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WO2012085625A1 - Procédé pour la préparation de fosamprénavir calcique et d'un intermédiaire utilisé dans sa préparation - Google Patents

Procédé pour la préparation de fosamprénavir calcique et d'un intermédiaire utilisé dans sa préparation Download PDF

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Publication number
WO2012085625A1
WO2012085625A1 PCT/IB2011/000481 IB2011000481W WO2012085625A1 WO 2012085625 A1 WO2012085625 A1 WO 2012085625A1 IB 2011000481 W IB2011000481 W IB 2011000481W WO 2012085625 A1 WO2012085625 A1 WO 2012085625A1
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WO
WIPO (PCT)
Prior art keywords
compound
calcium
process according
preparation
iii
Prior art date
Application number
PCT/IB2011/000481
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English (en)
Inventor
Surinder Kumar Arora
Ajinath Tukaram Pathade
Gaurav Kumar
Samir Shanteshwar Shabade
Dinesh Jayntibhai Paghdar
Purna Chandra Ray
Girij Pal Singh
Original Assignee
Lupin Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2012085625A1 publication Critical patent/WO2012085625A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention relates to a novel process for preparation of fosamprenavir calcium (I) and novel intermediate calcium (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitro-phenyl)- sulfonyl] (isobutyl) amino]- l-benzyl-2-phosphonooxy)propyl-carbamate (V)
  • Fosamprenavir calcium has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses; it is chemically known as calcium (3S) tetrahydro-3-furanyl(l S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]- l-benzyl-2- (phosphonooxy)propyl carbamate and represented by formula I.
  • the patent US 6 436 989 is product patent for fosamprenavir and its pharmaceutically acceptable salts. It provides process for preparation of fosamprenavir sodium salt (IA) from compound (II) as depicted in Scheme 1. However, this patent does not provide enabling process for preparation of fosamprenavir calcium (I).
  • a stable crystalline Form I of fosamprenavir calcium is disclosed in US 6 514 953, Form I of fosamprenavir calcium is obtained by crystallization from a mixture of ethanol and water. This patent mentions that Form I has good pharmaceutical properties making it suitable for formulation into tablets.
  • US 6 514 953 provides process for preparation of crystalline fosamprenvair calcium (I) as depicted in Scheme 2, wherein compound (IV) is subjected to catalytic reduction to obtain fosamprenavir sodium (IA) which is treated in situ with calcium acetate to form the resultant compound (I).
  • WO 2010/134045 further provides process for preparation of amorphous form, wherein crystalline fosamprenavir calcium, as prepared by example of US 6 514 953, is converted to amorphous fosamprenavir calcium by utilizing thin film dryer or spray dryer processes or isolating amorphous fosamprenavir calcium from a mixture of solvent and an anti-solvent.
  • PCT application WO 201 1/001383 provides crystalline Form II of fosamprenavir calcium and process for preparation of the same.
  • Fosamprenavir calcium as prepared by example of US 6 514 953, is converted to crystalline Form II by dissolving fosamprenavir calcium in a water miscible organic solvent comprising a propanol, treating the solution with water and isolating Form II from the mixture.
  • Costly reagents like DCC, TMSO-OTMS are utilized;
  • the present invention provides a novel process for preparation of fosamprenavir calcium suitable for large scale manufacture.
  • Figure 1 X-ray powder diffraction pattern of compound (V). SUMMARY OF THE INVENTION
  • the present invention provides novel intermediate Calcium (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitro-phenyl)-sulfonyl] (isobutyl) amino]- 1 -benzyl-2-phosphonooxy) propyl- carbamate (V) and process for its preparation comprising, reacting (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(hydroxy)propyl carbamate (II) with a phosphorylating agent to obtain (3S) tetrahydro-3-furanyl(l S,2R)-3-[[(4- nitrophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propyl carbamate (III); optionally converting compound
  • the present invention provides process for preparation of fosamprenavir calcium comprising, reacting a compound (V) with a reducing agent.
  • the present invention provides process for preparation of amorphous fosamprenavir calcium comprising reacting compound (V) with a reducing agent and conversion to amorphous form.
  • the present invention provides compound, calcium (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitro-phenyl)-sulfonyl] (isobutyl) amino]- l-benzyl-2- phosphonooxy)propyl-carbamate (V)
  • the present invention provides process for preparation of fosamprenavir calcium comprising:
  • the present invention provides process for preparation of amorphous fosamprenavir calcium comprising:
  • Compound of formula (II) reacts with a phosphorylating agent in presence of an organic base and optionally in presence of a solvent.
  • the phosphorylating agent is selected from phosphorous oxychloride, phosphorous pentachloride, preferably phosphorous oxychloride.
  • the organic base is selected from pyridine, triethylamine, diisopropylethylamine, preferably pyridine.
  • the solvent is selected from ketones like methyl ethyl ketone, methylisobutylketone, preferably methylisobutylketone; chlorinated solvents like dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, chlorobenzene.
  • Phosphorylation can be performed at a temperature range of -10 to 100°C, preferably 0 to 40°C, more preferably 10-20°C.
  • the phosphorylating agent phosphorous oxychloride may be employed in a range of 0.3 to 3.0 moles equivalent of compound (II), preferably 0.9 to 2.0 moles, more preferably 1.0 to 1.3 moles.
  • Compound of formula (III) can be converted to its sodium salt (IV) utilizing source of sodium ions selected from sodium bicarbonate, sodium carbonate.
  • the source of calcium ions is selected from calcium carbonate, calcium acetate, calcium chloride, calcium hydroxide, preferably calcium acetate.
  • the compound (V) is purified by slurry washing or crystallization, from a solvent selected from alcohol like methanol, ethanol, isopropanol; esters like ethylacetate; ketones like acetone; nitriles like acetonitrile; chlorinated solvents like dichloromethane, ethylene dichloride; ethers like tetrahydrofuran, diisopropyl ether; amides like dimethyl formamide; or mixture thereof; preferred solvent is methanol.
  • Compound (V) is treated with a suitable reducing agent in presence of an appropriate solvent.
  • Reducing agent is selected from alkali metals, transition metals and metal complexes or combination thereof; alkali metal hydrides selected from sodium borohydride or lithium aluminium hydride; transition metals selected from chromium, cobalt, iron, nickel, palladium, platinum, ruthenium, rhodium, titanium, zinc and their oxides which are optionally supported on active carbon; other reagents such as tin, iron and zinc hydrochlorides etc.
  • appropriate solvent is selected from an organic solvent, water or mixture thereof; organic solvent is selected from alcohols such as methanol, ethanol, isopropanol, butanol; ethers such as diisopropyl ether, tetrahydrofuran, dioxane, diglyme; acids such as acetic acid, propionic acid etc; or mixtures thereof.
  • the reduction is carried out preferably using palladium carbon in a mixture of alcohol and water.
  • fosamprenavir calcium was dissolved in ethanol and amorphous fosamprenavir calcium was precipitated by addition of diisoproyl ether;
  • amorphous fosamprenavir calcium can be prepared by subjecting a solution of alcohol and fosamprenavir calcium to an agitated thin film dryer and obtaining the amorphous form.
  • the manufacture of fosamprenavir calcium (I) by the process of present invention is simple and utilizes cheaper reagents; has less number of steps and suitable for commercial use.
  • the X-ray diffraction pattern was measured using Philips PANalytical, X'Pertpro machine with following parameters:
  • IR 3381.82, 1687.82, 1605.86, 1531.81 , 1350.42, 1313.09, 1 161.69, 1 108.55, 1088.30 cm - 1 ; X-ray powder diffraction pattern as depicted in Figure 1, which indicates amorphous material.
  • Example 2 Preparation of Calcium (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitro-phenyl)- sulfonyl](isobutyl)amino]-l -benzyl-2-phosphonooxy)propyl-carbamate (V) from (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- (phosphonooxy)propylcarbamate (III) To the solution of 25 g (0.040 mol) (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4- nitrophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy)propylcarbamate (III) in 250 ml
  • Example 3 Preparation of fosamprenavir calcium (I) To a mixture of 12 g (0.0183) calcium (3S) tetrahydro-3-furanyl (l S,2R)-3-[[(4-nitro- phenyl)-sulfonyl](isobutyl)amino]-l-benzyl-2-phosphonooxy)propyl-carbamate (V) as obtained in example 1 or 2 and 240 ml methanol was added 1.2 g 10% Pd/C and stirred under a hydrogen pressure of 20 kg (-300 psi) at 25-40°C for 12 hours. The reaction mixture was filtered and partially concentrated. To the concentrate was added 60 ml water and stirred at 25-28°C for 1 hour. The solid was filtered and dried under reduced pressure to obtain crude fosamprenavir calcium (I).
  • 3S calcium tetrahydro-3-furanyl
  • l S,2R -3-[[(4-nitro- phenyl

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouvel intermédiaire, le calcium (3S) tétrahydro-3-furanyl(1S,2R)-3-[[(4-nitro-phényl)-sulfonyl](isobutyl)amino]-1-benzyl-2-phosphonooxy)propyl-carbamate (V) de calcium et un procédé pour sa préparation consistant à faire réagir le (3S) tétrahydro-3-furanyl(1S,2R)-3-[[(4-nitrophényl)sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propyl carbamate (II) avec un agent de phosphorylation pour obtenir le (3S) tétrahydro-3-furanyl(1S,2R)-3-[[(4-nitrophényl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate (III); à convertir facultativement le composé (III) en son sel de sodium (IV); à ajouter des ions calcium au composé (III) ou au composé (IV); et à facultativement purifier le composé résultant (V). La présente invention concerne également un procédé pour la préparation de fosamprénavir calcique consistant à faire réagir un composé (V) avec un agent réducteur.
PCT/IB2011/000481 2010-12-21 2011-03-04 Procédé pour la préparation de fosamprénavir calcique et d'un intermédiaire utilisé dans sa préparation WO2012085625A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1425KO2010 2010-12-21
IN1425/KOL/2010 2010-12-21

Publications (1)

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WO2012085625A1 true WO2012085625A1 (fr) 2012-06-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172563A3 (fr) * 2011-06-14 2013-03-28 Hetero Research Foundation Nouveaux polymorphes de fosamprénavir calcique
CN103770316A (zh) * 2012-10-22 2014-05-07 克朗斯公司 具有用于供给空气的洁净室和干燥单元的吹塑机

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US6514953B1 (en) 1998-07-18 2003-02-04 Smithkline Beecham Corporation Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
WO2010134045A1 (fr) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Fosamprenavir calcique amorphe
WO2011001383A1 (fr) 2009-06-30 2011-01-06 Ranbaxy Laboratories Limited Forme cristalline de fosamprénavir calcium
WO2011033469A1 (fr) * 2009-09-16 2011-03-24 Ranbaxy Laboratories Limited Procédé pour préparer du fosamprénavir calcium

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US6514953B1 (en) 1998-07-18 2003-02-04 Smithkline Beecham Corporation Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
WO2010134045A1 (fr) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Fosamprenavir calcique amorphe
WO2011001383A1 (fr) 2009-06-30 2011-01-06 Ranbaxy Laboratories Limited Forme cristalline de fosamprénavir calcium
WO2011033469A1 (fr) * 2009-09-16 2011-03-24 Ranbaxy Laboratories Limited Procédé pour préparer du fosamprénavir calcium

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Process for the preparation of Calcium (2R,3S)-1-(4-amino-N-isobutylp henylsulfonamido)-4-phenyl-3-(((S)-tetrahydrofuran-3-yloxy)carbonylamino)butan-2-yl phosphate", IP.COM JOURNAL, 21 June 2010 (2010-06-21), XP013138772, ISSN: 1533-0001, Retrieved from the Internet <URL:http://ip.com/IPCOM/000196928> *
CHINESE JOURNAL OF PHARMACEUTICALS, vol. 37, no. 11, 2006, pages 723 - 726
PRIOR ART ARTICLES DRUGS OF THE FUTURE, vol. 26, no. 3, 2001, pages 224 - 231

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172563A3 (fr) * 2011-06-14 2013-03-28 Hetero Research Foundation Nouveaux polymorphes de fosamprénavir calcique
CN103770316A (zh) * 2012-10-22 2014-05-07 克朗斯公司 具有用于供给空气的洁净室和干燥单元的吹塑机
CN103770316B (zh) * 2012-10-22 2015-12-02 克朗斯公司 具有用于供给空气的洁净室和干燥单元的吹塑机

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