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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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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The Green ChemisTREE: 20 years after taking root with the 12 principles


Green Chemistry International

Green Chem., 2018, Advance Article DOI: 10.1039/C8GC00482J, Critical Review
Hanno C. Erythropel, Julie B. Zimmerman, Tamara M. de Winter, Laurene Petitjean, Fjodor Melnikov, Chun Ho Lam, Amanda W. Lounsbury, Karolina E. Mellor, Nina Z. Jankovic, Qingshi Tu, Lauren N. Pincus, Mark M. Falinski, Wenbo Shi, Philip Coish, Desiree L. Plata, Paul T. Anastas A broad overview of the achievements and emerging areas in the field of Green Chemistry.

The Green ChemisTREE: 20 years after taking root with the 12 principles

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Cadexomer Iodine


Image result for cadexomer iodine

Cadexomer Iodine

Cadex, Declat, Decrat, Dextrinomer iodine, Iodoflex, Iodosorb, NI-009

CAS 94820-09-4

Title: Cadexomer Iodine
Trademarks: Iodosorb (Perstorp)
Literature References: A hydrophilic modified starch polymer containing 0.9% (w/w) iodine within a helical matrix. Produced by the reaction of dextrin with epichlorohydrin coupled with ion exchange groups and iodine. Clinical use in venous ulcers: E. Skog et al., Br. J. Dermatol. 109, 77 (1983); M. C. Ormiston et al., Br. Med. J. 291, 308 (1985); L. Hillström, Acta Chir. Scand. Suppl. 544,53 (1988).
Therap-Cat: Vulnerary.
Keywords: Vulnerary.

Listed in 1984 (Perstorp, Finland). For the treatment of exudative and infectious wounds, such as venous ulcers. This product is in contact with wound exudate to form a non-adhesive protective layer and release antibacterial iodine

Image result for cadexomer iodine

Product of reaction of dextrin with epichlorohydrin coupled with ion-exchange groups and iodine

Cadexomer iodine is an iodophor that is produced by the reaction of dextrin with epichlorhydrin coupled with ion-exchange groups and iodine. It is a water-soluble modified starch polymer containing 0.9% iodine, calculated on a weight-weight basis, within a helical matrix.[1]

The Central Drugs Standard Control Organization (CDSCO) is the Central Drug Authority for discharging functions assigned to the Central Government under the Drugs and Cosmetics Act. One of the major functions of CDSCO is approval of new drugs in the country. During the month of March 2018, CDSCO has approved the following drugs classifying them as New Drug Approvals

Cadexomer Iodine Bulk & Powder 100 % w/w (contain 0.9 % w/v Iodine) or Cadexomer Iodine Ointment 500 mg (contains 0.9% w/v iodine)

For the treatment of chronic exuding wounds such as leg ulcers, pressure ulcers and diabetes ulcers infected traumatic and surgical wounds.

Cadexomer iodine is an iodophor that is produced by the reaction of dextrin with epichlorhydrin coupled with ion-exchange groups and iodine. It is a water-soluble modified starch polymer containing 0.9% iodine, calculated on a weight-weight basis, within a helical matrix.

In India, M/s Virchow Biotech Private Limited presented their proposal for grant of license to manufacture and market this product in India. The firm presented the Phase III Clinical trial report titled ‘Safety and efficacy of Dexadine (Cadexomer Iodine) in the treatment of chronic wounds’ before the CDSCO’s Subject Expert Committee on Antibiotics & Antivirals. After detailed deliberation, the committee recommended the manufacturing and marketing of the products (Cadexomer Iodine Ointment & Cadexomer Iodine Powder), as topical preparations for the treatment of chronic exuding wounds

History

Cadexomer iodine was developed in the early 1980s in Sweden by Perstorp AB, and given the name Iodosorb. The product was shown to be effective in the treatment of venous ulcers,.[2][3] More recently, it has been shown in studies in animals and humans that, unlike the iodophor povidone-iodine, Iodosorb causes an acceleration of the healing process in chronic human wounds. This is due to an increase in epidermal regeneration and epithelialization in both partial-thickness and full-thickness wounds.[4] In this way cadexomer iodine acts as a cicatrizant.

Properties

When formulated as a topical wound dressing Iodosorb adsorbs exudate and particulate matter from the surface of granulating wounds and, as the dressing becomes moist, iodine is released. The product thus has the dual effect of cleansing the wound and exerting a bactericidal action.

Uses

In addition to other manufacturers, Smith & Nephew distributes cadexomer iodine as Iodosorb and Iodoflex in many countries of the world for the treatment and healing of various types of wounds. The dosage forms are a paste dressing, an ointment and a gel, all of which contain 0.9% iodine.

PATENT

WO2001070242

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001070242

PATENT

WO 2008117300

https://patents.google.com/patent/WO2008117300A2/und

Improved Process for the Preparation Of
Cadexomer Iodine

The present invention describes an improved method for the preparation of cadexomer iodine. Cadexomer iodine is a hydrophilic modified starch polymer containing 0.9%w/w iodine within the helical matrix. It is used for its absorbent and antiseptic properties in the management of chronic wounds such as venous leg ulcers, pressure sores, etc. It is applied as a powder or as an ointment over the wound.
Background of the invention
Cadexomer iodine is an iodophor that releases iodine. It contains 0.9%w/w iodine in hydrophilic modified starch carrier. It is used for its absorbent and antiseptic properties, in the management of venous leg ulcers and pressure sores, burn wounds etc. It is applied as a powder of microbeads or ointment containing iodine 0.9%w/w. When applied to the wound it absorbs fluids, removing exudates, pus and debris. As they swell, iodine is released which kills bacteria. When the color of the gel changes it indicates that the dressing should be changed. It is structurally represented as shown figure 1 , and chemically is known as2-hydroxy methylene cross-linked (1-4) α-D-glucan wther containing iodine.

R=H, CH2COOH

Figure: ! Structural representation of cadexomer iodine

The method of preparation of cadexomer iodine and it applications in clinical use is described in the US patent 4,010,259(1977). The process basically consists of two steps. The step one involves preparation of water insoluble, gel forming, and water swell able organic hydrophilic carrier. The next stage involves complexation of iodine with the above organic polymeric carrier.
The carrier is prepared by a polymerization /cross-linking reaction of a polyhydroxylic organic substance by means of a bifunctional organic cross-linking agent of the type Y-R-Z, wherein Y and Z each represent epoxy groups or halogen atoms and R is an organic residue. In this polymerization/cross linking reaction each of the functional groups Y and Z react with a hydroxy group of the polyhydroxylic organic material to form ether bonds. The linking has to proceed to the extent that the formed polymer becomes insoluble in water, but is capable of absorbing water.
The polyhydroxylic starting material used is dextrin or carboxy methyl dextrin and the cross linking agent used for the polymerization reaction is a bifunctional glycerol derivative such as epichlorohydrin, which is capable of forming ether bridges. The reaction between polyhdyroxy starting material and cross-linking agent epichlorohydrin is carried out by emulsion/suspension of polymerization reaction. This type reaction requires specially designed reactors with efficient stirring and an agent to disperse/ stabilize the reaction mass.
The reaction conditions mentioned in the patent uses toluene/water emulsion system, and which is stabilized/dispersed using toluene solution of a mixture of mono and di-esters of ortho phosphoric acid. This process has the following disadvantages:

Disadvantages of the prior art process

1. During cross-linking, the reaction mixture gets dried-up and sticks to the reaction vessel.
2. Efficient stirring is not possible due to formation of lumps.
3. Particles size of the cross-linked carrier is not uniform.
4. Iodine incorporation to carrier is not efficient; hence large excess has to be used.

5. The color of the product obtained by this process is dark brown, whereas product is expected to be golden yellow in color.

6. Results are not reproducible and batch-to-batch variations observed.
7. The stabilizer solution referred in the patent (US 4,010,259) is a solution of a mixture of mono and di-esters of ortho phosphoric acid, which is not available commercially..

Essentially similar procedures are described in Fr, Demande 2,320,1 12 (1977),
Australian 506,419 (1980), Finn 59,014(1981 ), Dan Dk 150,781 ( 1989). However the chemical nature and details of composition of stabilizer solution are not disclosed in these patents also.
An improved method for the preparation of cadexomer iodine is now developed free of these problems and which can easily scaled up to manufacturing level.

ADVANTAGES OF PRESENT INVENTION

1. The particle size of cadexomer iodine by the present process is fine and uniform, which is highly suitable for powder and ointment formulations.
2. Iodine incorporation to the cross-linked dextrin is efficient and consistent and swelling is appropriate
3. The color of cadexomer iodine obtained is golden yellow which is consistent and as per the expected color of the product.
4. The process is simple and economical and can be carried out in regular reactor with out any extra investment on the specialized equipment
5. Present process uses the dispersing agents, which are available commercially.

The details of the invention are described in examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

Example 1
Commercial dextrin (5Og) is dissolved in sodium hydroxide (50ml of 3.1N) containing sodium borohydride (0.75g), to this dispersing agent; sorbitan monooleate (Span 80, 3.75g) dissolved in toluene (125ml) is added. Then of epichlorohydrin (10 g) is added and reaction mixture is heated at 700C for 5h. After completion of 5h, water (600ml) is added to the reaction mixture, and then neutralized to a pH of 6.5 with hydrochloric acid (2N). The product is filtered washed with acetone (500ml). The product is again washed with water (1000ml) and finally with acetone (300ml). The wet product is treated with a solution of iodine (7.8g) in acetone (196ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (150ml) and dried at 250C for 24h in a vacuum

desiccator.

Yield: 33g
Iodine content: .0.91 % w/w
Swelling capacity: 5.0ml/g

Example 2
Commercial dextrin (1Og) is dissolved in sodium hydroxide (10ml of 3.1N) containing sodium borohydride (0.15g); to this dispersing agent; cetrimide (0.25g) dissolved in toluene (25ml) is added. Then of epichlorohydrin (2.Og) is added and reaction mixture is heated at 700C for 5h. After completion of 5h, water (150 ml) is added, and then the reaction mixture was neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product was filtered and washed with acetone (100ml). Again the product washed with water (200ml) and finally with acetone (60ml). The wet product (carrier) is treated with a solution of iodine ( 1 ,6g) in acetone (40 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (40ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 4.2g
Iodine content: 0.91% w/w
Swelling capacity: 6.0ml/g

Example 3
Commercial dextrin (1Og) is dissolved in sodium hydroxide (10ml of 3.1N) containing sodium borohydride (0.15g), to this dispersing agent; glyceryl monostearate (0.25g) dissolved in toluene (25ml) is added. Then of epichlorohydrin (2.Og) is added and reaction mixture is heated at 700C for 5h. After the completion of 5h, water (150 ml) is added, and then the reaction mixture is neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product is filtered and washed with acetone (100ml). Again the product is washed with water (200ml) and finally with acetone (60ml). The wet product (carrier) is treated with a solution of iodine (1.6g) in acetone (40 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (40ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 3.3g
Iodine content: 0.9% w/w
Swelling capacity: 6.2ml/g

Example 4

Commercial carboxymethyl dextrin (20g) was dissolved in sodium hydroxide (20ml of 3.1N) containing sodium borohydride (0.3g), to this dispersing agent; glyceryl monostearate (1.Og) dissolved in toluene (75ml) is added. Then of epichlorohydrin (6.Og) is added and reaction mixture is heated at 700C for 5h After completion of 5h, water (280 ml) is added, then the reaction mixture is neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product is filtered and washed with acetone (250ml). Again the product is washed with water (500ml) and finally with acetone (150ml). The wet product (carrier) is treated with a solution of iodine (3.Ig) in acetone (60 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (60ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 16gms
Iodine content: 0.92 % w/w.
Swelling capacity: 5.8 ml per gram.

References

  1. Jump up^ Merck Index, 14th Edition, p262 Merck & Co. Inc.
  2. Jump up^ Skog, E. et al. (1983). A randomized trial comparing cadexomer iodine and standard treatment in the out-patient management of chronic venous ulcers. British Journal of Dermatology 109, 77. PMID 6344906
  3. Jump up^ Ormiston, M.C., Seymour, M.T., Venn, G.E., Cohen, R.I. and Fox, J.A. (1985). Controlled trial of Iodosorb in chronic venous ulcers. British Medical Journal (Clinical Research Edition) 291, 308-310. PMID 3962169
  4. Jump up^ Drosou Anna, Falabella Anna, and Kirsner Robert S. (2003) Antiseptics on Wounds: An area of controversy. Wounds 159(5) 149-166. http://cme.medscape.com/viewarticle/456300_2Retrieved 02/03/2009

Tang, M.B.; Tan, E.S.
Hailey-Hailey disease: Effective treatment with topical cadexomer iodine
J Derm Treat 2011, 22(5): 304

Early diagnosis and early corticosteroid administration improves healing of peristomal pyoderma gangrenosum in inflammatory bowel disease
Dis Colon Rectum 2009, 52(2): 311

Cadexomer iodine
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
CAS Number
ChemSpider
  • none

//////////////Cadexomer Iodine, ind 2018, Cadex, Declat, Decrat, Dextrinomer iodine, Iodoflex, Iodosorb, NI-009,

Clofarabine


Clofarabine.svg

ChemSpider 2D Image | Clofarabine | C10H11ClFN5O3

Clofarabine.png

Clofarabine

  • Molecular FormulaC10H11ClFN5O3
  • Average mass303.677 Da
(2R,3R,4S,5R)-5-(6-Amino-2-chlor-9H-purin-9-yl)-4-fluor-2-(hydroxymethyl)tetrahydrofuran-3-ol
(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxyméthyl)tétrahydrofuran-3-ol
CAS 123318-82-1 [RN]
2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine [ACD/IUPAC Name]
762RDY0Y2H
8422
9H-Purin-6-amine, 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)- [ACD/Index Name]
Cl-F-Ara-A
QA-3028
STOCK1N-71250
UD7473000
UNII:762RDY0Y2H

CENTRAL DRUGS STANDARD CONTROL ORGANIZATION
DIRECTOR GENERAL OF HEALTH SERVICES,
MINISTRY OF HEALTH AND FAMILY WELFARE,
GOVERNMENT OF INDIA

approved

Clofarabine Bulk & Injection 20 mg/20ml vial
For the treatment of patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate
16.01.2018

Clofarabine is a purine nucleoside antimetabolite marketed in the US and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia(ALL) in children after at least two other types of treatment have failed. It is not known if it extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy, if any, for managing other cancers.

Clofarabine is a purine nucleoside antimetabolite that is being studied in the treatment of cancer. It is marketed in the U.S. and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra.

Clofarabine is used in paediatrics to treat a type of leukaemia called relapsed or refractory acute lymphoblastic leukaemia (ALL), only after at least two other types of treatment have failed. It is not known if the drug extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out.

For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.

Approval

Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)

Image result for us flag

Side effects

  • Tumor lysis syndrome (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away.
  • Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
  • Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cellswhite blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
  • Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
  • Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
  • Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection. Clofarabine can also cause tachycardia and can affect the liver and kidneys.

Contraindications

  • pregnancy or planned pregnancy
  • breast-feeding
  • liver problems
  • kidney problems

Drug interactions

  • nephrotoxic drugs
  • hepatotoxic drugs

Delivery

  • By intravenous infusion.
  • Dosage is a 2-hour infusion (52 mg/m²) every day for five days. The cycle is repeated every 2 to 6 weeks.
  • Regular blood tests to monitor his or her blood cells, kidney function, and liver function.

Biology

Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine.[1] A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.[2]

Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate. The rate-limiting step in clofarabine metabolism is clofarabine-5´-diphosphosphate. Clofarabine-5´-triphosphate is the active-metabolite, and it inhibits ribonucleotide reductase, resulting in a decrease cellular dNTP concentrations, which promotes greater incorporation of clofarabine-5´-triphosphate during DNA synthesis. Embedded clofarabine-5´-monophosphate in the DNA promotes polymerase arrest at the replication fork, triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c-mediated apoptosis in vitro. Studies using cell lines have shown that clofarabine-5´-triphosphate can also be incorporated into RNA.[3]

Mechanisms of resistance and turnover have been reported. Clofarabine-resistance arises from decreased deoxycytidine kinase activity in vitro.[4] ABC transporter ABCG2 promotes export of clofarabine-5´-monophosphate and thus limits the cytotoxic effects of this analog in vivo.[5] Biochemically, clofarabine-5’-triphosphate was shown to be substrate for SAMHD1, thus potentially limiting the amount of active compound in cells.[6]

Image result for clofarabine synthesis

Synthesis

Production of Clofarabine
The reaction flask was added 2-chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D arabinose yl) adenine 1.5g (3mmol) and methanol 40ml,mixed with stirring. Then it was added sodium methoxide, 0.05g (content> 50%), the reaction was stirred for 40min. Then the mixture was cooled to room temperature, adjusted to pH 7 with acetic acid, filtered, and the filter cake was washed with an ice-methanol 10ml, added to the methanol 40ml, and heated to 63 °C, and then cooled to -10 o C. Still 1h, filtered, and the filter cake was washed with an ice-methanol 10ml, drained, dried under reduced pressure to give an off-white powdery solid clofarabine 0.48g. The yield is 54%.

Image result for clofarabine synthesis

CLIP

Image result for clofarabine synthesis

http://pubs.rsc.org/en/content/articlehtml/2017/ra/c6ra27790j

CLIP

Image result for clofarabine synthesis

SYN 1

JP 1993502014; US 5034518; WO 9014352

Reaction of 1,2:5,6-di-O-isopropylidene-3-O-tosyl-a-D-allofuranose (I) with KF in acetamide at 210 oC gives 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (II), which is treated with a 1:1 mixture of metha-nol and 0.7% aqueous H2SO4 to yield 3-deoxy-3-fluoro-1,2-isopropylidene-a-D-glucofuranose (III). Selective acylation of the sugar (III) with benzoyl chloride in pyridine affords the 6-O-benzoyl derivative (IV), which is treated with Amberlite IR-100 (H+) ion-exchange resin in hot dioxane to provide 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (V). The oxidative cleavage of glucofuranose (V) by means of KIO4 in water results in rearrangement to give 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D- arabinofuranose (VI), which is deformylated by means of NaOMe in methanol to provide 5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (VII). Acylation of the arabinofuranose (VII) with acetic anhydride in pyridine affords the 1,3-di-O-acetyl derivative (VIII), which is treated with HBr in AcOH/CH2Cl2 to yield 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (IX). Condensation of compound (IX) with 2-chloroadenine (X) by means of potassium tert-butoxide in different solvents gives the acylated 2-chloroadenosine derivative (XI), which is finally deacylated by means of NaOMe in methanol

Carbohydr Res 1975,42(2),233

Drugs Fut 2004,29(2),112

J Med Chem 1992,35(2),397

US 2003114663; WO 0311877

CA 2400470; EP 1261350; WO 0160383

References

  1. Jump up^ Parker WB, Allan PW, Hassan AE, Secrist JA 3rd, Sorscher EJ, Waud WR (Jan 2003). “Antitumor activity of 2-fluoror-2’deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase”. Cancer Gene Ther10 (1): 23–29. doi:10.1038/sj.cgt.7700520PMID 12489025.
  2. Jump up^ Bonate PL, Arthaud L, Cantrell WR Jr, Stephenson K, Secrist JA 3rd, Weitman S (Feb 2014). “Discovery and development of clofarabine: a nucleoside analogue for treating cancer”. nat Rev Drug Discov5 (10): 855–63. doi:10.1038/nrd2055PMID 17016426.
  3. Jump up^ Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). “Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs”. Chem Rev116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209PMID 27960273.
  4. Jump up^ Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F (1999). “Biochemical pharmacology and resistance to 2-chloro-2′-arabino-fluoro-2’deoxyadenosine, a novel analogue of cladribine in human leukemic cells”. Clin Cancer Res5 (9): 2438–44. PMID 10499616.
  5. Jump up^ Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, Sparreboom A, Schuetz JD (Mar 2011). “Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity”Cancer Res75 (1): 1781–91. doi:10.1158/0008-5472.CAN-10-1919PMC 3531552Freely accessiblePMID 21245102.
  6. Jump up^ Arnold LH, Kunzelmann S, Webb MR, Taylor IA (Jan 2015). “A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1”Antimicrob Agents Chemother59 (1): 186–92. doi:10.1128/AAC.03903-14PMC 4291348Freely accessiblePMID 25331707.

External links

Clofarabine
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Clinical data
Trade names Clolar, Evoltra
AHFS/Drugs.com Monograph
MedlinePlus a607012
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Intravenous
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  • In general: ℞ (Prescription only)
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Formula C10H11ClFN5O3
Molar mass 303.677 g/mol
3D model (JSmol)

//////////////////ind 2018, Clofarabine, Nucleotides

C1=NC2=C(N1C3C(C(C(O3)CO)O)F)N=C(N=C2N)Cl

FDA approves first therapy Crysvita (burosumab) for rare inherited form of rickets, x-linked hypophosphatemia


FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia

The U.S. Food and Drug Administration today approved Crysvita (burosumab), the first drug approved to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH), a rare, inherited form of rickets. XLH causes low levels of phosphorus in the blood. It leads to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a patient’s life.

April 17, 2018

Release

The U.S. Food and Drug Administration today approved Crysvita (burosumab), the first drug approved to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH), a rare, inherited form of rickets. XLH causes low levels of phosphorus in the blood. It leads to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a patient’s life.

“XLH differs from other forms of rickets in that vitamin D therapy is not effective,” stated Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “This is the first FDA-approved medication for the treatment of XLH and a real breakthrough for those living with this serious disease.”

XLH is a serious disease affecting approximately 3,000 children and 12,000 adults in the United States. Most children with XLH experience bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with XLH experience persistent discomfort or complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss.

The safety and efficacy of Crysvita were studied in four clinical trials. In the placebo-controlled trial, 94 percent of adults receiving Crysvita once a month achieved normal phosphorus levels compared to 8 percent of those receiving placebo. In children, 94 to 100 percent of patients treated with Crysvita every two weeks achieved normal phosphorus levels. In both children and adults, X-ray findings associated with XLH improved with Crysvita therapy. Comparison of the results to a natural history cohort also provided support for the effectiveness of Crysvita.

The most common adverse reactions in adults taking Crysvita were back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation. The most common adverse reactions in children were headache, injection site reaction, vomiting, decreased vitamin D and pyrexia (fever).

Crysvita was granted Breakthrough Therapy designation, under which the FDA provides intensive guidance to the company on efficient drug development, and expedites its review of drugs that are intended to treat serious conditions where clinical evidence shows the drug may represent a substantial improvement over other available therapies. Crysvita also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the 14th Rare Pediatric Disease Priority Review Voucher issued by the FDA since the program began.

The FDA granted approval of Crysvita to Ultragenyx Pharmaceutical Inc.

 

////////////fda 2018, Crysvita, burosumab, Breakthrough Therapy, priority review.  Ultragenyx Pharmaceutical Inc

WO 2018066004, NEW PATENT, INDOCO REMEDIES LIMITED, DORZOLAMIDE


Image result for indoco remedies

 (WO2018066004) PROCESS FOR THE PREPARATION OF DORAOLZMIDE HYDROCHLORIDE

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018066004&redirectedID=true

Applicants: INDOCO REMEDIES LIMITED [IN/IN]; Indoco House, 166 C.S.T. Road, Santacruz (East) Mumbai, Maharashtra 400098 (IN)
Inventors: SHETH, Nilima; (IN).
KUDUVA, Srinivasan Subramanian; (IN).
RAMESAN, Palangat Vayalileveetil; (IN).
PANANDIKAR, Aditi Milind; (IN)

nilima sheth

SHETH, Nilima

Image result for indoco remedies

Aditi Kare Panandikar, Managing Director, Indoco Remedies

Process for preparing dorzolamide hydrochloride is claimed. It is disclosed that dorzolamide hydrochloride is a carbonic anhydrase inhibitor. 

Trusopt is an ophthalmic solution containing the carbonic anhydrase inhibitor dorzolamide hydrochloride for treating intraocular pressure in patients with ocular hypertension or open-angle glaucoma, which was developed and launched by Merck & Co , and is also now marketed by Santen Pharmaceuticals and Mundipharma International . 

In April 2018, Newport Premium™ reported that Indoco Remedies was capable of producing commercial quantities of dorzolamide hydrochloride and holds an active US DMF since 2010

Dorzolamide hydrochloride is a carbonic anhydrase (CA) inhibitor. It is chemically represented by (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride; and is structurally represented

Formula I

It acts as an anti -glaucoma agent, in open-angle glaucoma and ocular hypertension. It is used in ophthalmic solutions to lower intraocular pressure (IOP).

The compound dorzolamide hydrochloride has been in the market for very long time. It is administered as a topical ophthalmic in the form of a solution and marketed under the brand name T rusopt.

Dorzolamide hydrochloride and process for its preparation are first described in the patent, US 4,797,413 (US 413 Patent) and its corresponding European patent, E P 0296879. The process described in US 413 patent involves reacting thiophene-2-thiol with but-2-enoic acid and further proceeds with formation of racemic 4- ( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide (dorzolamide base).

A number of further processes for the preparation of dorzolamide hydrochloride have been devised and in many of these, as well as in the above US 413 Patent, the last step of the process involves the removal of diastereomeric impurity from the racemic mixture of dorzolamide base. To obtain pure dorzolamide hydrochloride devoid of the diastereomeric impurity of cis-isomer from the racemic compound, as per the patent US ~413, racemic mixture of dorzolamide base is subjected to column chromatography and then resolution is carried out using resolving agent di-p-tol uoyl-L -tartaric acid monohydrate in n-propanol. The salt formed is treated with base to get dorzolamide free base, which is reacted with ethanolic hydrochloric acid to get dorzolamide hydrochloride. The compound is further recrystallised from mixture of solvents viz., methanol and isopropanol to get pure dorzolamide hydrochloride.

US 5,688,968 describes a process for preparation of dorzolamide hydrochloride, wherein chiral hydroxyl sulfone compound having fixed chirality, proceeds via Ritter reaction to obtain dorzolamide base having mixture of cis- and trans-isomer. The compound dorzolamide base is reacted with maleic acid to isolate maleate salt of dorzolamide. The salt is again converted to free base and then reacted with hydrochloric acid in ethyl acetate to get required pure trans-isomer of dorzolamide hydrochloride.

The PCT patent publication W 02006038222 discloses the preparation of dorzolamide hydrochloride, wherein the cis- and trans-isomer of racemic dorzolamide base is separated using resolution via chiral salt formation with di benzoyl -L -tartaric acid monohydrate or di-p-tol uoyl-L -tartaric acid monohydrate in methanol which on neutralization results in dorzolamide base. The base is then reacted with hydrochloric acid in isopropanol to give

dorzol amide hydrochloride which is recrystalised in isopropanol to obtain pure dorzol amide hydrochloride.

Another US patent US 7,109,353 discloses the process for preparation of dorzolamide hydrochloride, wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with mineral acid to form the corresponding salt, which is then converted to racemic trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide and resolved with di-p-toluoyl-D -tartaric acid followed by neutralization of the chiral salt to isolate trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in ethanol results in required trans-dorzolamide hydrochloride.

PCT patent publication WO2007122130 discloses the process for preparation of (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, wherein racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide having trans:cis diastereomeric mixture of 80:20 is treated with maleic acid in acetone to isolate racemic trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide maleate salt having trans:cis diastereomeric mixture of 95:5. The isolated maleate salt is then treated with base and reacted with (1 S)-(+)-10-camphorsulfonic acid to get corresponding (4S,6S)-4-(ethylamino)-6-methyl-5, 6-di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di ox i de ( 1 S ) -( + )- 10-camphorsulfonate salt, which is neutralized to give pure (4S,6S)-4-(ethylamino)-6- methyl -5, 6-di hydro-4H -thi eno[2,3- b] thi opyran-2-sulf onami de 7, 7-di oxi de.

PCT patent publication W 02008135770 discloses the process for the preparation of dorzolamide hydrochloride, wherein the racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with

carboxylic acid selected from the group consisting of fumaric acid, benzoic acid, acetic acid, salicylic acid and p-hydroxybenzoic acid, which selectively forms an acid addition salt with the trans- isomer and removes the undesirable c is- isomer from the mixture of cis and trans- isomers. The trans-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide acid addition salt is converted to trans-(e)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide by conventional methods. The compound trans-(e)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is resolved with di-p-toluoyl-L -tartaric acid followed by neutralization of the chiral salt yields the compound (4S,6S)4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, which on reaction with hydrochloric acid in isopropanol results in the required (4S,6S)4-( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide hydrochloride.

PCT patent publication WO2010061398 discloses the process for the preparation of dorzolamide hydrochloride, wherein the racemic 4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide is treated with maleic acid in water to get trans-dorzolamide maleate salt. The maleate salt is further neutralized and then resolution with di-p-toluoyl-L -tartaric acid followed by neutralization of the chiral salt yields (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in isopropanol results in the required pure trans-dorzolamide hydrochloride.

PCT patent publication WO2011101704 and corresponding Indian Patent application 426/C H E/2010 describes the process for the preparation of trans-dorzolamide hydrochloride by forming the maleate salt of racemic 4-( ethyl ami no) – 6- methyl -5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de 7, 7-di oxide. The maleate salt is further neutralized and then resolution with di-p-

toluoyl-L -tartaric acid followed by neutralization of the chiral salt yields trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide. The compound trans-(4S,6S)-4-(ethylamino)-6-methyl- 5.6- dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide on reaction with hydrochloric acid in isopropanol results in the required trans-(S,S)-dorzol amide hydrochloride.

Indian Patent application 3431 /M U M/2012 discloses the process wherein racemic 4-( ethyl ami no) -6- methyl – 5, 6- di hydro-4H -thi eno[2, 3- b] thi opy ran-2-sul f onami de

7.7- dioxide is resolved using di benzoyl- L -tartaric acid monohydrate or di-p-toluoyl-L -tartaric acid monohydrate in methanol followed by neutralization of the chiral salt and then the (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide thus obtained is treated with hydrochloric acid in isopropanol to result in the required trans-(S,S)-dorzolamide hydrochloride. The compound is further recrystallised in isopropanol to isolate pure dorzol amide hydrochloride.

The prior art processes disclosed as above have several drawbacks in the preparation of pure trans-dorzolamide hydrochloride viz.,

1. involves column chromatography for separation of the desired diastereomer;

2. involves preparation of corresponding diastereomeric salts and converting again to base before preparation and isolation of pure trans-dorzolamide hydrochloride;

3. involves additional step of reacting the racemic dorzolamide base with mineral acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and further resolved using resolving agent to form the corresponding salt, neutralization and isolation of the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride; and

4. involves an additional step of reacting the racemic dorzolamide base with carboxylic acid to isolate corresponding dorzolamide salt which is again converted to dorzolamide base and resolved using resolving agent to form the corresponding salt, neutralization and isolation of the chiral dorzolamide base before reacting with hydrochloric acid to obtain dorzolamide hydrochloride.

As is evident from the cursory review of the prior arts that the preparation of pure dorzolamide hydrochloride involves either column chromatography for isolation of trans- isomer followed by use of resolving agent or involves repeated preparations of chiral or diastereomeric salts, use of resolving agent followed by converting into dorzolamide base and then isolating pure dorzolamide hydrochloride devoid of the diastereomeric impurity of cis-isomer.

Therefore, there remains a need in the art to develop a simple and cost effective process for the preparation of dorzolamide hydrochloride which ameliorates the above drawbacks of the prior arts and makes the process industrially viable and economically advantageous. The present invention therefore seeks to address these issues by providing an improved and cost-effective process that can easily be scaled for industrial production of dorzolamide hydrochloride.

The present inventors have developed an alternative process for isolating pure dorzolamide hydrochloride substantially free from the cis-isomer without using the time consuming column chromatography technique, repeated preparation of chiral salts, diastereomeric salts and converting into base before hydrochloride salt formation to isolate pure trans-(S,S)-dorzolamide hydrochloride.

E xamples:

E xample 1 : Preparation of (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride:

In a dry flask charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (50.0 gm) in acetone (700 ml) under stirring and cooled to OeC. Maintaining the temperature at OeC to 5eC purged hydrochloric acid gas to adjust the pH to acidic between the range of 1-2. After attaining desired pH, maintained the reaction mass for two hours at OeC to 5eC under stirring. Filtered the precipitated compound (6S)-4-(ethylamino)-6-methyl-5, 6-di hydro-4H -thi eno[2,3- b] thi opyran-2-sulf onami de 7,7-di oxi de hydrochl ori de and washed the solid mass with chilled acetone (50 ml). Dried the compound at 60-65eC till constant weight.

Dry weight: 50 g

H PL C purity: 77.62% [cis-isomer: 22.11 % ]

E xample 2: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride [C rude dorzolamide hydrochloride]:

In a dry flask charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (19.0 g) and methanol (190 ml) at temperature of 25eC to 30eC. Under stirring raised the temperature of the reaction mass to reflux and maintained at reflux temperature for a period of two hours. After maintaining cooled the reaction mass gradually to 10eC to 15eC. Filtered the compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride and washed the solid mass with chilled methanol. Dried the compound at 60-65eC till constant weight.

Dry weight: 12.8 g

H PL C purity: 99.33% [cis-isomer: 0.5% ]

E xample 3: Purification of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride: In a dry flask charged trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (11.0 g), acetone (11 ml) and purified water (5.5 ml) at the temperature of 25eC to 30eC. Raised the temperature of the reaction slurry to reflux and maintained at reflux for one hour. Diluted the reaction mass with fresh acetone (44 ml) maintaining the temperature at reflux and continued maintaining at reflux temperature further for one hour. Cooled the reaction mass gradually to 10eC to 15eC and maintained. Filtered the compound pure (4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride solid mass and washed the pure compound with chilled acetone (11 ml). Dried at 55eC to 60eC till constant weight.

Dry weight: 8.8 g

H PL C purity: 99.89% [cis-isomer: not detected]

[T otal impurities: 0.11 % ]

E xample 4: Preparation of trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H -thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride [C rude dorzolamide hydrochloride]:

Charged (6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride (5.0 g), methanol (22.5 ml) and 2.5 ml purified water at temperature of 25eC to 30eC. Under stirring raised the temperature of the reaction mass to reflux and maintained at reflux temperature for a period of two hours. After maintaining cooled the reaction mass gradually to 30eC to 35eC. Filtered the solid compound trans-(4S,6S)-4-(ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride and washed with methanol (10 ml). Dried the compound at 60eC to 65eC till constant weight.

Dry weight: 3.2 g

H PL C purity: 99.47% [cis-isomer: 0.43% ]

////////WO 2018066004, NEW PATENT, INDOCO REMEDIES LIMITED, DORZOLAMIDE

WO 2018067805, NEW PATENT, SOTAGLIFLOZIN, TEVA


Image result

WO-2018067805

(WO2018067805) SOLID STATE FORMS OF SOTAGLIFLOZIN

TEVA PHARMACEUTICAL INDUSTRIES LTD.

GIAFFREDA, Stefano Luca; (IT).
MODENA, Enrico; (IT).
IANNI, Cristina; (IT).
MUTHUSAMY, Anantha Rajmohan; (IN).
KANNIAH, Sundara Lakshmi; (IN)

Stefano Luca Giaffreda at PolyCrystallineStefano Luca Giaffreda

Enrico Modena at PolyCrystallineEnrico Modena

Sundara Lakshmi KanniahSundara Lakshmi Kanniah
Novel crystalline forms of sotagliflozin (designated as Forms A and E) and their hydrate and monohydrate, processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating diabetes. Sotagliflozin is known to be an inhibitor of sodium glucose transporter-1 and -2, useful for treating insulin dependent diabetes and non-insulin dependent diabetes

Sotagliflozin has the chemical name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H- pyran-3,4,5-triol. Sotagliflozin has the following chemical structure:

[0003] Sotagliflozin is an orally available L-xyloside based molecule that apparently inhibits both sodium-glucose transporter type 1 (SGLT1) and type 2 (SGLT2). SGLT1 is primarily responsible for glucose and galactose absorption in the gastrointestinal tract, and SGLT2 is responsible for most of the glucose reabsorption performed by the kidney.

[0004] Sotagliflozin is known from WO 2008/109591. Amorphous forms and crystalline forms (i.e. Form 1 and Form 2) of Sotagliflozin are disclosed in WO2010/009197.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Sotagliflozin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving

formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Sotagliflozin.

EXAMPLES

Sotagliflozin Form-2 may be prepared according to WO2010/009197. Sotaglifiozin Form-2 may also be prepared according to Example 16 below.

Working examples:

Example- 1 : Preparation of Sotagliflozin (Amorphous Form)

[0080] 2 g of Sotagliflozin (Form-2) was taken in 250ml round bottom flask and applied vacuum (approx. 50 mbar) with continuous rotation of the flask. The flask was externally heated by hot air flow maintained at few centimetres from the rotating flask wall for few minutes until the compound melts at around 130°C and the melt was quenched to room temperature (25°C) with water bath. The amorphous solid (1.8 g) was scratched from the walls of the flask.

Example-2: Preparation of Sotagliflozin Form A

[0081] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of water, was left at variable temperature as follows: heating from 10°C to 50°C at the rate of 20°C/hr, held at 50°C for 3 hrs; cooling from 50°C to 10°C at the rate of 20°C/hr, held at 10°C for 3hrs; again heating from 10°C to 50°C at the rate of 10°C/hr, held at 50°C for 3hrs; again cooling from 50°C to 10°C at the rate of 10°C/hr, held at 10°Cfor 3hrs; further heating from 10°C to 50°C at the rate of 5°C/hr, held at 50°C for 3hrs; further cooling from 50°C to 10°C at the rate of 5°C/hr, held at 10°C for 3hrs; followed by raising the temperature from 10°C to 25°C at the rate of 10°C/hr, held at 25°C for 24hrs. The suspension was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form A has been confirmed by PXRD as presented in figure 1.

Example-3 : Preparation of Sotagliflozin Form B

[0082] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Toluene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD as presented in figure 2.

Example-4: Preparation of Sotagliflozin Form B

[0083] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Heptane at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-5 : Preparation of Sotagliflozin Form B

[0084] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Mesitylene at room temperature (20-25°C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-6: Preparation of Sotagliflozin Form B

[0085] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of p-Xylene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-7: Preparation of Sotagliflozin Form C

[0086] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Water at 50°C. The suspension was stirred for 72hrs which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form C has been confirmed by PXRD as presented in figure 3.

Example-8: Preparation of Sotagliflozin Form D

[0087] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of ethanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20 ml vial and left open to allow evaporation of the solvent (25°C/1 atm). Solid was observed after 3 days; it was collected and analyzed by PXRD. Sotagliflozin Form D has been confirmed by PXRD as presented in figure 4.

Example-9: Preparation of Sotagliflozin Form E

[0088] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of isopropyl acetate. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. The crystals were observed after 9 days; it was collected and analyzed by PXRD. Sotagliflozin Form E has been confirmed by PXRD as presented in figure 5.

Example-9: Preparation of Sotagliflozin Form F

[0089] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 2-propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened to allow evaporation of the solvent (4-7°C/l atm). The crystals were observed after 13 days; it was collected and analyzed by PXRD. Sotagliflozin Form F has been confirmed by PXRD as presented in figure 6.

Example- 10: Preparation of Sotagliflozin Form G

[0090] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 1 -propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. Solid was observed after 24 days; it was collected and analyzed by PXRD.

Sotagliflozin Form G has been confirmed by PXRD as presented in figure 7.

Example- 11 : Preparation of Sotagliflozin Form H

[0091] 15 mg of Sotagliflozin (Form- A) was kept in DVS (dynamic vapor sorption) instrument. The kinetic sorption measurement was performed at 25 °C in two full cycle of sorption and desorption as follows, from 40%RH to 90%RH, 90%RH to 0%RH then again from 0% to 90%RH, 90%RH to 0%RH. After completion of experiment, the powder was collected and analyzed by PXRD. Sotagliflozin Form H has been confirmed by PXRD as presented in figure 8.

Example- 12: Preparation of Sotagliflozin Form I

[0092] Procedure to prepare saturated solution: 1500 mg of Sotagliflozin were dissolved in 1ml of 2-Methoxyethanol and the solution was stirred overnight at 25°C; the solution was then filtered. Taken ΙΟΟμί from above saturated stock solution, 500μί of Diisopropylether was added drop by drop, no solid was observed left the solution overnight under stirring, added again 500μί of Diisopropylether into the entire solution. The solid was precipitated, stirred for 30min and filtered under vacuum. Sotagliflozin Form I has been confirmed by PXRD as presented in figure 9.

Example-13: Preparation of Sotagliflozin Form K

[0093] 10-20mg of Sotagliflozin (Form D) was kept for drying in a natural air convection oven (MPM instruments modelM40-VN) at 60°C for lh. Sotagliflozin Form K has been confirmed by PXRD as presented in figure 10.

Example-14: Preparation of Sotagliflozin Form E:

[0094] Sotagliflozin (2g) and ethyl acetate (6ml) were heated to reflux temperature (71-74°C). Heptane (6ml) was added at reflux, reaction mass was stirred for additional 15 minutes and then cooled to room temperature. Solid was precipitated out during cooling at about 57°C. A mixture of ethyl acetate and heptane (1 : 1 v/v, 24 ml) was added and the reaction mixture was heated to reflux temperature (71-74°C) to obtain a clear solution which was maintained for 15 minutes. Reaction mass was cooled to room temperature (25-30°C) and stirred for 3 hours. The slurry was filtered, washed with a mixture of ethyl acetate and heptane (l : lv/v, 8ml) and dried under vacuum at 50°C for 2Hrs. The obtained solid (1.8g) was analyzed by PXRD-Form E.

Example-15: Preparation of Sotagliflozin Form D:

[0095] 2g of sotagliflozin Form F was kept in glass petri-dish and exposed to 80%RH for 60hrs at room temperature. Solid was collected (2g) and analyzed for PXRD-Form D.

Example-16: Preparation of Sotagliflozin Form 2:

[0096] 50 gm of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(Methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (SOT-1) and 500ml of methanol were charged in round bottom flask, the slurry was cooled to 20°C then added sodium methoxide solution prepared in methanol (2.45gm of sodium methoxide in 50ml of methanol) at 20°C

over the period of 10 min and stirred the mass for 2hr at 20°C.The reaction completion was ensured by HPLC. Once the reaction is completed added 2.5gm Norit carbon to the reaction mass at 23°C and stirred for 30min. Filtered the reaction mass through Hyflo bed and washed with 20ml of methanol. Taken the filtrate into the flask and concentrated under vacuum at 45°C up to 3 volumes with respect to SOT-1 then cooled to 21°C over the period of 60 min, added 560ml of Water at 21°C over the period of 30min and stirred for 30min at 21 °C, the reaction mass left overnight (without stirring) and stirred for lhr. The obtained slurry was filtered under vacuum and washed with 55ml*3times of water then kept for suction at 20-30°C for 30min. The material was dried at 50-60°C for 9hrs under vacuum to obtain 35gm of Sotagliflozin. 5.7gm of Sotagliflozin (5.7gr, Sotagliflozin) and 28.5ml of Methyl ethyl ketone (28.5ml) were charged in round bottom flask, the slurry was stirred at 22-25°C for 5-10min gradually raised the temperature to 78°C then added 114 ml of n-Heptane (114ml) at 78°C over the period of 55min. Once the addition of n-heptane was completed, seeds of Form-2 (20 mg) were added, the slurry was gradually cooled down to 25-27°C over the period of 60 min. The obtained slurry was stirred for 2-3hrs at 25-27°C and the mass was kept overnight (without stirring) at 25-27°C then stirred for 3hr at 23 °C. The mass was filtered under vacuum and washed with 10ml of n-Heptane then kept for suction for 30min at 25-30°C. The material was dried at 50°C for 2hrs under vacuum to obtain Form-2 of Sotagliflozin.

Preparation of Form 2- Seeds

[0097] Sotagliflozin (2gr, amorphous) was dissolved in methyl ethyl ketone (10ml) The slurry was heated to 80°C, then n-Heptane (40ml) was added over 60mins. The hazy solution was cooled to 20-30° over 60mins and stirred for 3hr. The slurry was kept overnight at 20-30°C (without stirring). The obtained slurry was filtered under vacuum and washed with n-Heptane (10ml) . The material was dried at 50 °C for 4hrs under vacuum to obtain the 1.9gm of Sotagliflozin Form -2 as confirmed by PXRD.

///////////WO 2018067805, NEW PATENT,  SOTAGLIFLOZIN, TEVA

BMS-986118, for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)


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BMS-986118
BMS compd for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)
Cas 1610562-74-7
1H-Pyrazole-5-acetic acid, 1-[4-[[(3R,4R)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)-
Molecular Weight, 540.96, C25 H28 Cl F3 N4 O4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid

(-)-[(4S,5S)-1-(4-[[(3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid

  • (4S,5S)-1-[4-[[(3R,4R)-1-(5-Chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-1H-pyrazole-5-acetic acid
  • 2-[(4S,5S)-1-[4-[[1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl]-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid isomer 2

BMS-986118 is a GPR40 full agonist. GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia

Image result for bms

NOTE CAS OF , 1H-Pyrazole-5-acetic acid, 1-[4-[[(3S,4S)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)- IS 1610562-73-6

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Image result for BMS-986118,

SYNTHESIS

WO 2014078610

PAPER

https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00982

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

Abstract

Abstract Image

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitroIn vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

Compound 4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (4)

To a stirred solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (5.5 g, 9.9 mmol) in THF (90 mL) and water (9 mL) at room temperature was added 2 N LiOH solution (12 mL, 24 mmol). The reaction mixture was stirred at room temperature for 16 h, and 1 N HCl (25 mL, 25 mmol) was added at 0 °C to pH = 4–5. The solvent was evaporated, and the residue was extracted three times with EtOAc. The organic extracts were dried over Na2SO4; the solution was filtered and concentrated. The residue was recrystallized from isopropanol to give 4(neutral form) as white solid (4.3 g, 7.7 mmol, 78% yield).
1H NMR (500 MHz, DMSO-d6) δ ppm 12.52 (br s, 1H), 8.01 (s, 1H), 7.05 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 6.40 (s, 1H), 4.49–4.33 (m, 1H), 4.02 (td, J = 8.8, 4.1 Hz, 1H), 3.80 (s, 3H), 3.56–3.39 (m, 2H), 3.37–3.29 (m, 1H), 2.94–2.85 (m, 1H), 2.72–2.66 (m, 1H), 2.64 (dd, J = 16.1, 2.9 Hz, 1H), 2.49–2.41 (m, 1H), 2.22–2.05 (m, 1H), 2.01–1.86 (m, 1H), 1.68–1.50 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H).
 
13C NMR (126 MHz, DMSO-d6) δ 171.5, 163.7, 157.1, 152.5, 146.3, 139.7 (q, J = 34.7 Hz), 136.2, 121.7 (q, J = 269.3 Hz), 117.3, 117.2, 116.0, 100.4, 78.9, 65.6, 54.2, 53.4, 47.8, 44.2, 36.0, 34.9, 29.5, 17.4, 15.3. 19F NMR (471 MHz, DMSO-d6) δ −61.94 (s, 3F).
 
Optical rotation: [α]D(20)−11.44 (c 2.01, MeOH).
 
HRMS (ESI/HESI) m/z: [M + H]+ Calcd for C25H29ClF3N4O4 541.1824; Found 541.1813. HPLC (Orthogonal method, 30% Solvent B start): RT = 11.9 min, HI: 97%. m/zobs 541.0 [M + H]+.
 
Melting point = 185.5 °C.
PAPER

Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

Chemical and Synthetic DevelopmentBristol-Myers Squibb CompanyOne Squibb Drive, New Brunswick, New Jersey08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00022

Abstract

Abstract Image

The final two steps used to prepare greater than 1 kg of a compound evaluated as a treatment for type 2 diabetes are reported. The application of a palladium-catalyzed C–O coupling presented significant challenges due to the nature of the reactants, impurities produced, and noncrystalline coupling intermediate. Process development was able to address these limitations and enable production of kilogram quantities of the active pharmaceutical ingredient (API) in greater efficiency than a Mitsunobu reaction for formation of the key bond. The development of a sequence that telescopes the coupling with the subsequent ester hydrolysis to yield the API and the workup and final product crystallization necessary to produce high-quality drug substance without the need of column chromatography are discussed.

Bruce Ellsworth

Bruce Ellsworth, Director, Head of Fibrosis Discovery Chemistry at Bristol-Myers Squibb

Rick EwingRick Ewing, Head, External Partnerships, Discovery Chemistry and Molecular Technologies at Bristol-Myers Squibb
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PATENT
WO 2014078610
Original Assignee Bristol-Myers Squibb Company
Patent
Patent ID

Patent Title

Submitted Date

Granted Date

US9133163 DIHYDROPYRAZOLE GPR40 MODULATORS
2013-11-15
2014-05-22
US9604964 Dihydropyrazole GPR40 modulators
2013-11-15
2017-03-28
REF
1: Li Z, Qiu Q, Geng X, Yang J, Huang W, Qian H. Free fatty acid receptor
agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II
clinical development. Expert Opin Investig Drugs. 2016 Aug;25(8):871-90. doi:
10.1080/13543784.2016.1189530. PubMed PMID: 27171154.
2
Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
248th Am Chem Soc (ACS) Natl Meet (August 10-14, San Francisco) 2014, Abst MEDI 31
MEDI John Macor Sunday, August 10, 2014
Oral Session
General Oral Session – PM Session
Organizers: John Macor
Presiders: John Macor
Duration: 1:30 pm – 5:15 pm
1:55 pm 31 Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
Bruce A Ellsworth, Jun Shi, Elizabeth A Jurica, Laura L Nielsen, Ximao Wu, Andres H Hernandez, Zhenghua Wang, Zhengxiang Gu, Kristin N Williams, Bin Chen, Emily C Cherney, Xiang-Yang Ye, Ying Wang, Min Zhou, Gary Cao, Chunshan Xie, Jason J Wilkes, Heng Liu, Lori K Kunselman, Arun Kumar Gupta, Ramya Jayarama, Thangeswaran Ramar, J. Prasada Rao, Bradley A Zinker, Qin Sun, Elizabeth A Dierks, Kimberly A Foster, Tao Wang, Mary Ellen Cvijic, Jean M Whaley, Jeffrey A Robl, William R Ewing.

///////////BMS-986118, Preclinical, BMS, Bruce A. Ellsworth,  Jun Shi,  William R. Ewing,  Elizabeth A. Jurica,  Andres S. Hernandez,  Ximao Wu, DIABETES,

COc1cc(c(Cl)cn1)N4CCC(Oc2ccc(cc2)N3N=C([C@@H](C)C3CC(=O)O)C(F)(F)F)[C@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@H](C)C4

BMS-986195


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BMS-986195
  • Molecular FormulaC20H23FN4O2
  • Average mass370.421 Da
  • CAS: 1912445-55-6
1H-Indole-7-carboxamide, 5-fluoro-2,3-dimethyl-4-[(3S)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-
4-[(3S)-3-(2-Butynoylamino)-1-piperidinyl]-5-fluor-2,3-dimethyl-1H-indol-7-carboxamid
(S)-4-(3-(2-Butynoylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide
  • Originator Bristol-Myers Squibb
  • Class Anti-inflammatories; Antirheumatics
  • Mechanism of Action Agammaglobulinaemia tyrosine kinase inhibitors

Highest Development Phases

  • Phase I Rheumatoid arthritis

Most Recent Events

  • 30 Jan 2018 Bristol-Myers Squibb completes a phase I trial in Rheumatoid arthritis (In volunteers, In adults, Combination therapy) in USA (PO) (NCT03262740)
  • 10 Nov 2017 Bristol-Myers Squibb completes a phase I drug-drug interaction trial in Healthy volunteers (NCT03131973)
  • 03 Nov 2017 Safety, pharmacokinetic, and pharmacodynamic data from a pharmacokinetic trial in healthy volunteers presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017)
  • Image result for BMS-986195

BMS-986195 is a potent, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases essential in antigen-dependent B-cell signaling and function. BMS-986195 is more than 5000-fold selective for BTK over all kinases outside of the Tec family, and selectivity ranges from 9- to 1010-fold within the Tec family. BMS-986195 inactivated BTK in human whole blood with a rapid rate of inactivation (3.5×10-4 nM-1·min-1) and potently inhibited antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50 <1 nM) without effect on antigen-independent measures in the same cells.

Bristol-Myers Squibb is developing BMS-986195, an oral candidate for the treatment of rheumatoid arthritis. A phase I clinical trial in healthy adult volunteers is ongoing.

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Structure of BMS986195.
Credit: Tien Nguyen/C&EN

Presented by: Scott H. Watterson, principal scientist at Bristol-Myers Squibb

Target: Bruton’s tyrosine kinase (BTK)

Disease: Autoimmune diseases such as rheumatoid arthritis

Reporter’s notes: Completing another set of back-to-back presentations on the same target, Watterson revealed another BTK inhibitor also in Phase II clinical trials. Chemists made BMS-986195 in seven steps, and the molecule showed high levels of BTK inactivation in mice. The team aimed to develop an effective compound that required low doses and that had low metabolic degradation.

Patent

WO 2016065226

Inventor Saleem AhmadJoseph A. TinoJohn E. MacorAndrew J. TebbenHua GongQingjie LiuDouglas G. BattKhehyong NguScott Hunter WattersonWeiwei GuoBertrand Myra Beaudoin

Original Assignee Bristol-Myers Squibb Company

https://patents.google.com/patent/WO2016065226A1/en

PATENT

WO 2018045157

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E81EF2BDB127473D100AAA55455FC42B.wapp1nA?docId=WO2018045157&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

otein kinases, the largest family of human enzymes, encompass well over 500 proteins. Btk is a member of the Tec family of tyrosine kinases, and is a regulator of early B-cell development, as well as mature B-cell activation, signaling, and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. The magnitude and duration of BCR signals must be precisely regulated. Aberrant BCR-mediated signaling can cause dysregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases. Mutation of Btk in humans results in X-linked agammaglobulinaemia (XLA). This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T-cell-independent immune responses and marked attenuation of the sustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmune disease and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in standard murine preclinical models of systemic lupus erythematosus (SLE), Btk deficiency has been shown to result in a marked amelioration of disease progression. Moreover, Btk deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics (such as Rituxan) developed to deplete B-cells, represent an important approach to the treatment of a number of autoimmune and/or inflammatory diseases.

Because of Btk’s role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Btk deficiency in mice is associated with impaired IgE -mediated mast cell activation (marked diminution of T F-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evan’s syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren’s syndrome, peripheral neuropathies (e.g., Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cell survival in certain B-cell cancers. For example, Btk has been shown to be important for the survival of BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Thus inhibition of Btk activity can be useful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as Btk and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients.

WO 2016/065226 discloses indole carboxamide compounds useful as Btk inhibitors, including (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (Example 223), which has the structure:

Also disclosed is multistep synthesis process for preparing (S)-4-(3-(but-2-ynamido) piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide.

There are difficulties associated with the adaptation of the multistep synthesis disclosed in WO 2016/065226 to larger scale synthesis, such as production in a pilot plant or a manufacturing plant for commercial production. Further, there is a continuing need to find a process that has few synthesis steps, provides higher yields, and/or generates less waste.

Applicants have discovered a new synthesis process for the preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide that has fewer synthesis steps and/or provides higher yields than the process disclosed in WO 2016/065226. Furthermore, this process contains no metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing.

EXAMPLE 1

(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

Step 1 : Preparation of Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-fluorobenz

To a 250 mL ChemGlass reactor were charged methyl 2-amino-4,5-difluoro-benzoate (11.21 g, 59.90 mmol), tert-butyl N-[(3S)-3-piperidyl]carbamate (10 g, 49.930 mmol), potassium phosphate, dibasic (10.44 g, 59.94 mmol), and dimethyl sulfoxide (100 mL, 1400 mmol). The resulting thin slurry was heated to 95 to 100 °C and agitated at this temperature for 25 hours. The mixture was cooled to 50 °C. Methanol (100 mL) was added and followed by slow addition of water (50 mL). The mixture was aged at 50 °C for 30 minutes to result in a thick white slurry. Additional water (150 mL) was slowly charged to the above mixture and agitated at 50 °C for 1 hour. The slurry was cooled to 20 °C in 1 hour and aged at this temperature for 4 hours. The slurry was filtrated. The wet cake washed with 25% MeOH in water (30 mL), water (100 mL) and dried under vacuum at 60 °C for 24 h. Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate was obtained as a white solid (7 g, yield: 72.5%). ¾ MR (400MHz, METHANOLS) δ 7.34 (d, J=14.6 Hz, 1H), 6.27 (d, J=7.3 Hz, 1H), 3.83-3.71 (s, 3H), 3.68-3.57 (m., 1H), 3.50 -3.40 (m 1H), 3.39 -3.31 (m, 1H), 3.31-3.26 (m, 1H), 2.86-2.70 (m, 1H), 2.64 (t, J=10.0 Hz, 1H), 1.97-1.84 (m, 1H), 1.84-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.44 (s, 9H), 1.38 (m, 1H). LC-MS [M+H] 368.

Step 2: Preparation of Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate

To a reactor were charged methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (5.0 g), DPPOH (diphenyl phosphate, 6.81 g, 2 eq) and 3-hydroxybutanone (1.2 eq, 1.44 g), followed by addition of isopropyl acetate (100 mL, 20 mL/g). The mixture was allowed to warm up to 70 to 75 °C, resulting in a yellow solution. The solution was stirred at 70 to 75 °C for 30 h to complete the cyclization.

Water (2 mL) was added and the mixture was aged at 70 °C over 24 h to remove the Boc group. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (50 mL) was added and the mixture was stirred for 15 min. The organic layer was separated and washed with water (50 mL). The organic layer was then concentrated under vacuum (200 Torr) to -50 mL. The resulting slurry was stirred at 50 °C for 2 h and then heptane (100 mL) was added over 1 h. The mixture was cooled to room

temperature, stirred for 20 h, and then filtered. The cake was washed with heptane (50 mL). Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate, DPPOH salt was obtained as a light yellow solid. The wet-cake was added to a reactor. Isopropyl acetate (100 mL) was added, followed by addition of aqueous K3PO4 solution (4 g in water 50 mL). The mixture was stirred at room temperature for -half-hour, resulting in a two phase clear solution (pH >10 for aqueous). The organic layer was separated and washed with water (50 mL), and then concentrated under vacuum to a volume of 15 mL. The resulting slurry was stirred at room temperature for 4 h, then heptane (75 mL) was added over 1 h. The mixture was aged at room temperature for 24 h, then concentrated to a volume to -50 mL. The slurry was filtered. The cake was washed with heptane 20 mL and dried under vacuum at 50 °C for 24 h. Methyl (S)-4-(3- aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate was obtained as a light yellow solid (2.76 g, yield: 69%). ¾ NMR (400MHz, DMSO-d6) δ 10.64 (s, 1H), 7.33 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 3.14 (br. m., 1H), 3.07-2.90 (m, 2H), 2.84 (br. m., 1H), 2.70 (br. m., 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.87 (br. m., 1H), 1.67 (br. m., 3H). LC-MS: M+H= 320.

Alternative Preparation

Step 2: Preparation of ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt

To a reactor were charged ethyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (1.0 g, limiting reagent), DPPOH (diphenyl phosphate, 1.97 g, 3.0 eq) and 3-hydroxybutanone (1.4 eq, 0.32 g), followed by addition of toluene (20 mL, 20 mL/g). The mixture was allowed to warm up to 80-90 °C, resulting in a yellow solution. The solution was stirred at 80-90 °C for 10 h to complete the

cyclization. Water (0.4 mL, 0.4 ml/g) was added and the mixture was aged at 80-90 °C for 8 hours. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (15 mL, 15 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was washed with toluene (7.5 mL, 7.5 mL/g). To combined organic layers water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. To the organic layer water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. The organic layer was concentrated under vacuum (100 Torr) to 8 mL (8 ml/g). Following concentration the reaction mixture was cooled to 20-25 °C and MTBE (20 mL, 20 mL/g) was added. Trifluoroacetic acid (1.2 eq., 0.36 g) was slowly added to make the salt maintaining temperature at 20-25 °C. The resulting slurry was aged for 4 hours and then filtered. The filtered solids are washed with MTBE (8 mL, 8 mL/g) and the cake

was dried under vacuum at 50 °C. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt was obtained as a white to tan crystalline material (85% yield, 1.0 g). ¾ NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.16-7.88 (m, 2H), 7.37 (d, 7=13.6 Hz, 1H), 4.38 (q, 7=7.1 Hz, 2H), 3.18-3.01 (m, 3H), 2.96 (br s, 1H), 2.35 (s, 6H), 2.30 (s, 1H), 2.12 (br d, 7=9.3 Hz, 1H), 1.78 (br s, 2H), 1.45-1.31 (m, 4H), 1.10 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 165.1, 165.1, 158.4, 158.1, 135.4, 134.7, 134.6, 132.2, 128.8, 128.2, 126.9, 126.8, 118.7, 115.7, 110.6, 110.3,108.7, 108.6, 106.6, 106.5, 83.5, 79.8, 60.5, 54.9, 51.7, 48.7, 47.2, 28.4, 26.8, 23.6, 14.2, 11.1, 10.2

Step 3A: Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 40 mL vial was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by the addition of N,N-dimethylformamide (12.0 mL, 8.0 mL/g). The vial was purged with N2. Formamide (1.49 mL, 37.6 mmol) was added followed by sodium methoxide solution in methanol (35 wt%, 1.29 mL, 3.76 mmol). The resulting solution was heated at 50 °C over 8 hours. The reaction mixture was cooled down to room temperature and the reaction was quenched with water (12.0 mL, 8.0 mL/g). 2-methyltetrahydrofuran (30 mL, 20 mL/g) was added to the mixture. The mixture was shaken vigorously. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL, 10 mL/g) two more times. Organic extracts were then washed with brine and water (15 mL each, 10 mL/g). The organic layer was evaporated. Solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow solid (1.04 g, 69% yield). ¾ NMR (500MHz, DMSO-d6) δ 10.60 (br. s.,

1H), 7.91 (br. s., 1H), 7.40 (d, 7=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Step 3B: Alternative Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 100 mL Hastelloy high pressure EasyMax reactor was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by addition of 7 N ammonia solution in methanol (45.0 mL, 30.0 mL/g) followed by addition of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (1.33 g, 9.39 mmol). The reactor was sealed and purged with N2 three times. The reactor was then heated to 80 °C for 24 hrs. The reaction mixture was cooled to room temperature and the vessel contents were purged with N2 three times. Volatiles were concentrated to ~6 mL (4 mL/g) and water (24 mL, 16 mL/g) was added. The yellow precipitate was collected and filtered. The precipitate was washed with methanol/water mixture (20:80 v/v, 6 mL, 4 mL/g), and then water (18 mL, 12 mL/g). The solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow crystalline material (0.93 g, 62% yield). ¾ MR (500MHz, DMSO-de) δ 10.60 (br. s., 1H), 7.91 (br. s., 1H), 7.40 (d, J=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Alternative Preparation:

Step 3C: Preparation of (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt

Ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt (1.0 g, limiting reagent) and formamide (5 mL, 5 mL/g) were added to a nitrogen inerted reactor. The temperature was maintained at 20-25 °C. To the reactor was added a solution of 20 wt% potassium t-butoxide in THF. The reaction mixture was allowed to sit for 6 hours. To reaction mixture was added Me-THF (15 mL, 15 mL/g) and 12.5 wt % aqueous NaCl (5 mL, 5 mL/g). The reaction mixture was stirred for 0.5 hour. The organic layer was separated, 5 wt% aqueous NaCl (1 mL, 1 mL/g) and 0.25 N aqueous NaOH (4 mL, 4 mL/g) were added, and then stirred for 0.5 hour. The organic layer was separated and 5 wt% aqueous NaCl (5 mL, 5 mL/g) was added, the mixture was stirred for 0.5 hour, and organic phase was separated. The rich organic phase was dried distillation at a pressure of 100 mtorr with Me-THF to obtain KF in 1.5-4wt% range at 5 mL Me-THF volume. The volume was adjusted to 15 mL Me-THF by adding Me-THF (10 mL, 10 mL/g) and EtOH (4 mL, 4 mL/g). Next, 2-butynoic acid (1.0 eq., 0.19 g) was added and the mixture was agitated for 10 hrs. The resulting slurry was filtered. The cake was washed with Me-THF (10 mL, 10 mL/g) and dried under vacuum at 75 °C to afford (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (0.7 g, 80% yield) as white crystalline powder. ¾ NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.98 (br s, 1H), 7.50-7.32 (m, 2H), 3.32 (br d, J=8.6 Hz, 2H), 3.21 (br t, J=10.5 Hz, 1H), 3.13-2.89 (m, 3H), 2.32 (d, J=5.1 Hz, 5H), 2.11 (br d, J=10.9 Hz, 1H), 1.81-1.67 (m, 4H), 1.55-1.28 (m, 1H).

Step 4A: Preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF, 12.77 kg, 13.5 L). Reactor-1 was purged with N2 to inert. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (3.0 kg, 1.0 equiv) was charged followed by 2-butynoic acid (0.854 kg, 1.04 equiv). Reactor-1 was rinsed with DMF (1.42 kg, 1.5 L). The mixture was sparged with N2 for 20 min. Triethylamine (2.99 kg, 3.0 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). TBTU (O-(Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium tetrafluorob orate, 3.256 kg, 1.04 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). The reaction mixture was agitated for 1.5 h at 20 °C. MeTHF (46.44 kg, 60 L) was charged to the batch. The reaction was quenched with LiCl (20 wt%, 26.76 kg, 24 L) at 20 °C. The bottom aqueous layer was discharged as waste. The organic layer was washed with 2N HCl solution (24.48 kg, 24 L), 10 wt% sodium bicarbonate solution (25.44 kg, 24 L) and deionized water (24.0 kg, 24 L). THF (26.61 kg, 30 L) was charged into Reactor-1. The rich organic stream in MeTHF/TFIF was polish filtered. The stream was distilled down to 15 L at 75-100 Torn Constant volume distillation was carried out at 15 L with THF feed (39.92 kg, 45 L). The stream was heated to 60 °C for 1 hr and cooled to 50 °C. MTBE (33.30 kg, 45 L) was charged slowly over 2 h. The slurry was aged at 50 °C for 4 h and cooled to 20 °C over 2 h, and aged at 20 °C for >2 h. The 1st drop slurry was filtered and was rinsed with MTBE (8.88 kg, 12 L) twice. Wet cake was dried under vacuum 60 to 70 °C at 25 mbar overnight (>15 h). Reactor-1 was thoroughly cleaned with IPA. The dry cake was charged into Reactor-1 followed by the charge of IPA (47.10 kg, 60 L). The batch was heated to 60 °C to achieve full dissolution and cooled to 40 °C. Rich organic (24 L) was transferred to Reactor-2 for crystallization. The stream was distilled at 24 L constant volume and 100 mbar using remaining rich organic from reactor-1 as distillation feed. Following distillation completion, the batch was heated to 60 °C, aged at 60 °C for 2 h, cooled to 20 °C over 2 h, and aged at 20 °C over 2 h. The slurry was filtered. IPA (1.18 kg) was used to rinse the reactor and washed the cake. The wet cake was dried under vacuum at 70 °C and 25 mbar for >15 h. The dry cake (2.196 kg, 63.2% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C NMR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Step 4B: Alternative preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF 4.5 mL, 4.5 mL/g). Reactor-1 was purged with N2 to inert. (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (1.0 g, limiting reagent) was charged followed by 2-butynoic acid (0.065g, 0.3 equiv.). The mixture was inerted with N2 for 20 min. N-methylmorpholine (0.78 g, 3.0 equiv) was charged. Next,

diphenylphosphinic chloride (0.79 g, 1.3 equiv) was charged over 0.5 h while maintaining the reaction temperature at 20-25 °C. The reaction mixture was agitated for 1.5 hour at 20 °C. Me-THF (14 mL, 14 mL/g) was charged to the reaction mixture. The reaction was quenched with the addition of aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C. The bottom aqueous layer was discharged as waste. Aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C was added to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. Deionized water (6 mL, 6 mL/g) was charged to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. THF (8 mL, 8 mL/g) was charged into Reactor-1 and the mixture was

concentrated under vacuum to remove Me-THF and water, and reconstituted in 4 L/kg of THF. The mixture was heated to 60 °C and stirred for 1 hour; the temperature was reduced to 50 °C and MTBE (12 mL, 12 mL/g) was added. The mixture was aged for 4 hours while maintaining the temperature of 50 °C and then cooled to room temperature. The solids were filtered and washed with MTBE (6.5 mL, 6.5 mL/g). The solids of crude were dried at 70 °C under vacuum for 12 hours.

Crude (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was charged to Reactor-2, followed by THF (12 mL, 12 mL/g). The mixture was stirred for 0.5 hour. The solution was polish filtered. The solution was concentrated under vaccuum to remove THF and reconstituted in EtOH (7 mL, 7 mL/g). (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide seeds (0.01 g, 0.01 g/g) were added, the mixture was heated to 60 °C and aged for 2 hours, n-heptane (21 mL, 21 mL/g) was added slowly over 4 hours. The mixture was aged for additional 2 hours at 60 °C, followed by cooldown to room temperature. The slurry was filtered, washed with n-heptane (6 mL, 6 mL/g), and dried under vacuum at 70 °C for 12 hours. The dry cake (0.68 g, 71% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C MR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Applicants have discovered a new synthesis process for the preparation of (S)-4- (3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide which offers significant advantages.

The new synthesis process utilizes fewer synthesis steps (4 vs 8) than the process disclosed in WO 2016/065226.

Additionally, the process of the present invention provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall

yield of 22% (step 1 : 73.%, step 2: 69%, step 3 : 69%, step 4: 63%). In comparison, (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was prepared according to the process of WO 2016/065226, which provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall yield of 2.9% yield (step 1 : 91%, step 2: 71%, step 3 : 35%, step 4: 88%, step 5: 80%, step 6: 29%, step 7: 99%, step 8: 63%).

Furthermore, the process of the present invention does not include any transition metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing. In comparison, the process disclosed in WO 2016/065226 employed lead (Pb) in process step (8) and included a potentially genotoxic hydrazine intermediate in process step 8.

The process of the present invention has an estimated manufacturing cycle time of approximately 6 months versus a estimated manufacturing cycle time of approximately 12 months for the process disclosed in WO 2016/065226.

REFERENCE

http://acrabstracts.org/abstract/bms-986195-is-a-highly-selective-and-rapidly-acting-covalent-inhibitor-of-brutons-tyrosine-kinase-with-robust-efficacy-at-low-doses-in-preclinical-models-of-ra-and-lupus-nephritis/

/////////////////BMS-986195, Phase I,  Rheumatoid arthritis, BMS

NC(=O)c2cc(F)c(c1c(C)c(C)nc12)N3CCC[C@@H](C3)NC(=O)C#CC

Anagrelide アナグレリド ,


68475-42-3.png

Anagrelide2DACS.svg

Anagrelide アナグレリド;

QA-0023

BL 4162A
Imidazo[2,1-b]quinazolin-2(3H)-one, 6,7-dichloro-5,10-dihydro-
BL-4162A
BMY-26538-01
GALE-401
KRN-654
SPD-422
6,7-Dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one
CAS: 68475-42-3
C10H7Cl2N3O, 256.0881
INGREDIENT UNII CAS
Anagrelide Hydrochloride VNS4435G39 58579-51-4

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EMA

2018/2/15 EMA APPROVED Anagrelide Anagrelide Mylan Mylan S.A.S.

Cardiovascular agent

Anagrelide hydrochloride is a cyclic phosphodiesterase III inhibitor that was launched in 1997 in the U.S. by Shire Pharmaceuticals for the treatment of essential thrombocythemia and other myeloproliferative disorders

Anagrelide was assigned orphan drug status by the FDA in 1986, by the Japanese Ministry of Health in 2004 and by the European Commission in January 2001 for the treatment of essential thrombocythemia.

Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.[1]

Anagrelide controlled release (GALE-401) is in phase III clinical trials by Galena Biopharma for the treatment of ET.[2]

Medical uses

Anagrelide is used to treat essential thrombocytosis, especially when the current treatment of the patient is insufficient.[3] Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors:[4][5]

  • age over 60 years
  • platelet count over 1000×109/L
  • a history of thrombosis

According to a 2005 Medical Research Council randomized trial, the combination of hydroxyurea with aspirin is superior to the combination of anagrelide and aspirin for the initial management of ET. The hydroxyurea arm had a lower likelihood of myelofibrosisarterial thrombosis, and bleeding, but it had a slightly higher rate of venous thrombosis.[3] Anagrelide can be useful in times when hydroxyurea proves ineffective.

Side-effects

Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea and dizziness.

The same MRC trial mentioned above also analyzed the effects of anagrelide on bone marrow fibrosis, a common feature in patients with myelofibrosis. The use of anagrelide was associated with a rapid increase in the degree of reticulin deposition (the mechanism by which fibrosis occurs), when compared to those in whom hydroxyurea was used. Patients with myeloproliferative conditions are known to have a very slow and somewhat variable course of marrow fibrosis increase. This trend may be accelerated by anagrelide. Interestingly, this increase in fibrosis appeared to be linked to a drop in hemoglobin as it progressed. Fortunately, stopping the drug (and switching patients to hydroxyurea) appeared to reverse the degree of marrow fibrosis. Thus, patients on anagrelide may need to be monitored on a periodic basis for marrow reticulin scores, especially if anemia develops, or becomes more pronounced if present initially.[6]

Less common side effects include: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, renal impairment/failure and seizure.

Due to these issues, anagrelide should not generally be considered for first line therapy in ET.

Mechanism of action

Anagrelide works by inhibiting the maturation of platelets from megakaryocytes.[7] The exact mechanism of action is unclear, although it is known to be a phosphodiesterase inhibitor.[8] It is a potent (IC50 = 36nM) inhibitor of phosphodiesterase-II.[citation needed] It inhibits PDE-3 and phospholipase A2.[9]

Synthesis

Phosphodiesterase inhibitor with antiplatelet activity.

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Synthesis 1[10][11] Synthesis 2

Anagrelide-synthesis.svg

Anagrelide synthesis.svg

Condensation of benzyl chloride 1 with ethyl ester of glycine gives alkylated product 2. Reduction of the nitro group leads to the aniline and reaction of this with cyanogen bromidepossibly gives cyanamide 3 as the initial intermediate. Addition of the aliphatic would then lead to formation of the quinazoline ring (4). Amide formation between the newly formed imide and the ester would then serve to form the imidazolone ring, whatever the details of the sequence, there is obtained anagrelide (5).

PATENT

https://patents.google.com/patent/WO2010005480A2/en

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PATENT

US20130211083A1

Image result

PATENTS

https://patents.google.com/patent/EP2373654A1/en

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SYN

CA 1137474, WO 0208228

The nitration of 1,2,3-trichlorobenzene (I) with concentrated HNO3 gives 2,3,4-trichloronitrobenzene (II), which by reaction with cuprous cyanide in hot pyridine is converted to 2,3-dichloro-6-nitrobenzonitrile (III). The reduction of (III) with borane in THF yields 2,3-dichloro-6-nitrobenzylamine (IV), which by reaction with ethyl bromoacetate (V) by means of triethylamine in refluxing dioxane affords ethyl N-(2,3-dichloro-6-nitrobenzyl)glycinate (VI). The reduction of (VI) with SnCl2 in concentrated HCl gives ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.

The reaction of 3-chloroaniline (X) with choral hydrate (XI) and hydroxylamine gives isonitroso-3-chloroacetanilide (XII), which is cyclized by means of H2SO4 to 4-chloroisatin (XIII). Chlorination of (XIII) with SO2Cl2 affords 4,5-dichloroisatin (XIV), which is oxidized with H2O2 yielding 5,6-dichloroanthranilic acid (XV). The reduction of (XV) with borane in THF gives 6-amino-2,3-dichlorobenzyl alcohol (XVI), which by reaction with SOCl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (XVII). This compound is condensed with ethyl glycinate (XVIII) by means of triethylamine in refluxing methylene chloride to give ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.

SYN

WO 0208228

The nitration of 2,3-dichlorobenzaldehyde (I) with HNO3/H2SO4 gives 2,3-dichloro-6-nitrobenzaldehyde (II), which is reduced with NaBH4 in methanol, yielding 2,3-dichloro-6-nitrobenzyl alcohol (III). The reaction of (III) with SOCl2 and TEA affords the benzyl chloride (IV), which is condensed with glycine ethyl ester (V) by means of TEA to provide the adduct (VI). The reduction of the nitro group of (VI) with SnCl2 in aq. HCl or H2 over PtO2/C in ethanol gives the expected amino derivative (VII), which is cyclized with CN-Br in toluene to yield the iminoquinazoline (VIII). Finally, this compound is further cyclized by means of TEA in water to afford the target imidazoquinazolinone.

US 3932407

The condensation of 2-nitro-6-chlorobenzyl chloride (I) with ethyl glycinate (II) by means of triethylamine in refluxing ethanol gives ethyl N-(2-nitro-6-chlorobenzyl)glycinate (III), which is reduced with H2 over Pd/C in ethanol yielding ethyl N-(2-amino-6-chlorobenzyl)glycinate (IV). The cyclization of (IV) with cyanogen bromide (A) in refluxing ethanol affords 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (V), which is finally chlorinated with Cl2 and FeCl3 in hot nitromethane.

PATENTS

CN 103254197

US 3932407

WO 2002008228

CN 102757434

WO 2012052781

WO 2005080398

PATENT

WO 2008096145

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Applicants: CIPLA LIMITED [IN/IN]; 289 Bellasis Road, Mumbai Central, Mumbai 400 008 (IN) (For All Designated States Except US).
PATHI, Srinivas, Laxminarayan [IN/IN]; (IN) (For US Only).
KANKAN, Rajendra, Narayanrao [IN/IN]; (IN) (For US Only).
RAO, Dharmaraj, Ramachandra [IN/IN]; (IN) (For US Only).
CURTIS, Philip, Anthony [GB/GB]; (GB) (MW only)
Inventors: PATHI, Srinivas, Laxminarayan; (IN).
KANKAN, Rajendra, Narayanrao; (IN).
RAO, Dharmaraj, Ramachandra; (IN)

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Yusuf Hamied

Anagrelide, is a potent reducer of platelet count induced by a variety of aggregating agents and has the following structure


( Formula II)

TJS 4146718 disckre? the process for the preparation ->f ethyl-N-(2,3-dich’oro-6 n:tr^benzyl) glycine hydrochloride from 1,2,3-trichlorobenzene as depicted in Scheme I via 2,3-dichloro-6-nitrobenzonitrile, which involves the use of poisonous reagents, such as cuprous cyanide. Cyanation is carried out at a temperature of 1650C which is highly exothermic, uncontrollable and not scalable. 2, 3-dichloro-6-nitrobenzonitri]e has extreme toxic and skin-irritant properties. Diborane is a flammable gas, used for the reduction of 2, 3-dichloro-6-nitrobenzonitrile. The reduction reaction is exothermic, uncontrollable and not feasible industrially.

Scheme I :

1 ,2,3-Tπchlorobenzene 2,3 ,4-Trichloronitro 2,3-Dichloro-6-nitro
benzene benzonitπle

Ethyl-N-(2,3-dichloro-6-mtrobenzyl) 2,3-Dichloro-6-nitro
glycine hydrochloride benzylamme

US 5801245 discloses process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride from 2,3-dichloro toluene as depicted in Scheme II.

2,3-dichloro-toluene 2,3-dichloro-6-nιtrotoluene

+ H2NCH2COOEt HCI HCI 

2,3-dιchloro-6-nitro Glycine ethyl ester ethyl-N-(2,3-dιchloro-6-nιtro benzyl bromide hydrochloride benzyl)glycιne HCI

The reaction involves a radical halogenation of the toluene group. The material is purified by column chromatography at each stage which makes the process more tedious and it is not viable industrially. The use of a chromatographic solvent, such as chloroform (which is a known carcinogen), is disadvantageous with respect to industrial application.

US 2003/0060630 discloses a method for making ethyl-N-(2, 3-dichloro-6-nitro benzyl)glycine hydrochloride form 2,3-dichloro benzaldehyde as depicted in Scheme III.

Scheme III :

2,3-Dichloro benzaldehyde 2,3-Dichloro-6-mtro 2,3-Dichloro-6-nitro
benzaldehyde benzylalcohol

Step c Thionyl chloride

Ethyl-N-(2,3-dichloro-6-nitrobenzyl) 2,3 -Dichloro-6-nitro
glycine hydrochloride benzyl chloride

In step (b), the reduction reaction is earned out in high boiling solvents like toluene. The reduction in step (b) and the chlorination in step (c) are sluggish. Also, the chlorination reaction is exothermic and uncontrollable, which leads to formation of more impurities and thereby resulting in low yield (page 4, column 2, and page 5, column 1 : 65 %) . Hence, this prior art process is not viable for industrial scale up.

Because of the difficulties encountered in the processes disclosed in the prior art, there is a need to develop more efficient and economical synthetic route for the preparation of ethyl-N- (2,3-dichloro-6-nitrobenzyl)glycine hydrochloride, which is suitable for industrial scale up. The present invention relates to a new process for the synthesis of Ethyl-N-(2, 3-dichloro-6-nitrobenzyl)glycine hydrochloride.

Scheme IV :

2,3-Dichloro-6-nitro 2, 3-Dichloro-6-nitro
benzaldehyde benzylalcohol
( III ) ( IV ) ( V )
Acetonitπle
H2NCH9COOEt
HCl(g) in DPA / Ethyl acetate

Ethyl-N-(2,3-dichloro-6-nitroberizyl)
glycine hydrochloride ( I )

EXAMPLES

Example 1
Preparation of 2, 3-dichloro-6-nitro benzyl methane sulphonate, a compound of formula

(V):
Methylene chloride (2000 ml) and sodium borohydride (120 g) were charged to a clean and dry flask and chilled to 0-50C. Methanol (100 ml) was added slowly over a period of 20 minutes followed by 2,3-dichloro-6-nitro benzaldehyde solution (500 g in 2000 ml of methylene chloride) over a period of 2 hours maintaining the temperature at 0-50C and the contents were stirred at 0-50C for 1 hour. After completion of reaction, water (3000 ml) was added and stirred for 10 minutes. The organic layer was separated, dried over sodium sulphate and was filtered to get a clear filtrate.

To the clear filtrate triethylamine (460 ml), was slowly added over a period of 1 hour at 10- 5 150C, then methane sulphonyl chloride (325 ml) was added drop wise over a period of 2 hours maintaining temperature of 10-150C and the reaction mass was allowed to attain room temperature. Further the reaction mass was stirred at room temperature for 5 hours and after completion of reaction, the organic layer was washed with water (1000 ml) twice, followed by IN HCl solution (1000 ml) twice, 5% Sodium bicarbonate solution (1000 ml) twice, water 0 (1000 ml) twice and was dried over sodium sulfate. The clear organic layer was concentrated under vacuum below 4O0C to give the title compound which was used in the next step.

Example 2
Preparation of ethyl N-(2,3-dichIoro-6-nitrobenzyl)gIycine hydrochloride, a compound of formula (I) :
2,3-dichloro-6-nitro benzyl methane sulphonate ( Examplel ) was dissolved in acetonitrile (2400 ml). To this reaction mass were charged anhydrous Potassium carbonate (480 g), dimethyl amino pyridine (480 mg) and glycine ethyl ester (240 g) at room temperature. The contents were stirred at 37-4O0C for 24 hours. After completion of reaction, the insolubles were filtered, washed with acetonitrile (120 ml). The clear filtrate was concentrated and stripped off usin” ethyl acetate (240 ml).

Further ethyl acetate (1200 ml) was added, chilled the contents to 5-100C, adjusted the pH to 2.0 using IP A-HCl at 5-1O0C. The contents were stirred at 5-100C for 1 hour. The solids were filtered, washed with chilled ethyl acetate (120 ml) and dried under vacuum at room temperature for 4 hours to give the title compound (595 g, 76 % yield, 98.5% HPLC purity).

Example 3
Preparation of Anagrelide , a compound of formula (II)

a) Preparation of Ethyl-5,6-dichloro-3,4-dihydro-2[lH]-imino quinazolin-3-acetate hydrobromide A solution of stannous chloride dihydrate (1850 gms) in concentrated HCl (6.7 liters ) was added slowly to a cooled solution of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (595gms) in concentrated HCl (5.15 liters) maintaining temperature 15-200C over a period of 2 hours. The contents were heated slowly to 40-450C and stirred for 1 hour at 40-450C. After completion of reaction, the contents were cooled to 15-2O0C, maintained for 15 minutes and filtered.

The solids thus obtained were suspended in water (2.9 liters), adjusted the pH of the reaction mass to 8.0-9.0 using potassium carbonate solution (prepared by dissolving 376 gms of potassium carbonate in 4.25 liters of water) at 0-50C, extracted into toluene (3.0 liters><3), dried over sodium sulphate and clarified.

To the clear toluene layer, added Cyanogen bromide solution (prepared by dissolving 222 gms of cyanogen bromide in 655 ml of toluene) in 30 minutes maintaining temperature 15-200C and stirred at 25-300C for 2 hours. The contents were heated slowly to 105-1100C and maintained for 16 hours at 105-1100C. After completion of reaction, the mass was cooled to 15-2O0C and stirred for 45 minutes. Filtered the material, washed with chilled toluene (1.3 liters). The material was slurried in toluene (470 ml) at 15-200C for 1 hour, filtered, washed with cold toluene (160 ml) and dried under vacuum at 50-600C for 8 hours to give the title compound (445 gms ).

b) Preparation of 6,7-Dichloro-l,5-dihydroimidazo[2,l-b]quinazolin-2(3H)-one [Anagrelide]
A mixture of ethyl-5,6-dichloro-3,4-dihydro-2(lH)-iminoquinazolin-3-acetate hydrobromide (445 gms), isopropyl alcohol (4.45 liters) and triethylamine (246 ml) was refluxed for 2 hours. After completion of reaction, the mixture was cooled to 20-250C, filtered, washed with chilled isopropyl alcohol (1.0 liters) and dried under vacuum at 50-550C for 6 hours to give the title compound (285 gms).

Publication numberPriority datePublication dateAssigneeTitle
WO2010070318A1 *2008-12-172010-06-24Shire LlcProcess for the preparation of anagrelide and analogues
US8133996B22007-02-062012-03-13Cipla LimitedProcess for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride
KR20170102484A *2015-01-132017-09-11닛산 가가쿠 고교 가부시키 가이샤방향족 아민 화합물의 제조 방법
WO2016114312A1 *2015-01-132016-07-21日産化学工業株式会社反応混合物中のスズ化合物の処理方法
Publication numberPriority datePublication dateAssigneeTitle
US4208521A *1978-07-311980-06-17Bristol-Myers CompanyProcess for the preparation of imidazo[2,1-b]quinazolinones
EP0514917A1 *1991-05-221992-11-25Egis GyogyszergyarProcess for and 2-(cyanoimino)-quinazoline derivatives useful as intermediates in the preparation of 6,7-di-(chloro)-1,5-di(hydro)-imidazo-[2,1-b]quinazolin-2[3H]-one and process for preparing the 2-(cyanoimino)-quinazoline derivatives
US20030060630A1 *2000-07-262003-03-27Shire Us Inc.Method for the manufacture of Anagrelide
Family To Family Citations
US4146718A *1978-04-101979-03-27Bristol-Myers CompanyAlkyl 5,6-dichloro-3,4-dihydro-2(1h)-iminoquinazoline-3-acetate hydrohalides
JPH051255B2 *1984-05-231993-01-07Sumitomo Chemical Co
CA2171073A1 *1995-12-041997-06-05Philip C. LangProcess for the preparation of ethyl-n-(2,3 dichloro-6- nitrobenzyl) glycine
CN1335847A *1998-12-042002-02-13藤泽药品工业株式会社磺酰胺化合物及其药物用途
WO2008096145A12007-02-062008-08-14Cipla LimitedProcess for the preparation of ethyl-n-(2, 3-dichloro-6-nitrobenzyl) glycine hydrochloride

REF

  1. Jump up^ Voglová J, Maisnar V, Beránek M, Chrobák L (2006). “[Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase]”. Vnitr̆ní lékar̆ství (in Czech). 52 (9): 819–22. PMID 17091608.
  2. Jump up^ https://globenewswire.com/news-release/2016/12/28/901925/0/en/Galena-Biopharma-Confirms-Regulatory-Pathway-for-GALE-401-Anagrelide-Controlled-Release.html
  3. Jump up to:a b Harrison CN, Campbell PJ, Buck G, et al. (July 2005). “Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia”. N. Engl. J. Med353 (1): 33–45. doi:10.1056/NEJMoa043800PMID 16000354.
  4. Jump up^ Reilly, John T. (1 February 2009). “Anagrelide for the treatment of essential thrombocythemia: a survey among European hematologists/oncologists”. Hematology14(1): 1–10. doi:10.1179/102453309X385115PMID 19154658.
  5. Jump up^ Brière, Jean B (1 January 2007). “Essential thrombocythemia”Orphanet Journal of Rare Diseases2 (1): 3. doi:10.1186/1750-1172-2-3PMC 1781427Freely accessiblePMID 17210076.
  6. Jump up^ Campbell PJ, Bareford D, Erber WN, et al. (June 2009). “Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy”J. Clin. Oncol27 (18): 2991–9. doi:10.1200/JCO.2008.20.3174PMC 3398138Freely accessiblePMID 19364963.
  7. Jump up^ Petrides PE (2006). “Anagrelide: what was new in 2004 and 2005?”. Semin. Thromb. Hemost32 (4 Pt 2): 399–408. doi:10.1055/s-2006-942760PMID 16810615.
  8. Jump up^ Jones GH, Venuti MC, Alvarez R, Bruno JJ, Berks AH, Prince A (February 1987). “Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide”. J. Med. Chem30 (2): 295–303. doi:10.1021/jm00385a011PMID 3027338.
  9. Jump up^ Harrison CN, Bareford D, Butt N, et al. (May 2010). “Guideline for investigation and management of adults and children presenting with a thrombocytosis”. Br. J. Haematol149(3): 352–75. doi:10.1111/j.1365-2141.2010.08122.xPMID 20331456.
  10. Jump up^ W. N. Beverung, A. Partyka, U.S. Patent 3,932,407USRE 31617; T. A. Jenks et al., U.S. Patent 4,146,718 (1976, 1984, 1979 all to Bristol-Myers).
  11. Jump up^ Yamaguchi, Hitoshi; Ishikawa, Fumiyoshi (1981). “Synthesis and reactions of 2-chloro-3,4-dihydrothienopyrimidines and -quinazolines”. Journal of Heterocyclic Chemistry18: 67. doi:10.1002/jhet.5570180114.

External links

Anagrelide
Title: Anagrelide
CAS Registry Number: 68475-42-3
CAS Name: 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one
Additional Names: 6,7-dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one
Molecular Formula: C10H7Cl2N3O
Molecular Weight: 256.09
Percent Composition: C 46.90%, H 2.76%, Cl 27.69%, N 16.41%, O 6.25%
Literature References: Phosphodiesterase inhibitor with antiplatelet activity. Prepn: W. N. Beverung, A. Partyka, US 3932407USRE 31617; T. A. Jenks et al., US 4146718 (1976, 1984, 1979 all to Bristol-Myers); H. Yamaguchi, F. Ishikawa, J. Heterocycl. Chem.18, 67 (1981). Antithrombotic and platelet aggregation inhibiting properties: J. S. Fleming, J. P. Buyniski, Thromb. Res. 15, 373 (1979). Mode of action studies: S. S. Tang, M. M. Frojmovic, J. Lab. Clin. Med. 95, 241 (1980); S. Seiler et al., J. Pharmacol. Exp. Ther. 243, 767 (1987). GC-MS determn in human plasma: E. H. Kerns et al., J. Chromatogr. 416, 357 (1987). Clinical reduction of platelet counts: W. A. Andes et al., Thromb. Haemostasis 52, 325 (1984). Clinical trials to control thrombocytosis in chronic myeloproliferative diseases: M. N. Silverstein et al., N. Engl. J. Med. 318, 1292 (1988); Anagrelide Study Group, Am. J. Med. 92,69 (1992). Review of pharmacology and clinical experience: P. E. Petrides, Expert Opin. Pharmacother. 5, 1781-1798 (2004).
Derivative Type: Hydrochloride monohydrate
CAS Registry Number: 58579-51-4
Manufacturers’ Codes: BL-4162A; BMY-26538-01
Trademarks: Agrylin (Shire); Thromboreductin (AOP Orphan Pharm.); Xagrid (Shire)
Molecular Formula: C10H7Cl2N3O.HCl.H2O
Molecular Weight: 310.56
Percent Composition: C 38.67%, H 3.25%, Cl 34.25%, N 13.53%, O 10.30%
Properties: Off-white powder. Very slightly sol in water; sparingly sol in DMSO, DMF. Also prepd as the hemihydrate; crystals from ethanolic HCl, mp >280°.
Melting point: mp >280°
Therap-Cat: Antithrombocythemic.
Keywords: Antithrombocythemic.
Anagrelide
Anagrelide2DACS.svg
Clinical data
Trade names Agrylin
AHFS/Drugs.com Monograph
MedlinePlus a601020
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Hepatic, partially through CYP1A2
Biological half-life 1.3 hours
Excretion Urine (<1%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C10H7Cl2N3O
Molar mass 256.088 g/mol
3D model (JSmol)

/////////Anagrelide, アナグレリド , EU 2018, EMA 2018, SHIRE, FDA 1997. orphan drug status

VNRX-5133 from VENATORX PHARMACEUTICALS


 img
str1
VNRX-5133
CAS: 1613268-23-7
Chemical Formula: C19H28BN3O5
Molecular Weight: 389.26
3-(2-((1r,4r)-4-((2-aminoethyl)amino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
 ( R)-3-( 2-( trans-4-( 2-aminoethylamino)cvclohexyl)acetamido)-2-hvdroxy-3-,4-dihydro-2H-benzo[el [l,21oxaborinine-8-carboxylic acid
Image result for VNRX-5133
  • Originator VenatoRx Pharmaceuticals
  • Developer  National Institute of Allergy and Infectious Diseases; VenatoRx Pharmaceuticals
  • Class Antibacterials; Cephalosporins; Small molecules
  • Mechanism of Action Beta lactamase inhibitors; Cell wall inhibitors

Highest Development Phases

  • Phase I Bacterial infections

Most Recent Events

  • 19 Mar 2018 VenatoRx Pharmaceuticals plans phase III pivotal trials in mid-2018
  • 03 Jan 2018 VNRX 5133 receives Fast Track designation for Bacterial infections (complicated urinary tract infections and complicated intra-abdominal infections) [IV-infusion] in USA
  • 03 Jan 2018 VNRX 5133 receives Qualified Infectious Disease Product status for Intra-abdominal infections in USA
  • clip
  • https://cen.acs.org/articles/96/web/2018/03/Drug-structures-made-public-New-Orleans.html

str4Credit: Tien Nguyen/C&EN

Presented by: Christopher J. Burns, president and chief executive officer of VenatoRx Pharmaceuticals

Target: β-lactamase enzymes, enzymes that inactivate β-lactam-based antibiotics enabling bacteria to resist their attacks

Disease: Gram-negative bacterial infections

Reporter’s notes: Another story with humble beginnings, this time with Burns and two colleagues sitting in a Panera Bread, with an idea. They wanted to offer a new compound in the class of β-lactam antibiotics, drugs which are “well-liked” by doctors, Burns said, and make up 60% of all antibiotic prescriptions. However, bacteria have developed defenses against these compounds in the form of β-lactamases, or as Burns dubbed them, “PAC-men.” These enzymes can chew up 1000 β-lactams per second, he said. VNRX-5133 was active against both serine-β-lactamases and metallo-β-lactamases in enzyme assays. It is being developed in combination with the antibiotic cefepime. VNRX-5133 fends off the PAC-men’s attacks, allowing cefepime to combat infection. The compound has gone through Phase I clinical trials and will be skipping ahead to Phase III later this year.

PATENT

WO 2014089365

Applicants: VENATORX PHARMACEUTICALS, INC [US/US]; 30 Spring Mill Drive Malvern, PA 19355 (US)
Inventors: BURNS, Christopher, J.; (US).
DAIGLE, Denis; (US).
LIU, Bin; (US).
MCGARRY, Daniel; (US).
PEVEAR, Daniel C.; (US).
TROUT, Robert E. Lee; (US)

https://patents.google.com/patent/WO2014089365A1/en

Christopher J. Burns, Ph.D.
President and Chief Executive Officer

Dr. Burns is Co-Founder, President and Chief Executive Officer of VenatoRx. He brings over 25 years of corporate and R&D experience within both major (RPR/Aventis) and specialty (ViroPharma, Protez…https://www.venatorx.com/leadership/

Antibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins,

cephalosporins, and carbapenems) are widely used because they have a strong bactericidal effect and low toxicity.

[0004] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as “serine” or “metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

EXAMPLE 15 : ( R)-3-( 2-( trans-4-( 2-aminoethylamino)cvclohexyl)acetamido)-2-hvdroxy-3-,4-dihydro-2H-benzo[el [l,21oxaborinine-8-carboxylic acid

Step 1 : Synthesis of (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e] [ 1 ,2]oxaborinine-8-carboxylic acid.

[00240] To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (Example 6, 15 mg) in MeOH (2 mL) was added tert-butyl 2-oxoethylcarbamate (20 mg). Pd/C (10% by weight, 10 mg) was added and the reaction mixture was stirred under ¾ balloon overnight. The reaction mixture was filtrated and the solvent was then removed under reduced pressure and the residue was carried on to the next step without further purification. ESI-MS m/z 490.1 (MH)+.

Step 2: Synthesis of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid.

[00241] To (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (20 mg) in a flask was added 1 mL 4N HC1 in dioxane. The resulting reaction mixture was stirred at RT for 2hr. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 390 (MH)+.

Step 2: (R)-3-(2-(trans-4-((2-aminoethylamino)methyl)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e] [ 1 ,2]oxaborinine-8-carboxylic acid

[00229] Prepared from 3-[2-(2-{4-[(2-tert-Butoxycarbonylamino-ethylamino)-methyl]-cyclohexyl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BC13 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 404 (MH)+.

/////////////////////////////VNRX-5133; VNRX5133; VNRX 5133, phase 1, VenatoRx Pharmaceuticals, BACTERIAL INFECTIONS, Christopher J. Burns

 NCCN[C@@H]1CC[C@@H](CC(NC2B(O)OC(C(C(O)=O)=CC=C3)=C3C2)=O)CC1

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