WO2009128091A2 - Forme cristalline de l'intermédiaire acide (7-[4-(4-fluorophényl)-6-isopropyl-2-(n-méthyl-n-méthylsulfonylamino)pyrimidin-5-yl]-(3r,5s)-dihydroxy-(e)-6-hepténoïque, son procédé de fabrication et son utilisation - Google Patents

Forme cristalline de l'intermédiaire acide (7-[4-(4-fluorophényl)-6-isopropyl-2-(n-méthyl-n-méthylsulfonylamino)pyrimidin-5-yl]-(3r,5s)-dihydroxy-(e)-6-hepténoïque, son procédé de fabrication et son utilisation Download PDF

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Publication number
WO2009128091A2
WO2009128091A2 PCT/IN2009/000116 IN2009000116W WO2009128091A2 WO 2009128091 A2 WO2009128091 A2 WO 2009128091A2 IN 2009000116 W IN2009000116 W IN 2009000116W WO 2009128091 A2 WO2009128091 A2 WO 2009128091A2
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WO
WIPO (PCT)
Prior art keywords
methyl
isopropyl
pyrimidin
methylsulfonylamino
rosuvastatin
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2009/000116
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English (en)
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WO2009128091A3 (fr
Inventor
Sanjay Mahajan
Madhuresh Sethi
Purna Chandra Ray
Debashish Datta
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Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories Ltd
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Publication date
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Publication of WO2009128091A2 publication Critical patent/WO2009128091A2/fr
Anticipated expiration legal-status Critical
Publication of WO2009128091A3 publication Critical patent/WO2009128091A3/fr
Ceased legal-status Critical Current

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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

  • This invention in general relates to a process for producing (7-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6-heptenoic acid (Rosuvastatin) or pharmaceutically acceptable salts thereof.
  • the present invention provides a crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)- pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate, process for producing the same and employing the same for producing rosuvastatin or pharmaceutically acceptable salts thereof.
  • Rosuvastatin calcium chemically known as 7-[4-(4-fluorophenyl)-6-isopropyl-2-
  • Formula-I Rosuvastatin calcium is marketed as "CRESTOR" for the treatment of hyperlipidaemia and acts by inhibiting HMG-CoA reductase enzymes in mammals.
  • the daily dose of rosuvastatin is between 5mg to 40mg orally for reducing the LDL cholesterol level in the mammals.
  • Compound-A is a key intermediate for producing Rosuvastatin Calcium.
  • a crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate characterized by PXRD having peaks at 9.7, 16.2, 18.01, 18.9, 19.3, 21.2, 22.5 and 24.5 ( ⁇ ) 0.2 degree two theta.
  • a process for producing the crystalline form of methyl 7-[4-(4-flourophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5- oxo-(E)-6-heptenate comprising crystallizing the methyl 7-[4-(4-flourophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo- (E)- ⁇ -heptenate from a solution including at least one organic solvent.
  • a process for producing crystalline form of methyl 7-[4-(4- flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3- hydroxy- 5 -oxo-(E)-6-heptenate comprising deprotecting the silyl group of compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)- pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate and treating with an organic solvent.
  • Figure 1 illustrates characteristic X-ray powder diffraction pattern for the crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate.
  • the present invention relates to a crystalline form of 7-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)- 6-heptenoic acid intermediate methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate (Compound-A/rosuvastatin intermediate) and a novel process for the preparation thereof. Also, the present invention discloses an improved process for the preparation of pharmaceutical acceptable salts of rosuvastatin using the crystalline form of rosuvastatin intermediate.
  • the polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of the polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the crystalline form of rosuvastatin intermediate Compound-A is characterized by PXRD having peaks at about 9.7, 16.2, 18.01, 18.9, 19.3, 21.2, 22.5 and 24.5 ( ⁇ ) 0.2 2 ⁇ values as depicted in figure 1.
  • the crystalline rosuvastatin intermediate "Compound-A” is characterized by analytical techniques including, but are not limited to X-ray powder diffraction pattern, moisture content and/or melting point.
  • Another embodiment of the present invention is to provide a process for the preparation of the crystalline form of rosuvastatin intermediate Compound-A, wherein the process comprises of deprotecting the silyl group of methyl 7-[4-(4-flourophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate and crystallizing with an organic solvent.
  • deprotection is carried out by the conventional methods, for example as disclosed in EP 0521471 and WO 03/097614. In another embodiment of the present invention, deprotection is carried out by using copper (II) halide or its hydrates such as copper (II) chloride dihydrate.
  • the residue obtained after deprotecting the methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl] -(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6- heptenate is crystallized with an organic solvent to obtain the crystalline form of rosuvastatin intermediate Compound-A, wherein the solvent is selected from Ci-C 5 alcohols preferably isopropyl alcohol.
  • the crystallization is performed by heating a reaction mixture of the crystalline intermediate in the solvent to obtain a solution, followed by cooling, wherein heating is carried out to a temperature of about 40
  • Compound-A comprises of deprotecting the compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5- oxo-(E)-6-heptenate and further purifying in an organic solvent such as Ci-C 5 alcohols.
  • Another embodiment of the present invention is to provide an improved process for the preparation of rosuvastatin or its pharmaceutically acceptable salts thereof, wherein, the said process comprises of converting the crystalline form of rosuvastatin intermediate Compound-A to rosuvastatin or its pharmaceutically acceptable salts thereof as depicted in Scheme I.
  • rosuvastatin salt is selected from calcium, magnesium and sodium.
  • M is Metal ion such as Calcium, Magnesium and Sodium
  • Compound-A is reduced to Compound-C by following conventional methods, for example as disclosed in EP 0521471B1, US 20050159615 and WO 03/097614 and
  • Compound-C is further converted to rosuvastatin pharmaceutically acceptable salts by following conventional methods, for example as disclosed in EP 0521471B1, EP
  • Compound-B Compound 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-5-pyrimidine carbaldehyde (100 g) and (3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene (183 g) were taken in acetonitrile (1500 ml) and refluxed for 14 hours. After completion of the reaction, the reaction mass was concentrated. Cyclohexane was added to the reaction mass and solid was filtered.
  • the obtained residue was taken in isopropyl alcohol and heated to 40-45 °C followed by cooling to 10-15 0 C.
  • the obtained solid was filtered and washed with diisopropyl ether.
  • the filtered solid was dried to yield methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate.
  • XRD of the dried sample showed it to be crystalline.
  • Tetrahydrofuran (1800 ml) was taken in a flask and cooled to -90 °C. To this sodiumborohydride (10 g) and diethyl methoxyborane (1.0 M solution in THF) was added and maintained for 30 minutes.
  • Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)- pyrimidin-5-yl]-(3R,5S)-dihydroxy -(E)- ⁇ -heptenate 100 g was added to ethyl alcohol (900 ml).
  • aqueous sodium hydroxide 8.0 g sodium hydroxide dissolved in 500 ml of water
  • the reaction mixture was heated to room temperature and maintained for 1-2 hours.
  • Rosuvastatin Sodium 100 g was dissolved in water (1000 ml) and stirred at room temperature for 15 minutes.
  • calcium chloride solution 29.2 g of calcium chloride dehydrate dissolved in 500 ml of water
  • the obtained solid was filtered and washed with water and dried to yield Rosuvastatin Calcium.

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

Abstract

L'invention porte sur une forme cristalline du 7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-hepténate de méthyle (intermédiaire de la rosuvastatine), sur un procédé pour la fabrication de celle-ci et sur l'utilisation de celle-ci pour la fabrication de rosuvastatine ou de sels pharmaceutiquement acceptables de celle-ci.
PCT/IN2009/000116 2008-02-20 2009-02-20 Forme cristalline de l'intermédiaire acide (7-[4-(4-fluorophényl)-6-isopropyl-2-(n-méthyl-n-méthylsulfonylamino)pyrimidin-5-yl]-(3r,5s)-dihydroxy-(e)-6-hepténoïque, son procédé de fabrication et son utilisation Ceased WO2009128091A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN430/CHE/2008 2008-02-20
IN430CH2008 2008-02-20

Publications (2)

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WO2009128091A2 true WO2009128091A2 (fr) 2009-10-22
WO2009128091A3 WO2009128091A3 (fr) 2010-11-04

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121598A1 (fr) * 2010-03-29 2011-10-06 Biocon Limited Forme cristalline d'ester méthylique d'acide 7-[4-(4-fluorophényl)-6-isopropyl-2-(méthanesulfonyl-méthyl-amino)-pyrimidin-5-yl]-3(r)-hydroxy-5-oxo-hept-6-énoïque et procédé associé
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
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
WO2015030001A1 (fr) * 2013-08-30 2015-03-05 日産化学工業株式会社 Procédé de préparation de 5-hydroxy-3-cétoesters optiquement actifs
CN105153040A (zh) * 2015-10-15 2015-12-16 江苏师范大学 瑞舒伐他汀钙新晶型及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1872841A (zh) * 2005-06-01 2006-12-06 信谊药厂 瑞舒伐他汀钙及其关键中间体的制备方法
WO2008067440A2 (fr) * 2006-11-29 2008-06-05 Dr. Reddy's Laboratories Ltd. Sel de déshydroabiétylamine de rosuvastatine

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121598A1 (fr) * 2010-03-29 2011-10-06 Biocon Limited Forme cristalline d'ester méthylique d'acide 7-[4-(4-fluorophényl)-6-isopropyl-2-(méthanesulfonyl-méthyl-amino)-pyrimidin-5-yl]-3(r)-hydroxy-5-oxo-hept-6-énoïque et procédé associé
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
US9315470B2 (en) 2013-02-20 2016-04-19 F.I.S.—Fabbrica Italiana Sintetiei S.p.A. Convenient process for the preparation of statins
US9932361B2 (en) 2013-02-20 2018-04-03 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Convenient process for the preparation of statins
WO2015030001A1 (fr) * 2013-08-30 2015-03-05 日産化学工業株式会社 Procédé de préparation de 5-hydroxy-3-cétoesters optiquement actifs
JPWO2015030001A1 (ja) * 2013-08-30 2017-03-02 日産化学工業株式会社 光学活性５−ヒドロキシ−３−ケトエステル類の製造方法
US9701642B2 (en) 2013-08-30 2017-07-11 Nissan Chemical Industries, Ltd. Method for producing optically active 5-hydroxy-3-ketoester
JP2019135249A (ja) * 2013-08-30 2019-08-15 日産化学株式会社 光学活性５−ヒドロキシ−３−ケトエステル類の製造方法
CN105153040A (zh) * 2015-10-15 2015-12-16 江苏师范大学 瑞舒伐他汀钙新晶型及其制备方法
CN105153040B (zh) * 2015-10-15 2018-04-13 江苏师范大学 瑞舒伐他汀钙新晶型及其制备方法

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