WO2006059346A2 - An improved process for lactonization to produce highly pure statins - Google Patents
An improved process for lactonization to produce highly pure statins Download PDFInfo
- Publication number
- WO2006059346A2 WO2006059346A2 PCT/IN2005/000392 IN2005000392W WO2006059346A2 WO 2006059346 A2 WO2006059346 A2 WO 2006059346A2 IN 2005000392 W IN2005000392 W IN 2005000392W WO 2006059346 A2 WO2006059346 A2 WO 2006059346A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvents
- improved process
- water
- lactonization
- statins
- Prior art date
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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
- the present invention particularly relates to a process for lactonization to produce simvastatin. More particularly, the invention relates to a process for lactonization of simvastatin hydroxyacid or its salts that avoids use of strong corrosive acids and drastic heat conditions. Specifically the process can be carried out at moderate temperature resulting in the title product with purity greater than 99% and dimer impurity to a level of less than 0.05%. Still more particularly, the invention relates to a process for lactonization to produce simvastatin involving using a mixture of carboxylic acid anhydride and water miscible organic solvent. Preferably, the solvent used may be nitrile solvent.
- 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 semisynthetic and totally synthetic routes. 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 & well established safety profile.
- statins of formula II The use of highly pure statins is exceedingly desirable in preparation of pharmaceutical compositions/ formulations as it would avoid accumulation of impurities during prolonged usage and reduce the possible side effects during medical treatment.
- dihydroxy acid or its salt of formula I is the common intermediate for producing statins of formula II.
- R is H or CH3 and X ix H or a metal cation or a NH4 cation.
- lactonization is a process wherein, a dihydroxy acid losses one molecule each of ammonia and water to form an intramolecular ester (lactone).
- lactone an intramolecular ester
- the reaction is catalyzed by an acid and a dehydrating agent, Lactonization is an equilibrium process represented, in the case of statins, by the following equation:
- US patent no. 5,393,893 discloses a process wherein the lactonization is carried out in a two-phase system of an organic system, in which the lactone is soluble, and an aqueous acid, whereby the formed water is displaced from the organic layer containing the lactone, to the aqueous layer.
- the preferred weak acid is acetic acid and
- recovering is carried out by using anti-solvent such as hexane, heptane, cyclohexane or water, preferably water.
- anti-solvent such as hexane, heptane, cyclohexane or water, preferably water.
- US 20040077884 claims that the process disclosed in this invention yields a product having impurities ⁇ 0.1%.
- the process comprises lactonizing hydroxy acid salt with a mixture of glacial acetic acid and acetonitrile in anhydrous conditions at a temperature in the range of about 50 to 8O 0 C and precipitating statins by adding water.
- the invention claims consistent production of simvastatin at moderate temperature with more than 99.5% purity and dimmer content less than 0.1 Vo.
- the examples illustrate the yield in the range of 89 to 90 %, HPLC purity of 99.55 to 99.63% and dimer impurity of 0,04 to 0.07%.
- the main change is employing acetonitrile in conjunction with acetic acid and precipitating with water in turn making process user and environment friendly, economic and easy to scale up for commercial manufacture.
- the mechanism in this process, as described relates to removal of ammonia formed, as a by-product, using mixture of acetic acid and acitonitrile however, it is unable to remove water which is also formed as a by-product of lactonisation reaction.
- the reaction gets completed in about five to seven hours.
- the amount of acetic acid used is at least three to five parts by volume per part of starting material and the amount acitonitrile used is 10 to 20 parts by volume preferably 15 parts by volume of the starting material.
- the process also claims an advantage of easy isolation by addition of water.
- the main aim of the present invention is to provide a process of lactonization to produce highly pure statins.
- the other object of the present invention is to provide a process for lactonization to produce simvastatin.
- Another object of the present invention is to provide a process for lactonization of simvastatin hydroxyacid or its salts that avoids use of strong corrosive acids and drastic heat conditions thereby making the process environment friendly on industrial scale.
- Yet other object of the present invention is to provide a process that can be carried out at moderate temperature resulting in the title product with higher yield and purity.
- statin of formula II by conventional methods optionally purifying the said title compound employing ethyl acetate and hexane for recrystallisation wherein (a) the solvent used is nitrile solvents, ketonic solvents, hydrocarbon solvents, ethereal solvents, ester solvents and/or halogenated solvents and (b) recovery of statins is conducted by adding water proviso the solvent used is water miscible or by conventional crystallization method in case solvent used is water immiscible.
- the reaction is performed in presence of a stabilizer like butylated hydroxyl toluene, butylated hydroxyl anisole.
- the carboxylic acid anhydride employed may be such as acetic anhydride or propionic anhydride.
- the laconization may be performed at a temperature of 10-40° C and typically for a period of 5 to 30 hours.
- Solvents used may be nitrile solvents like acetonitrile, propionitrile; ketonic solvents like acetone, methyl isobutyl ketone, methyl ethyl ketone; hydrocarbon solvents like hexanes, heptanes, cyclohexane, benzene, toluene, xylenes; ester solvents like, ethyl acetate; ether solvents like, diethyl ether, diisopropyl ether, tetrahydrofuran and halogenated solvents like dichloromethane, chloroform.
- the amount of acid anhydride used is 1 to 5 parts by volume per part of the starting material.
- EXAMPLE l Simvastatin ammonium salt (50 g) of formula I is reacted with acetic anhydride (125 g) in acetonitrile (750 ml) at 20-25 0 C for 20-25 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 drying of the cake to yield 45 g of Simvastatin, which is purified to give the final Simvastatin having dimer impurity ⁇ 0.05%.
- acetic anhydride 125 g
- acetonitrile 750 ml
- Simvastatin ammonium salt (50g) of formula 1 is reacted with acetic anhydride (75g) in
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2401/DEL/2004 | 2004-12-01 | ||
IN2401DE2004 | 2004-12-01 |
Publications (2)
Publication Number | Publication Date |
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WO2006059346A2 true WO2006059346A2 (en) | 2006-06-08 |
WO2006059346A3 WO2006059346A3 (en) | 2006-09-08 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IN2005/000392 WO2006059346A2 (en) | 2004-12-01 | 2005-11-30 | An improved process for lactonization to produce highly pure statins |
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WO (1) | WO2006059346A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009114121A (en) * | 2007-11-06 | 2009-05-28 | Kaneka Corp | Method for producing simvastatin |
CN101381356B (en) * | 2008-10-23 | 2012-05-23 | 河北科技大学 | Preparation method of simvastatin |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916239A (en) * | 1988-07-19 | 1990-04-10 | Merck & Co., Inc. | Process for the lactonization of mevinic acids and analogs thereof |
US5917058A (en) * | 1997-10-28 | 1999-06-29 | Ranbaxy Laboratories Limited | Process of lactonization in the preparation of statins |
US20040077884A1 (en) * | 2001-05-18 | 2004-04-22 | Ramesh Dandala | Process for lactonization to produce highly pure simvastatin |
-
2005
- 2005-11-30 WO PCT/IN2005/000392 patent/WO2006059346A2/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916239A (en) * | 1988-07-19 | 1990-04-10 | Merck & Co., Inc. | Process for the lactonization of mevinic acids and analogs thereof |
US5917058A (en) * | 1997-10-28 | 1999-06-29 | Ranbaxy Laboratories Limited | Process of lactonization in the preparation of statins |
US20040077884A1 (en) * | 2001-05-18 | 2004-04-22 | Ramesh Dandala | Process for lactonization to produce highly pure simvastatin |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009114121A (en) * | 2007-11-06 | 2009-05-28 | Kaneka Corp | Method for producing simvastatin |
CN101381356B (en) * | 2008-10-23 | 2012-05-23 | 河北科技大学 | Preparation method of simvastatin |
Also Published As
Publication number | Publication date |
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WO2006059346A3 (en) | 2006-09-08 |
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