WO2010023678A1 - Procédé de préparation d'intermédiaire de rosuvastatine - Google Patents

Procédé de préparation d'intermédiaire de rosuvastatine Download PDF

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Publication number
WO2010023678A1
WO2010023678A1 PCT/IN2008/000655 IN2008000655W WO2010023678A1 WO 2010023678 A1 WO2010023678 A1 WO 2010023678A1 IN 2008000655 W IN2008000655 W IN 2008000655W WO 2010023678 A1 WO2010023678 A1 WO 2010023678A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
preparation
pyrimidin
methyl
Prior art date
Application number
PCT/IN2008/000655
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English (en)
Inventor
Sreenivasa Prasad Anegondi
Shanmughasamy Rajmahendra
Jibin Joseph
Pullela Venkata Srinivas
Original Assignee
Biocon Limited
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Filing date
Publication date
Application filed by Biocon Limited filed Critical Biocon Limited
Publication of WO2010023678A1 publication Critical patent/WO2010023678A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to improved process for the preparation of intermediates which is useful for the preparation of rosuvastatin and its pharmaceutically acceptable salts.
  • Rosuvastatin and process for its preparation is disclosed in US Patent US 5,260,440.
  • the process disclosed therein involves distinct chemical steps and both, uneconomical and time consuming.
  • the principle objective of the present invention is to develop a process for the preparation of intermediates involved in preparation of rosuvastatin. Another objective of the present invention is to provide a process for the preparation of intermediates involved in preparation of rosuvastatin and its pharmaceutically acceptable salt.
  • the present invention provides for a process for ,the preparation of the compound IX comprises,
  • R 2 is or
  • R 2 is or
  • the present invention is in relation to a process for the preparation of the compound IX comprises,
  • R 2 is or
  • oxidizing agent is selected from the group MCPBA, Hydrogen peroxide and Peraceticacid.
  • alkali and alkaline earth metal bases are selected from Potassium carbonate, Sodium ethoxide and sodium methoxide
  • suitable solvent is selected from the group toluene, tetrahydrofuran, Dimethylsulfoxide, Dimethylformamide and N- methylpyrrolidine.
  • the present invention relates to a compo ⁇ nd of formula V
  • the present invention relates to a compound of formula
  • R 2 is or
  • the primary object of the present invention is the provision of improved processes for the preparation of an intermediate (IX) using a compound of formula VIII which is used for the preparation of Rosuvastatin and its pharmaceutically acceptable salts.
  • Rj is or
  • R 2 is or
  • the present invention is directed to a series of synthesis schemes for the preparation of HMG CoA reductase inhibitors.
  • the process of the present invention is outlined in Scheme-I and Scheme-II Intermediate of formula IX is prepared using novel intermediate VIII. N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2;yl]-N-methyl- methanesulfonamide is reacted with thiol compound of formula R
  • R is or in the presence of the base selected from the group BuLi, Potassium carbonate, Sodium ethoxide, sodium methoxide and Cesium carbonate to provide the compound of the formula V. which is further oxidized with an oxidizing agent selected from the group MCPBA, Hydrogen peroxide, Peraceticacid to result in formula VIII which is further reacted with an aldehyde of formula X gives the compound of formula IX.
  • the Present invention has following advantages over known method: 1. Clean process
  • the compound of general formula-IX may be used to form a dihydroxy acid HMG' CoA reductase inhibitor by subjecting the compound of formula-IX to acidic conditions to remove the acetonide and form ⁇ Hoi compound, which upon treating with a base such as an alkali metal hydroxide to form Formula XII followed by treating with corresponding alkali or alkaline earth metal salts in a suitable solvent to get Rosuvastatin calcium.
  • Intermediate IX is an important intermediate for the preparation of Rosuvastatin calcium which is a HMG Co-A reductase inhibitors.
  • R is or . in presence of a suitable base selected from the group BuLi, Potassium carbonate, Sodium ethoxide, sodium methoxide and. Cesium carbonate with or without a suitable solvent to provide a novel sulfide compound of formula V.
  • a suitable base selected from the group BuLi, Potassium carbonate, Sodium ethoxide, sodium methoxide and. Cesium carbonate with or without a suitable solvent to provide a novel sulfide compound of formula V.
  • step 2 The compound obtained from step 1 is oxidized with oxidizing agents selected from the group MCPBA, Hydrogen peroxide, Peraceticacid results novel compound of formula VIII.
  • the process of the present invention is an improved, economical, commercially feasible and clean method for preparing novel intermediate used for the preparation of HMG CoA reductase inhibitors.
  • the process of the present invention is outlined in Scheme-I, Scheme-II and Scheme-Ill.
  • N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methanesulfonamide 1Og was taken in tetrahydrofuran (6OmL) and methanol (2OmL) and chilled the reaction mixture to 5 to 1O 0 C. Added sodiumborohydride (0.9Ig) in 4 lots. Stirred for 2 h at 5°C and slowly raised the temperature to 25°C. Quenched the reaction mixture with saturated ammonium chloride solution to pH 7 - 8. Added 5OmL ethylacetate and separated the layers. Extracted the aqueous layer with ethyl acetate (6OmL).
  • N-[4 ⁇ (4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methanesulfonamide (1Og) was taken in 5OmL of toluene and dissolved at 30° C. Added 49% aqueous hydrogenbromide solution(7.5mL) and refluxed at HO 0 C azeotropically for 3-4 hours. Brought the reaction mixture to 25° C and quenched the reaction mixture with 5% sodium bicarbonate solution to pH 7-7.5. Separated the organic layer and given water wahes. Extracted the aqueous layer with toluene (20 mL).
  • 2-mercaptopyridine (II) 3.23g was taken in 16mL tetrahydrofuran and chilled to -25 to -30° C and added 30% n-butyl lithium(l 1.OmL) drop wise at -5 to -10 ° C and stirred at the same temperature for one hour.
  • 3,5-Bis(tri fluoromethyl) thiophenol (V) 7.4g was taken in 35mL tetrahydrofuran and chilled to -25 to -30° C and added 30% n-BuLi (11.3 mL) drop wise at -5 to -10° C and stirred at the same temperature for one hour.
  • Example-8 Preparation of (6- ⁇ 2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yI]-vinyl ⁇ -2,2-dimethyI-[l,3]dioxan-4- ⁇ -acetic acid tert-butyl ester (IX).
  • N-[4-(4-Fluoro-phenyl)-6-isopropyl-5-(pyridine-2-sulfonylmethyl)-pyrimidin-2-yl]-N- methyl-methanesulfonamide(IV) 7g was taken in Dimethylsulfoxide (35 mL). Heated to 35-40°C.Added potassium carbonate (6.07g) and stirred for 15 minutes .Added (6- Formyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 4.1g dissolved in 14mL Dimethylsulfoxide drop wise. Heated to 75 - 80° C and stirred for 12 h.
  • N-[5-(3,5-Bis-trifluoromethyl-benzene sulfonyl methyl)-4-(4-fluoro-phenyl)-6- isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide(VII) 7g was taken in Dimethylsulfoxide (35 mL). Heated to 35-4O 0 C. Added potassium carbonate (4.733g) and stirred for 15 minutes. Added (6-Formyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 3.24g dissolved in 14mL dimethylsulfoxide drop wise.
  • Rosuvastatin calcium (6- ⁇ 2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin- 5-yl]-vinyl ⁇ -2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (IX) 1Og was taken in 145mL acetonitrile and added 200ml of (0.02M) hydrochloric acid solution slowly at 35° C-40° C and stirred at the same temperature for 3 hrs.

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation d'intermédiaires impliqués dans la préparation de la rosuvastatine. En particulier, l'invention proposée permet de pallier les inconvénients associés aux procédés connus. Ainsi, la présente invention concerne un procédé qui est propre, rentable, susceptible d'être utilisé à l'échelle industrielle et permet des rendements élevés avec un produit sensiblement pur.
PCT/IN2008/000655 2008-08-27 2008-10-10 Procédé de préparation d'intermédiaire de rosuvastatine WO2010023678A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN02081/CHE/2008 2008-08-27
IN2081CH2008 2008-08-27

Publications (1)

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WO2010023678A1 true WO2010023678A1 (fr) 2010-03-04

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011083495A2 (fr) * 2010-01-07 2011-07-14 Msn Laboratories Limited Procédé de préparation de dérivés protégés par un dihydroxy et nouveaux composés intermédiaires
WO2011104725A2 (fr) 2010-02-23 2011-09-01 Cadila Healthcare Limited Inhibiteurs de l'hmg-coa réductase et procédé pour leur préparation
WO2011086584A3 (fr) * 2010-01-18 2011-09-15 Msn Laboratories Limited Procédé amélioré pour la préparation d'intermédiaires amides et leur utilisation
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
EP2617703A1 (fr) 2012-01-17 2013-07-24 Corning Incorporated Oxydation hypohalogéneuse catalysée améliorée de groupes d'alcool
CN104520294A (zh) * 2012-06-08 2015-04-15 未来精密化工有限公司 结晶2-[(4r,6s)-6-甲酰基-2,2-二甲基-1,3-二噁烷-4-基]乙酸叔丁酯及其制备方法
CN108997324A (zh) * 2018-08-21 2018-12-14 南京欧信医药技术有限公司 瑞舒伐他汀钙中间体的制备方法
CN109456300A (zh) * 2018-08-21 2019-03-12 南京欧信医药技术有限公司 高纯度瑞舒伐他汀钙中间体的制备方法
CN109574938A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125547A2 (fr) * 2006-05-03 2007-11-08 Manne Satyanarayana Reddy Nouveau procédé faisant intervenir des statines et leurs sels acceptables sur le plan pharmaceutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125547A2 (fr) * 2006-05-03 2007-11-08 Manne Satyanarayana Reddy Nouveau procédé faisant intervenir des statines et leurs sels acceptables sur le plan pharmaceutique

Non-Patent Citations (2)

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Title
ALONSO ET AL.: "Synthetic Applications of pi-Electron-Deficient Sulfones", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 180, no. 5-6, 2005, pages 1119 - 1131 *
BLAKEMORE: "The modified Julia olefination: alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds", J. CHEM. SOC., PERKIN TRANS. I, 2002, pages 2563 - 2585 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
WO2011083495A2 (fr) * 2010-01-07 2011-07-14 Msn Laboratories Limited Procédé de préparation de dérivés protégés par un dihydroxy et nouveaux composés intermédiaires
WO2011083495A3 (fr) * 2010-01-07 2011-10-13 Msn Laboratories Limited Procédé de préparation de dérivés protégés par un dihydroxy et nouveaux composés intermédiaires
WO2011086584A3 (fr) * 2010-01-18 2011-09-15 Msn Laboratories Limited Procédé amélioré pour la préparation d'intermédiaires amides et leur utilisation
US8987444B2 (en) 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof
WO2011104725A2 (fr) 2010-02-23 2011-09-01 Cadila Healthcare Limited Inhibiteurs de l'hmg-coa réductase et procédé pour leur préparation
WO2013109670A1 (fr) 2012-01-17 2013-07-25 Corning Incorporated Oxydation rapide catalysée par acides hypohalogéneux de groupes alcool
EP2617703A1 (fr) 2012-01-17 2013-07-24 Corning Incorporated Oxydation hypohalogéneuse catalysée améliorée de groupes d'alcool
CN104520294A (zh) * 2012-06-08 2015-04-15 未来精密化工有限公司 结晶2-[(4r,6s)-6-甲酰基-2,2-二甲基-1,3-二噁烷-4-基]乙酸叔丁酯及其制备方法
CN104520294B (zh) * 2012-06-08 2017-04-26 未来精密化工有限公司 结晶2‑[(4r,6s)‑6‑甲酰基‑2,2‑二甲基‑1,3‑二噁烷‑4‑基]乙酸叔丁酯及其制备方法
CN109574938A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的合成方法
CN109574938B (zh) * 2017-09-28 2022-04-22 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的合成方法
CN108997324A (zh) * 2018-08-21 2018-12-14 南京欧信医药技术有限公司 瑞舒伐他汀钙中间体的制备方法
CN109456300A (zh) * 2018-08-21 2019-03-12 南京欧信医药技术有限公司 高纯度瑞舒伐他汀钙中间体的制备方法

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