSN 1745-5057.
  2. Jump up^ Chen C, Wu D, Guo Z, Xie Q, Reinhart GJ, Madan A, Wen J, Chen T, Huang CQ, Chen M, Chen Y, Tucci FC, Rowbottom M, Pontillo J, Zhu YF, Wade W, Saunders J, Bozigian H, Struthers RS (2008). “Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor”. J. Med. Chem51 (23): 7478–85. doi:10.1021/jm8006454PMID 19006286.
  3. Jump up^ Thomas L. Lemke; David A. Williams (24 January 2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1411–. ISBN 978-1-60913-345-0.
  4. Jump up to:a b AdisInsight: Elagolix.
  5. Jump up to:a b c d Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (2009). “Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix”J. Clin. Endocrinol. Metab94 (2): 545–51. doi:10.1210/jc.2008-1695PMC 2646513Freely accessiblePMID 19033369.
  6. Jump up^ Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study”. Reprod Sci21 (3): 363–71. doi:10.1177/1933719113497292PMID 23885105.
  7. Jump up^ Carr B, Dmowski WP, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density”Reprod Sci21 (11): 1341–51. doi:10.1177/1933719114549848PMC 4212335Freely accessiblePMID 25249568.

External links

Citing Patent Filing date Publication date Applicant Title
WO2014143669A1 Mar 14, 2014 Sep 18, 2014 AbbVie Inc . Compositions for use in treating heavy menstrual bleeding and uterine fibroids
EP2881391A1 Dec 5, 2013 Jun 10, 2015 Bayer Pharma Aktiengesellschaft Spiroindoline carbocycle derivatives and pharmaceutical compositions thereof
US8084614 Apr 4, 2008 Dec 27, 2011 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8263588 Apr 4, 2008 Sep 11, 2012 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8481738 Nov 10, 2011 Jul 9, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8507536 Aug 10, 2012 Aug 13, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8952161 Jun 5, 2013 Feb 10, 2015 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US9034850 Nov 19, 2010 May 19, 2015 Sk Chemicals Co., Ltd. Gonadotropin releasing hormone receptor antagonist, preparation method thereof and pharmaceutical composition comprising the same
US9422310 Jan 8, 2015 Aug 23, 2016 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
Patent ID

Patent Title

Submitted Date

Granted Date

US9382214 Processes for the preparation of uracil derivatives
2014-06-19
2016-07-05
US2014288031 METHODS OF TREATING HEAVY MENSTRUAL BLEEDING
2014-03-14
2014-09-25
Patent ID

Patent Title

Submitted Date

Granted Date

US2010190692 METHODS FOR REDUCING GNRH-POSITIVE TUMOR CELL PROLIFERATION
2010-02-05
2010-07-29
US8273716 USE OF LHRH ANTAGONISTS FOR INTERMITTENT TREATMENTS
2009-09-03
US8765948 PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES
2011-04-28
US2010092463 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
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US2010061976 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
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US9701647 Tetrazolones as a carboxylic acid bioisosteres
2016-08-10
2017-07-11
US9439888 Tetrazolones as a carboxylic acid bioisosteres
2016-01-25
2016-09-13
US7419983 Gonadotropin-releasing hormone receptor antagonists and methods related thereto
2007-08-16
2008-09-02
US7176211 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
2006-06-08
2007-02-13
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2005-02-17
2006-06-06
Elagolix
Elagolix.svg
Clinical data
Synonyms NBI-56418; ABT-620
Routes of
administration
By mouth
Drug class GnRH analogueGnRH antagonistantigonadotropin
Pharmacokinetic data
Biological half-life 2.4–6.3 hours[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C32H30F5N3O5
Molar mass 631.590 g/mol
3D model (JSmol)

///////////////ELAGOLIX, NBI 56418, UNII:5B2546MB5Z, ABT 620, priority review status, PHASE 3, AbbVie, Neurocrine Biosciences, Endometriosis

CC1=C(C(=O)N(C(=O)N1CC2=C(C=CC=C2F)C(F)(F)F)CC(C3=CC=CC=C3)NCCCC(=O)O)C4=C(C(=CC=C4)OC)F

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Ombitasvir オムビタスビル水和物 For Hepatitis C (HCV)


STR1

Ombitasvir Hydrate, 1456607-70-7

Ombitasvir.svg

Ombitasvir 1258226-87-7

Ombitasvir; ABT-267; ABT 267; UNII-2302768XJ8; 1258226-87-7;

C50H67N7O8
Molecular Weight: 894.10908 g/mol

Anti-Viral Compounds [US2010317568]

Methyl ((R)-1-((S)-2-((4-((2S,5S)-1-(4-(tert-butyl)phenyl)-5-(4-((R)-1-((methoxycarbonyl)-L-valyl)pyrrolidine-2-carboxamido)phenyl)pyrrolidin-2-yl)phenyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate,

Dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate, 

methyl N-[(2S)-1-[(2S)-2-[[4-[(2S,5S)-1-(4-tert-butylphenyl)-5-[4-[[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

オムビタスビル水和物
Ombitasvir Hydrate

C50H67N7O8.4 1/2H2O : 975.18
[1456607-70-7]

Abbvie Inc.  innovator

Phase II clinical development at AbbVie (previously Abbott) for the treatment of chronic hepatitis C infection in combination with ABT-450/ritonavir and, in combination with peginterferon alpha-2a/ribavirin (pegIFN/RBV) in treatment naïve Hepatitis C virus (HCV) genotype 1 infected patients.

Ombitasvir is Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2diyl]})biscarbamate hydrate. The molecular formula is C50H67N7O8•4.5H2O (hydrate) and the molecular weight for the drug substance is 975.20 (hydrate).

Ombitasvir is in phase II clinical development at AbbVie (previously Abbott) for the treatment of chronic hepatitis C infection in combination with ABT-450/ritonavir and, in combination with peginterferon alpha-2a/ribavirin (pegIFN/RBV) in treatment naïve Hepatitis C virus (HCV) genotype 1 infected patients.

Ombitasvir is part of a fixed-dose formulation with ABT-450/ritonavir that is approved in the U.S. and the E.U.

In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie. In 2013, breakthrough therapy designation was assigned in the U.S. for the treatment of genotype 1 hepatitis C in combination with ABT-450, ritonavir and ABT-333, with and without ribavirin.

Ombitasvir (Viekira PakTM) (Technivie)

Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection. In the United States, it is approved by theFood and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1,[1][2] and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.[3][4]

Ombitasvir acts by inhibiting the HCV protein NS5A.[5]

Ombitasvir is an orally available inhibitor of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) replication complex, with potential activity against HCV. Upon oral administration and after intracellular uptake, ombitasvir binds to and blocks the activity of the NS5A protein. This results in the disruption of the viral RNA replication complex, blockage of HCV RNA production, and inhibition of viral replication. NS5A, a zinc-binding and proline-rich hydrophilic phosphoprotein, plays a crucial role in HCV RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family; HCV infection is associated with the development of hepatocellular carcinoma (HCC).

Ombitasvir.png
Ombitasvir hydrate is a NS5A non-nucleoside polymerase inhibitor which is approved as part of a four drug combination for the
treatment of adults with genotype 1 hepatitis C virus infection including those with compensated cirrhosis.REF 6,7

The four drug combination treatment consists of ombitasvir, paritaprevir (XXVII), ritonavir, and dasabuvir (X). This combination treatment is marketed as Viekira PakTM and was developed by Abbvie as an all oral treatment that eliminates the need for pegylated interferon-a injections.

The synthesis of ombitasvir hydrate is shown in Scheme 34.REF 8   Alkylation of 1-(4-nitrophenyl)ethanone (209)
with 2-bromo-1-(4-nitrophenyl)ethanone (208) in the presence of zinc chloride produced diketone 210 in 61% yield.

Asymmetric reduction of the diketone using N,N-diethylaniline borane with (S)-()-a,a-diphenyl-2-pyrrolidinemethanol (211) and trimethoxyborate gave diol 212 in 61% yield and 99.3% ee.

The diol was then treated with methanesulfonic anhydride to generate the corresponding bis-mesylate which was reacted with 4-tert-butylaniline to give pyrrolidine 213 in 51% yield over the two steps.

Hydrogenolysis of the nitro groups was accomplished using Raney nickel catalyst to give bis-aniline 214.

Separately, (L)-valine (216,Scheme 35) was reacted with methyl chloroformate to give the corresponding methyl carbamate in 90% yield which was coupled to L-proline benzyl ester in the presence of EDC and HOBt to give the corresponding dipeptide in 90% yield.

Hydrogenolysis of the benzyl ester group of the protected dipeptide using Pd/alumina catalyst produced dipeptide acid 215. Aniline 214 was treated with two equivalents of acid 215 in the presence of 1-propanephosphonic acid cyclic anhydride (T3P). The crude product was recrystallized from ethanol and heptane to give ombitasvir hydrate (XXV). No yields were provided to the final steps of this synthesis.

STR1

STR1

6 Gamal, N.; Andreone, P. Drugs Today (Barc) 2015, 51, 303.

7. DeGoey, D. A.; Randolph, J. T.; Liu, D.; Pratt, J.; Hutchins, C.; Donner, P.;Krueger, A. C.; Matulenko, M.; Patel, S.; Motter, C. E.; Nelson, L.; Keddy, R.;Tufano, M.; Caspi, D. D.; Krishnan, P.; Mistry, N.; Koev, G.; Reisch, T. J.;Mondal, R.; Pilot-Matias, T.; Gao, Y.; Beno, D. W.; Maring, C. J.; Molla, A.;Dumas, E.; Campbell, A.; Williams, L.; Collins, C.; Wagner, R.; Kati, W. M. J.
Med. Chem. 2014, 57, 2047.
8. DeGoey, D. A.; Kati, W. M.; Hutchins, C. W.; Donner, P. L.; Krueger, A. C.;Randolph, J. T.; Motter, C. E.; Nelson, L. T.; Patel, S. V.; Matulenko, M. A.;Keddy, R. G.; Jinkerson, T. K.; Soltwedel, T. N.; Liu, D.; Pratt, J. K.; Rockway, T.W.; Maring, C. J.; Hutchinson, D. K.; Flentge, C. A.; Wagner, R.; Tufano, M. D.;Betebenner, D. A.; Lavin, M. J.; Sarris, K.; Woller, K. R.; Wagaw, S. H.; Califano,
J. C.; Li, W.; Caspi, D. D.; Bellizzi, M. E. US Patent 2010317568A1, 2010.

CLIP

STR1

DeGoey, DA, Discovery of ABT-267, a Pan-genotypic Inhibitor of HCV NS5A,  J. Med. Chem., 2014, 57 (5), pp 2047-2057

 http://pubs.acs.org/doi/full/10.1021/jm401398x

Abstract Image

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5Ranalogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7–19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.

Dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (38)…desired and Dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (39)…….undesired

…………….. The resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous NaHCO3, brine (2×) and dried with Na2SO4. The drying agent was filtered off and the solution was concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel, eluting with a solvent gradient of 2–8% methanol in dichloromethane to give a 1:1 mixture of trans-pyrrolidine isomers (290 mg, 96%). The mixture was separated on a Chiralpak AD-H column, eluting with a mixture of 1 part (2:1 isopropanol/ethanol) and 2 parts hexanes (0.1% TFA).

Compound 38 was the first of two stereoisomers to elute (101 mg, 99% ee by chiral HPLC). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (d, J = 6.61 Hz, 6H), 0.93 (d, J = 6.72 Hz, 6H), 1.11 (s, 9H), 1.63 (d, J = 5.42 Hz, 2H), 1.80–2.04 (m, 8H), 2.09–2.19 (m, 2H), 2.44–2.47 (m, 2H), 3.52 (s, 6H), 3.59–3.66 (m, 2H), 3.77–3.84 (m, 2H), 4.02 (t, J = 8.40 Hz, 2H), 4.42 (dd, J = 7.86, 4.83 Hz, 2H), 5.14 (d, J = 6.18 Hz, 2H), 6.17 (d, J = 8.67 Hz, 2H), 6.94 (d, J = 8.78 Hz, 2H), 7.13 (d, J = 8.46 Hz, 4H), 7.31 (d, J= 8.35 Hz, 2H), 7.50 (d, J = 8.35 Hz, 4H), 9.98 (s, 2H).

MS (ESI) m/z 894.9 (M + H)+.

Compound39 was the second of two stereoisomers to elute. 1H NMR (400 MHz, DMSO-d6) δ 0.87 (d, J = 6.51 Hz, 6H), 0.92 (d, J = 6.72 Hz, 6H), 1.11 (s, 9H), 1.63 (d, J = 5.53 Hz, 2H), 1.82–2.04 (m, 8H), 2.09–2.18 (m, 2H), 2.41–2.47 (m, 2H), 3.52 (s, 6H), 3.58–3.67 (m, 2H), 3.75–3.84 (m, 2H), 4.02 (t, J = 7.26 Hz, 2H), 4.43 (dd, J = 7.92, 4.88 Hz, 2H), 5.14 (d, J = 6.18 Hz, 2H), 6.17 (d, J = 8.78 Hz, 2H), 6.94 (d, J = 8.67 Hz, 2H), 7.12 (d, J = 8.46 Hz, 4H), 7.31 (d, J = 8.35 Hz, 2H), 7.49 (d, J = 8.46 Hz, 4H), 9.98 (s, 2H). MS (ESI) m/z 895.0 (M + H)+.

PATENT

WO 2011156578

dimethyl (2S,2,S)-l,l ‘-((2S,2’S)-2,2′-(4,4’-((2S,5S)-l-(4-fert-butylphenyl)pyrrolidine- 2,5-diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3- methyl- l-oxobutane-2,l-diyl)dicarbamate

Figure imgf000003_0001

PATENT

US 20100317568

Example 34

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000133_0002

Example 34A l-(4-fer?-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50 °C for 4 h. The resulting mixture was diluted into ethyl acetate, treated with IM HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1 :9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).

Example 34B 4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline and 4,4′-((2R,5R)-1-(4-fert- butylphenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product from Example 34A (1.1 g, 2.47 mmol) in ethanol (20 ml) and

THF (20 ml) was added PtC>2 (0.22 g, 0.97 mmol) in a 50 ml pressure bottle and stirred under 30 psi hydrogen at room temperature for 1 h. The mixture was filtered through a nylon membrane and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (20% to 60%). The title compound eluted as the first of 2 stereoisomers (trans isomer, 0.51 g, 54%).

Example 34C

(2S,2’S)-tert-Butyl 2,2′-(4,4′-((2S,5S)-1-(4-fer/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- 1 -carboxylate and (2S,2’S)-tert-Butyl 2,2′- (4,4′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate To a mixture of the product from Example 34B (250 mg, 0.648 mmol), (S)-1-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (307 mg, 1.427 mmol) and HATU (542 mg, 1.427 mmol) in DMSO (10 ml) was added Hunig’s base (0.453 ml, 2.59 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (10% to 50%) to give the title compound (500 mg, 99%).

Example 34D

(2S,2’S)-N,N’-(4,4′-((2S,5S)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))dipyrrolidine-2-carboxamide and (2S,2’S)-N,N’-(4,4′-((2R,5R)-1-(4-tert- butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide To the product from Example 34C (498 mg, 0.638 mmol) in dichloromethane (4 ml) was added TFA (6 ml). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was partitioned between 3: 1 CHCl3dsopropyl alcohol and saturated aq. NaHCO3. The aqueous layer was extracted by 3: 1 CHCl3:isopropyl alcohol again. The combined organic layers were dried over

Figure imgf000135_0001

filtered and concentrated to give the title compound (345 mg, 93%).

Example 34E Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

The product from Example 34D (29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3- methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg,

0.110 mmol) and N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2 ml). The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the title compound (13 mg, 29%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.85 – 0.95 (m, 12 H) 1.11 (s, 9 H) 1.59 – 1.65 (m, 2 H) 1.79 – 2.04 (m, 8 H) 2.10 – 2.18 (m, 2 H) 2.41-2.46 (m, 2H) 3.52 (s, 6 H)

3.57 – 3.67 (m, 2 H) 3.76 – 3.86 (m, 2 H) 4.00 (t, J=7.56 Hz, 2 H) 4.39 – 4.46 (m, 2 H) 5.15 (d, J=7.00

Hz, 2 H) 6.17 (d, J=7.70 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20

Hz, 2 H) 7.50 (d, J=8.24 Hz, 4 H) 9.98 (s, 2 H); (ESI+) m/z 895 (M+H)+. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 35

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000135_0002………………desired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the first of the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV Ib- Conl replicon assays in the presence of 5% FBS.

Example 36 Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000136_0001…….undesired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the second of 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.87

(d, J=6.51 Hz, 6 H) 0.92 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.53 Hz, 2 H) 1.82 – 2.04 (m, 8

H) 2.09-2.18 (m, 2 H) 2.41 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.58 – 3.67 (m, 2 H) 3.75 – 3.84 (m, 2 H) 4.02

(t, J=7.26 Hz, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H) 6.94 (d, J=8.67 Hz, 2 H) 7.12 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.49 (d, J=8.46 Hz, 4 H)

9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 37 Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000136_0002……………desired

Example 37A (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5 °C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5 °C for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50 °C to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3 x 20 ml) and dried to give the title compound as a white solid (23.2 g, 77% yield).

Example 37B

(S)- 1 -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of the product from Example 37A (1Og, 36.7 mmol) in acetonitrile (20 inL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HCl (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25% NaCl (2 x 10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give the title compound (10.67g) as a white solid.

The compound of Example 37B can also be prepreared according to the following procedure: To a flask was charged L- valine (35 g, 299 mmol), IN sodium hydroxide solution (526 ml,

526 mmol) and sodium carbonate (17.42 g, 164 mmol). The mixture was stirred for 15 min to dissolve solids and then cooled to 15 °C. Methyl chloroformate (29.6 g, 314 mmol) was added slowly to the reaction mixture. The mixture was then stirred at rt for 30 min. The mixture was cooled to 15 °C and pH adjusted to -5.0 with concentrated HCl solution. 100 inL of 2-methytetrahydrofuran (2- MeTHF) was added and the adjustment of pH continued until the pH reached ~ 2.0. 150 mL of 2- MeTHF was added and the mixture was stirred for 15 min. Layers were separated and the aqueous layer extracted with 100 mL of 2-MeTHF. The combined organic layer was dried over anhyd Na2SC^ and filtered, and Na2SC^ cake was washed with 50 mL of 2-MeTHF. The product solution was concentrated to ~ 100 mL, chased with 120 mL of IPAc twice. 250 mL of heptanes was charged slowly and then the volume of the mixture was concentrated to 300 mL. The mixture was heated to 45 °C and 160 mL of heptanes charged. The mixture was cooled to rt in 2h, stirred for 30 min, filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 inL). The wetcake was dried at 55 °C for 24 h to give 47.1 g of Moc-L- VaI-OH product as a white solid (90%).

Moc-L- VaI-OH (15O g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 ml) were charged to a flask. The mixture was stirred for 15 min to give a clear solution. EDC hydrochloride (172 g, 899 mmol) was charged and mixed for 20 min. The mixture was cooled to 13

°C and (L)-proline benzyl ester hydrochloride (207 g, 856 mmol) charged. Triethylamine (109 g,

1079 mmol) was then charged in 30 min. The resulting suspension was mixed at rt for 1.5 h. The reaction mixture was cooled to 15 °C and 1500 mL of 6.7% NaHCO3 charged in 1.5 h, followed by the addition of 1200 mL of water over 60 min. The mixture was stirred at rt for 30 min, filtered and washed with water/DMF mixture (1 :2, 250 mL) and then with water (1500 mL). The wetcake was dried at 55 °C for 24 h to give 282 g of product as a white solid (90%).

The resulting solids (40 g) and 5% Pd/ Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6 x 20 psig) followed by a hydrogen purge (6 x 30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane was added (120 mL), and the solution was stirred until solids formed. After an addition 2 – 3 hours additional heptane was added drop-wise (240 mL), the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound.

Example 37C

(lR,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate

The product from Example 32 (5.01 g, 13.39 mmol) was combined with 2- methyltetrahydrofuran (70 mL) and cooled to -5 °C, and N,N-diisopropylethylamine (6.81 g, 52.7 mmol) was added over 30 seconds. Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5 mmol) in 2-methyltetrahydrofuran (30 mL) was prepared and added to the diol slurry over 3 min., maintaining the internal temperature between -15 °C and -25 °C. After mixing for 5 min at -15 °C, the cooling bath was removed and the reaction was allowed to warm slowly to 23 °C and mixed for 30 minutes. After reaction completion, the crude slurry was carried immediately into the next step.

Example 37D

(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine

To the crude product solution from Example 37C (7.35 g, 13.39 mmol) was added 4-tert- butylaniline (13.4 g, 90 mmol) at 23 °C over 1 minute. The reaction was heated to 65 °C for 2 h. After completion, the reaction mixture was cooled to 23 °C and diluted with 2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). After partitioning the phases, the organic phase was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt% aq. NaCl (100 mL), and the phases were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mL), dried over MgSO/t, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2- methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2- methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45 °C in a vacuum oven for 16 h to provide the title compound (3.08 g, 51% 2-step yield).

Example 37E

4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline

To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt% (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8 x 20 psig) followed by purging with hydrogen (8 x 30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title compound, which was dried and used directly in the next step.

Example 37F dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, l- phenylene)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diy 1) die arb amate To a solution of the product from Example 37E (1.64 g, 4.25 mmol) in DMF (20 ml), the product from Example 37B (2.89 g, 10.63 mmol), and HATU (4.04 g, 10.63 mmol) in DMF (15OmL) was added triethylamine (1.07 g, 10.63 mmol), and the solution was stirred at room temperature for 90 min. To the reaction mixture was poured 20 mL of water, and the white precipitate obtained was filtered, and the solid was washed with water (3×5 mL). The solid was blow dried for Ih. The crude material was loaded on a silica gel column and eluted with a gradient starting with ethyl acetate/ heptane (3/7), and ending with pure ethyl acetate. The desired fractions were combined and solvent distilled off to give a very light yellow solid, which was dried at 45 °C in a vacuum oven with nitrogen purge for 15 h to give the title compound (2.3 g, 61% yield). 1H NMR (400 MHz, DMSO- D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H).

Alternately, the product from example 37E (11.7 g, 85 wt%, 25.8 mmol) and the product from example 37B (15.45 g, 56.7 mmol) are suspended in EtOAc (117 mL), diisopropylethylamine (18.67 g, 144 mmol) is added and the solution is cooled to 0 °C. In a separate flask, 1-propanephosphonic acid cyclic anhydride (T3P®) (46.0 g, 50 wt% in EtOAc, 72.2 mmol) was dissolved in EtOAc (58.5 mL), and charged to an addition funnel. The T3P solution is added to the reaction mixture drop-wise over 3-4 h and stirred until the reaction is complete. The reaction is warmed to room temperature,and washed with IM HCl/7.5 wt% NaCl (100 mL), then washed with 5% NaHCO3 (100 mL), then washed with 5% NaCl solution (100 mL). The solution was concentrated to approximately 60 mL, EtOH (300 mL) was added, and the solution was concentrated to 84 g solution.

A portion of the EtOH solution of product (29 g) was heated to 40 °C, and added 134 g 40 w% EtOH in H2O. A slurry of seeds in 58 wt/wt% EtOH/H2O was added, allowed to stir at 40 °C for several hours, then cooled to 0 °C. The slurry is then filtered, and washed with 58wt/wt% EtOH/H2O. The product is dried at 40 – 60 °C under vacuum, and then rehydrated by placing a tray of water in the vacuum oven to give the title compound. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

PATENT

Example 34

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000133_0002

Example 34A l-(4-fer?-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50 °C for 4 h. The resulting mixture was diluted into ethyl acetate, treated with IM HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1 :9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).

Example 34B 4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline and 4,4′-((2R,5R)-1-(4-fert- butylphenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product from Example 34A (1.1 g, 2.47 mmol) in ethanol (20 ml) and

THF (20 ml) was added PtC>2 (0.22 g, 0.97 mmol) in a 50 ml pressure bottle and stirred under 30 psi hydrogen at room temperature for 1 h. The mixture was filtered through a nylon membrane and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (20% to 60%). The title compound eluted as the first of 2 stereoisomers (trans isomer, 0.51 g, 54%).

Example 34C

(2S,2’S)-tert-Butyl 2,2′-(4,4′-((2S,5S)-1-(4-fer/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- 1 -carboxylate and (2S,2’S)-tert-Butyl 2,2′- (4,4′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate To a mixture of the product from Example 34B (250 mg, 0.648 mmol), (S)-1-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (307 mg, 1.427 mmol) and HATU (542 mg, 1.427 mmol) in DMSO (10 ml) was added Hunig’s base (0.453 ml, 2.59 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (10% to 50%) to give the title compound (500 mg, 99%).

Example 34D

(2S,2’S)-N,N’-(4,4′-((2S,5S)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))dipyrrolidine-2-carboxamide and (2S,2’S)-N,N’-(4,4′-((2R,5R)-1-(4-tert- butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide To the product from Example 34C (498 mg, 0.638 mmol) in dichloromethane (4 ml) was added TFA (6 ml). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was partitioned between 3: 1 CHCl3dsopropyl alcohol and saturated aq. NaHCO3. The aqueous layer was extracted by 3: 1 CHCl3:isopropyl alcohol again. The combined organic layers were dried over

Figure imgf000135_0001

filtered and concentrated to give the title compound (345 mg, 93%).

Example 34E Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

The product from Example 34D (29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3- methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg,

0.110 mmol) and N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2 ml). The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the title compound (13 mg, 29%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.85 – 0.95 (m, 12 H) 1.11 (s, 9 H) 1.59 – 1.65 (m, 2 H) 1.79 – 2.04 (m, 8 H) 2.10 – 2.18 (m, 2 H) 2.41-2.46 (m, 2H) 3.52 (s, 6 H)

3.57 – 3.67 (m, 2 H) 3.76 – 3.86 (m, 2 H) 4.00 (t, J=7.56 Hz, 2 H) 4.39 – 4.46 (m, 2 H) 5.15 (d, J=7.00

Hz, 2 H) 6.17 (d, J=7.70 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20

Hz, 2 H) 7.50 (d, J=8.24 Hz, 4 H) 9.98 (s, 2 H); (ESI+) m/z 895 (M+H)+. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 35

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000135_0002………….desired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the first of the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV Ib- Conl replicon assays in the presence of 5% FBS.

Example 36 Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000136_0001……….undesired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the second of 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.87

(d, J=6.51 Hz, 6 H) 0.92 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.53 Hz, 2 H) 1.82 – 2.04 (m, 8

H) 2.09-2.18 (m, 2 H) 2.41 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.58 – 3.67 (m, 2 H) 3.75 – 3.84 (m, 2 H) 4.02

(t, J=7.26 Hz, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H) 6.94 (d, J=8.67 Hz, 2 H) 7.12 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.49 (d, J=8.46 Hz, 4 H)

9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 37 Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000136_0002………………desired

Example 37A (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5 °C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5 °C for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50 °C to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3 x 20 ml) and dried to give the title compound as a white solid (23.2 g, 77% yield).

Example 37B

(S)- 1 -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of the product from Example 37A (1Og, 36.7 mmol) in acetonitrile (20 inL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HCl (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25% NaCl (2 x 10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give the title compound (10.67g) as a white solid.

The compound of Example 37B can also be prepreared according to the following procedure: To a flask was charged L- valine (35 g, 299 mmol), IN sodium hydroxide solution (526 ml,

526 mmol) and sodium carbonate (17.42 g, 164 mmol). The mixture was stirred for 15 min to dissolve solids and then cooled to 15 °C. Methyl chloroformate (29.6 g, 314 mmol) was added slowly to the reaction mixture. The mixture was then stirred at rt for 30 min. The mixture was cooled to 15 °C and pH adjusted to -5.0 with concentrated HCl solution. 100 inL of 2-methytetrahydrofuran (2- MeTHF) was added and the adjustment of pH continued until the pH reached ~ 2.0. 150 mL of 2- MeTHF was added and the mixture was stirred for 15 min. Layers were separated and the aqueous layer extracted with 100 mL of 2-MeTHF. The combined organic layer was dried over anhyd Na2SC^ and filtered, and Na2SC^ cake was washed with 50 mL of 2-MeTHF. The product solution was concentrated to ~ 100 mL, chased with 120 mL of IPAc twice. 250 mL of heptanes was charged slowly and then the volume of the mixture was concentrated to 300 mL. The mixture was heated to 45 °C and 160 mL of heptanes charged. The mixture was cooled to rt in 2h, stirred for 30 min, filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 inL). The wetcake was dried at 55 °C for 24 h to give 47.1 g of Moc-L- VaI-OH product as a white solid (90%).

Moc-L- VaI-OH (15O g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 ml) were charged to a flask. The mixture was stirred for 15 min to give a clear solution. EDC hydrochloride (172 g, 899 mmol) was charged and mixed for 20 min. The mixture was cooled to 13

°C and (L)-proline benzyl ester hydrochloride (207 g, 856 mmol) charged. Triethylamine (109 g,

1079 mmol) was then charged in 30 min. The resulting suspension was mixed at rt for 1.5 h. The reaction mixture was cooled to 15 °C and 1500 mL of 6.7% NaHCO3 charged in 1.5 h, followed by the addition of 1200 mL of water over 60 min. The mixture was stirred at rt for 30 min, filtered and washed with water/DMF mixture (1 :2, 250 mL) and then with water (1500 mL). The wetcake was dried at 55 °C for 24 h to give 282 g of product as a white solid (90%).

The resulting solids (40 g) and 5% Pd/ Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6 x 20 psig) followed by a hydrogen purge (6 x 30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane was added (120 mL), and the solution was stirred until solids formed. After an addition 2 – 3 hours additional heptane was added drop-wise (240 mL), the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound.

Example 37C

(lR,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate

The product from Example 32 (5.01 g, 13.39 mmol) was combined with 2- methyltetrahydrofuran (70 mL) and cooled to -5 °C, and N,N-diisopropylethylamine (6.81 g, 52.7 mmol) was added over 30 seconds. Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5 mmol) in 2-methyltetrahydrofuran (30 mL) was prepared and added to the diol slurry over 3 min., maintaining the internal temperature between -15 °C and -25 °C. After mixing for 5 min at -15 °C, the cooling bath was removed and the reaction was allowed to warm slowly to 23 °C and mixed for 30 minutes. After reaction completion, the crude slurry was carried immediately into the next step.

Example 37D

(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine

To the crude product solution from Example 37C (7.35 g, 13.39 mmol) was added 4-tert- butylaniline (13.4 g, 90 mmol) at 23 °C over 1 minute. The reaction was heated to 65 °C for 2 h. After completion, the reaction mixture was cooled to 23 °C and diluted with 2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). After partitioning the phases, the organic phase was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt% aq. NaCl (100 mL), and the phases were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mL), dried over MgSO/t, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2- methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2- methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45 °C in a vacuum oven for 16 h to provide the title compound (3.08 g, 51% 2-step yield).

Example 37E

4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline

To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt% (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8 x 20 psig) followed by purging with hydrogen (8 x 30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title compound, which was dried and used directly in the next step.

Example 37F dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, l- phenylene)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diy 1) die arb amate To a solution of the product from Example 37E (1.64 g, 4.25 mmol) in DMF (20 ml), the product from Example 37B (2.89 g, 10.63 mmol), and HATU (4.04 g, 10.63 mmol) in DMF (15OmL) was added triethylamine (1.07 g, 10.63 mmol), and the solution was stirred at room temperature for 90 min. To the reaction mixture was poured 20 mL of water, and the white precipitate obtained was filtered, and the solid was washed with water (3×5 mL). The solid was blow dried for Ih. The crude material was loaded on a silica gel column and eluted with a gradient starting with ethyl acetate/ heptane (3/7), and ending with pure ethyl acetate. The desired fractions were combined and solvent distilled off to give a very light yellow solid, which was dried at 45 °C in a vacuum oven with nitrogen purge for 15 h to give the title compound (2.3 g, 61% yield). 1H NMR (400 MHz, DMSO- D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H).

Alternately, the product from example 37E (11.7 g, 85 wt%, 25.8 mmol) and the product from example 37B (15.45 g, 56.7 mmol) are suspended in EtOAc (117 mL), diisopropylethylamine (18.67 g, 144 mmol) is added and the solution is cooled to 0 °C. In a separate flask, 1-propanephosphonic acid cyclic anhydride (T3P®) (46.0 g, 50 wt% in EtOAc, 72.2 mmol) was dissolved in EtOAc (58.5 mL), and charged to an addition funnel. The T3P solution is added to the reaction mixture drop-wise over 3-4 h and stirred until the reaction is complete. The reaction is warmed to room temperature,and washed with IM HCl/7.5 wt% NaCl (100 mL), then washed with 5% NaHCO3 (100 mL), then washed with 5% NaCl solution (100 mL). The solution was concentrated to approximately 60 mL, EtOH (300 mL) was added, and the solution was concentrated to 84 g solution.

A portion of the EtOH solution of product (29 g) was heated to 40 °C, and added 134 g 40 w% EtOH in H2O. A slurry of seeds in 58 wt/wt% EtOH/H2O was added, allowed to stir at 40 °C for several hours, then cooled to 0 °C. The slurry is then filtered, and washed with 58wt/wt% EtOH/H2O. The product is dried at 40 – 60 °C under vacuum, and then rehydrated by placing a tray of water in the vacuum oven to give the title compound. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Intermediates

Example 32

( 1 R,4R)- 1 ,4-bis(4-mtrophenyl)butane- 1 ,4-diol

Figure imgf000132_0002

To (S)-(-)-α,α-diphenyl-2-pyrrohdinemethanol (2 71 g, 10 70 mmol) was added THF (80 mL) at 23 °C The very thin suspension was treated with t11methyl borate (1 44 g, 13 86 mmol) over 30 seconds, and the resulting solution was mixed at 23 °C for 1 h The solution was cooled to 16-19 °C, and N,N-diethylanilme borane (21 45 g, 132 mmol) was added dropwise via syringe over 3-5 mm (caution vigorous H2 evolution), while the internal temperature was maintained at 16-19 °C After 15 mm, the H2 evolution had ceased To a separate vessel was added the product from Example IA (22 04 g, 95 wt%, 63 8 mmol), followed by THF (80 mL), to form an orange slurry After cooling the slurry to 11 °C, the borane solution was transferred via cannula into the dione slurry over 3-5 min During this period, the internal temperature of the slurry rose to 16 °C After the addition was complete, the reaction was maintained at 20-27 °C for an additional 2 5 h After reaction completion, the mixture was cooled to 5 °C and methanol (16 7 g, 521 mmol) was added dropwise over 5-10 mm, maintaining an internal temperature <20 °C (note vigorous H2 evolution) After the exotherm had ceased (ca 10 mm), the temperature was adjusted to 23 °C, and the reaction was mixed until complete dissolution of the solids had occurred Ethyl acetate (300 mL) and 1 M HCl (120 mL) were added, and the phases were partitioned The organic phase was then washed successively with 1 M HCl (2 x 120 mL), H2O (65 mL), and 10% aq NaCl (65 mL) The orgamcs were dried over MgSO4, filtered, and concentrated in vacuo Crystallization of the product occurred during the concentration The slurry was warmed to 50 °C, and heptane (250 inL) was added over 15 min. The slurry was then allowed to mix at 23 °C for 30 min and filtered. The wet cake was washed with 3: 1 heptane:ethyl acetate (75 mL), and the orange, crystalline solids were dried at 45 °C for 24 h to provide the title compound (15.35 g, 99.3% ee, 61% yield), which was contaminated with 11% of the meso isomer (vs. dl isomer).

References

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  2. “FDA approves Viekira Pak to treat hepatitis C”. Food and Drug Administration. December 19, 2014.
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  4. “FDA approves Technivie for treatment of chronic hepatitis C genotype 4”. Food and Drug Administration. July 24, 2015.
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Ombitasvir
Ombitasvir.svg
Systematic (IUPAC) name
Methyl ((R)-1-((S)-2-((4-((2S,5S)-1-(4-(tert-butyl)phenyl)-5-(4-((R)-1-((methoxycarbonyl)-L-valyl)pyrrolidine-2-carboxamido)phenyl)pyrrolidin-2-yl)phenyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
Clinical data
Trade names Viekira Pak (with ombitasvir, paritaprevir, ritonavir and dasabuvir), Technivie (with ombitasvir, paritaprevir, and ritonavir)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability not determined
Protein binding ~99.9%
Metabolism amide hydrolysis followed by oxidation
Onset of action ~4 to 5 hours
Biological half-life 21 to 25 hours
Excretion mostly with feces (90.2%)
Identifiers
CAS Number 1258226-87-7
PubChem CID 54767916
ChemSpider 31136214
ChEBI CHEBI:85183 Yes
Synonyms ABT-267
Chemical data
Formula C50H67N7O8
Molar mass 894.11 g/mol

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Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)

/////Ombitasvir Hydrate, 1456607-70-7, Ombitasvir,  1258226-87-7, Viekira PakTM, Technivie, ABT-267, ABT 267, UNII-2302768XJ8, オムビタスビル 水和物 , phase II,  clinical development ,  AbbVie, Abbott,  chronic hepatitis C infection,  combination with ABT-450/ritonavir,  peginterferon alpha-2a/ribavirin (pegIFN/RBV), naïve Hepatitis C virus (HCV) genotype 1 infected patients.

O=C(Nc1ccc(cc1)[C@@H]5CC[C@@H](c3ccc(NC(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)N5c4ccc(cc4)C(C)(C)C)[C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C

Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia


Figure imgf000008_0001

 

Duvelisib

Infinity and AbbVie partner to develop and commercialise duvelisib for cancer

INK 1197; IPI 145; 8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone

1(2H)-Isoquinolinone, 8-chloro-2-phenyl-3-((1S)-1-(9H-purin-6-ylamino)ethyl)-
8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one

 

(S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

UNII-610V23S0JI; IPI-145; INK-1197;

Originator…….. Millennium Pharmaceuticals

Molecular Formula C22H17ClN6O
Molecular Weight 416.86
CAS Registry Number 1201438-56-3

 
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer. 

 

Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K gamma, to treat patients with cancer.

Duvelisib has shown clinical activity against different blood cancers, such as indolent non-Hodgkin’s lymphoma (iNHL) and chronic lymphocytic leukemia (CLL).

AbbVie executive vice-president and chief scientific officer Michael Severino said: “We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers.”

http://www.pharmaceutical-technology.com/news/newsinfinity-abbvie-partner-develop-commercialise-duvelisib-cancer-4363381?WT.mc_id=DN_News 

 

Duvelisib (IPI-145,  INK-1197), an inhibitor of PI3K-delta and –gamma, originated at Takeda subsidiary Intellikine. It is now being developed by Infinity Pharmaceuticals, which began a phase III trial in November, following US and EU grant of orphan drug status for both CLL and small lymphocytic leukemia

INK-1197 is a dual phosphatidylinositol 3-Kinase delta (PI3Kdelta) and gamma (PI3Kgamma) inhibitor in phase III clinical development at Infinity Pharmaceuticals for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. The company is also carring phase II trials for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma) are currently under way.
IPI-145 is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma. The PI3K-delta and PI3K-gamma isoforms are preferentially expressed in leukocytes (white blood cells), where they have distinct and non-overlapping roles in key cellular functions, including cell proliferation, cell differentiation, cell migration and immunity. Targeting PI3K-delta and PI3K-gamma may provide multiple opportunities to develop differentiated therapies for the treatment of blood cancers and inflammatory diseases.
Licensee Infinity Pharmaceuticals is developing INK-1197. In 2014, Infinity licensed Abbvie for joint commercialization in the U.S. and exclusive commercialization elsewhere. Originator Millennium Pharmaceuticals had also been developing the compound; however, no recent development has been reported for this research. In 2013, orphan drug designations were assigned by the FDA and the EMA for the treatment of chronic lymphocytic leukemia, for the treatment of small lymphocytic lymphoma and for the treatment of follicular lymphoma.

currently enrolling patients DYNAMO™, a Phase 2 study designed to evaluate the activity and safety of IPI-145 in approximately 120 people with refractory indolent non-Hodgkin lymphoma (iNHL) and DUO™, a Phase 3 clinical study of IPI-145 in approximately 300 people with relapsed/refractory chronic lymphocytic leukemia (CLL). These studies are supported by Phase 1 data reported at the 2013 American Society of Hematology (ASH) Annual Meeting which showed that IPI-145 was well tolerated and clinically active in a broad range of malignancies, including iNHL and CLL. These studies are part of DUETTS™, a worldwide investigation of IPI-145 in blood cancers.

Chemical structure for Duvelisib

WO 2011008302

http://www.google.com/patents/WO2011008302A1?cl=en

Reaction Scheme 1

Reaction Scheme 2:

201 202 203

204 205

Reaction Scheme 3:

Reaction Scheme 4A:

Reaction Scheme 4B:

2

Example 14b: Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)

(compound 4904)

Scheme 27b. The synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)

(compound 4904) is described.

[00493] The compound of Formula 4904 (compound 292 in Table 4) was synthesized using the synthetic transformations as described in Examples 12 and 14a, but 2-chloro-6-methyl benzoic acid (compound 4903) was used instead of 2, 6 ,dimethyl benzoic acid (compound 4403). By a similar method, compound 328 in Table 4 was synthesized using the synthetic transformations as described starting from the 2-chloro-6-methyl m-fluorobenzoic acid.

 

…………………………………….

http://www.google.com/patents/WO2012097000A1?cl=en  OR   http://www.google.com/patents/US8809349?cl=en

Formula (I):

(I),

or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the method comprises any one, two, three, four, five, six, seven, or eight, or more of the following steps:

“Formula (I)” includes (S)-3-(l -(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one in its imide tautomer shown below as (1-1) and in its lactim tautomer shown below as (1-2):

(1-1)………………………………………………………………………………… (1-2)

[0055] FIG. 27 shows an FT-IR spectra of Polymorph Form C.

 

 

[0056] FIG. 28 shows a ‘H-NMR spectra of Polymorph Form C.

 

 

[0057] FIG. 29 shows a 13C-NMR spectra of Polymorph Form C.

 

Example 1

Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 1A

1 2

[00563] Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate (HOBt»H20), triethylamine, Ν,Ο-dimethylhydroxylamine hydrochloride, and EDCI in dimethylacetamide (DMA) at

10 °C. The reaction was monitored by proton NMR and deemed complete after 2.6 hours, affording Compound 2 as a white solid in 95% yield. The R-enantiomer was not detected by proton NMR using (R)-(- ) -alpha-ace tylmandelic acid as a chiral-shift reagent.

[00564] Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H- pyran (DHP) in ethyl acetate at 75 °C for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC) purity by HPLC analysis.

[00565] Compound 5 (3.30 kg) was treated with thionyl chloride and a catalytic amount of DMF in methylene chloride at 25 °C for five hours. The reaction was monitored by HPLC which indicated a 97.5% (AUC) conversion to compound 6. Compound 6 was treated in situ with aniline in methylene chloride at 25 °C for 15 hours. The reaction was monitored by HPLC and afforded Compound 7 as a brown solid in 81% yield with >99% (AUC) purity by HPLC analysis. [00566] Compound 2 was treated with 2.0 M isopropyl Grignard in THF at -20 °C. The resulting solution was added to Compound 7 (3.30 kg) pre -treated with 2.3 M n-hexyl lithium in tetrahydrofuran at -15 °C. The reaction was monitored by HPLC until a 99% (AUC) conversion to Compound 8 was observed.

Compound 8 was treated in situ with concentrated HC1 in isopropyl alcohol at 70 °C for eight hours. The reaction was monitored by HPLC and afforded Compound 9 as a brown solid in 85% yield with 98% (AUC) purity and 84% (AUC) ee by HPLC analysis.

Example ID

[00567] Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55 °C for 1-2 hours. The batch was filtered and treated with ammonium hydroxide in deionized (DI) water to afford enantiomerically enriched Compound 9 as a tan solid in 71% yield with >99% (AUC) purity and 91% (AUC) ee by HPLC analysis.

Example 2

Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 2A

[00568] To Compound 7 (20.1 g) was charged 100 mL of anhydrous THF. The resulting solution was cooled to about -10 °C and 80 mL of n-hexyl lithium (2.3 M in hexanes, 2.26 equiv.) was slowly added (e.g. , over about 20 min). The resulting solution was stirred at about -10 °C for about 20 min.

[00569] To Compound 2 (26.5 g; 1.39 equiv.) was charged 120 mL of anhydrous THF. The resulting mixture was cooled to about -10 °C and 60 mL of isopropyl magnesium chloride (2.0 M in THF, 1.47 equiv.) was slowly added (e.g. , over about 15-20 min). The resulting mixture was then stirred at about -10 °C for about 20 min. The mixture prepared from Compound 2 was added to the solution prepared from Compound 7 while maintaining the internal temperature between about -10 and about 0 °C. After the addition was complete (about 5 min), the cold bath was removed, and the resulting mixture was stirred at ambient temperature for about 1 h, then cooled. [00570] A solution of 100 mL of anisole and 33 mL of isobutyric acid (4.37 equiv.) was prepared. The anisole solution was cooled to an internal temperature of about -3 °C. The above reaction mixture was added to the anisole solution such that the internal temperature of the anisole solution was maintained at below about 5 °C. The ice bath was then removed (after about 15 min, the internal temperature was about 7 °C). To the mixture, 100 mL of 10 wt aqueous NaCl solution was rapidly added (the internal temperature increased from about 7 °C to about 15 °C). After stirring for about 30 min, the two phases were separated. The organic phase was washed with another 100 mL of 10 wt aqueous NaCl. The organic phase was transferred to a flask using 25 mL of anisole to facilitate the transfer. The anisole solution was then concentrated to 109 g. Then, 100 mL of anisole was added.

[00571] To the approximately 200 mL of anisole solution was added 50 mL of TFA (8 equiv.) while maintaining the internal temperature below about 45-50 °C. The resulting solution warmed to about 45-50 °C and stirred for about 15 hrs, then cooled to 20-25 °C. To this solution was added 300 mL of MTBE dropwise and then the resulting mixture was held at 20-25 °C for 1 h. The mixture was filtered, and the wet cake washed with approximately 50 mL of MTBE. The wet cake was conditioned on the filter for about 1 h under nitrogen. The wet cake was periodically mixed and re-smoothed during conditioning. The wet cake was then washed with 200 mL of MTBE. The wet cake was further conditioned for about 2 h (the wet cake was mixed and resmoothed after about 1.5 h). The wet cake was dried in a vacuum oven at about 40 °C for about 18 h to afford Compound 9»TFA salt in about 97.3% purity (AUC), which had about 99.1 % S- enantiomer (e.g. , chiral purity of about 99.1 %).

[00572] Compound 9»TFA salt (3 g) was suspended in 30 mL of EtOAc at about 20 °C. To the EtOAc suspension was added 4.5 mL (2.2 eq.) of a 14% aqueous ammonium hydroxide solution and the internal temperature decreased to about 17 °C. Water (5 mL) was added to the biphasic mixture. The biphasic mixture was stirred for 30 min. The mixing was stopped and the phases were allowed to separate. The aqueous phase was removed. To the organic phase (combined with 5 mL of EtOAc) was added 10 mL of 10% aqueous NaCl. The biphasic mixture was stirred for about 30 min. The aqueous phase was removed. The organic layer was concentrated to 9 g. To this EtOAc mixture was added 20 mL of i-PrOAc. The resulting mixture was concentrated to 14.8 g. With stirring, 10 mL of n-heptane was added dropwise. The suspension was stirred for about 30 min, then an additional 10 mL of n-heptane was added. The resulting suspension was stirred for 1 h. The suspension was filtered and the wet cake was washed with additional heptane. The wet cake was conditioned for 20 min under nitrogen, then dried in a vacuum oven at about 40 °C to afford Compound 9 free base in about 99.3% purity (AUC), which had about 99.2% S-enantiomer (e.g., chiral purity of about 99.2%).

Example 2B [00573] A mixture of Compound 7 (100 g, 0.407 mol, 1 wt) and THF (500 mL, 5 vol) was prepared and cooled to about 3 °C. n-Hexyllithium (2.3 M in hexanes, 400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes while maintaining the temperature below about 6 °C. The resulting solution was stirred at 0 ± 5 °C for about 30 minutes. Concurrently, a mixture of Compound 2 (126 g, 0.541 mol, 1.33 equiv) and THF (575 mL, 5.8 vol) was prepared. The resulting slurry was charged with isopropylmagnesium chloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85 minutes while maintaining the temperature below about 5 °C. The resulting mixture was stirred for about 35 minutes at 0 ± 5 °C. The Compound 2 magnesium salt mixture was transferred to the Compound 7 lithium salt mixture over about 1 hour while maintaining a temperature of 0 ± 5 °C. The solution was stirred for about 6 minutes upon completion of the transfer.

[00574] The solution was added to an about -5 °C stirring solution of isobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5 vol) over about 20 minutes during which time the temperature did not exceed about 6 °C. The resulting solution was stirred for about 40 minutes while being warmed to about 14 °C. Then, a 10% sodium chloride solution (500 mL, 5 vol) was rapidly added to the reaction. The temperature rose to about 21 °C. After agitating the mixture for about 6 minutes, the stirring was ceased and the lower aqueous layer was removed (about 700 mL). A second portion of 10% sodium chloride solution (500 mL, 5 vol) was added and the mixture was stirred for 5 minutes. Then, the stirring was ceased and the lower aqueous layer was removed. The volume of the organic layer was reduced by vacuum distillation to about 750 mL (7.5 vol).

[00575] Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and the resulting mixture was agitated at about 45 °C for about 15 hours. The mixture was cooled to about 35 °C and MTBE (1.5 L, 15 vol) was added over about 70 minutes. Upon completion of the addition, the mixture was agitated for about 45 minutes at about 25-30 °C. The solids were collected by vacuum filtration and conditioned under N2 for about 20 hours to afford Compound 9*TFA salt in about 97.5% purity (AUC), which had a chiral purity of about 99.3%.

[00576] Compound 9»TFA salt (100 g) was suspended EtOAc (1 L,10 vol) and 14% aqueous ammonia (250 mL, 2.5 vol). The mixture was agitated for about 30 minutes, then the lower aqueous layer was removed. A second portion of 14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer. The mixture was stirred for 30 minutes, then the lower aqueous layer was removed. Isopropyl acetate (300 mL, 3 vol) was added, and the mixture was distilled under vacuum to 500 mL (5 vol) while periodically adding in additional isopropyl acetate (1 L, 10 vol).

[00577] Then, after vacuum-distilling to a volume of 600 mL (6 vol), heptanes (1.5 L, 15 vol) were added over about 110 minutes while maintaining a temperature between about 20 °C and about 30 °C. The resulting slurry was stirred for about 1 hour, then the solid was collected by vacuum filtration. The cake was washed with heptanes (330 mL, 3.3 vol) and conditioned for about 1 hour. The solid was dried in an about 45 °C vacuum oven for about 20 hours to afford Compound 9 free base in about 99.23% purity (AUC), which has a chiral purity of about 99.4%.

Example 3

Chiral Resolution of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9)

[00578] In some instances, (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) obtained by synthesis contained a minor amount of the corresponding (R)-isomer. Chiral resolution procedures were utilized to improve the enantiomeric purity of certain samples of (S)-3-(l-aminoethyl)-8- chloro-2-phenylisoquinolin- 1 (2H)-one.

[00579] In one experiment, Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at about 55 °C for about 1 to about 2 hours. The mixture was filtered and treated with ammonium hydroxide in deionized (DI) water to afford Compound 9 in greater than about 99% (AUC) purity, which had a chiral purity of about 91% (AUC).

[00580] In another procedure, MeOH (10 vol.) and Compound 9 (1 equiv.) were stirred at 55 ± 5 °C. D- Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for about 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. The cake was returned to the reactor and water (16 vol.) was charged. The mixture was stirred at 25 ± 5 °C. NH4OH was then charged over about 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the cake was washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9 free base with a chiral purity of about 99.0%.

Example 4

Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00581] A mixture of Compound 7 (1 equiv.) and anhydrous THF (5 vol.) was prepared. Separately, a mixture of Compound 2 (1.3 equiv.) and anhydrous THF (5 vol.) was prepared. Both mixtures were stirred for about 15 min at about 20 to about 25 °C and then cooled to -25 ± 15 °C. n-Hexyl lithium (2.05 equiv.) was added to the Compound 7 mixture, maintaining the temperature at > 5 °C. i-PrMgCl (1.33 equiv.) was added to the Compound 2 mixture, maintaining the temperature at > 5 °C. The Compound 2 mixture was transferred to the Compound 7 mixture under anhydrous conditions at 0 ± 5 °C. The resulting mixture was warmed to 20 ± 2 °C and held for about 1 h. Then, the reaction was cooled to -5 ± 5 °C, and 6 N HC1 (3.5 equiv.) was added to quench the reaction, maintaining temperature at below about 25 °C. The aqueous layer was drained, and the organic layer was distilled under reduced pressure until the volume was 2-3 volumes. IPA (3 vol.) was added and vacuum distillation was continued until the volume was 2-3 volumes. IPA (8 vol.) was added and the mixture temperature was adjusted to about 60 °C to about 75 °C. Cone. HC1 (1.5 vol.) was added and the mixture was subsequently held for 4 hours. The mixture was distilled under reduced pressure until the volume was 2.5-3.5 volumes. The mixture temperature was adjusted to 30 ± 10 °C. DI water (3 vol.) and DCM (7 vol.) were respectively added to the mixture. Then, NH4OH was added to the mixture, adjusting the pH to about 7.5 to about 9. The temperature was adjusted to about 20 to about 25 °C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol.). The combined DCM layers were distilled until the volume was 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation was continued until the volume was 3 volumes. The temperature was adjusted to about 15 to about 30 °C. Heptane (12 vol.) was charged to the organic layer, and the mixture was held for 30 min. The mixture was filtered and filter cake was washed with heptane (3 vol.). The cake was vacuum dried at about 45 °C afford Compound 9.

[00582] Then, MeOH (10 vol.) and Compound 9 (1 equiv.) were combined and stirred while the temperature was adjusted to 55 ± 5 °C. D-Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to the cake and the mixture was stirred at 25 ± 5 °C. NH4OH was charged over 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the resulting cake washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9.

[00583] To a mixture of i-PrOH (4 vol.) and Compound 9 (1 equiv.) was added Compound 4 (1.8 equiv.), Et3N (2.5 equiv.) and i-PrOH (4 vol.). The mixture was agitated and the temperature was adjusted to 82 ± 5 °C. The mixture was held for 24 h. Then the mixture was cooled to about 20 to about 25 °C over about 2 h. The mixture was filtered and the cake was washed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford Compound 10.

To a mixture of EtOH (2.5 vol.) and Compound 10 (1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixture was agitated at about 20 to about 25 °C. Cone. HC1 (3.5 equiv.) was added and the temperature was adjusted to 35 ± 5 °C. The mixture was held for about 1.5 h. The mixture was cooled to 25 ± 5 °C and then polish filtered to a particulate free vessel. NH4OH was added, adjusting the pH to about 8 to about 9. Crystal seeds of Form C of a compound of Formula (I) (0.3 wt ) were added to the mixture which was held for 30 minutes. DI water (13 vol.) was added over about 2 h. The mixture was held for 1 h and then filtered. The resulting cake was washed with DI water (4 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned for about 24 h and then DCM (5 vol.) was added. This mixture was agitated for about 12 h at about 20 to about 25 °C. The mixture was filtered and the cake washed with DCM (1 vol.). The cake was conditioned for about 6 h. The cake was then vacuum-dried at 50 ± 5 °C. To the cake was added DI water (10 vol.), and i-PrOH (0.8 vol.) and the mixture was agitated at 25 ± 5 °C for about 6 h. An XRPD sample confirmed the compound of Formula (I) was Form C. The mixture was filtered and the cake was washed with DI water (5 vol.) followed by n-heptane (3 vol.). The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford a compound of Formula (I) as polymorph Form C. Example 5

Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 5A

[00584] Compound 9 (2.39 kg) was treated with Compound 4 and triethylamine in isopropyl alcohol at 80 °C for 24 hours. The reaction was monitored by HPLC until completion, affording 8-chloro-2-phenyl-3- ((lS)-l-(9-(tetrahydro-2H^yran-2-yl)-9H^urin-6-ylamino)ethyl)isoquinolin-l(2H)-one (compound 10) as a tan solid in 94% yield with 98% (AUC) purity by HPLC analysis.

[00585] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (compound 10) (3.63 kg) was treated with HC1 in ethanol at 30 °C for 2.3 hours. The reaction was monitored by HPLC until completion, and afforded a compound of Formula (I) as a tan solid in 92% yield with >99% (AUC) purity and 90.9% (AUC) ee by HPLC analysis.

Example 5B

[00586] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (0.72 mmol), 6-chloro- 9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA

(279 mg, 2.16 mmol) were dissolved in «-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-l(2H)-one (Compound 10), as a white solid (60% yield). [00587] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHC03 aqueous solution and the pH was adjusted to about 7-8. The mixture was extracted with CH2C12 (50 mL x 3), dried over anhydrous Na2S04, and filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexanes (1 : 1). The solid was collected by filtration and dried in vacuo to afford the product (S)-3-(l-(9H-purin-6-ylamino) ethyl)-8-chloro-2-phenylisoquinolin- l(2H)-one (Formula (I)) (90% yield) as a white solid as polymorph Form A.

Example 5C

[00588] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) and 6-chloro-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82 °C for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35 °C to remove the tetrahydropyranyl group to yield (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.

Example 6

Synthesis of (S)-3-(l-(9H^urin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00589] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (150 g; 90% ee) and 6- chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5 °C, held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25 °C for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48 °C for two and half days to give 227 g (90.1 %) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94 ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.

[00590] The intermediate (Compound 10) (200 g) was slurried in an ethanol (900 mL; 4.5 vol) / water (300 mL; 1.5 vol) mixture at 22 °C followed by addition of cone. HC1 (300 mL; 1.5 vol) and holding for one and half hours at 25-35 °C. Addition of HC1 resulted in complete dissolution of all solids producing a dark brown solution. Ammonium hydroxide (260 mL) was added adjusting the pH to 8-9. Product seeds of polymorph Form C (0.5 g) (Form A seeds can also be used) were then added and the batch which was held for ten minutes followed by addition of water (3 L; 15 vol) over two hours resulting in crystallization of the product. The batch was held for 3.5 hours at 20-25 °C and then filtered. The cake was washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol) and vacuum dried at 52 °C for 23 hours to give 155.5 g (93.5%) of product with 99.6% (AUC) purity and 93.8% ee (chiral HPLC).

Example 7

-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00591] A mixtue of isopropanol (20.20 kg, 8 vol.), Compound 9 (3.17 kg, 9.04 mol, 1 eq.), Compound 4 (4.61 kg, 16.27 mol, 1.8 eq.) and triethylamine (2.62 kg, 20.02 mol, 2.4 eq.) was prepared and heated to an internal temperature of 82 ± 5 °C. The mixture was stirred at that temperature for an additional about 24 h. The temperature was adjusted to 20 ± 5 °C slowly over a period of about 2 h and the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a Sharkskin paper. The filter cake was rinsed sequentially with IPA (5.15 kg, 3 vol.), purified water (80.80 kg, 25 vol.) and n-heptane (4.30 kg, 2 vol.). The cake was further dried for about 4 days in vacuo at 50 ± 5 °C to afford Compound 10.

[00592] To a mixture of ethanol (17.7 kg, 5 vol.) and Compound 10 (4.45 kg, 8.88 mol. 1.0 eq.) was added purified water (8.94 kg, 2 vol.). To this mixture was slowly added concentrated HC1 (3.10 kg, 3.5 eq.) while maintaining the temperature below about 35 °C. The mixture was stirred at 30 ± 5 °C for about 1.5 h and HPLC analysis indicated the presence the compound of Formula (I) in 99.8% (AUC) purity with respect to compound 10.

[00593] Then, the compound of Formula (I) mixture was cooled to 25 ± 5 °C. The pH of the mixture was adjusted to about 8 using pre filtered ammonium hydroxide (1.90 kg). After stirring for about 15 min, Form C crystal seeds (13.88 g) were added. After stirring for about 15 min, purified water (58.0 kg, 13 vol.) was charged over a period of about 2 h. After stirring the mixture for 15 h at 25 ± 5 °C, the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper. The filter cake was rinsed with purified water (18.55 kg, 4 vol.) followed by pre -filtered n-heptane (6.10 kg, 2 vol.). After conditioning the filter cake for about 24 h, HPLC analysis of the filter cake indicated the presence the compound of Formula (I) in about 99.2% (AUC) purity.

[00594] To the filter cake was added dichloromethane (29.9 kg, 5 vol.) and the slurry was stirred at 25 ± 5 °C for about 24 h. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with DCM (6.10 kg, 1 vol.). After conditioning the filter cake for about 22 h, the filter cake was dried for about 2 days in vacuo at 50 ± 5 °C to afford the compound of Formula (I) in 99.6% (AUC) purity. The compound of Formula (I) was consistent with a Form A reference by XRPD.

[00595] To this solid was added purified water (44.6 kg, 10 vol.) and pre filtered 2-propanol (3.0 kg, 0.8 vol.). After stirring for about 6 h, a sample of the solids in the slurry was analyzed by XRPD and was consistent with a Form C reference. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with purified water (22.35 kg, 5 vol.) followed by pre filtered n-heptane (9.15 kg, 3 vol.). After conditioning the filter cake for about 18 h, the filter cake was dried in vacuo for about 5 days at 50 ± 5 °C.

[00596] This process afforded a compound of Formula (I) in about 99.6% (AUC) purity, and a chiral purity of greater than about 99% (AUC). An XRPD of the solid was consistent with a Form C reference standard. :H NMR (DMSO-<i6) and IR of the product conformed with reference standard.

…………………………..

http://www.google.com/patents/US20140120083

In some embodiments, the compound has the following structure:

Figure US20140120083A1-20140501-C00331

which is also referred to herein as Compound 292.

In some embodiments, a polymorph of a compound disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012-0184568 (“the ‘568 publication”), which is hereby incorporated by reference in its entirety.

In one embodiment, the compound is Form A of Compound 292, as described in the ‘568 publication. In another embodiment, the compound is Form B of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form C of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form D of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form E of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form F of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form G of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form H of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form I of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form J of Compound 292, as described in the ‘568 publication.

In specific embodiments, provided herein is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application. In specific embodiments, provided herein is a pharmaceutically acceptable form of Compound 292, which is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application.

Any of the compounds (PI3K modulators) disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.

Chemical entities described herein can be synthesized according to exemplary methods disclosed in U.S. Patent Publication No. US 2009/0312319, International Patent Publication No. WO 2011/008302A1, and U.S. Patent Publication No. 2012-0184568, each of which is hereby incorporated by reference in its entirety, and/or according to methods known in the art.

 

……………………………………………

KEY     Duvelisib, IPI-145,  INK-1197, AbbVie, INFINITY, chronic lymphocytic leukemia, phase 3, orphan drug

 

WO2013088404A1 Dec 14, 2012 Jun 20, 2013 Novartis Ag Use of inhibitors of the activity or function of PI3K
WO2014004470A1 * Jun 25, 2013 Jan 3, 2014 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors
WO2014072937A1 Nov 7, 2013 May 15, 2014 Rhizen Pharmaceuticals Sa Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor
US7449477 * Nov 22, 2004 Nov 11, 2008 Eli Lilly And Company 7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (protein kinase B)
US20090312319 * Jul 15, 2009 Dec 17, 2009 Intellikine Certain chemical entities, compositions and methods
US20100168153 * Nov 16, 2007 Jul 1, 2010 Novartis Ag Salts and crystall forms of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile
WO2013012915A1 Jul 18, 2012 Jan 24, 2013 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
WO2013012918A1 Jul 18, 2012 Jan 24, 2013 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
WO2013032591A1 Jul 18, 2012 Mar 7, 2013 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
WO2013049332A1 Sep 27, 2012 Apr 4, 2013 Infinity Pharmaceuticals, Inc. Inhibitors of monoacylglycerol lipase and methods of their use
WO2013088404A1 Dec 14, 2012 Jun 20, 2013 Novartis Ag Use of inhibitors of the activity or function of PI3K
WO2013154878A1 Apr 3, 2013 Oct 17, 2013 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2014004470A1 * Jun 25, 2013 Jan 3, 2014 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors
WO2014071105A1 Nov 1, 2013 May 8, 2014 Infinity Pharmaceuticals, Inc. Treatment of rheumatoid arthritis and asthma using p13 kinase inhibitors
WO2014071109A1 Nov 1, 2013 May 8, 2014 Infinity Pharmaceuticals, Inc. Treatment of cancers using pi3 kinase isoform modulators
WO2014072937A1 Nov 7, 2013 May 15, 2014 Rhizen Pharmaceuticals Sa Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor
WO2001081346A2 Apr 24, 2001 Nov 1, 2001 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
US6800620 Jan 6, 2003 Oct 5, 2004 Icos Contacting leukocytes, osteoclasts with an enzyme inhibitors, a 9h-purin-3h-quinazolin-4-one derivatives, treating bone-resorption disorder, antiproliferative agents treating leukemia cells
US20060276470 * Aug 18, 2003 Dec 7, 2006 Jackson Shaun P (+-)-7-Methyl-2-morpholin-4-yl-9-(1-phenylaminoethyl)-pyrido[1,2-a]pyrimidin-4-one, for example; selective inhibitors of phosphoinositide (PI) 3-kinase beta for use in anti-thrombotic therapy
US20080032960 * Apr 4, 2007 Feb 7, 2008 Regents Of The University Of California PI3 kinase antagonists

AbbVie’s glioblastoma multiforme therapy receives orphan drug designation


ABT-414 is in phase I/II clinical development at AbbVie for the treatment of squamous cell carcinoma. The product is also in early clinical development for the treatment of glioblastoma multiforme.

In 2014, orphan drug designation was received in the U.S. and E.U. by AbbVie for the treatment of glioblastoma multiforme.

EGFR antibody-drug conjugate (cancer), Abbott; ABT-414; EGFR antibody-drug conjugate (cancer), AbbVie; EGFR-ADC (cancer), AbbVie; ABT-806-MMAF conjugate; anti-EGFR antibody-MMAF conjugate, AbbVie; EGFR-ADC (cancer), Abbott

 

AbbVie’s glioblastoma multiforme therapy receives orphan drug designation
AbbVie has obtained orphan drug designation from the European Medicines Agency (EMA) and the US FDA for its anti-epidermal growth factor receptor monoclonal antibody drug conjugate, ABT-414, as a treatment for glioblastoma multiforme.

AbbVie has obtained orphan drug designation from the European Medicines Agency (EMA) and the US FDA for its anti-epidermal growth factor receptor monoclonal antibody drug conjugate, ABT-414, as a treatment for glioblastoma multiforme.

read at

 

http://www.pharmaceutical-technology.com/news/newsabbvies-glioblastoma-multiforme-therapy-receives-orphan-drug-designation-4335836?WT.mc_id=DN_News

 

AbbVie’s ABT-414 Receives FDA and EMA Orphan Drug Designation

AbbVie announced that the EMA and the FDA have granted orphan drug status to its investigational compound ABT-414, an anti-epidermal growth factor receptor antibody drug conjugate. It is currently being evaluated for safety and efficacy in patients with glioblastoma multiforme. Glioblastoma multiforme is the most common and most aggressive type of malignant primary brain tumor. Each year in the United States and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma multiforme, which has a five-year survival rate of approximately 4 percent.

“The orphan drug designation is an important regulatory advancement as we further our development in recurrent glioblastoma multiforme, a disease that is uniformly fatal with limited treatment options,” said Gary Gordon, M.D., vice president, oncology clinical development, AbbVie. “We are pleased to continue developing ABT-414 in Phase II trials in patients with glioblastoma multiforme based on the results of our Phase I program.” Read the press release

 

 

AbbVie oncology clinical development vice-president Gary Gordon said: “The orphan drug designation is an important regulatory advancement as we further our development in recurrent glioblastoma multiforme, a disease that is uniformly fatal with limited treatment options.

“We are pleased to continue developing ABT-414 in Phase II trials in patients with glioblastoma multiforme based on the results of our Phase I programme.”

AbbVie is currently evaluating the safety and efficacy of ABT-414 in patients with glioblastoma multiforme, the most aggressive type of malignant primary brain tumour.

In May, the company presented results from the Phase I clinical trial evaluating ABT-414 in combination with temozolomide in patients with recurrent or unresectable glioblastoma multiforme.

The Phase I trial was designed to assess the toxicities, pharmacokinetics and recommended Phase II dose of ABT-414 when administered every other week in combination with temozolomide.

Other important assessments included adverse events, pharmacokinetic parameters, objective response and tumour tissue epidermal growth factor receptor biomarkers.

The study results showed four objective responses, including one complete response.

AbbVie has developed ABT-414 with components in-licenced from Life Science Pharmaceuticals and Seattle Genetics.

ABT-414 is also being evaluated in clinical trials for the treatment of patients with squamous cell tumours.

About ABT-414
ABT-414 is an anti-EGFR (epidermal growth factor receptor) monoclonal antibody drug conjugate (ADC). As an ADC, ABT-414 is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells. Developed by AbbVie researchers with components in-licensed from Life Science Pharmaceuticals, ABT-414 is currently being investigated for the treatment of glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor. ABT-414 is also in clinical trials for the treatment of patients with squamous cell tumors. ABT-414 is an investigational compound and its efficacy and safety have not been established by the FDA.

About Glioblastoma Multiforme
Glioblastoma is the most common and most aggressive type of malignant primary brain tumor. Each year in the U.S. and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma, which has a five year survival rate of less than 3 percent. Prior to diagnosis, most patients experience a serious symptom of glioblastoma, such as a seizure. Typically patients succumb to the disease approximately 15 months after diagnosis. Treatment for glioblastoma remains challenging and no long-term treatments are currently available. Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy. More than 8,700 patients are enrolled in industry-sponsored clinical studies.

ref………

A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM)
50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2021

ABT-414: An anti-EGFR antibody drug conjugate for the treatment of glioblastoma patients
18th Annu Sci Meet Soc Neuro-Oncol (November 21-24, San Francisco) 2013, Abst ET-079

ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors
25th EORTC-NCI-AACR Symp Mol Targets Cancer Ther (October 19-23, Boston) 2013, Abst A250

A Phase I/II Study Evaluating the Safety, Pharmacokinetics and Efficacy of ABT-414 in Subjects With Advanced Solid Tumors Likely to Over-Express the Epidermal Growth Factor Receptor (EGFR) (NCT01741727)
ClinicalTrials.gov Web Site 2012, December 07

AbbVie’S Investigational Oncology Compound ABT-199/GDC-0199, Venetoclax


ChemSpider 2D Image | 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide | C45H50ClN7O7SVenetoclax.svg

ABT 199, RG 7601, GDC 0199

Venetoclax

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

SYNTHESIS UPDATED BELOW …………..


CAS 1257044-40-8 [RN]

2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

ABT 199

  • Molecular Formula: C45H50ClN7O7S
  • Average mass: 868.439209 Da
  • Monoisotopic mass: 867.318115 Da
  • 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

NORTH CHICAGO, Ill., May 31, 2014/NEWS.GNOM.ES/ — AbbVie (NYSE: ABBV) released interim results from a Phase Ib clinical trial of ABT-199/GDC-0199, an investigational B-cell lymphoma 2 (BCL-2) selective inhibitor, in combination with rituximab (Abstract 7013). Results showed anoverall response rate (ORR) of 84 percent, in patients with relapsed/refractory chronic lymphocytic leukemia(CLL), the most common leukemia in the UnitedStates. These results were presented at the 50thAnnual Meeting of the American Society of ClinicalOncology (ASCO), May 30 – June 3 in Chicago.

http://news.gnom.es/pr/abbvie-presents-new-results-from-studies-of-investigational-oncology-compound-abt-199gdc-0199-at-the-2014-american-society-of-clinical-oncology

ABT-199.png

ABT-199 is a so-called BH3-mimetic drug, which is designed to block the function of the protein Bcl 2. In 1988, it was discovered that Bcl-2 allowed leukaemia cells to become long-lived, a discovery made at the Walter and Eliza Hall Institute by Professors David Vaux, Suzanne Cory and Jerry Adams. Subsequent research led by them and other institute scientists, including Professors Andreas Strasser, David Huang, Peter Colman and Keith Watson, has explained much about how Bcl-2 and related molecules function to determine if a cell lives or dies. These discoveries have contributed to the development of a new class of drugs called BH3-mimetics that kill, and thereby rapidly remove, leukaemic cells by blocking Bcl-2. (source:http://www.wehi.edu.au).

 

Highlights of recent research using this agent

GDC-0199 (RG7601) is a novel small molecule Bcl-2 selective inhibitor designed to restore apoptosis, also known as programmed cell death, by blocking the function of a pro-survival Bcl-2 family protein. The Bcl-2 family proteins, which are expressed at high levels in many tumors, play a central role in regulating apoptosis and, consequently, are thought to impact tumor formation, tumor growth and resistance.

Venetoclax (previously: GDC-0199, ABT-199, RG7601 )[1] is a small molecule oral drug being investigated to treat chronic lymphocytic leukemia (CLL).[2][3]

In 2015, the FDA granted Breakthrough Therapy Designation to venetoclax for CLL in previously treated (relapsed/refractory) patients with the 17p deletion genetic mutation.[3]

Mechanism of action

Venetoclax (a BH3-mimetic[4]) acts as a Bcl-2 inhibitor, ie. it blocks the anti-apoptotic B-cell lymphoma-2 (BCL2) protein, leading toprogrammed cell death in CLL cells.[2]

Clinical trials

A phase 1 trial established a dose of 400mg/day.[2]

A trial of venetoclax in combination with rituximab had an encouraging complete response rate.[5]

A phase 2 trial met its primary endpoint which was overall response rate.[3] Interim results from a Phase 2b trial are encouraging, especially in patients with the 17p deletion.[2]

A phase 3 trial (NCT02005471)[1] has started.[3]

NOW IN PHASE 3  UPDATED…………

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (hereafter, “Compound 1”) is a potent and selective Bcl-2 inhibitor having, inter alia, antitumor activity as an apoptosis-inducing agent. Compound 1 has the formula:

Figure US20140275540A1-20140918-C00001

Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. U.S. Patent Publication No. 2010/0305122 describes Compound 1, and other compounds which exhibit potent binding to a Bcl-2 family protein, and pharmaceutically acceptable salts thereof. U.S. Patent Publication Nos. 2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1. The disclosures of U.S. 2010/0305122; 2012/0108590; 2012/0157470 and 2012/0277210 are hereby incorporated by reference in their entireties.

 

str1

PATENT

US 2015183783

http://www.google.com/patents/US20150183783

PATENT

CN 104370905

http://www.google.com/patents/CN104370905A?cl=en

str1

ABT-199 is developed AbbVie Bel-2 inhibitors, I trial (NCT01328626) enrolled 84 patients with relapsed type / refractory CLL / SLL patients and 44 cases of relapsing / refractory non-Hodgkin lymphoma patients. ABT-199 treatment response CLL / SLL rate of 79% (complete response rate of 22%), median duration of response time was 20.5 months; ABT-199 treatment of non-Hodgkin’s lymphoma response rate of 48% (complete response rate was 7.5%). The efficacy of ABT-199 is capable of obinutuzumab, idelalisib, ibrutinib rival, is expected to become the first listed Bcl_2 inhibitors, ABT-199 is currently ongoing Phase III clinical study.

ABT-199 compound CAS number 1257044-40-8, the compound is structured as follows:

 

Figure CN104370905AD00051

Patent W02012058392, W02012071336, W02010138588 et al. Discloses the preparation of ABT-199 in order to -IH- 5-bromo-pyrrolo [2, 3-b] pyridine as raw material to protect hydroxylation, after replacing the compound 5, and reaction of compound 6, hydrolysis to give compound 9, compound 10 and compound 9 obtained by condensation of ABT-199, a specific line as follows:

Figure CN104370905AD00052

use of 2-fluoro-4-nitrobenzoate (A) as a raw material, and substituted 5-hydroxy-7-aza-indole (B), reduction to produce compound ( D), the compound (D) with the compound by cyclization after (H) substitution, hydrolysis to yield compound (J), and then with the compound (K) to afford ABT-199.

Figure CN104370905AC00021

Preparation of a compound of Example (F) of the

Example

Figure CN104370905AD00062

First step: Synthesis of Compound (C)

  2-fluoro-4-nitrobenzoate in IL three-necked flask 50. 0g, dissolved with dimethylformamide N’N- 250ml, was added successively 5-hydroxy-7-aza-indole indole 33. 6g, potassium carbonate 34. 7g, the reaction was heated to 50 degrees under nitrogen gas protection for 2 hours, poured into 2L of ice water was added and extracted three times with ethyl acetate, the organic phase was dried with saturated sodium chloride spin dry to give Compound (C) crude 82. 0g, crude without purification in the next reaction direct investment.

Step two: Synthesis of Compound (D)

  The compound of the previous step (C) of the crude product was dissolved in methanol 400ml, was added 10% palladium on carbon 4. 0g, through the reaction of hydrogen at atmospheric pressure, after the end of the reaction by TLC spin solvent to give compound (D) The crude product 73. 2g, crude without purification in the next reaction direct investment.

The third step: Synthesis of compound (F)

  Take the previous step the compound (D) crude 20. 0g, t-butanol were added 150ml, compound (E) 10. g, potassium carbonate 9. 7g, completion of the addition the reaction was refluxed for 48 hours the reaction solution was cooled, added acetic acid ethyl ester was diluted, washed with water three times, the combined aqueous phases extracted once with ethyl acetate, the combined ethyl acetate phases twice, dried over anhydrous sodium sulfate and the solvent was spin, the crude product obtained was purified by silica gel column chromatography to give 13. 9g, three-step overall yield of 57.4%.

Preparation Example II Compound (H),

 

Figure CN104370905AD00071

[0029] Take compound (G) (prepared according to W02012058392 method) 5. 0g, dissolved with 50ml of dichloromethane, was added triethylamine 5. 6ml, the reaction solution was cooled to 0-5 ° with stirring, was added dropwise methanesulfonyl chloride 2. 7g, the addition was complete the reaction was warmed to room temperature overnight, after the end of the reaction by TLC the reaction was quenched with water, the organic phase was dried over anhydrous sodium sulfate and the solvent was spin, purified by silica gel column chromatography to give compound (H) 6. 5g , a yield of 99%.

Three ABT-199 Preparation of  Example

Figure CN104370905AD00072

First step: Synthesis of Compound (I)

  In IOOml three-necked flask were added the compound (F) 2. 5g, compound ⑶2. 3g, potassium carbonate I. 9g, Ν ‘was added and reacted at 50 degrees N- dimethylformamide 15ml, nitrogen atmosphere, TLC detection After the reaction, the reaction solution was poured into ice-water, extracted with ethyl acetate twice added ethyl acetate phase was dried over anhydrous sodium sulfate spin, and purified by silica gel column chromatography to give compound (I) 3. 6g, yield 88 %.

Step two: Synthesis of Compound (J)

  In IOml single jar Compound (I) I. 0g, followed by adding water 5ml, ethanol 5ml, tetrahydrofuran 5ml, sodium hydroxide 136mg, the reaction was stirred at room temperature the reaction, ethyl acetate was added after dilution of the reaction by TLC, adjusted with IN hydrochloric acid PH4-5, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and spin dried to give compound (J) 907mg, 93% yield.

Step two: Synthesis of ABT-199

In a 25ml single neck flask was added the compound (J) 100mg, EDCI67mg, dichloromethane 10ml, the reaction was stirred for 30 minutes, was added the compound (K) (prepared in accordance with W02012058392) 55mg, finally added a catalytic amount of DMAP, the force After opening the reaction was stirred overnight, after the end of the reaction by TLC the solvent was spin, HPLC purified preparation obtained by pure ABT-199 ^ 9811, 65% yield.

PATENT

WO 2014165044

http://www.google.com/patents/WO2014165044A1?cl=en

PATENT

US 2014275540

http://www.google.com/patents/US20140275540

Figure US20140275540A1-20140918-C00031

 

  • An exemplary reaction according to Scheme 2 is shown below.Figure US20140275540A1-20140918-C00033
    Scheme 3 below. Compound (E) is commercially available or may be prepared by techniques known in the art, e.g., as shown in U.S. Pat. No. 3,813,443 and Proceedings of the Chemical Society, London, 1907, 22, 302.
  • Scheme 4 below. Compound (M) is commercially available or may be prepared by techniques known in the art, e.g., as shown in GB 585940 and J. Am. Chem. Soc., 1950, 72, 1215-1218.
  • In another embodiment, the compound of formula (1) is prepared from compound (D) and compound (I) as shown in Scheme 5 below. Compound (J) may be prepared by techniques known in the art, e.g., as shown in WO 2009/117626 and Organometallics, 2008, 27 (21), 5605-5611.
  • Example 1 Synthesis of tert-butyl 4-bromo-2-fluorobenzoate (Compound (C))
    To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4-bromo-2-fluoro1-iodobenzene, “Compound (A)” (5 g, 1.0 eq) and THF (25 ml). The solution was cooled to −5° C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 1 h. Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. After 1 h, the solution was quenched with 10% citric acid (10 ml), and then diluted with 25% NaCl (10 ml). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3×10 ml). The crude oil was diluted with THF (5 ml), filtered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency=67%, potency adjusted yield=88%) was taken to the next step without further purification. 1H NMR (DMSO-d6): δ 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H), 7.74 (t, J=8.2 Hz, 1H).
  • Example 2 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (Compound (D))
  • To a 3 L three-neck Morton flask were charged 1H-pyrrolo[2,3-b]pyridin-5-ol (80.0 g, 1.00 eq.), tert-butyl 4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20° C. for 15 min. The resulting solution was cooled to about zero to 5° C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 mL) was added slowly over 30 min while maintaining the internal temperature at NMT 10° C., and rinsed with DMF (30 mL). The reaction mixture was stirred at 10° C. for 1 hour (an off-white slurry) and adjusted the internal temperature to ˜45° C. over 30 min. The reaction mixture was stirred at 45-50° C. for 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion % by HPLC). The solution was cooled to ˜20° C. The solution was stirred at 20° C. overnight.
  • Water (1200 mL) was added slowly to the reaction mixture at <30° C. over 1 hour (slightly exothermic). The product slurry was adjusted to ˜20° C., and mixed for NLT 2 hours. The crude product was collected by filtration, and washed with water (400 mL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50° C. overnight to give the crude product (236.7 g).
  • Re-crystallization or Re-slurry: 230.7 g of the crude product, (potency adjusted: 200.7 g) was charged back to a 3 L three-neck Morton flask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refluxing temperature over 1 hr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refluxing temperature (78° C.). The slurry was mixed at refluxing temperature for 30 min., and cooled down slowly to down to ˜−10° C. at a rate of approximate 10° C./hour), and mixed for 2 hr. The product was collected by filtration, and rinsed with heptane (200 ml).
  • The solid was dried under vacuum at ˜50° C. overnight to give 194.8 g, 86% isolated yield of the product as an off-white solid. MS-ESI 389.0 (M+1); mp: 190-191° C. (uncorrected). 1H NMR (DMSO-d6): δ 1.40 (s, 9H), 6.41 (dd, J=3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J=8.3, 1.8 Hz, 1H), 7.51 (t, J=3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).
  • Example 3 Synthesis of 2-chloro-4,4-dimethylcyclohexanecarbaldehyde (Compound (F))
  • To a 500 mL RB flask were charged anhydrous DMF (33.4 g, 0.456 mol) and CH2Cl2 (80 mL). The solution was cooled down <−5° C., and POCl3 (64.7 g, 0.422 mol) added slowly over 20 min @<20° C. (exothermic), rinsed with CH2Cl2 (6 mL). The slightly brown solution was adjusted to 20° C. over 30 min, and mixed at 20° C. for 1 hour. The solution was cooled back to <5° C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, ˜0.292 mol) was added, and rinsed with in CH2Cl2 (10 mL) (slightly exothermic) at <20° C. The solution was heated to refluxing temperature, and mixed overnight (21 hours).
  • To a 1000 mL three neck RB flask provided with a mechanical stirrer were charged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution, 130 g of 12% brine, and 130 mL of CH2Cl2. The mixture was stirred and cooled down to <5° C. The above reaction mixture (clear and brown) was transferred, quenched into it slowly while maintaining the internal temperature <10° C. The reaction vessel was rinsed with CH2Cl2 (10 mL). The quenched reaction mixture was stirred at <10° C. for 15 min. and allowed to rise to 20° C. The mixture was stirred 20° C. for 15 min and allowed to settle for 30 min. (some emulsion). The lower organic phase was separated. The upper aq. phase was back extracted with CH2Cl2 (50 mL). The combined organic was washed with a mixture of 12% brine (150 g)-20% K3PO4 aq. solution (40 g). The organic was dried over MgSO4, filtered and rinsed with CH2Cl2 (30 ml). The filtrate was concentrated to dryness under vacuum to give a brown oil (57.0 g, potency=90.9 wt % by qNMR, ˜100%). 1H NMR (CDCl3): δ 0.98 (s, 6H), 1.43 (t, J=6.4 Hz, 2H), 2.31 (tt, J=6.4, 2.2 Hz, 2H), 2.36 (t, J=2.2 Hz, 2H), 10.19 (s, 1H).
  • Example 4 Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde (Compound (G))
  • To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL). The mixture was stirred at 20° C. for 5 min. 21.0 wt % K2CO3 aq. solution (76.0 g) was added. The mixture was stirred at room temperature (rt) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N2 for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N2. The reaction mixture was evacuated and purged with N2 for three times (an orange colored mixture). The bottle was back filled with N2 and heated to ˜35° C. in an oil bath (bath temp ˜35° C.). The mixture was stirred at 30° C. overnight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample from the upper organic phase for reaction completion, typically starting material <2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO3-2% L-Cysteine aq. solution (100 mL) were added. The mixture was stirred at 20° C. for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO3 aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ˜1/3 volume (˜35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. 1HNMR (CDCl3): δ 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).
  • Example 5 Synthesis of tert-butyl 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate (Compound (H))
  • To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ˜29.5° C. in 15 min cooling may be needed). The yellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
  • 12.5 wt % brine (500 g) was added slowly to quench the reaction. The mixture was stirred at 20° C. for NLT 30 min and allowed to settle for NLT 15 min. The lower aq. phase (˜560 mL) was separated (note: leave any emulsion in the upper organic phase). The organic phase was washed with 10% citric acid solution (500 g×2). 500 g of 5% NaHCO3 aq. solution was charged slowly into the flask. The mixture was stirred at 20° C. for NLT 30 min., and allowed to settle for NLT 15 min. The upper organic phase was separated. 500 g of 25% brine aq. solution was charged. The mixture was stirred at 20° C. for NLT 15 min., and allowed to settle for NLT 15 min. The upper organic phase was concentrated to ˜200 mL volume under vacuum. The solution was adjusted to −30° C., and filtered off the inorganic salt. Toluene (50 mL) was used as a rinse. The combined filtrate was concentrated to ˜100 mL volume. Acetonitrile (400 mL) was added, and the mixture heated to ˜80° C. to achieve a clear solution. The solution was cooled down slowly to 20° C. slowly at rate 10° C./hour, and mixed at 20° C. overnight (the product is crystallized out at ˜45-50° C., if needed, seed material may be added at 50° C.). The slurry was continued to cool down slowly to ˜−10° C. at rate of 10° C./hours. The slurry was mixed at ˜−10° C. for NLT 6 hours. The product was collected by filtration, and rinsed with pre-cooled acetonitrile (100 mL). The solid was dried under vacuum at 50° C. overnight (72.0 g, 85%). MS-ESI: 419 (M+1); mp: 109-110° C. (uncorrected); 1H NMR (CDCl3): δ 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, J=6.5 Hz, 2H), 2.07 (s, br, 2H), 2.18 (m, 4H), 2.24 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 (m, 2H).
  • Example 6 Synthesis of 1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine dihydrochloride (Compound (I))
  • To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the Boc reductive amination product (Compound (H), 72.0 g) and IPA (720 mL). The mixture was stirred at rt for 5 min, and 59.3 g of concentrated hydrochloride aq. solution added to the slurry. The reaction mixture was adjusted to an internal temperature of ˜65° C. (a clear and colorless solution achieved). The reaction mixture was agitated at ˜65° C. for NLT 12 hours.
  • The product slurry was cooled down to −5° C. slowly (10° C./hour). The product slurry was mixed at ˜−5° C. for NLT 2 hours, collected by filtration. The wet cake was washed with IPA (72 mL) and dried at 50° C. under vacuum overnight to give 73.8 g (95%) of the desired product as a bis-hydrochloride IPA solvate (purity >99.5% peak area at 210 nm). MS-ESI: 319 (M+1); 1HNMR (CDCl3): δ 0.86 (s, 6H), 1.05 (d, J=6.0 Hz, 6H, IPA), 1.42 (t, J=6.1 Hz, 2H), 2.02 (s, br, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89 (septet, J=6.0 Hz, 1H, IPA), 7.11 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).
  • Example 7 Synthesis of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-benzenesulfonamide (Compound (N))
  • To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an internal temperature of 80° C. and agitated for no less than 12 hours.
  • The product solution was cooled down to 40° C. and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20° C. Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10° C. and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40° C. for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75° C. under vacuum to give 12.7 g of the desired product in 99.9% purity and in 91% weight-adjusted yield. 1H NMR (DMSO-d6): δ 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH2, 2H), 7.81 (dd, J=9.1, 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH).
  • Example 8 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (Compound (K))
  • General Considerations:
  • this chemistry is considered air and moisture sensitive. While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent formation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use.
  • To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% K3PO4 (285 ml) was added and the biphasic mixture was stirred for 30 min. The layers were separated and the organic layer was washed with 25% NaCl (145 ml). The organic layer concentrated to 120 g and used in the coupling reaction without further purification.
  • NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution −30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen for NLT 45 min. Pd2dba3 (0.646 g), Compound (J) (0.399 g), and Compound (D) (40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitrogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 μm inline filter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml).
  • The resulting mixture was heated to 55° C. with stirring for NLT 16 h, then cooled to 22° C. The mixture was diluted with 12% NaCl (300 g) followed by THF (300 ml). The layers were separated.
  • The organic layer was stirred with a freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 ml). After 1 h the layers were separated.
  • The organic layer was stirred with a second freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 ml). After 1 h the layers were separated. The organic layer was washed with 12% NaCl (300 g), then filtered through a 0.45 μm inline filter. The filtered solution was concentrated in vacuo to ˜300 mL, and chased three times with heptane (600 mL each) to remove THF.
  • The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 ml). The mixture was heated to 75° C., held for 15 min, and then cooled to 65° C. over NLT 15 min. Seed material was charged and the mixture was held at 65° C. for 4 hours. The suspension was cooled to 25° C. over NLT 8 h, then held at 25° C. for 4 hours. The solids were filtered and washed with cyclohexane (90 ml) and dried at 50° C. under vacuum.
  • Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155° C. 1H NMR (DMSO-d6): δ 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J=6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02-3.19 (m, 4H), 6.33 (dd, J=3.4, 1.9 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.72 (dd, J=9.0, 2.4 Hz, 1H), 6.99-7.06 (m, 2H), 7.29 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 2H), 7.41-7.44 (m, 1H), 7.64 (t, J=6.7 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 11.53 (s, 1H).
  • Example 9 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (Compound (L))
  • Solution preparation: 10% KH2PO4 (aq): KH2PO4 (6 g) in water (56 g); 2:1 heptane/2-MeTHF:heptane (16 mL) in 2-MeTHF (8 mL).
  • Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55° C. until reaction completion. The reaction mixture was cooled to 22° C., washed with the 10% KH2PO4 solution (31 g) twice. The organic layer was then washed with water (30 g).
  • After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (˜19 mL) and heated to no less than 50° C. Heptane (23 ml) was slowly added. The resulting suspension was cooled to 10° C. Solids were then collected by vacuum filtration with recirculation of the liquors and the filter cake washed with 2:1 heptane/2-MeTHF (24 ml). Drying of the solids at 80° C. under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. 1H NMR (DMSO-d6): δ 0.91 (s, 6H), 1.37 (t, J=6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J=9.0, 2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44 (t, J=3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) & 11.59 (m, 1H).
  • Example 10 Synthesis of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (Compound (I))
  • Solution preparation prior to reaction: 10% Acetic Acid:Acetic Acid (37 mL) in water (333 g); 5% NaHCO3:NaHCO3 (9 g) in water (176 g); 5% NaCl:NaCl (9 g) in water (176 g).
  • Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25° C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et3N (8.7 g) and dichloromethane (120 mL). The resulting Acid (Compound (L)) solution was slowly charged to the initial suspension of Compound (N) and agitated until reaction completion.

STR1

  • STR1
  • N,N-dimethylethylenediamine (9.4 g) was then charged to the reaction mixture with continued agitation. The reaction mixture was warmed to 35° C. and washed with 10% Acetic acid solution (185 mL) twice. The lower organic layer was diluted with more dichloromethane (75 mL) and methanol (12.5 mL). The organic, product layer was then washed with 5% NaHCO3 solution (185 mL) and then washed with 5% NaCl solution (185 mL) at 35° C. The lower, organic layer was separated and then concentrated to 8 vol (˜256 mL) diluted with methanol (26 mL) and warmed to 38° C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10° C. and then filtered. The wet cake was washed twice with a 1:1 mix of dichloromethane and ethyl acetate (˜2 vol, 64 mL). After drying the wet cake at 90° C., 32 g (84%) of Compound (I) was isolated.
  • 1H NMR (DMSO-d6): δ 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.37 (dd, J=3.4, 1.9 Hz, 1H), 6.66 (dd, J=9.1, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J=9.3, 2.3 Hz, 1H), 8.02 (d, J=2.61 Hz, 1H), 8.54 (d, J=2.33 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H, NH), 11.65 (m, 1H).

 

Figure US20140275540A1-20140918-C00001

PATENT

str1

 

 

str1

 

str1

Patent Submitted Granted
APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES [US2014275082] 2014-02-10 2014-09-18
Processes For The Preparation Of An Apoptosis-Inducing Agent [US2014275540] 2014-03-12 2014-09-18
APOPTOSIS INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES [US2010305122] 2010-12-02
Panel of micrornas that silence the MCL-1 gene and sensitize cancer cells to ABT-263 [US8742083] 2010-12-23 2014-06-03
Treatment Of Cancers Using PI3 Kinase Isoform Modulators [US2014377258] 2014-05-30 2014-12-25
METHODS OF TREATMENT USING SELECTIVE BCL-2 INHIBITORS [US2012129853] 2011-11-22 2012-05-24
INHIBITION OF MCL-1 AND/OR BFL-1/A1 [US2015051249] 2013-03-14 2015-02-19
COMBINATION THERAPY OF A TYPE II ANTI-CD20 ANTIBODY WITH A SELECTIVE BCL-2 INHIBITOR [US2014248262] 2013-09-06 2014-09-04

References

External links

  • ABT-199 inc formula and structure

References

 1: Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2
inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Jan 6. doi: 10.1038/nm.3048. [Epub ahead of print] PubMed PMID: 23291630.

Venetoclax
Venetoclax.svg
Systematic (IUPAC) name
4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Identifiers
CAS Number 1257044-40-8
PubChem CID: 49846579
ChemSpider 29315017
Chemical data
Formula C45H50ClN7O7S
Molecular mass 868.44 g/mol

/////////

CC1(CCC(=C(C1)c2ccc(cc2)Cl)CN3CCN(CC3)c4ccc(c(c4)Oc5cc6cc[nH]c6nc5)C(=O)NS(=O)(=O)c7ccc(c(c7)[N+](=O)[O-])NCC8CCOCC8)C

OR

CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C

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