WO2002094804A1 - Procede permettant la lactonisation pour la production de simvastatine - Google Patents
Procede permettant la lactonisation pour la production de simvastatine Download PDFInfo
- Publication number
- WO2002094804A1 WO2002094804A1 PCT/IN2002/000122 IN0200122W WO02094804A1 WO 2002094804 A1 WO2002094804 A1 WO 2002094804A1 IN 0200122 W IN0200122 W IN 0200122W WO 02094804 A1 WO02094804 A1 WO 02094804A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- simvastatin
- lactonization
- xylenes
- reaction
- minutes
- Prior art date
Links
- IHMXVSZXHFTOFN-UHFFFAOYSA-N CCC1OCCC1 Chemical compound CCC1OCCC1 IHMXVSZXHFTOFN-UHFFFAOYSA-N 0.000 description 1
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
Definitions
- This invention relates to a process for lactonization to produce simvastatin
- Lovastatin, simvastatin, pravastatin, atorvastat ⁇ n and mevastatin 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.
- the use of highly pure simvastatin is exceedingly desirable in preparation of a pharmaceutical form as it would avoid accumulation of impurities during prolonged usage and would reduce the possible side effects during medical treatment.
- dimer impurity is difficult to separate from the desired lactone even with repeated crystallization.
- the presence of dimer lowers the purity of the simvastatin product.
- US Patent 4.916,239 describes another process where the lactonization reaction has been earned out by treating hydroxyacid ammonium salt in a mixture of acetic add and water, and in the presence of a strong acid catalyst. This process requires gradual addition of water in several lots to effect crystallization of the lactonized product from the reaction medium to shift the equilibrium to the lactone side and this drives the lactonization to completion. This process is not amenable to industrial scale due to effluent generation and low purity of simvastatin product even though dimer content obtained is reported to be less than 0.2%.
- the reaction is to be carried out essentially for a period of 5-7 hours and extensive water washing of the product is required to remove traces of acetic acid.
- the aim of the present invention is to provide a highly efficient method for lactonization to produce simvastatin of greater than 99% purity in high yield.
- An example where simvastatin of greater than 99.5% purity has been achieved is cited in WO 99/42601 wherein the product was purified by successive crystallizations from aqueous acetone and from ethyl acetate.
- Z is H or NFL, in an organic solvent elected from xylenes, ethylbenzene and mixtures thereof at a temperature of 130 to 140° C.
- the organic solvent is preferably xylenes and Z is NH 4 Detailed Description of the Invention:
- the instant invention relates to a novel process of lactonizing hydroxyacid ammonium salt in xylenes at reflux temperature.
- the lactonization reaction is efficiently accomplished within 30 minutes in pres «ence of an antioxident under a constant purge of nitrogen.
- the level of dimer impurity in the rseaction mixture under the present cyclization conditions is restricted to less than 0.4% and isolation of the simvastatin lactone from the reaction mass reduces it further to less than 0.2% as recommended in Pharma Europa, Vol. 10, No. 3, September, 1998.
- This kind of smooth reaction and the product stability at high temperature were not anticipated and this observation constitutes an important part of the present invention.
- the amount of xylenes is 20 to 50 parts by volume per part of the starting material. However, preferably 25 parts by volume is enough to carryout the lactonization recation.
- the said reaction can be conducted in different solvents having boiling range above 110° C such as ethylbenzene. The reaction is carried out at 110 to 140° C but preferably at 130-140° C.
- an antioxident is added and nitrogen is bubbled through the reaction mass. Suitable antioxidents include butylated hydroxytoluene and butylated hydroxyanisole.
- Product is isolated by distilling off xylenes and crystallization from cyclohexene to give simvastatin of greater than 99% purity. This can be further re-crystaliized from methanol and water to consistently attain more than 99.4% purity.
- the lactonization reaction is conducted by heating simvastatin ammonium salt in xylenes at 135-140° C for 30 minutes.
- simvastatin ammonium salt in xylenes at 135-140° C for 30 minutes.
- extended heating in xylenes gives dimer to the extent of 0.65% against 1.2% in toluene.
- the major advantages realized in the present lactonization conditions as compared to the prior art are increased process productivity and product purity.
- the reaction period is typically 30 minutes that demonstrates a greater efficiency. Xylenes are fully recovered and recycled in the process and no aqueous effluent is generated.
- Simvastatin (83 g., 0.198 moles) was dissolved in methanol (830 ml.) at 10-15° C and DM water (830 ml.) was added slowly over a period of one hour. The product slurry was cooled to 3-5° C and was maintained at this temperature for 1 hour. The product was then filtered and washed with chilled methanol/water mixture (1:1 v/v, 50 ml.) and dried in vacuo at 50-55° C to obtain simvastatin (80 g., 96.4%) in pharmaceutically accepted 99.55% HPLC purity. The level of dimer was ⁇ 0.2% (0.18%).
- Hydroxyadd a ⁇ nmonium salt of Formula II required in lactonization is prepared by the following procedure:
- Reaction mixture was then cooled to 60° C and the solvents were removed in vacuo.
- the residue was diluted with water (25 ml) and cooled to 10° C. pH of the solution was adjusted to 7.0 by adding 3N aqueous hydrochloric add (265 ml). Ethyl acetate (800 ml) was added and the pH was further lowered to 5.0 with 3N aqueous hydrochloric add. After stirring for 10 minutes at 15° C, layers were separated and aqueous layer was extraded with ethyl acetate (125 ml). Combined organic layers were diluted with methanol (250 ml) and warmed to 25-30° C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200220005A SI21235A (sl) | 2001-05-18 | 2002-05-16 | Postopek laktonizacije za proizvodnjo simvastatina |
EP02749274A EP1294706A1 (fr) | 2001-05-18 | 2002-05-16 | Procede permettant la lactonisation pour la production de simvastatine |
JP2002591477A JP2004520445A (ja) | 2001-05-18 | 2002-05-16 | シンバスタチンを生成するためのラクトン化法 |
SK70-2003A SK702003A3 (en) | 2001-05-18 | 2002-05-16 | A process for lactonization to produce simvastatin |
BG107475A BG107475A (bg) | 2001-05-18 | 2003-01-17 | Лактонизационен метод за получаване на симвастатин |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN401/MAS/2001 | 2001-05-18 | ||
IN401CH2001 | 2001-05-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002094804A1 true WO2002094804A1 (fr) | 2002-11-28 |
Family
ID=11097002
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2002/000122 WO2002094804A1 (fr) | 2001-05-18 | 2002-05-16 | Procede permettant la lactonisation pour la production de simvastatine |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1294706A1 (fr) |
JP (1) | JP2004520445A (fr) |
BG (1) | BG107475A (fr) |
SI (1) | SI21235A (fr) |
SK (1) | SK702003A3 (fr) |
WO (1) | WO2002094804A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1316552A1 (fr) * | 2001-12-03 | 2003-06-04 | CJ Corporation | Procédé de lactonisation dans la préparation de statines |
WO2005012279A1 (fr) * | 2003-08-04 | 2005-02-10 | Biocon Limited | Procede de lactonisation |
WO2008044243A3 (fr) * | 2006-10-09 | 2010-02-11 | Manne Satyanarayana Reddy | Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables |
US7777056B2 (en) | 2004-03-30 | 2010-08-17 | Lupin Ltd. | Method for manufacture of 4-hydroxy pyran-2-one derivatives |
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 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0299656A1 (fr) * | 1987-07-10 | 1989-01-18 | Merck & Co. Inc. | Procédé pour l'alkylation de l'alpha-C du groupe 8-acyle de mévinoline et de ses analogues |
EP0955297A1 (fr) * | 1998-04-22 | 1999-11-10 | Ranbaxy Laboratories, Limited | Un procédé amélioré pour la préparation des statines |
WO2001030773A2 (fr) * | 1999-10-27 | 2001-05-03 | Merck & Co., Inc. | Procede de lactonisation |
-
2002
- 2002-05-16 WO PCT/IN2002/000122 patent/WO2002094804A1/fr not_active Application Discontinuation
- 2002-05-16 SK SK70-2003A patent/SK702003A3/sk unknown
- 2002-05-16 SI SI200220005A patent/SI21235A/sl not_active IP Right Cessation
- 2002-05-16 JP JP2002591477A patent/JP2004520445A/ja active Pending
- 2002-05-16 EP EP02749274A patent/EP1294706A1/fr not_active Withdrawn
-
2003
- 2003-01-17 BG BG107475A patent/BG107475A/bg unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0299656A1 (fr) * | 1987-07-10 | 1989-01-18 | Merck & Co. Inc. | Procédé pour l'alkylation de l'alpha-C du groupe 8-acyle de mévinoline et de ses analogues |
EP0955297A1 (fr) * | 1998-04-22 | 1999-11-10 | Ranbaxy Laboratories, Limited | Un procédé amélioré pour la préparation des statines |
WO2001030773A2 (fr) * | 1999-10-27 | 2001-05-03 | Merck & Co., Inc. | Procede de lactonisation |
Non-Patent Citations (1)
Title |
---|
ASKIN D ET AL: "SYNTHESIS OF SYNVINOLIN: EXTREMELY HIGH CONVERSION ALKYLATION OF ANESTER ENOLATE", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 56, no. 16, 2 August 1991 (1991-08-02), pages 4929 - 4932, XP000676448, ISSN: 0022-3263 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1316552A1 (fr) * | 2001-12-03 | 2003-06-04 | CJ Corporation | Procédé de lactonisation dans la préparation de statines |
AU2002311322B2 (en) * | 2001-12-03 | 2005-06-30 | Cj Healthcare Corporation | Processing Method of Lactonization in the Preparation of Statins |
AU2002311322B8 (en) * | 2001-12-03 | 2005-10-27 | Cj Healthcare Corporation | Processing Method of Lactonization in the Preparation of Statins |
WO2005012279A1 (fr) * | 2003-08-04 | 2005-02-10 | Biocon Limited | Procede de lactonisation |
US7777056B2 (en) | 2004-03-30 | 2010-08-17 | Lupin Ltd. | Method for manufacture of 4-hydroxy pyran-2-one derivatives |
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 |
US8987444B2 (en) | 2010-01-18 | 2015-03-24 | Msn Laboratories Private Limited | Process for the preparation of amide intermediates and their use thereof |
Also Published As
Publication number | Publication date |
---|---|
JP2004520445A (ja) | 2004-07-08 |
SI21235A (sl) | 2003-12-31 |
EP1294706A1 (fr) | 2003-03-26 |
BG107475A (bg) | 2004-01-30 |
SK702003A3 (en) | 2003-12-02 |
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