WO2002094803A1 - A process for lactonization to produce highly pure simvastatin - Google Patents
A process for lactonization to produce highly pure simvastatin Download PDFInfo
- Publication number
- WO2002094803A1 WO2002094803A1 PCT/IN2002/000121 IN0200121W WO02094803A1 WO 2002094803 A1 WO2002094803 A1 WO 2002094803A1 IN 0200121 W IN0200121 W IN 0200121W WO 02094803 A1 WO02094803 A1 WO 02094803A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lactonization
- formula
- simvastatin
- highly pure
- produce highly
- Prior art date
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
Definitions
- a process for lactonization to produce highly pure simvastatin of Formula 1 A process for lactonization to produce highly pure simvastatin of Formula 1.
- This invention relates to a process for lactonization to produce highly pure simvastatin
- Lovastatin, sirwvastatin, pravastatin, atorvastatin and mevastatin are well known potent antihypercholesSerolemic 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 hypercholesterelemia with minimum side effects and well established safely profile.
- the use of highly pure sin astatin is exceedingly desirable in preparation of a pharmaceutical product as it would avoid accumulation of impurities during prolonged usage and would reduce the possible side effects during medical treatment.
- simvastatin In most of the synthetic methods known to manufacture simvastatin (Formula 1) shown below, the compound of formula IlKalso shown below, is the common intermediate, which is cyclized to obtain simvastatin and thus lactonization constitutes an essential step of the synthesis.
- US Patent 4,916,239 describes another process where the lactonization reaction has been carried out by treating hydroxyacid ammonium salt in a mbdure of acetic acid 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%.
- US Patent 5,917,058 provides an alternate process to lactonize hydroxyacid or its salt by treatment with acetic acid under anhydrous conditions.
- the purity of the final product obtained by this procedure is not more than 99%.
- the aim of the present invention is to obtain highly pure simvastatin that contains dimeric impurity less than 0.1 %.
- 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 NH 4 .
- the process further comprises adding water to the reaction mixture, thereby causing simvastatin of Formula 1 to precipitate from the reaction mixture.
- the instant invention relates to a novel process for lactonization of simvastatin hydroxyadd or its salt that avoids the use of strong corrosive adds and drastic heat conditions.
- This process allows lactonization reaction to proceed in a mixture of acetic add and acetonitrille at moderate temperatures and consistently provides simvastatin of greater than 99.5% purity with dimer content less than 0.1%.
- the process of this invention comprises heating a solution of simvastatin hydroxyacid in its salt form, most preferably the ammonium salt (Formula II) in a mixture of acetic add and acetonitrile under anhydrous conditions at a temperature that vary from 50° C to 80° C and preferably at 65-70° C.
- a solution of simvastatin hydroxyacid in its salt form most preferably the ammonium salt (Formula II) in a mixture of acetic add and acetonitrile under anhydrous conditions at a temperature that vary from 50° C to 80° C and preferably at 65-70° C.
- the lactonization reaction is typically accomplished within about 5 to 7 hours.
- the amount of acetic acid used is at least 3 to 5 parts by volume per part of the starting material.
- the amount of acetonitrile is 10 to 20 parts by volume per part of the starting material and preferably 15 parts by volume may be used.
- the lactonized product is isolated after completion of reaction by addition of water.
- Major advantage of the present invention as compared to the prior art procedures is the high product purity where the level of dimer impurity has been greatly reduced to less than 0.1%.
- the addition of water to the reaction mixture directly provides lactone as a homogeneous slurry that makes the filtration operation very easy at large scale and work up involves no solvent concentration or neutralization step prior to pro ⁇ uct isolation.
- simvastatin was 97.55%, unreacted starting material 0.66% and dimer impurity 0.07%. Thereafter, reaction mixture was cooled to 10- 15° C and water (350 ml.) was added slowly over as period of 30 minutes and stirring was continued for 30 minutes. The product was filtered, washed with water (2x10 ml.) and dissolved in methanol (90 ml.) at 25-30° C. The solution was cooled to 5-10° C and water (82 ml.) was added in 30 minutes. The produd thus crystallized was stirred at 5-10° C, filtered and washed with cold methanol/water mixture (1:1 v/v, 8 ml.). Produd was dried to constant weight in vacuo at 45-50° C to obtain simvastatin (8.3 g., 90%). Chromatographic purity (HPLC) 99.55% and dimer impurity 0.07%.
- HPLC Chromatographic purity
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02743614A EP1387835A1 (en) | 2001-05-18 | 2002-05-16 | A process for lactonization to produce highly pure simvastatin |
SI200220004A SI21234A (en) | 2001-05-18 | 2002-05-16 | A process for lactonization to produce highly pure simvastatin |
SK69-2003A SK692003A3 (en) | 2001-05-18 | 2002-05-16 | A process for lactonization to produce highly pure simvastatin |
JP2002591476A JP2004520444A (en) | 2001-05-18 | 2002-05-16 | Lactonization method for producing high-purity simvastatin |
BG107477A BG107477A (en) | 2001-05-18 | 2003-01-17 | A rpocess for lactonization to produce highly pure simvastatin |
US10/602,463 US6825362B2 (en) | 2001-05-18 | 2003-06-23 | Process for lactonization to produce highly pure simvastatin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN402CH2001 | 2001-05-18 | ||
IN402/MAS/2001 | 2001-05-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002094803A1 true WO2002094803A1 (en) | 2002-11-28 |
Family
ID=29765110
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2002/000121 WO2002094803A1 (en) | 2001-05-18 | 2002-05-16 | A process for lactonization to produce highly pure simvastatin |
Country Status (7)
Country | Link |
---|---|
US (1) | US6825362B2 (en) |
EP (1) | EP1387835A1 (en) |
JP (1) | JP2004520444A (en) |
BG (1) | BG107477A (en) |
SI (1) | SI21234A (en) |
SK (1) | SK692003A3 (en) |
WO (1) | WO2002094803A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7777056B2 (en) | 2004-03-30 | 2010-08-17 | Lupin Ltd. | Method for manufacture of 4-hydroxy pyran-2-one derivatives |
CN112759570A (en) * | 2021-02-08 | 2021-05-07 | 龙曦宁(上海)医药科技有限公司 | Method for synthesizing simvastatin impurity D |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006059346A2 (en) * | 2004-12-01 | 2006-06-08 | Morepen Laboratories Limited | An improved process for lactonization to produce highly pure statins |
ATE552825T1 (en) | 2006-04-26 | 2012-04-15 | Rosemont Pharmaceuticals Ltd | LIQUID ORAL COMPOSITIONS |
EP2288378A4 (en) * | 2008-04-16 | 2011-12-14 | Univ Utah Res Found | Pharmacological targeting of vascular malformations |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5917058A (en) * | 1997-10-28 | 1999-06-29 | Ranbaxy Laboratories Limited | Process of lactonization in the preparation of statins |
US5939564A (en) * | 1997-10-28 | 1999-08-17 | Ranbaxy Laboratories Limited | Process of lactonization in the preparation of statins |
WO2001030773A2 (en) * | 1999-10-27 | 2001-05-03 | Merck & Co., Inc. | Lactonization process |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6573385B1 (en) * | 1999-11-11 | 2003-06-03 | Biocon India Limited | Process for manufacturing simvastatin and novel intermediates thereof |
KR100407758B1 (en) * | 2001-08-27 | 2003-12-01 | 씨제이 주식회사 | Process of lactonization in the preparation of statins |
-
2002
- 2002-05-16 SI SI200220004A patent/SI21234A/en not_active IP Right Cessation
- 2002-05-16 EP EP02743614A patent/EP1387835A1/en not_active Withdrawn
- 2002-05-16 SK SK69-2003A patent/SK692003A3/en unknown
- 2002-05-16 WO PCT/IN2002/000121 patent/WO2002094803A1/en not_active Application Discontinuation
- 2002-05-16 JP JP2002591476A patent/JP2004520444A/en active Pending
-
2003
- 2003-01-17 BG BG107477A patent/BG107477A/en unknown
- 2003-06-23 US US10/602,463 patent/US6825362B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5917058A (en) * | 1997-10-28 | 1999-06-29 | Ranbaxy Laboratories Limited | Process of lactonization in the preparation of statins |
US5939564A (en) * | 1997-10-28 | 1999-08-17 | Ranbaxy Laboratories Limited | Process of lactonization in the preparation of statins |
WO2001030773A2 (en) * | 1999-10-27 | 2001-05-03 | Merck & Co., Inc. | Lactonization process |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7777056B2 (en) | 2004-03-30 | 2010-08-17 | Lupin Ltd. | Method for manufacture of 4-hydroxy pyran-2-one derivatives |
CN112759570A (en) * | 2021-02-08 | 2021-05-07 | 龙曦宁(上海)医药科技有限公司 | Method for synthesizing simvastatin impurity D |
CN112759570B (en) * | 2021-02-08 | 2023-04-14 | 龙曦宁(上海)医药科技有限公司 | Method for synthesizing simvastatin impurity D |
Also Published As
Publication number | Publication date |
---|---|
SK692003A3 (en) | 2003-12-02 |
SI21234A (en) | 2003-12-31 |
US20040077884A1 (en) | 2004-04-22 |
EP1387835A1 (en) | 2004-02-11 |
US6825362B2 (en) | 2004-11-30 |
JP2004520444A (en) | 2004-07-08 |
BG107477A (en) | 2004-01-30 |
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