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WO2009054693A2 - Procédé de préparation d'atorvastatine - Google Patents

Procédé de préparation d'atorvastatine Download PDF

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Publication number
WO2009054693A2
WO2009054693A2 PCT/KR2008/006290 KR2008006290W WO2009054693A2 WO 2009054693 A2 WO2009054693 A2 WO 2009054693A2 KR 2008006290 W KR2008006290 W KR 2008006290W WO 2009054693 A2 WO2009054693 A2 WO 2009054693A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
give
tert
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2008/006290
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English (en)
Other versions
WO2009054693A3 (fr
Inventor
Young Mook Lim
Young Taek Han
Byung Goo Lee
Yoon Seok Song
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daewoong Pharmaceutical Co Ltd
Daewoong Bio Inc
Original Assignee
Daewoong Pharmaceutical Co Ltd
Daewoong Bio Inc
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 Daewoong Pharmaceutical Co Ltd, Daewoong Bio Inc filed Critical Daewoong Pharmaceutical Co Ltd
Publication of WO2009054693A2 publication Critical patent/WO2009054693A2/fr
Publication of WO2009054693A3 publication Critical patent/WO2009054693A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for preparing the cholesterol biosynthesis inhibitor, atorvastatin, (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl- 4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-dihydroxyheptanoic acid calcium salt, which comprises a step of preparing a beta-keto ester compound using a diazoacetate compound.
  • Atorvastatin of the following formula 1 [Formula 1]
  • the stereoselectivity of atorvastatin in Reaction Scheme 1 depends on tert-butyl[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl]acetate of formula 3, and thus, it is important to use highly pure compound of formula 3.
  • the compound of formula 3 since the compound of formula 3 is in a liquid phase, its purification process (purification by silica gel) is delicate. Thus, the process of Reaction Scheme 1 cannot be readily applied to industrial production, and its yield may not be high. Therefore, many researches have been performed to increase the stereoselectivity of atorvastatin.
  • the compound of formula 3 may be effectively prepared by pressurized hydrogenation reaction using a metal catalyst, as depicted in the following Reaction Scheme 2:
  • P and Pi each represent amino-protecting group.
  • the process of Reaction Scheme 3 comprises the steps of reacting an aldehyde compound with an ester compound to introduce stereoselectivity, and synthesizing the stereoselective beta-keto ester compound using butyl lithium.
  • butyl lithium is highly explosive as well as requires extremely low temperature, and thus, it is not easy to be used industrially.
  • the present inventors have extensively studied to prepare atorvastatin having good stereoselectivity using a process that is economical as well as easy to be applied industrially.
  • the present invention provides a new, meaningful process for effectively preparing atorvastatin that can be advantageously used in an industrial production.
  • the present invention will be explained more specifically.
  • the present invention provides a process for preparing atorvastatin of formula 1, which comprises the steps of (a) reacting an alkyl aldehyde compound of formula 4 with a diazoacetate of formula 5 in the presence of a catalyst to give a beta-keto ester compound of formula 6, (b) deprotecting the compound of formula 6 to give a compound of formula 7, (c) reducing the compound of formula 7 to give a compound of formula 8, (d) converting the compound of formula 8 to a lactone compound of formula 9 which is then converted to a calcium salt. [Formula 4]
  • R represents C 1 -C 4 -alkyl
  • P represents a silyl-containing protecting group
  • the catalyst may include a Lewis acid and montmorillonite K-IO.
  • a Lewis acid boron trifluoride, tin chloride (II) or (IV), aluminum chloride (III), etc.
  • tin chloride II
  • IV aluminum chloride
  • montmorillonite K-IO montmorillonite K-IO is used. It is a kind of zeolite, and most appropriate in an industrial production since it is environmentally friendly.
  • Ethyl diazoacetate among the starting compounds alkyl diazoacetate of formula 5 is commercially available (Aldrich, Cas. No: 623-73-4), and thus, easy to be applied in a mass production.
  • Another starting compound of formula 4 may be prepared as separately explained below.
  • the silyl-containing protecting group of the beta-keto ester compound prepared in step (a) is removed.
  • the deprotection reaction may be carried out by the conventional method to remove the silyl-containing protecting group, i.e., using hydrochloric acid solution or fluoride ion.
  • a lactone may be formed under strong acid or strong base condition, pH is adjusted to neutral to weak acidic (pH 6.0-7.0) during the reaction.
  • a typical polar solvent such as for example, ethyl acetate, tetrahydrofuran, acetone, 1,4-dioxane, dimethylformamide, dimethylsulfoxide, etc. may be used, among which acetone and tetrahydrofuran are most appropriate in the aspects of reactivity and process application.
  • step (c) reaction as US 5,273,995 describes, the compound of formula 7 is reduced with triethylborane and sodium borohydride so that it may have a stereoselectivity to give the compound of formula 8.
  • the atorvastatin lactone of formula 9 is prepared from the compound of formula 8, and the compound of formula 9 is converted to its calcium salt to give the desired compound of formula 1.
  • the detailed reaction conditions may refer to US 4,681,893, US 5,273,995, KR-A-2003-59253, WO 2005/033078, etc.
  • the compound of formula 4 the starting material in the process of Reaction Scheme 4, can be prepared by a process which comprises the steps of (i) reacting a compound of formula 10 with a compound of formula 11 to give a pyrrole compound of formula 12, (ii) removing the carboxyl-protecting group of the compound of formula 12 to give a compound of formula 13, (iii) subjecting the compound of formula 13 to an amidation reaction to give a compound of formula 14, and (iv) oxidizing the alcohol group of the compound of formula 14 to an aldehyde group.
  • the starting compound of formula 11 in the above reaction may be easily prepared by a process of the following Reaction Scheme 6.
  • the secondary alcohol group of the compound of formula 15 that is commercially available and has a high ee% value (Aldrich, cas: 141942-85-0) is protected.
  • the protecting group should be selected in view of the stability of the compound. That is, a strong base such as sodium hydroxide, etc. is used in the hydrolysis of the methyl ester group of the compound of formula 15, and thus, a protecting group that is stable under a base condition should be selected.
  • silyl-containing protecting groups such as for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylethoxysilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, etc. may be used, among which tert-butyldimethylsilyl group is most appropriate since it shows considerable stability under a base condition and is easily available.
  • the solvent that can be used tetrahydrofuran, ethyl acetate, dimethylsulfoxide, dimethylformamide, 1,4-dioxane, etc. may be mentioned.
  • Dimethylformamide is most appropriate since hydrochloride of imidazole, the side product that results during the reaction, can be dissolved and easily removed.
  • the protected comound is hydrolyzed by sodium hydroxide at room temperature, and then reduced by boron dimethylsulfide.
  • the nickel catalyst preferably Raney-nickel catalyst, may be used in the hydrogenation reduction reaction to give the compound of formula 11.
  • the typical hydrogenation reduction reaction usually requires high pressure and temperature, but the present process that uses Raney-nickel catalyst has the advantage of preparing the compound of formula 11 with considerably high yield under mild conditions (relatively low hydrogen pressure and temperature).
  • the pyrrole formation reaction is carried out using a compound having methyl ester group, like the compound of formula 16.
  • a compound having methyl ester group like the compound of formula 16.
  • the present inventors have prepared a compound having 4-methoxybenzyl ester group, i.e., the compound of formula 17, instead of the compound having methyl ester group, which decreases the production of side products in the subsequent pyrrole formation reaction.
  • the pyrrole formation is achieved by reacing the compound of formula 10 having 4-methoxybenzyl ester group with the compound of formula 11. This reaction is performed by adding pivalic acid and removing water by using Dean-Stack apparatus in a solvent mixture of heptane, tetrahydrofuran and toluene to give the compound of formula 12.
  • the compound of formula 13 is obtained by removing 4-methoxybenzyl group using Pd(OH) 2 /C catalyst, the compound of formula 14 is obtained by substituting with phenylamide group, and the compound of formula 4 is obtained by oxidizing the alcohol group to an aldehyde group using Dess-Martin periodinane reagent.
  • Oxidation of the alcohol group may be achieved when conventional oxidizing agents such as N- bromosuccinimide (NBS), chromic acid, Oxone, sodium hyperchloride, etc. are used.
  • N- bromosuccinimide (NBS) N- bromosuccinimide
  • chromic acid Oxone
  • sodium hyperchloride etc.
  • Dess-Martin periodinane reagent is most appropriate since it shows high selectivity and yield in the synthesis of aldehyde from alcohol.
  • Dess-Martin periodinane reagent is preferably used in the amount of 1 to 1.5 eq. with respect to the compound of formula 14, and as the solvent nonpolar solvents such as methylene chloride, chloroform, carbon tetrachloride, etc., preferably methylene chloride is used.
  • reaction mixture was cooled, and subjected to phase separation by adding 12Om-C of ethyl acetate and 15Om-C of water.
  • the aqueous layer was removed.
  • 300m£ of IN aqueous hydrochloric acid solution was added to separate the phases from which the aqueous layer was removed.
  • the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to remove ethyl acetate.
  • reaction mixture was filtered to remove the excess calcium hydroxide, and cooled to room temperature.
  • To this solution was added 2m£ of distilled water while stirring. The resulting solution was stirred for 12 h at room temperature to produce crystal which was then filtered under vacuum.
  • the present invention provides a process which can prepare atorvastatin having stereoselectivity economically and safely in the industrial scale production.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation de l'inhibiteur de la biosynthèse du cholestérol atorvastatine, un sel de calcium d'acide (3R,5R)-7-[2-(4-fluorophényl)-5-isopropyl-3-phényl-4- (phénylcarbamoyl)-lH-pyrrol-l-yl]-3,5-dihydroxyheptanoïque, lequel procédé comprend une étape lors de laquelle on prépare un composé béta cétoester à l'aide d'un composé diazoacétate.
PCT/KR2008/006290 2007-10-25 2008-10-24 Procédé de préparation d'atorvastatine Ceased WO2009054693A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020070108007A KR100921195B1 (ko) 2007-10-25 2007-10-25 아토르바스타틴의 제조 방법
KR10-2007-0108007 2007-10-25

Publications (2)

Publication Number Publication Date
WO2009054693A2 true WO2009054693A2 (fr) 2009-04-30
WO2009054693A3 WO2009054693A3 (fr) 2009-06-18

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/006290 Ceased WO2009054693A2 (fr) 2007-10-25 2008-10-24 Procédé de préparation d'atorvastatine

Country Status (3)

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KR (1) KR100921195B1 (fr)
TW (1) TW200925149A (fr)
WO (1) WO2009054693A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110372677A (zh) * 2019-07-25 2019-10-25 浙江海森药业股份有限公司 一种无溶剂法制备阿托伐他汀关键中间体l1的新方法
CN114539119A (zh) * 2020-11-26 2022-05-27 广东东阳光药业有限公司 一种阿托伐他汀的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5003080A (en) * 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
KR100651653B1 (ko) * 2004-07-23 2006-12-01 한국화학연구원 광학 활성을 갖는2-[6-(아미노알킬)-1,3-다이옥산-4-일]아세트산 유도체의제조방법

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110372677A (zh) * 2019-07-25 2019-10-25 浙江海森药业股份有限公司 一种无溶剂法制备阿托伐他汀关键中间体l1的新方法
CN114539119A (zh) * 2020-11-26 2022-05-27 广东东阳光药业有限公司 一种阿托伐他汀的制备方法

Also Published As

Publication number Publication date
KR100921195B1 (ko) 2009-10-13
WO2009054693A3 (fr) 2009-06-18
TW200925149A (en) 2009-06-16
KR20090042097A (ko) 2009-04-29

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