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WO2007099561A1 - Procédé de préparation de rosuvastatine calcique - Google Patents

Procédé de préparation de rosuvastatine calcique Download PDF

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Publication number
WO2007099561A1
WO2007099561A1 PCT/IN2007/000083 IN2007000083W WO2007099561A1 WO 2007099561 A1 WO2007099561 A1 WO 2007099561A1 IN 2007000083 W IN2007000083 W IN 2007000083W WO 2007099561 A1 WO2007099561 A1 WO 2007099561A1
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WO
WIPO (PCT)
Prior art keywords
rosuvastatin
calcium
temperature
acid
solution
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/IN2007/000083
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English (en)
Inventor
Dhimant Jasubhai Patel
Rajiv Kumar
Shri Prakash Dhar Dwivedi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
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 Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Publication of WO2007099561A1 publication Critical patent/WO2007099561A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

  • the present invention relates to improved process for preparing Rosuvastatin Calcium, which is chemically known as hemi calcium salt of (E) -7-[4-(4-flu ' rophenyI)- 6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R, 5S)-3, 5- dihydroxy-6-heptenoic acid of formula (I).
  • Rosuvastatin calcium is a HMG CoA reductase inhibitor and useful for the treatment hypercholesterolemia, hyperlipoproteinemia and atherosclerosis
  • Rosuvastatin that is chemically known as (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid and its salts, which are HMG CoA reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin.
  • Lovastatin (disclosed in U.S. Pat. No. 4321938) and simvastatin (disclosed in U.S. Pat. No. 4444784) are administered in the lactone form. After absorption, the lactone ring is opened in the liver by chemical or enzymatic hydrolysis, and the active hydroxy acid is generated.
  • Pravastatin (disclosed in U.S. Pat. No. 4346227), Fluvastatin (disclosed in U.S. Pat. No. 4739073) and cerivastatin (disclosed in U.S. Pat No.
  • Atorvastatin and two new 'superstates' i.e. rosuvastatin and pitavastatin are administered as calcium salts.
  • Rosuvastatin Calcium (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid and its salts is a HMG-CoA reductase inhibitor, a superstatin developed by Shionogi for the treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996, Direct Communication, Shionogi 8 Feb. 1999 and 25 Feb. 2000). It can lower LDL-cholesterol and triglycerides more effectively than the first generation drugs. Rosuvastatin calcium has the following structure being shown by formula (I)
  • Rosuvastatin calcium is marketed under the trade name of CRESTOR for treatment of a mammal such as a human. Accordingly CRESTOR is administered in a daily dose of from about 5 mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5 mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hypercholesterolemia and aggressive lipid targets (>192 mg/dL), and the 40 mg dose for patients who have not been responsive to lower doses.
  • WO 03/032995 further discloses a method of preventing dementia by administering to a patient rosuvastatin.
  • U.S. Pat. No. 5,260,440 discloses the process to produce rosuvastatin salt.
  • the process of U.S. Pat. No. 5,260,440 starts with the methyl ester of rosuvastatin, known an (methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (methyl rosuvastatin)).
  • the process for preparation of the intermediates disclosed in the '440 patent is incorporated herein by reference.
  • rosuvastatin sodium is prepared from its methyl ester according to Example 1 (6) by adding sodium hydroxide to a solution of the methyl ester in ethanol, followed inter alia by distillation, followed by addition of ether to the residue obtained from distillation.
  • the present applicants found that diethyl ether may not be used in production; after distillation of the solvent, the present applicants obtained a viscous oil that hardly precipitates in diethyl ether.
  • WO2005068435 discloses a method of preparation of the amorphous hemi- calcium salt of Rosuvastatin by a one-pot manufacturing process from the Rosuvastatin ester or lactone intermediate.
  • the invention describes use of alkali metal hydroxides for the purpose of the hydrolysis of Rosuvastatin ester or lactone intermediate in a suitable solvent system, which is subjected to the treatment of Calcium acetate or Calcium hydroxide to afford amorphous hemicalcium salt of Rosuvastatin without isolating any intermediate alkali metal salt of Rosuvastatin.
  • WO2004/014872 disclosed an improved process for manufacturing rosuvastatin calcium salt
  • various ammonium salts of Rosuvastatin is subjected to the treatment of inorganic bases containing alkali metal cations.
  • the in-situ obtained Rosuvastatin alkali metal salt is converted to its corresponding calcium salt by means of reacting Rosuvastatin alkali metal salt with calcium chloride dihydrate.
  • US 2005/0080134 Al discloses the process for preparation of rosuvastatin calcium from C 1 to C 4 alkyl ester of rosuvastatin with a base in presence of a C 1 to C 4 alcohol.
  • the patent applications also disclose the process for preparation of rosuvastatin calcium by use of phase transfer catalyst. The process mainly concern with the hydrolysis of ester with alkali. The process includes the absence of impurities at different RRT's when compared with those of CRESTOR tablets when measured with area percentage of HPLC as the scope of invention.
  • WO 2005/040134 Al discloses the amorphous rosuvastatin calcium having purity of more than 99% with diastereoisomeric impurity less than 0.5% by HPLC.
  • the process for preparation of amorphous rosuvastatin calcium, from a solution of rosuvastatin calcium in one or more organic solvents, recovering the amorphous form of rosuvastatin calcium by removal of solvent i.e. either by distillation, distillation under vacuum, evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under vacuum, decantation, and centrifugation is also the scope of present invention.
  • the main object of the present invention is to provide a process for preparation of Rosuvastatin and its pharmaceutically acceptable salts.
  • FIG.l It represents X-ray diffraction of amorphous rosuvastatin calcium
  • F1G.2 It rcprcbcnlb HPLC chromatogram of solid rosuvastatin calcium
  • DETAILED DESCRIPTION According to the present invention, there is provided a improved process for the preparation of Rosuvastatin diol ester of formula (Ia), which comprises
  • the organic acid can be selected from the group comprising of oxalic acid, maleic acid, citric acid, acetic acid, preferably oxalic acid.
  • the deprotection can be performed in the polar solvent selected from Ci to C 4 alcoholic solvent is methanol, ethanol, propanol, isopropanol and butanol or acetonitrile, preferably methanol.
  • the process as described herein as the preferred embodiment is carried out a higher temperature of about 50 0 C to about 55°C, which is gradually cooled to about 4O 0 C and further to about 10 0 C to about 2O 0 C.
  • the addition of base like liquor ammonia is carried out preferably at lower temperature of 1O 0 C to 2O 0 C to adjust the pH of about less than 10, preferably of 8 to 9.
  • Rosuvastatin diol ester (Ia) obtained by deprotection reaction can be isolated and subsequently converted to its calcium salt or without isolating it can be converted to its calcium salt.
  • a process of preparing amorphous rosuvastatin calcium substantially free of impurities comprising the steps of: a) reacting tert-butyl (E)- (6- ⁇ 2- [4- (4-fluorophenyl)-6-isopropy2- [methyl (methylsulfonyl) amino]pyrimidin-5-yl] vinyl ⁇ - (4R, 6S)-2,2-dimethyl[l s 3] dioxan-4yl) acetate of formula (II)
  • step (e) is alkali hydroxides preferably sodium or potassium hydroxide.
  • the addition of acid like HCl in step (e) is carried out at lower temperature of about 10 0 C to 2O 0 C thereby adjusting the pH of about less than 9, preferably of 7.5 to 8.5.
  • Rosuvastatin obtained by deprotection reaction is treated with calcium chloride in presence of alkali metal hydroxide such as sodium hydroxide to give rosuvastatin calcium.
  • amorphous rosuvastatin calcium having purity greater than 99.65% and does not having detectable level of impurities when measured by area percentage of HPLC at RRT 1.26, 1.31, 1.41, 1.56, 1.71 and 3.99.
  • the present invention further provides a process for preparing amorphous rosuvastatin calcium substantially free of impurities comprising the steps of: a) reacting a diol protected alkyl ester derivative of formula (II)
  • the process for preparing rosuvastatin calcium according to present invention is simple, easy safe and yields Rosuvastatin Calcium with single individual impurity, less than 0.1%.
  • the Impurity Profile Determination of Rosuvastatin calcium comprised testing a sample using HPLC.
  • the HPLC testing parameters included a column of Hypersil BDS C18 5 ⁇ m 4.6*250 mm (Part No. 28105-020 or equivalent column) at a temperature of 25°C and eluted with a two solvent system.
  • a first reservoir, Reservoir A contained 0.005 M ammonium formate dissolved in 1000 ml water, adjusted to pH 4.0 with H 3 PO 4
  • a second reservoir, Reservoir B contained acetonitrile.
  • the gradient was as follows: at the initial time, 40% Reservoir A and 60% Reservoir B; time 28.5 min 36% Reservoir A and 64% Reservoir B; and at time 43.0 min 36% Reservoir A and 64% Reservoir B, and at time 50 min 40% Reservoir A and 60% Reservoir B.
  • the system equilibrated further for 10 min and a flow rate of 1.0 ml/min.
  • the detector was set for 245 nm.
  • the sample volume was 10 ⁇ L and the diluent was acetonitrile: water 50:50.
  • the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
  • the sample was prepared by weighing accurately about 10 mg of Rosuvastatin
  • Impurity Profile Determination % impurity area impurity in sample X lOO

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

Abstract

La présente invention concerne un procédé de préparation de rosuvastatine calcique amorphe d'une pureté supérieure à 99,65 % essentiellement exempte d'impuretés telle que mesurée par le pourcentage de surface établi par HPLC à des temps de rétention relatifs de 1,26, 1,31, 1,41, 1,56, 1,71 et 3,99.
PCT/IN2007/000083 2006-02-27 2007-02-26 Procédé de préparation de rosuvastatine calcique Ceased WO2007099561A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN271/MUM/2006 2006-02-27
IN271MU2006 2006-02-27

Publications (1)

Publication Number Publication Date
WO2007099561A1 true WO2007099561A1 (fr) 2007-09-07

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PCT/IN2007/000083 Ceased WO2007099561A1 (fr) 2006-02-27 2007-02-26 Procédé de préparation de rosuvastatine calcique

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7582759B2 (en) 2005-02-22 2009-09-01 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
WO2009143776A1 (fr) * 2008-05-27 2009-12-03 常州制药厂有限公司 Procédé de préparation de la rosuvastatine calcique et de ses intermédiaires
WO2009156173A1 (fr) 2008-06-27 2009-12-30 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique comprenant une statine
EP2138165A1 (fr) 2008-06-27 2009-12-30 KRKA, tovarna zdravil, d.d., Novo mesto Composition pharmaceutique comportant de la statine
WO2010069593A1 (fr) 2008-12-19 2010-06-24 Krka, D. D., Novo Mesto Utilisation de composés amphiphiles pour la cristallisation régulée de statines et d'intermédiaires de statines
US7777034B2 (en) 2003-11-24 2010-08-17 Teva Pharmaceutical Industries Ltd. Crystalline ammonium salts of rosuvastatin
US7851624B2 (en) 2003-12-24 2010-12-14 Teva Pharamaceutical Industries Ltd. Triol form of rosuvastatin and synthesis of rosuvastatin
US7884226B2 (en) 2007-07-12 2011-02-08 Teva Pharmaceutical Industries, Ltd. Purification of rosuvatatin intermediate by thin film evaporation and chemical method
EP2327682A1 (fr) 2009-10-29 2011-06-01 KRKA, D.D., Novo Mesto Utilisation de composés amphiphiles pour la crystallisation controlée de statines et d'intermediaires de statines.
EP2334667A4 (fr) * 2008-09-09 2011-10-26 Biocon Ltd Procédé de préparation d acétonide de rosuvastatine calcique
WO2012073055A1 (fr) 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'intermédiaires pharmaceutiques de haute pureté
US8212035B2 (en) 2007-02-08 2012-07-03 Aurobindo Pharma Ltd. Process for preparation of rosuvastatin calcium field of the invention
US8318933B2 (en) 2006-10-31 2012-11-27 Aurobindo Pharma Ltd Process for preparing rosuvastatin calcium
WO2013111946A1 (fr) * 2012-01-27 2013-08-01 코오롱생명과학 주식회사 Procédé de préparation de rosuvastatine et composé intermédiaire utilisé pour préparer de la rosuvastatine
CN104788387A (zh) * 2015-04-17 2015-07-22 浙江海森药业有限公司 高纯度瑞舒伐他汀钙的制备方法
CN109580789A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种液相色谱法分离测定瑞舒伐他汀叔丁酯及其光学异构体的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103977A2 (fr) * 2003-05-21 2004-12-02 Ciba Specialty Chemicals Holding Inc. Procede de preparation de derives de pyrimidine
WO2005023778A2 (fr) * 2003-08-28 2005-03-17 Teva Pharmaceutical Industries Ltd. Procede de preparation de sels calciques de rosuvastatine
CN1821242A (zh) * 2006-02-16 2006-08-23 亚邦化工集团有限公司 制备二羟基酸HMG－CoA还原酶抑制剂的新方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103977A2 (fr) * 2003-05-21 2004-12-02 Ciba Specialty Chemicals Holding Inc. Procede de preparation de derives de pyrimidine
WO2005023778A2 (fr) * 2003-08-28 2005-03-17 Teva Pharmaceutical Industries Ltd. Procede de preparation de sels calciques de rosuvastatine
CN1821242A (zh) * 2006-02-16 2006-08-23 亚邦化工集团有限公司 制备二羟基酸HMG－CoA还原酶抑制剂的新方法

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7777034B2 (en) 2003-11-24 2010-08-17 Teva Pharmaceutical Industries Ltd. Crystalline ammonium salts of rosuvastatin
US7851624B2 (en) 2003-12-24 2010-12-14 Teva Pharamaceutical Industries Ltd. Triol form of rosuvastatin and synthesis of rosuvastatin
US7612203B2 (en) 2005-02-22 2009-11-03 Teva Pharmaceutical Industries Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US8063211B2 (en) 2005-02-22 2011-11-22 Teva Pharmaceutical Industries, Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US7582759B2 (en) 2005-02-22 2009-09-01 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
US8318933B2 (en) 2006-10-31 2012-11-27 Aurobindo Pharma Ltd Process for preparing rosuvastatin calcium
US8212035B2 (en) 2007-02-08 2012-07-03 Aurobindo Pharma Ltd. Process for preparation of rosuvastatin calcium field of the invention
US7884226B2 (en) 2007-07-12 2011-02-08 Teva Pharmaceutical Industries, Ltd. Purification of rosuvatatin intermediate by thin film evaporation and chemical method
US8765947B2 (en) 2008-05-27 2014-07-01 Changzhou Pharmaceutical Factory Preparation method of Rosuvastatin calcium and its intermediates
US8653265B2 (en) 2008-05-27 2014-02-18 Changzhou Pharmaceutical Factory Preparation method of rosuvastatin calcium and its intermediates
WO2009143776A1 (fr) * 2008-05-27 2009-12-03 常州制药厂有限公司 Procédé de préparation de la rosuvastatine calcique et de ses intermédiaires
EP2138165A1 (fr) 2008-06-27 2009-12-30 KRKA, tovarna zdravil, d.d., Novo mesto Composition pharmaceutique comportant de la statine
WO2009156173A1 (fr) 2008-06-27 2009-12-30 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique comprenant une statine
EP2334667A4 (fr) * 2008-09-09 2011-10-26 Biocon Ltd Procédé de préparation d acétonide de rosuvastatine calcique
WO2010069593A1 (fr) 2008-12-19 2010-06-24 Krka, D. D., Novo Mesto Utilisation de composés amphiphiles pour la cristallisation régulée de statines et d'intermédiaires de statines
EP2327682A1 (fr) 2009-10-29 2011-06-01 KRKA, D.D., Novo Mesto Utilisation de composés amphiphiles pour la crystallisation controlée de statines et d'intermediaires de statines.
WO2012073055A1 (fr) 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'intermédiaires pharmaceutiques de haute pureté
WO2013111946A1 (fr) * 2012-01-27 2013-08-01 코오롱생명과학 주식회사 Procédé de préparation de rosuvastatine et composé intermédiaire utilisé pour préparer de la rosuvastatine
CN104788387A (zh) * 2015-04-17 2015-07-22 浙江海森药业有限公司 高纯度瑞舒伐他汀钙的制备方法
CN109580789A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种液相色谱法分离测定瑞舒伐他汀叔丁酯及其光学异构体的方法
CN109580789B (zh) * 2017-09-28 2021-06-22 安徽省庆云医药股份有限公司 一种液相色谱法分离测定瑞舒伐他汀叔丁酯及其光学异构体的方法

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