WO2007052309A2 - Processus ameliore de fabrication de statines - Google Patents

Processus ameliore de fabrication de statines Download PDF

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Publication number
WO2007052309A2
WO2007052309A2 PCT/IN2006/000435 IN2006000435W WO2007052309A2 WO 2007052309 A2 WO2007052309 A2 WO 2007052309A2 IN 2006000435 W IN2006000435 W IN 2006000435W WO 2007052309 A2 WO2007052309 A2 WO 2007052309A2
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WO
WIPO (PCT)
Prior art keywords
lovastatin
reaction
hexane
butyl
butylamide
Prior art date
Application number
PCT/IN2006/000435
Other languages
English (en)
Other versions
WO2007052309A3 (fr
Inventor
Sanjay Suri
Tapan Kashyap
Girish Chandra Pundir
Netar Singh
Original Assignee
Morepen Laboratories 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 Morepen Laboratories Limited filed Critical Morepen Laboratories Limited
Publication of WO2007052309A2 publication Critical patent/WO2007052309A2/fr
Publication of WO2007052309A3 publication Critical patent/WO2007052309A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes

Definitions

  • the present invention particularly relates to an improved process that involves isolation of intermediate product of formula.
  • statins are well known potent antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase.
  • This class of compounds referred to generally as statins, are produced either by natural fermentation process or through semi-synthetic and totally synthetic means thereof.
  • Two of the most popular compounds in this therapeutic category are Simvastatin and Atorvastatin.
  • the former is one of the most prescribed drugs in the treatment of primary hypercholesterolemia with minimum side effects and well established safety profile.
  • lactone ring of Lovastatin is not hydrolyzed, but the required side chain is directly attached to the main ring.
  • This approach has been adopted by US patent US 4,444,784.
  • Another approach is adopted and disclosed in US Patent Nos. US 4,582,915; US 4,820,850.
  • lactone ring of Lovastatin is first hydrolyzed using different bases followed by hydroxyl protection to give dihydroxy protected intermediate which is further C- methylated using methyl halide and lithium pyrrolidide prepared externally by reaction of butyl lithium and pyrrolidine.
  • C-Methylated intermediate is further converted to Simvastatin through a sequence of reactions.
  • the process of the present invention employs lithium pyrrolidide preparated in-situ by reacting n-butyl lithium and pyrrolidine. Due to this technological advancement, reaction of C-Methylation goes to completion leaving no unreacted dihydroxy intermediate after reaction thereby resulting into higher yields and better quality of final product.
  • the main objective of the present invention is to provide an improved process for manufacturing statins obviating most of the drawbacks of the existing prior art.
  • Another object is to provide a process that provides isolation of substantially pure intermediate product in solid form thereby leaving most of the impurities in mother liquor.
  • Another object is to provide a process that involves C-Methylation of the said intermediate directly or after hydroxyl protection using in-situ generated lithium pyrrolidide, which is useful for making 3-hydroxy lactone containing products.
  • Yet other object is to provide a process that is economical and high yielding.
  • Yet another object is to provide a process resulting in to a little product with substantially reduced impurities.
  • step I Isolating step I intermediate in solid form by crystallization in a suitable solvent followed by centrifugation or filtration for removal of impurities and traces of base (used in step (I) in mother liquor) and 2) C-methylation of step I or step II product generating lithium pyrrolidide in-situ to get smooth reaction completion.
  • the present invention provides an improved process for manufacturing statins comprising the following steps: i) crystallizing in a known manner such as herein described lovastatin butylamide from the reaction mass resulting from the reaction between lovastatin and butyl amine ii) optionally subjecting to hydroxyl protection the said lovastatin butylamide obtained in step (i) to get a diprotected lovastatin butylamide, iii) C-Methylating lovastatin butylamide/ diprotected lovastatin butylamide employing lithium pyrrolidide prepared in situ by reacting butyl lithium and pyrrolidine, followed by iv) isolating the title product by conventional methods, and converting to its pharmacologically acceptable salt by known methods.
  • the crystallization in step (i) may be effected in organic solvent.
  • the organic solvent used for crystallization in step (i) may be any low polar hydrocarbon solvent like hexane, heptane, xylenes, benzene, toluene etc.; any ethereal solvent like isopropyl ether methyl ter butyl ether, diethyl ether etc. But more preferable is hexane and cyclohexane and most preferable is hexane.
  • Step (i) product may further optionally be hydroxyl protected before C-methylation.
  • C-methylation is carried out using in-situ generated lithium pyrrolidide by reaction of butyl lithium and pyrrolidine in a suitable organic solvent at low temperature.
  • the suitable organic solvent used for C-methylation may be aliphatic ether that includes without limitation to tetrahydrofuran, methyl-t-butyl ether, hydrocarbons like hexane, cyclohexane or a mixture thereof. More preferred solvent being tetrahydrofuran, hexane and cyclohexane or a mixture of two or more of these solvents.
  • C-Methylation may preferably be carried out at low temperature of -80 to 0 0 C. The more preferred temperature being -60 to -20 0 C. The most preferred temperature being -40 to -30 0 C.
  • Lovastatin butyl amide-step I product 100 g Lovastatin (HPLC purity 85%) was reacted with 90 g n-butyl amine under refluxing. Un-reacted amine was distilled off. 800 ml of Hexane was added to the residue and the resultant mass was stirred to get complete crystallization. Crystallized mass was filtered and washed with hexane. 100 gram of the title compound was obtained after drying having HPLC purity 99.65%.
  • step I product 100 g was added to 180 ml of dimethylformamide. Mass was stirred at 60-65 0 C after adding 45 g of imidazole and 105 g of tertiary butyl dimethylsilyl chloride. Reaction mass was extracted with cyclohexane after dilution with water. Organic layer was washed further with sodium bicarbonate solution. Oily residue, 140 g, was obtained after recovery of cyclohexane.
  • step II product 100 g was added to 1.5 ltr of tetrahydrofuran. Mass was cooled to -
  • Reaction mass from example 4 was refluxed for 1-3 hr after adding 10%, 600 ml sodium hydroxide solution to get reaction completion. Solvent was removed under reduced pressure to get hazy reaction mass. 500 ml of water was added followed by cooling to 10-15 0 C. pH was adjusted to 4.8-5.0 by dilute hydrochloric acid. Reaction mass was extracted with 1.8 ltr ethyl acetate. Organic layer was diluted with methanol. pH was adjusted to 9.0-9.5 with dilute ammonia solution. Mass was cooled to get crystallization. 75 g product was isolated after filtration and drying.
  • Simvastatin ammonium salt from example 5 (50 g) is reacted with acetic anhydride (125 g) in acetonitrile (750 ml) at 20-25 0 C for 10-15 hours. Reaction mass is cooled and water is added slowly to bring about crystallization of the product. Slurry is filtered and washed with water followed by purification in ethyl acetate-hexane and recrystallization in methanol-water to give the final Simvastatin 40 g having Lovastatin impurity ⁇ 0.7%, dimmer impurity ⁇ 0.05% and product purity > 98.5%.

Abstract

La présente invention concerne un processus amélioré de fabrication de statine qui consiste: (i) a faire réagir une lovastatine avec une amine butyle de façon à produire une amide lovastatine, (ii) à isoler cette butylamide lovastatine sous forme solide par cristallisation, à partir d'un solvant organique, (iii) éventuellement à la soumettre à une protection hydroxyle pour obtenir une butylamide lovastatine diprotégée, (iv) à soumettre cette amide protégée ou non protégée ainsi obtenue à une C- méthylation en utilisant une pyrrolidide de lithium préparée in situ par la réaction de lithium butyle et de pyrrolidine, à isoler le produit titre par des procédés classiques et à le transformer en sel répondant aux normes pharmaceutiques par des procédés connus.
PCT/IN2006/000435 2005-11-03 2006-11-01 Processus ameliore de fabrication de statines WO2007052309A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2943DE2005 2005-11-03
IN2943/DEL/2005 2005-11-03

Publications (2)

Publication Number Publication Date
WO2007052309A2 true WO2007052309A2 (fr) 2007-05-10
WO2007052309A3 WO2007052309A3 (fr) 2008-01-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000435 WO2007052309A2 (fr) 2005-11-03 2006-11-01 Processus ameliore de fabrication de statines

Country Status (1)

Country Link
WO (1) WO2007052309A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008044243A3 (fr) * 2006-10-09 2010-02-11 Manne Satyanarayana Reddy Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables
CN102532184A (zh) * 2010-12-21 2012-07-04 北大方正集团有限公司 洛伐酰胺的二羟基保护方法及辛伐他汀的制备方法
JP2012522514A (ja) * 2009-04-01 2012-09-27 ダニスコ・ユーエス・インク 変化した特性を有するα−アミラーゼ変異体を含む組成物及び方法
US8455640B2 (en) 2006-05-03 2013-06-04 Msn Laboratories Limited Process for statins and its pharmaceutically acceptable salts thereof
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
US8987444B2 (en) 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof
CN108976190A (zh) * 2017-12-21 2018-12-11 北大方正集团有限公司 一种从洛伐他汀结晶母液中回收洛伐他汀的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6472542B1 (en) * 2001-11-29 2002-10-29 Fermic S.A. De C.V. Method for alkylating the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6472542B1 (en) * 2001-11-29 2002-10-29 Fermic S.A. De C.V. Method for alkylating the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455640B2 (en) 2006-05-03 2013-06-04 Msn Laboratories Limited Process for statins and its pharmaceutically acceptable salts thereof
WO2008044243A3 (fr) * 2006-10-09 2010-02-11 Manne Satyanarayana Reddy Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables
US8404841B2 (en) 2006-10-09 2013-03-26 Msn Laboratories Limited Process for the preparation of statins and their pharmaceutically acceptable salts thereof
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
JP2012522514A (ja) * 2009-04-01 2012-09-27 ダニスコ・ユーエス・インク 変化した特性を有するα−アミラーゼ変異体を含む組成物及び方法
US8987444B2 (en) 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof
CN102532184A (zh) * 2010-12-21 2012-07-04 北大方正集团有限公司 洛伐酰胺的二羟基保护方法及辛伐他汀的制备方法
CN102532184B (zh) * 2010-12-21 2015-04-29 北大方正集团有限公司 洛伐酰胺的二羟基保护方法及辛伐他汀的制备方法
CN108976190A (zh) * 2017-12-21 2018-12-11 北大方正集团有限公司 一种从洛伐他汀结晶母液中回收洛伐他汀的方法
CN108976190B (zh) * 2017-12-21 2020-09-04 北大方正集团有限公司 一种从洛伐他汀结晶母液中回收洛伐他汀的方法

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