WO2009118598A1 - Procédé pour la fabrication de rosuvastatine calcique ayant une pureté élevée - Google Patents

Procédé pour la fabrication de rosuvastatine calcique ayant une pureté élevée Download PDF

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Publication number
WO2009118598A1
WO2009118598A1 PCT/IB2009/000570 IB2009000570W WO2009118598A1 WO 2009118598 A1 WO2009118598 A1 WO 2009118598A1 IB 2009000570 W IB2009000570 W IB 2009000570W WO 2009118598 A1 WO2009118598 A1 WO 2009118598A1
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WO
WIPO (PCT)
Prior art keywords
rosuvastatin
formula
alkyl ester
process according
mixture
Prior art date
Application number
PCT/IB2009/000570
Other languages
English (en)
Inventor
Gangadhara Bhima Shankar Nangi
Sukumar Nandi
Sambhu Prasad Sarma Mallela
Ramesh Dandala
Sivakumaran Meenakshisunderam
Original Assignee
Aurobindo Pharma 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.)
Filing date
Publication date
Application filed by Aurobindo Pharma Limited filed Critical Aurobindo Pharma Limited
Publication of WO2009118598A1 publication Critical patent/WO2009118598A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • Rosuvastatin which is an antihyperchlolesterolemic drug, is chemically known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimid-in- 5-yl]-(3R,5S)-3,5-dihydroxy-hept-6-enoic acid calcium (2:1) salt of Formula I.
  • the present invention also relates to an improved process for preparing Rosuvastatin alkyl ester of Formula II,
  • the present invention also provides further conversion of Rosuvastatin alkyl ester of Formula II to Rosuvastatin calcium, with high purity.
  • the present invention relates to an improved process for the preparation of Rosuvastatin alkyl ester of Formula II, which comprises preparing a solution of Rosuvastatin keto ester of Formula III in an organic solvent or a mixture of organic solvents and adding a solution of dialkylalkoxyborane in a mixture of three or more organic solvents at low temperature to the above solution. Thereafter, the reaction mass is stirred at same temperature and treated with a source of hydride ion.
  • the organic solvent is selected from the group consisting of an ethereal solvent selected from C 2 -Cg ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofuran; alcoholic solvent selected from C 1 -C 4 alcohol such as methanol, ethanol, butanol and aprotic solvents such as toluene, alkyl esters such as ethyl acetate, methyl acetate, chlorinated solvents such as methylene chloride, chloroform.
  • an ethereal solvent selected from C 2 -Cg ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofuran
  • alcoholic solvent selected from C 1 -C 4 alcohol such as methanol, ethanol, butanol and aprotic solvents such as toluene, alkyl esters such as ethyl acetate, methyl acetate, chlorinated solvents
  • Rosuvastatin alkyl ester of Formula II which comprises providing a solution of dialkylalkoxyborane and source of hydride ion at low temperature in a mixture of three or more organic solvents. Dissolving Rosuvastatin keto ester of Formula III in an organic solvent or a mixture of organic solvents and adding this solution to above solution at low temperature. Thereafter, the reaction mass is stirred to yield Rosuvastatin alkyl ester of Formula II.
  • the dialkylalkoxyborane is selected from diethylmethoxyborane, dimethylmethoxyborane, diethylethoxyborane, dimethylethoxyborane.
  • diethylmethoxyborane is used as chelating agent.
  • a solution of dialkylalkoxyborane is prepared by adding a tetrahydrofuran solution of dialkylalkoxyborane to a solvent mixture selected from the group consisting of an ethereal solvent selected from C 2 -C 8 ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofuran; alcoholic solvent selected from Cj-C 4 alcohol such as methanol, ethanol, butanol and aprotic solvents such as toluene, alkyl esters such as ethyl acetate, methyl acetate, chlorinated solvents such as methylene chloride, chloroform; or mixture of three or more solvents.
  • a solvent mixture selected from the group consisting of an ethereal solvent selected from C 2 -C 8 ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofuran
  • alcoholic solvent selected from Cj-C 4
  • the reaction mixture is maintained for 30 min to 8 h; preferably 5-6 h at temperature -70 0 C to -80°C.
  • Reaction is quenched at — 80 0 C to -50 0 C by adding quenching agent to the reaction mass.
  • the quenching agent is selected from water, acetic acid, aqueous hydrochloric acid, acetone, trifluoroacetic acid, aqueous hydrogen peroxide, ammonium chloride, sodium bicarbonate, aqueous acidic buffer or mixture thereof.
  • Preferred agents are acidic buffer or acetic acid.
  • Aqueous acidic buffer is made from potassium dihydrogen phosphate, triethyl amine and orthophosphoric acid having pH in range of 2-4.
  • reaction mass After quenching the reaction, the reaction mass is diluted with water and extracted with solvents like ethyl acetate, toluene, methylene chloride and the like and preferably with ethyl acetate.
  • Another embodiment of the invention provides a process for improving the quality of the Rosuvastatin alkyl ester of Formula II, by recrystallization.
  • the above reaction mass was stirred for 2 hours for complete disappearance of the starting material (3- keto-5-hydiOxy ethyl Rosuvastatin) by HPLC and quenched by adding to a buffer solution of pH : 3 (100 ml).
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml).
  • the combined organic layer was washed with 2% aqueous sodium bicarbonate (50 ml x 2) followed by aqueous sodium chloride (20% w/w, 50 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé perfectionné pour préparer de la Rosuvastatine calcique représentée par la Formule I, (I) ayant une bonne qualité.
PCT/IB2009/000570 2008-03-24 2009-03-16 Procédé pour la fabrication de rosuvastatine calcique ayant une pureté élevée WO2009118598A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN713CH2008 2008-03-24
IN713/CHE/2008 2008-03-24

Publications (1)

Publication Number Publication Date
WO2009118598A1 true WO2009118598A1 (fr) 2009-10-01

Family

ID=40677849

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/000570 WO2009118598A1 (fr) 2008-03-24 2009-03-16 Procédé pour la fabrication de rosuvastatine calcique ayant une pureté élevée

Country Status (1)

Country Link
WO (1) WO2009118598A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011021058A1 (fr) * 2009-08-17 2011-02-24 Aurobindo Pharma Limited Procédé de fabrication de rosuvastatine calcique à l'aide d'un ester éthylique de rosuvastatine cristalline
EP2602249A1 (fr) 2011-12-06 2013-06-12 F.I.S. Fabbrica Italiana Sintetici S.p.A. Synthèse de rosuvastatine au moyen de co-cristaux
JP2013543884A (ja) * 2010-11-29 2013-12-09 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ 高純度の医薬品中間体の製法
ITVI20130039A1 (it) * 2013-02-20 2014-08-21 F I S Fabbrica Italiana Sint I S P A Processo per la preparazione di intermedi chiave per la sintesi di statine
CN108299310A (zh) * 2018-01-31 2018-07-20 浙江科技学院 一种制备高稳定性瑞舒伐他汀钙的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063728A2 (fr) * 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Procede de preparation de statines a rapport syn/anti eleve
WO2007017117A1 (fr) * 2005-07-28 2007-02-15 Lek Pharmaceuticals D.D. Processus destine a la synthese de calcium rosuvastatine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063728A2 (fr) * 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Procede de preparation de statines a rapport syn/anti eleve
WO2007017117A1 (fr) * 2005-07-28 2007-02-15 Lek Pharmaceuticals D.D. Processus destine a la synthese de calcium rosuvastatine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN K-M ET AL: "1 3-SYN DIASTEREOSELECTIVE REDUCTION OF BETA HYDROXYKETONES UTILIZING ALKOXYDIALKYLBORANES", TETRAHEDRON LETTERS, vol. 28, no. 2, 1987, pages 155 - 158, XP002531067, ISSN: 0040-4039 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011021058A1 (fr) * 2009-08-17 2011-02-24 Aurobindo Pharma Limited Procédé de fabrication de rosuvastatine calcique à l'aide d'un ester éthylique de rosuvastatine cristalline
US20120149905A1 (en) * 2009-08-17 2012-06-14 Sambhu Prasad Sarma Mallela Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
US8846915B2 (en) * 2009-08-17 2014-09-30 Aurobindo Pharma Ltd. Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
JP2013543884A (ja) * 2010-11-29 2013-12-09 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ 高純度の医薬品中間体の製法
EP2602249A1 (fr) 2011-12-06 2013-06-12 F.I.S. Fabbrica Italiana Sintetici S.p.A. Synthèse de rosuvastatine au moyen de co-cristaux
US8815862B2 (en) 2011-12-06 2014-08-26 F.I.S. Fabbrica Italiana Sintetici S.P.A. Co-crystal intermediates of rosuvastatin and methods of using same
EP2769979A1 (fr) 2013-02-20 2014-08-27 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé pour la préparation d'intermédiaires clés pour la synthèse de statines
WO2014128022A1 (fr) * 2013-02-20 2014-08-28 F.I.S. - Fabbrica Italiana Sintetici S.P.A. Procédé pratique pour la préparation de statines
ITVI20130039A1 (it) * 2013-02-20 2014-08-21 F I S Fabbrica Italiana Sint I S P A Processo per la preparazione di intermedi chiave per la sintesi di statine
CN104321320A (zh) * 2013-02-20 2015-01-28 意大利合成制造有限公司 制备他汀的方便方法
US9315470B2 (en) 2013-02-20 2016-04-19 F.I.S.—Fabbrica Italiana Sintetiei S.p.A. Convenient process for the preparation of statins
KR101736727B1 (ko) 2013-02-20 2017-05-17 에프.아이.에스. 파브리카 이탈리아나 신테티치 에스.피.에이. 스타틴의 편리한 제조방법
CN104321320B (zh) * 2013-02-20 2017-05-31 意大利合成制造有限公司 制备他汀的方便方法
US9932361B2 (en) 2013-02-20 2018-04-03 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Convenient process for the preparation of statins
CN108299310A (zh) * 2018-01-31 2018-07-20 浙江科技学院 一种制备高稳定性瑞舒伐他汀钙的方法

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