WO2005012279A1 - Procede de lactonisation - Google Patents

Procede de lactonisation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
reaction
less
Prior art date
Application number
PCT/IN2003/000264
Other languages
English (en)
Inventor
Ravindra Chandrapa
Achraya Poornaprajna
Sambasivam Ganesh
Original Assignee
Biocon 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 Biocon Limited filed Critical Biocon Limited
Priority to PCT/IN2003/000264 priority Critical patent/WO2005012279A1/fr
Priority to AU2003263579A priority patent/AU2003263579A1/en
Publication of WO2005012279A1 publication Critical patent/WO2005012279A1/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

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

Landscapes

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

Abstract

L'invention concerne un procédé pour l'élaboration de composé de formule (II) qui consiste à traiter un composé de formule (I) avec de l'acide sulfurique, lequel est ajouté en une fois, à moins de 0,8 équivalent par rapport au composé de formule (I), à une température de moins de -15° C, pendant une durée inférieure à une heure, dans un solvant miscible avec l'eau, de préférence de l'acétonitrile, sachant que G est aryle ou hétéroaryle ou alkyle non substitué ou substitué et que X est H ou métal ou amine.
PCT/IN2003/000264 2003-08-04 2003-08-04 Procede de lactonisation WO2005012279A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2003/000264 WO2005012279A1 (fr) 2003-08-04 2003-08-04 Procede de lactonisation
AU2003263579A AU2003263579A1 (en) 2003-08-04 2003-08-04 Lactonization process

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000264 WO2005012279A1 (fr) 2003-08-04 2003-08-04 Procede de lactonisation

Publications (1)

Publication Number Publication Date
WO2005012279A1 true WO2005012279A1 (fr) 2005-02-10

Family

ID=34113375

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000264 WO2005012279A1 (fr) 2003-08-04 2003-08-04 Procede de lactonisation

Country Status (2)

Country Link
AU (1) AU2003263579A1 (fr)
WO (1) WO2005012279A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1110959A1 (fr) * 1999-06-29 2001-06-27 Kaneka Corporation Procede de lactonisation selective
WO2002000615A2 (fr) * 2000-06-30 2002-01-03 Ranbaxy Laboratories Limited Procede d'isolation de lovastatine
WO2002094804A1 (fr) * 2001-05-18 2002-11-28 Aurobindo Pharma Limited Procede permettant la lactonisation pour la production de simvastatine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1110959A1 (fr) * 1999-06-29 2001-06-27 Kaneka Corporation Procede de lactonisation selective
WO2002000615A2 (fr) * 2000-06-30 2002-01-03 Ranbaxy Laboratories Limited Procede d'isolation de lovastatine
WO2002094804A1 (fr) * 2001-05-18 2002-11-28 Aurobindo Pharma Limited Procede permettant la lactonisation pour la production de simvastatine

Also Published As

Publication number Publication date
AU2003263579A1 (en) 2005-02-15

Similar Documents

Publication Publication Date Title
US6525205B2 (en) Lactonization process
JPH09188672A (ja) メビン酸及びその類似体のラクトン化方法
CA2205745C (fr) Methode pour preparer la baccatine iii et ses derives a partir de la 10-desacetylbaccatine iii
CN113788766A (zh) 一种阿托伐他汀钙中间体的制备方法
JP2003525935A (ja) 低下したレベルの二量体不純物を伴うロバスタチン及びシンバスタチンの精製方法
KR100313668B1 (ko) (ｒ)-4-시아노-3-히드록시부티르산 에스테르의 제조방법
US6756507B2 (en) Process for the preparation of sodium salts of statins
WO2005012279A1 (fr) Procede de lactonisation
RU2214407C2 (ru) Усовершенствованный способ лактонизации при получении статинов
JP3946521B2 (ja) シンバスタチンの製造方法
BG107477A (bg) Лактонизационен метод за получаване на симвастатин с висока чистота
US7566792B2 (en) Method for the manufacture of Lovastatin
KR100322630B1 (ko) 심바스타틴및 이의 중간체 화합물을 제조하는 방법
US7094912B2 (en) Process for the preparation of 4-oxytetrahydropyran-2-ones
EP1786765B1 (fr) Processus ameliore de lactonisation dans la fabrication de statines
JP2008510797A (ja) ４−フルオロ−α−［２−メチル−１−オキソプロピル］γ−オキソ−Ｎ−β−ジフェニルベンゼンブタンアミドの製造方法
CZ303914B6 (cs) Zpusob prípravy simvastatinu a jeho derivátu
WO2004096789A1 (fr) Procede pour preparer des intermediaires de statines
EP1551796A1 (fr) Synthese de syntheton ameliore

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP