WO2005012279A1 - Lactonization process - Google Patents

Lactonization process Download PDF

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Publication number
WO2005012279A1
WO2005012279A1 PCT/IN2003/000264 IN0300264W WO2005012279A1 WO 2005012279 A1 WO2005012279 A1 WO 2005012279A1 IN 0300264 W IN0300264 W IN 0300264W WO 2005012279 A1 WO2005012279 A1 WO 2005012279A1
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formula
compound
acid
reaction
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PCT/IN2003/000264
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French (fr)
Inventor
Ravindra Chandrapa
Achraya Poornaprajna
Sambasivam Ganesh
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Biocon Limited
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Priority to PCT/IN2003/000264 priority Critical patent/WO2005012279A1/en
Priority to AU2003263579A priority patent/AU2003263579A1/en
Publication of WO2005012279A1 publication Critical patent/WO2005012279A1/en

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    • 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 relates to a novel lactonization process, useful for preparing 3-hydroxy lactone-containing products, such as 3-hydroxy-3- methylglutaryl coenzyme A (HMG -CoA) reductase inhibitors.
  • HMG -CoA 3-hydroxy-3- methylglutaryl coenzyme A
  • Lovastatin, simvastatin, compactin, pravastatin and analogs thereof are potent antihyper-cholesterolernic agents that reduce cholesterol biosynthesis by inhibiting the enzyme HMG— CoA reductase.
  • This class of compounds, called statins are known to exist in open ring hydroxy acid as well as in lactone ring.
  • the open ring hydroxy acid form can be represented by a structural formula I as well as the lactone form can be represented by a structural formula II.
  • the open hydroxy acid form of the statins (Formula I) is biologically active.
  • the lactonized forms (II) of the statins are metabolized to the active open-ring 3,5-dihydroxy acid form in the body.
  • Lovastatin and simvastatin are marketed worldwide in their lactonized form.
  • Open ring, sodium salt of compactin is used for the manufacture of Pravastatin.
  • Pravastatin is marketed as its sodium salt.
  • Lactone forms of compactin and pravastatin are useful intermediates for the preparation of highly pure respective compounds.
  • the lactonization of free hydroxy acid or its salt to lactone form is an essential step.
  • U.S. Pat. No. 4,916,239 discloses a process for lactonization by carrying out the at room temperature by ammonium salt of a mevinic acid with a mixture of acetic acid and water, in the presence of a strong acid catalyst and precipitating the lactone product by adding water.
  • the process suffers from the following disadvantages: a) the addition of water to effect crystallization of the product and drive the equilibrium toward the lactone side provides insufficient force to take the reaction to completion, resulting in contamination of the final product with unconverted starting material. This requires an additional purification step to produce a high purity product.
  • WO 01/30773 discloses a process for preparing a 3-hydroxy lactone- containing statin from a salt of its corresponding open-ring 3,5-dihydroxy acid comprising the steps of (i) adding 0.8 to 1. 1 equivalents of strong mineral acid per equivalent of 3,5-dihydroxy acid salt to a stirring mixture of the 3,5- dihydroxy acid salt in an aprotic organic solvent to protonate the salt and form the corresponding 3,5-dihydroxy acid; ( ⁇ ) adding 0.8 to 1.1 equivalents of strong mineral acid per equivalent of 3,5-dihydroxy acid to the stirring reaction mixture to cause lactonization; (i ⁇ ) adding an excess of additional strong mineral acid to the stirring reaction mixture in an amount sufficient to cause crystallization of the 3-hydroxy lactone-containing product ; (iv) collecting and washing the 3-hydroxy lactone-containing product; and (v) drying the washed 3-hydroxy lactone-containing product.
  • the mineral acids disclosed in this application are hydrochloric acid, hydrobromic acid, perfluoroacetic acid, perchloric acid, phosphoric acid and nitric acid.
  • This process suffers from the following disadvantages: a) being tedious, requiring repetitive addition of strong mineral acid and b) requires the acid in high quantity (more than 3 equivalents of the product). c) Time consuming
  • the prior art processes suffer from several disadvantages and are also not convenient to operate at a large scale for a variety of reasons, like operationally tedious, lengthy, inefficient, expensive, environmentally hazardous on an industrial scale and formation of impurities in the product.
  • the instant invention provides a novel single-pot lactonization/purification process that can be used to produce 3-hydroxy lactone containing products, including statins, that avoids the aforementioned problems and provides a higher quality lactone product having a lower amount of total on a commercial scale.
  • the process employs only less than 0.8 equivalent of sulphuric acid and is added in a single lot.
  • the reaction is completed in a short period of time (30 minutes).
  • the reaction is carried out at a temperature below — 15°C, thereby avoiding formation of undesired side products.
  • the instant process eliminates the need for a separate lactonization, crystallization and purification step.
  • the novel process described herein also results in a better yield and greater throughput in only one step.
  • the first aim of this invention is to provide a simple, one step process for lactonization, crystallization and purification for preparing 3- hydroxy lactone-containing products in high yield and purity, using sulphuric acid.
  • the second aim is to employ the instant process for the preparation of 3-hydroxy lactone-containing HMG-CoA reductase inhibitors of class called statins, in high yield.
  • the third aim is to employ the process conditions that reduce the impurity levels in lactone product.
  • the fourth aim is to employ the process conditions that are scalable at commercial large level.
  • the process of instant invention comprises of: a) treating a salt of compound of formula I with sulphuric acid, wherein the sulphuric acid is added in one portion, in a quantity less than 0.8 equivalents of the salt; at a temperature less than -15°C; in a water miscible solvent, preferably acetonitrile, stirring for a time of about 30 minutes; b) obtaining the lactone of formula IT.
  • the aim of the present invention is to provide a process for preparation of lactone of statin of formula I where the process is simple, single step, fast, economic, less hazzardous and clean.
  • the process of instant invention is less hazardous because the reaction is carried out at a temperature less than — 15°C.
  • the instant invention does not employ higher temperatures since. refluxing is not a part of the process.
  • the process of instant invention is clean because it results in a substantially pure product.
  • the instant invention results in a lactone product with minimum or devoid of impurities.
  • the process of this invention comprises treating the open hydroxy acid of the statins, preferably in their salt form, most preferably in their ammonium salt form with sulphuric acid at a temperature less than — 15°C, preferably between — 15°C to -25°C.
  • the sulphuric acid is used at less than 0.8 equivalents of statin.
  • the sulphuric acid is added only once at the start of the reaction.
  • the reaction is completed in a time less than one hour, preferably in a time less than 30 minutes.
  • the reaction can be carried out in a water miscible solvent, preferably acetonitrile.
  • the reaction mixture is chilled and filtered to obtain the product of formula II.
  • the product is isolated by adding water.
  • the product is isolated by extracting into a water immicible solvent selected from ethyl acetate, isobutyl acetate or butyl acetate.
  • Butylated hydroxyanisole or a stabiliser can be used in the process for stabilisation effect which does not play any part in the ⁇ actonisation process.
  • Example 5 Lovastatin A suspension of Lovastatin ammonium salt ( 10 Kg, 22.7 mol) and butylated hydroxyanisole (100 g) in acetonitrile (60 L) was chilled to about

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The instant invention discloses a process for preparation of compound of formula (II) comprising treatment of compound of formula (I) with sulphuric acid, wherein the sulphuric acid is added in one portion, at less than 0.8 equivalents of compound of formula (I); at a temperature less than -150 C; for a time less than 1 hour; in a water miscible solvent, preferably acetonitrile, where G = unsubstituted or substituted alkyl, aryl or hetero aryl and X = H or metal or amine.

Description

TITLE OF THE INVENTION LACTONIZATION PROCESS FIELD OF THE INVENTION The present invention relates to a novel lactonization process, useful for preparing 3-hydroxy lactone-containing products, such as 3-hydroxy-3- methylglutaryl coenzyme A (HMG -CoA) reductase inhibitors. BACKGROUND OF THE INVENTION Lovastatin, simvastatin, compactin, pravastatin and analogs thereof are potent antihyper-cholesterolernic agents that reduce cholesterol biosynthesis by inhibiting the enzyme HMG— CoA reductase. This class of compounds, called statins, are known to exist in open ring hydroxy acid as well as in lactone ring. The open ring hydroxy acid form can be represented by a structural formula I as well as the lactone form can be represented by a structural formula II. The open hydroxy acid form of the statins (Formula I) is biologically active. The lactonized forms (II) of the statins are metabolized to the active open-ring 3,5-dihydroxy acid form in the body. Lovastatin and simvastatin are marketed worldwide in their lactonized form. Open ring, sodium salt of compactin is used for the manufacture of Pravastatin. Pravastatin is marketed as its sodium salt. Lactone forms of compactin and pravastatin are useful intermediates for the preparation of highly pure respective compounds. In the process of manufacture of statins, the lactonization of free hydroxy acid or its salt to lactone form is an essential step.
Figure imgf000002_0001
Formula I where G = unsubstituted or substituted alkyl, aryl or hetero aryl and X = H or metal or amine
Figure imgf000003_0001
Formula II where G = unsubstituted or substituted alkyl, aryl or hetero aryl U.S. Pat. No. 4,444,784 discloses heating dihydroxy acid in a neutral solvent with continuous removal of the by-product, water. The process suffers from the following disadvantages: a) When applying the technique of water removal to drive the equilibrium toward the desired lactone product, higher temperatures are required which promote an undesirable esterification reaction between the 3- hydroxy group of the 3-hydroxylactone with the precursor free acid to produce a dimeric impurity. Elimination of the dirner impurity, from the product is difficult without compromising on yield. b) At higher temperatures, other impurities are also likely to go up due to degardation of the product. c) The time taken for the reaction is very long. U.S. Pat. No. 4,916,239 discloses a process for lactonization by carrying out the at room temperature by ammonium salt of a mevinic acid with a mixture of acetic acid and water, in the presence of a strong acid catalyst and precipitating the lactone product by adding water. The process suffers from the following disadvantages: a) the addition of water to effect crystallization of the product and drive the equilibrium toward the lactone side provides insufficient force to take the reaction to completion, resulting in contamination of the final product with unconverted starting material. This requires an additional purification step to produce a high purity product. b) when a water-miscible protic solvent such as acetic acid is used for the lactonization, an esterification reaction between the solvent and the 3- hydroxy group of the 3-hydroxylactone occurs to produce 3-O-acylated lactone and corresponding 3-O-acylated open-ring 5-hydroxy acid as side -products. These impurities are not effectively removed, even after a subsequent purification step. U.S. Pat. No. 4,820,850 discloses heating the free acid or its salt, e.g., the ammonium salt, to reflux temperature (usually 100-110° C.) in high boiling hydrocarbon solvents such as toluene for 7-8 hours. This process suffers from the following disadvantage: a) of being hazardous as carried out at very high temperature and b) the time required to complete the reaction is long as it involves refluxing for prolonged hours. US 6,562,984 discloses a process comprising a lactonization process using a lactonization agent selected from methane sulphonic acid, phosphorous pentoxide, acidic ion exchange resin, molecular sieves, acid clay, acidic silica gel and combination thereof. This process suffers from the following disadvantages: a) formation of impure product (formation of dimer impurities more than 0.05%). b) expensive reagents. WO 01/30773 discloses a process for preparing a 3-hydroxy lactone- containing statin from a salt of its corresponding open-ring 3,5-dihydroxy acid comprising the steps of (i) adding 0.8 to 1. 1 equivalents of strong mineral acid per equivalent of 3,5-dihydroxy acid salt to a stirring mixture of the 3,5- dihydroxy acid salt in an aprotic organic solvent to protonate the salt and form the corresponding 3,5-dihydroxy acid; (ϋ) adding 0.8 to 1.1 equivalents of strong mineral acid per equivalent of 3,5-dihydroxy acid to the stirring reaction mixture to cause lactonization; (iϋ) adding an excess of additional strong mineral acid to the stirring reaction mixture in an amount sufficient to cause crystallization of the 3-hydroxy lactone-containing product ; (iv) collecting and washing the 3-hydroxy lactone-containing product; and (v) drying the washed 3-hydroxy lactone-containing product. The mineral acids disclosed in this application are hydrochloric acid, hydrobromic acid, perfluoroacetic acid, perchloric acid, phosphoric acid and nitric acid. This process suffers from the following disadvantages: a) being tedious, requiring repetitive addition of strong mineral acid and b) requires the acid in high quantity (more than 3 equivalents of the product). c) Time consuming Thus, the prior art processes suffer from several disadvantages and are also not convenient to operate at a large scale for a variety of reasons, like operationally tedious, lengthy, inefficient, expensive, environmentally hazardous on an industrial scale and formation of impurities in the product. The instant invention provides a novel single-pot lactonization/purification process that can be used to produce 3-hydroxy lactone containing products, including statins, that avoids the aforementioned problems and provides a higher quality lactone product having a lower amount of total on a commercial scale. The process employs only less than 0.8 equivalent of sulphuric acid and is added in a single lot. The reaction is completed in a short period of time (30 minutes). The reaction is carried out at a temperature below — 15°C, thereby avoiding formation of undesired side products. The instant process eliminates the need for a separate lactonization, crystallization and purification step. The novel process described herein also results in a better yield and greater throughput in only one step.
SUMMARY OF THE INVENTION The first aim of this invention is to provide a simple, one step process for lactonization, crystallization and purification for preparing 3- hydroxy lactone-containing products in high yield and purity, using sulphuric acid. The second aim is to employ the instant process for the preparation of 3-hydroxy lactone-containing HMG-CoA reductase inhibitors of class called statins, in high yield. The third aim is to employ the process conditions that reduce the impurity levels in lactone product. The fourth aim is to employ the process conditions that are scalable at commercial large level. The process of instant invention comprises of: a) treating a salt of compound of formula I with sulphuric acid, wherein the sulphuric acid is added in one portion, in a quantity less than 0.8 equivalents of the salt; at a temperature less than -15°C; in a water miscible solvent, preferably acetonitrile, stirring for a time of about 30 minutes; b) obtaining the lactone of formula IT.
Figure imgf000006_0001
Formula I Formula II where G = unsubstituted or substituted alkyl, aryl or hetero aryl and X = H or metal or arnine
DETAILED DESCRIPTION OF THE INVENTION The aim of the present invention is to provide a process for preparation of lactone of statin of formula I where the process is simple, single step, fast, economic, less hazzardous and clean.
Figure imgf000007_0001
Formula I where G = unsubstituted or substituted alkyl, aryl or hetero aryl and X = H or metal or amine The present invention discloses a novel process for preparation of the lactone form of HMG— CoA reductase inhibitors from their open hydroxy acid form. The process of instant invention is simple because it involves only one addition of sulphuric acid and any salt of the compound of formula I and obtaining lactone of formula II.
Figure imgf000007_0002
Formula II wherein G = unsubstituted or substituted alkyl, aryl or hetero aryl The process of instant invention involves only one step i.e., any salt of compound of formula I is treated with sulphuric acid which results in formation of compound of formula II. The process of instant invention is fast because the reaction of the instant invention reaches completion in a time less than 30 minutes. The process of instant invention is economic because it involves use of only sulphuric acid as reagent. The instant invention does not employ any other reactant, reagent or catalyst for lactonization, crystallization, purification or obtaining the final product. The process optionally employs a single solvent in relatively low volumes. The process of instant invention is less hazardous because the reaction is carried out at a temperature less than — 15°C. The instant invention does not employ higher temperatures since. refluxing is not a part of the process. The process of instant invention is clean because it results in a substantially pure product. The instant invention results in a lactone product with minimum or devoid of impurities. Specifically, the process of this invention comprises treating the open hydroxy acid of the statins, preferably in their salt form, most preferably in their ammonium salt form with sulphuric acid at a temperature less than — 15°C, preferably between — 15°C to -25°C. The sulphuric acid is used at less than 0.8 equivalents of statin. The sulphuric acid is added only once at the start of the reaction. The reaction is completed in a time less than one hour, preferably in a time less than 30 minutes. The reaction can be carried out in a water miscible solvent, preferably acetonitrile. After the reaction is over the reaction mixture is chilled and filtered to obtain the product of formula II. Alternatively after the reaction is over, the product is isolated by adding water. Alternatively after the reaction is over, the product is isolated by extracting into a water immicible solvent selected from ethyl acetate, isobutyl acetate or butyl acetate. Butylated hydroxyanisole or a stabiliser can be used in the process for stabilisation effect which does not play any part in the ^actonisation process. Major advantages of the instant invention as compared to the prior art processes are cost effectiveness, less cumbersome isolation, high yield, increased efficiency, enhanced purity of product, environment- friendly operations, lesser operation time, less hazards and only one step. The following specific examples illustrate the process of this invention, but they should not be construed as lirniting the scope of this invention in any way. EXAMPLES Example 1: Simvasatin A suspension of Simvastatin ammonium salt ( 10 Kg, 22.82 mol) and butylated hydroxyanisole (100 g) in acetonitrile (60 L) was chilled to about — 20° C. concentrated sulphuric acid (1.68 Kg, 17.12 mol) was added to the suspension in one portion and stirred for 30 minutes maintaining the temperature between —17 to —22° C. After completion of reaction (by TLC), product was filtered, the cake washed with water (until pH of filtrate is neutral) and dried. Yield: 8.5 Kg; Purity by HPLC: 99.5% Example 2: Simvastatin A suspension of Simvastatin ammonium salt ( 25 Kg, 57.05 mol) and butylated hydroxyanisole (250 g) in acetonitrile (150 L) was chilled to about - 20° C. concentrated sulphuric acid (3.92 Kg, 40.0 mol) was added to the suspension in one portion and stirred for 30 minutes maintaining the temperature between —17 to —22° C. After completion of reaction (by TLC), water (300 L) was added to the reaction mixture and stirred for 30 minutes at room temperature. The product was filtered, the cake was washed with water (until pH of filtrate is neutral) and dried. Yield: 22.0 Kg; Purity by HPLC: 99.7% Example 3: Simvastatin A suspension of Simvastatin ammonium salt ( 1 Kg, 2.282 mol) and butylated hydroxyanisole (10 g) in acetonitrile (6.0 L) was chilled to about
- 20° C. concentrated sulphuric acid (157 g, 1.6 mol) was added to the suspension in one portion and stirred for 30 minutes maintaining the temperature between —17 to —22° C. After completion of reaction (by TLC), water (12 L) was added and reaction mixture was extracted with ethyl acetate (3 x 10 L). Combined ethyl acetate extract was washed with water and brine and concentrated to about 1.5 L. Petroleum ether (8.0 1) was added under stirring. Product was filtered and dried. Yield: 900 g; Purity by HPLC: 99.4% Example 4: Pravastatin lactone A suspension of Pravastatin ammonium salt ( 9 Kg, 20.1 mol) and butylated hydroxyanisole (100 g) in acetonitrile (54 L) was chilled to about — 20° C. concentrated sulphuric acid (1.28 Kg, 13.0 mol) was added to the suspension in one portion and stirred for 30 minutes niaintaining the temperature between -17 to -22° C. After completion of reaction (by TLC), product was filtered, the cake washed with water (until pH of filtrate is neutral) and dried. Yield: 7.0 Kg; Purity by HPLC: 99.5% Example 5: Lovastatin A suspension of Lovastatin ammonium salt ( 10 Kg, 22.7 mol) and butylated hydroxyanisole (100 g) in acetonitrile (60 L) was chilled to about
- 20° C. concentrated sulphuric acid (1.67 Kg, 17.02 mol) was added to the suspension in one portion and stirred for 30 minutes niaintaining the temperature between —17 to —22° C. After completion of reaction (by TLC), product was filtered, the cake washed with water (until pH of filtrate is neutral) and dried. Yield: 9.0 Kg; Purity by HPLC: 99.6 %

Claims

We claim:
1) A process for affording substantially pure compound of formula II which comprises
Figure imgf000012_0001
Formula II where G = unsubstituted or substituted alkyl, aryl or hetero aryl treatment of salt of compound of formula I with sulphuric-acidr
Figure imgf000012_0002
Formula I where G = unsubstituted or substituted alkyl, aryl or hetero aryl X = H or metal or amine at a temperature less than — 15°C; for a reaction time less than one hour; in a water miscible solvent, preferably acetonitrile; wherein the sulphuric acid is added in one portion at the start of the reaction at less than 0.8 equivalents of compound of formula I. 2) A process as claimed in claim 1 wherein said water miscible solvent is acetonitrile. 3) A process as in claim 1, wherein the compound of formula 1, is simvastatin.
4) A process as in claim 1, wherein the compound of formula 1, is lovastatin.
5) A process as in claim 1, wherein the compound of formula 1, is pravastatin. 6) A process as in claim 1, wherein the compound of formula 1, is compactin.
7) A process as in claim 1, wherein the compound of formula 1, is atorvastatin. 8) A process as in claim 1, wherein the compound of formula 1, is fluvastatin.
9) A process as in claim 1 , wherein the compound of formula 1, is - rosuvastatin.
10) A process for affording substantially pure compound of formula II which comprises treatment of salt of compound of formula I with concentrated sulphuric acid, at a temperature between— 15°C to -25°C; for a reaction time less than 30 minutes; in acetonitrile; wherein the sulphuric acid is added in one shot at the start of the reaction at less than 0.8 equivalents of compound of formula I, wherein the compound of formula I is selected from acid or salt of simvastatin, lovastatin, prvastatin, compactin, atorvastatin, fluvastatin or rosuyastatin.
PCT/IN2003/000264 2003-08-04 2003-08-04 Lactonization process WO2005012279A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1110959A1 (en) * 1999-06-29 2001-06-27 Kaneka Corporation Process for selective lactonization
WO2002000615A2 (en) * 2000-06-30 2002-01-03 Ranbaxy Laboratories Limited Process for the isolation of lovastatin
WO2002094804A1 (en) * 2001-05-18 2002-11-28 Aurobindo Pharma Limited A process for lactonization to produce simvastatin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1110959A1 (en) * 1999-06-29 2001-06-27 Kaneka Corporation Process for selective lactonization
WO2002000615A2 (en) * 2000-06-30 2002-01-03 Ranbaxy Laboratories Limited Process for the isolation of lovastatin
WO2002094804A1 (en) * 2001-05-18 2002-11-28 Aurobindo Pharma Limited A process for lactonization to produce simvastatin

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