WO2008103016A1 - Atorvastatin intermediates and method for producing the same - Google Patents

Atorvastatin intermediates and method for producing the same Download PDF

Info

Publication number
WO2008103016A1
WO2008103016A1 PCT/KR2008/001069 KR2008001069W WO2008103016A1 WO 2008103016 A1 WO2008103016 A1 WO 2008103016A1 KR 2008001069 W KR2008001069 W KR 2008001069W WO 2008103016 A1 WO2008103016 A1 WO 2008103016A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
acid
compound
atorvastatin
ethyl
Prior art date
Application number
PCT/KR2008/001069
Other languages
English (en)
French (fr)
Inventor
In Hwa Chung
Original Assignee
Sungwun Pharmacopia Corporation
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 Sungwun Pharmacopia Corporation filed Critical Sungwun Pharmacopia Corporation
Publication of WO2008103016A1 publication Critical patent/WO2008103016A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to a compound of Formula 1(FIG. 1, where R is an alkyl having three or more carbon atoms, phenylethyl or a substituted phenylethyl) that can be used as a key intermediate to get atorvastatin of Formula 3, and a novel preparation method for producing a high purity atorvastatin intermediate at a high efficiency.
  • U.S. Pat. No. 5,003,080 as a cited reference of the patents discloses a synthetic process for the preparation of atorvastatin by reacting (4R) ⁇ 6-(2- aminoethyl )2,2-dimethyl-l,3-dioxane ⁇ 4-acetate and 4-fluoro-alpha-[2-methyl-l- oxopropyl]-gamma-oxo-N-beta-diphenylbenzenebutaneamide to produce a lactone compound followed by deprotection and hydrolysis to give the product.
  • 4R 4-(2- aminoethyl )2,2-dimethyl-l,3-dioxane ⁇ 4-acetate
  • 4-fluoro-alpha-[2-methyl-l- oxopropyl]-gamma-oxo-N-beta-diphenylbenzenebutaneamide to produce a lactone compound followed by deprotection and hydrolysis to give the product.
  • 5,216,174 describes a process for the preparation of atorvastatin by reacting hydroxyphenylamino-2-isopropylcarbonyl-3-phenyl-4-(4- fluorophenyl)l,4-dioxobutane with R,R-6-(2-aminoethyl)2,2-dimethyl-l,3- dioxane-4-acetic acid.
  • 6-65,226 and 4-69,355 describe a process for the preparation of 3,5,6- trihydroxy hexanoic acid ester derivatives from 4-chloroacetic acid ester and from maleic acid, respectively.
  • U.S. Pat. No. 5,278,313 describes a process for the preparation of (4R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4- acetate from 4-chloro-3-hydroxybutyric acid.
  • U.S. Pat. No. 6,867,306 discloses a process for the synthesis of a boronate compound. In the process, 1,3-diol is reacted with an industrially usable phenyl boronic acid in toluene and refluxed. Although the process may be able to synthesize an optical, high purity intermediate, its cost is very high and is thus industrially unfavorable.
  • the present invention provides a compound of structure represented by Formula 1, [6-(2-amino-ethyl)-2-R-[l,3,2]dioxaborinane-4-yl]- acetic acid t-butyl ester.
  • Another aspect of the present invention provides a preparation method of [6-(2-amino-ethyl)-2-R-[l,3,2]dioxaborinane-4-yl]-acetic acid t-butyl ester, which includes a step of reacting a boronic acid derivative with 6- cyano-3,5-dihydroxy-hexanoic acid t-butyl ester.
  • a boronate compound of structure represented by Formula 2 is provided as another intermediate.
  • Still another aspect of the present invention provides a preparation method of an atorvastatin intermediate of Formula 2(FIG. 2, where R is an alkyl having three or more, preferably from 3 to 12, carbon atoms, phenylethyl or a substituted phenylethyl) , which uses a boronate compound of
  • the present invention is therefore excellent in industrial utility in that it can synthesize a high purity atorvastatin with compounds of Formula 1 and Formula 2 as intermediates.
  • FIG. 1 is a Formula 1.
  • FIG. 2 is a Formula 2.
  • FIG. 3 is a Formula 3.
  • FIG. 4 is a Reaction Formula 1.
  • FIG. 5 is a Reaction Formula 2.
  • FIG. 6 is a Reaction Formula 3.
  • FIG. 7 is a Reaction Formula 4.
  • FIG. 8 is a structural formula of the compound prepared in the example
  • FIG. 9 is a structural formula of the compound prepared in the example
  • FIG. 10 is a structural formula of the compound prepared in the example
  • FIG. 11 is a structural formula of the compound prepared in the example
  • FIG. 12 is a structural formula of the compound prepared in the example
  • FIG. 13 is a structural formula of the compound prepared in the example
  • FIG. 14 is a structural formula of the compound prepared in the example
  • FIG. 15 is a structural formula of the compound prepared in the example
  • FIG. 16 is a structural formula of the compound prepared in the example
  • boronic acids are prepared to find out the efficacy of a boronate as a selective protecting group for 1,3-diol.
  • a vinyl derivative such as acetylene, a styrene derivative or the like is used for the Reaction Formula.
  • Dibromoborane dimethylsulfide in an amount of 1.1 to 1.1 equivalent weight was refluxed for 10 - 15 hours, extracted with a suitable organic solvent such as ethylacetate or methylene chloride, and concentrated to give diverse kinds of boronic acid (1) of the Reaction Formula 1.
  • boronic acid (1) obtained from the Reaction Formula 1 reacted with 1,3-diol compound (2) to obtain a boronate compound (3) as in Reaction Formula 2.
  • the boronic acid (1) may be used in an amount of 0.5 to 2.5 equivalent weight, it is more preferable to use it in amount of 2.0 equivalent weight.
  • the solvent include, but are not limited to, dichloromethane, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, etc. Among them toluene is most preferably used.
  • the reaction should continue for 10 ⁇ 40 hours at 40 - 130 ° C, more preferably, 10 ⁇ 15 hours at 90 ⁇ 120 ° C .
  • the 1,3-diol compound (2) of the Reaction Formula 2 was prepared by Reaction Formula 3(FIG. 6).
  • Reaction Formula 3 4-cyano ⁇ 3- hydroxybutyric acid ethyl ester (4) was reacted with an acetate (5) to produce a beta-ketoester(6) .
  • the acetate (5) was reacted with a base such as lithium di isopropylamide or butyl lithium in tetrahydrofuran(THF) at -40 ⁇ -70 ° C to generate anions, and reacted with 4-cyano ⁇ 3-hydroxybutyric acid ethyl ester (4).
  • Examples of the acetate (5) include, but are not limited to, methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, t-butyl acetate, isopropyl acetate, and so on. Among them t-butyl acetate is most preferably used.
  • the beta-ketoester (6) was reduced with sodium borohydride in presence of tetrahydrofuran(THF) as the solvent to give a 1,3-diol compound (7) .
  • the compound of Formula 2 can be prepared easily by Paar-Knorr reaction between 2-[2-(4-fluorophenyl )-2-oxo-l-phenyl-ethyl ]-4-methyl-3-oxo-pentanoic acid phenylamide (8) in the Reaction Formula 4, a key substance for the synthesis of atorvastatin that is suggested in many studies and has been supplied industrially, and a boronate compound of Formula 1.
  • a reaction solvent include, but are not limited to, acetonitrile, methylene chloride, THF, benzene, toluene, xylene, etc. Among them toluene or xylene is most preferably used.
  • an acid catalyst is desired to cause dehydration of two molecules.
  • acid catalyst include, but are not limited to, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Among them toluenesulfonic acid is most preferably used. Although vary depending on the solvent used, the reaction continues for 20 ⁇ 50 hours at 40 ⁇ 130 ° C, more preferably, 25 ⁇ 35 hours at 90 ⁇ 130 ° C.
  • the boronate compound (9) in the Reaction Formula 4(FIG. 7) produces high purity atorvastatin by a suitable hydrolysis reaction.
  • the boronate compound (9) in the Reaction Formula 4 was dissolved in ethyl acetate or dichloromethane, and a suitable base, preferably sodium hydroxide, was added thereto, and allowed to stand 2 - 5 hours for hydrolysis. When the reaction is over, hydrochloric acid was added to the resulting solution to acidify it. Finally, the acidic solution was treated with calcium hydroxide to give the target compound, i.e. atorvastatin calcium.
  • a suitable base preferably sodium hydroxide
  • the present invention can be advantageously used in industry as an effective method for synthesizing a high purity atorvastatin using compounds of Formula 1 and Formula 2 as intermediates.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
PCT/KR2008/001069 2007-02-22 2008-02-22 Atorvastatin intermediates and method for producing the same WO2008103016A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2007-0017767 2007-02-22
KR1020070017767A KR100881617B1 (ko) 2007-02-22 2007-02-22 아토바스타틴 제조를 위한 중간체 및 그의 제조방법

Publications (1)

Publication Number Publication Date
WO2008103016A1 true WO2008103016A1 (en) 2008-08-28

Family

ID=39710258

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/001069 WO2008103016A1 (en) 2007-02-22 2008-02-22 Atorvastatin intermediates and method for producing the same

Country Status (2)

Country Link
KR (1) KR100881617B1 (ko)
WO (1) WO2008103016A1 (ko)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015513556A (ja) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法
CN105461593A (zh) * 2015-12-31 2016-04-06 江西科苑生物药业有限公司 一种6-氰基-5-羟基-3-氧代己酸叔丁酯的连续制备方法
CN112430197A (zh) * 2020-11-30 2021-03-02 江苏阿尔法药业有限公司 一种3-氧代-5-羟基-6-氰基己酸叔丁酯的合成方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120011249A (ko) 2010-07-28 2012-02-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
KR101339648B1 (ko) * 2012-05-10 2013-12-09 (주) 에프엔지리서치 신규한 아토바스타틴 중간체 및 이를 이용한 아토바스타틴의 제조 방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004104011A1 (en) * 2003-05-26 2004-12-02 Biocon Limited Novel process for preparation of [6-(2-amino-ethyl)-2-aryl-[1,3,2]dioxaborinan-4-yl]- acetic esters
US6867306B2 (en) * 2001-01-19 2005-03-15 Biocon Limited Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds
US20050261354A1 (en) * 2004-04-29 2005-11-24 John Griffin Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase

Family Cites Families (1)

* 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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6867306B2 (en) * 2001-01-19 2005-03-15 Biocon Limited Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds
WO2004104011A1 (en) * 2003-05-26 2004-12-02 Biocon Limited Novel process for preparation of [6-(2-amino-ethyl)-2-aryl-[1,3,2]dioxaborinan-4-yl]- acetic esters
US20050261354A1 (en) * 2004-04-29 2005-11-24 John Griffin Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015513556A (ja) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法
CN105461593A (zh) * 2015-12-31 2016-04-06 江西科苑生物药业有限公司 一种6-氰基-5-羟基-3-氧代己酸叔丁酯的连续制备方法
CN112430197A (zh) * 2020-11-30 2021-03-02 江苏阿尔法药业有限公司 一种3-氧代-5-羟基-6-氰基己酸叔丁酯的合成方法
CN112430197B (zh) * 2020-11-30 2023-05-05 江苏阿尔法药业股份有限公司 一种3-氧代-5-羟基-6-氰基己酸叔丁酯的合成方法

Also Published As

Publication number Publication date
KR100881617B1 (ko) 2009-02-17
KR20080078127A (ko) 2008-08-27

Similar Documents

Publication Publication Date Title
RU2269515C2 (ru) Способ синтеза аторвастатина и промежуточный фенилборонат (варианты)
KR102630456B1 (ko) 브리바라세탐의 제조 방법
US5998633A (en) Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid
SK280940B6 (sk) Spôsob syntézy (4r-cis)-1,1-dimetyletyl-6-kyanometyl-2,2- -dimetyl-1,3-dioxán-4-acetátu a medziprodukty tohto spôsobu
US7812179B2 (en) Process for the preparation of atorvastatin and intermediates
Li et al. An efficient enantioselective synthesis of florfenicol via a vanadium-catalyzed asymmetric epoxidation
WO2008103016A1 (en) Atorvastatin intermediates and method for producing the same
WO2006095362A1 (en) Process for preparing levetiracetam
KR100598079B1 (ko) 신규의 보로네이트 에스테르
KR100980379B1 (ko) 광학활성을 갖는 5-히드록시-3-옥소헵타노에이트 유도체의제조방법
WO2002096915A1 (en) Process for producing optically pure δ - hydroxy-β -ketoester derivatives
KR101130717B1 (ko) ＨＭＧ-ＣｏＡ 환원 저해제의 제조를 위한 키랄 중간체의제조방법
KR100968576B1 (ko) 2-아실-3-아미노-2-알케노에이트의 제조방법
KR100763770B1 (ko) 아토르바스타틴 합성에 유용한 광학활성 중간체의 제조방법
KR100529703B1 (ko) 키랄 중간체의 제조방법 및 그를 이용한 아토바스타틴의제조방법
US6291696B2 (en) Preparation of tris (trimethylsilyl) silylethyl esters
KR100613687B1 (ko) 아토르바스타틴의 제조방법
KR100645371B1 (ko) 두 고리형 테트라하이드로퓨란 화합물과 이의 제조방법
JP2004026790A (ja) ピロリジン誘導体及びその製造方法
KR20050060281A (ko) 심바스타틴의 제조 방법
JP2010280606A (ja) エポキシ基含有アクリル酸エステル誘導体の製造法
JPWO2003095446A1 (ja) １−（４−ピリジル）−４−ピペリドンの製造方法
KR20090077335A (ko) 알릴알렌 유도체와 이의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08723107

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC DATED 01.12.2009

122 Ep: pct application non-entry in european phase

Ref document number: 08723107

Country of ref document: EP

Kind code of ref document: A1