EP1178980A1 - Sels d'intermediaires de 2,2-dimethyl-1,3-dioxane et leur procede de preparation - Google Patents

Sels d'intermediaires de 2,2-dimethyl-1,3-dioxane et leur procede de preparation

Info

Publication number
EP1178980A1
EP1178980A1 EP00927612A EP00927612A EP1178980A1 EP 1178980 A1 EP1178980 A1 EP 1178980A1 EP 00927612 A EP00927612 A EP 00927612A EP 00927612 A EP00927612 A EP 00927612A EP 1178980 A1 EP1178980 A1 EP 1178980A1
Authority
EP
European Patent Office
Prior art keywords
acid
dimethyl
carboxylic acid
formula
process according
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.)
Withdrawn
Application number
EP00927612A
Other languages
German (de)
English (en)
Inventor
Péter Kotay Nagy
Zoltán Greff
Jozsef Barkoczy
Gyula Simig
Lászlo BALAZS
Imre Doman
Zoltán RAtkai
Péter SERES
Ferenc Bartha
Györgyi VERECZKEYNE DONATH
Kálmán NAGY
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.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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 Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of EP1178980A1 publication Critical patent/EP1178980A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

  • This invention relates to new pharmaceutical intermediates and a process for the preparation thereof.
  • the invention relates more particularly to salts of (4R- -cis)-(1 , 1 -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3- -dioxane-4-acetate formed with organic acids.
  • the aminoethyl derivative of the Formula I is prepared by fractionated distillation carried out at 125-135°C/0.05 Hgmm.
  • the purity of the product is not higher than 96 %.
  • the disadvantage of this process is that fractionated distillation in high vacuo is a complicated purification method which is only circumstantially feasible on industrial scale.
  • reaction scheme B The process set forth in US patent No. 5,103,024 and the corresponding Hungarian patent No. 213,731 is shown on reaction scheme B.
  • the compound of the Formula I is purified by column chromatography.
  • the drawback of this process is that column chromatography requires large investments and is but difficultly feasible, particularly on industrial scale.
  • the purity of the product obtained does not exceed 98.2 %.
  • the present invention is based on the recognition that the compound of the Formula I forms stable salts with organic acids. This recognition is so much the more surprising as it is known from prior art that ketales are instable in the presence of acids.
  • the two hydroxy groups of the amine derivative of the Formula I are protected by a ketale ring. It was unforeseen that said ketale group would be resistant to organic acids under the reaction conditions used.
  • the salts of the present invention are not only stable at room temperature but remain stable even during recrystallization from an organic solvent carried out at higher temperature.
  • the following acids may be used for salt formation: an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
  • the following acids are used: acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, fumaric acid, maleic acid, benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo- -benzoic acid, 4-tert.
  • butyl-benzoic acid benzenesulfonic acid, methanesulfonic acid, p-methyl-benzenesulfonic acid, p-bromo- -benzenesulfonic acid, nicotic acid, tetrahydrofurane-2- -carboxylic acid or tiophen-3-carboxylic acid.
  • pivalic acid is used.
  • the reaction may be carried out in an apolar, dipolar aprotic or protic solvent.
  • an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, nitrile, alcohol or ether may be used. It is preferred to use one of the following solvents: hexane, heptane, petrolether, toluene, benzene, xylene, dichloro methane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofurane, dioxane or diethyl ether.
  • a solvent mixture may also be used as reaction medium. It is preferred to use a mixture of heptane and toluene; hexane and toluene; hexane, toluene and tetrahydrofurane; heptane, toluene and tetrahydrofurane; or hexane and diethyl ether.
  • the compound of the Formula I and the organic acid are reacted in the form of solutions formed with the same solvent.
  • the compound of the Formula I and the organic acid in a molar ratio of 0.5-5, preferably 0.5-2, particularly preferably 0.5-1.2.
  • the compound of the Formula I and the organic acid are admixed preferably at room temperature and the reaction may be performed under heating or at room temperature. One may preferably work at the boiling point of the reaction mixture.
  • the reaction mixture may be worked up by simple methods. One may proceed preferably by cooling the reaction mixture, isolating the precipitated salt of the compound of the Formula I by filtration or centrifugation, washing the salt with an organic solvent and drying.
  • the salt may be purified by recrystallization.
  • a crude compound of the Formula I is used as starting material. In this case the expensive and complicated purification of the compound of the Formula I is eliminated.
  • the compound of the Formula I is purified by simple recrystallization which can be carried out significantly easier than fractionated distillation performed in high vacuo and column chromatography used in the known methods.
  • the present invention provides a product of higher purity than the prior art methods. After a single recrystallization step the purity of the product is > 99 % (according to gas chromatography), after two-fold recrystallization the purity amounts to > 99.95 %. The purity of the product obtained by known methods is lower than 98 %.
  • the process of the present invention can be easily carried out on industrial scale too.
  • the scaling-up causes no problems.
  • the fractionated distillation performed in high vacuo and column chromatography requires considerable investments and is but difficultly feasible on industrial scale.
  • the compound of the Formula I is stable and can be stored for a long period of time without decomposition in the form of salts formed with organic acids.
  • atorvastatin meeting the requirements of Pharmacopoeia can be prepared.
  • Example 1 Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
  • Example 1

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des sels de (4R-cis) -(1,1-diméthyl -éthyl) -6-(2-aminoéthyl) -2,2-diméthyl -1,3-dioxane -4-acétate de formule (I), ces sels étant formés avec des acides organiques. Les nouveaux sels de cette invention sont stables et aptes à être facilement purifiés par recristallisation. Les nouveaux sels de cette invention constituent par ailleurs de précieux intermédiaires pharmaceutiques pouvant être utilisés par exemple pour préparer un agent hypolipidémique ci-après dénommé atorvastatine (selon la dénomination DCI). Cette invention concerne enfin la préparation de nouveaux sels du composé de formule (I) susmentionné.
EP00927612A 1999-05-06 2000-05-05 Sels d'intermediaires de 2,2-dimethyl-1,3-dioxane et leur procede de preparation Withdrawn EP1178980A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU9901526 1999-05-06
HU9901526A HU227840B1 (en) 1999-05-06 1999-05-06 Intermediates of atorvastatin synthesis and process for producing them
PCT/HU2000/000042 WO2000068221A1 (fr) 1999-05-06 2000-05-05 Sels d'intermediaires de 2,2-dimethyl-1,3-dioxane et leur procede de preparation

Publications (1)

Publication Number Publication Date
EP1178980A1 true EP1178980A1 (fr) 2002-02-13

Family

ID=89998261

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00927612A Withdrawn EP1178980A1 (fr) 1999-05-06 2000-05-05 Sels d'intermediaires de 2,2-dimethyl-1,3-dioxane et leur procede de preparation

Country Status (14)

Country Link
EP (1) EP1178980A1 (fr)
JP (1) JP2002544207A (fr)
KR (1) KR20020033617A (fr)
CN (1) CN1349522A (fr)
AU (1) AU4600200A (fr)
CA (1) CA2373077A1 (fr)
CZ (1) CZ20013965A3 (fr)
HK (1) HK1046271A1 (fr)
HR (1) HRP20010846A2 (fr)
HU (1) HU227840B1 (fr)
PL (1) PL351145A1 (fr)
RU (1) RU2001133066A (fr)
SK (1) SK15842001A3 (fr)
WO (1) WO2000068221A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0011120D0 (en) 2000-05-09 2000-06-28 Avecia Ltd Process
NL1015744C2 (nl) 2000-07-19 2002-01-22 Dsm Nv Werkwijze voor de bereiding van 2-(6-gesubstitueerde-1,3-dioxan-4-yl) azijnzuurderivaten.
WO2002057229A1 (fr) 2001-01-19 2002-07-25 Biocon India Limited FORME V CRISTALLINE DE SEL HEMICALCIQUE D'ACIDE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIQUE (ATORVASTATINE)
WO2003004456A1 (fr) 2001-07-06 2003-01-16 Teva Pharmaceutical Industries Ltd. Procede de preparation de derives d'acide 7-amino syn 3,5-dihydroxy heptanoique via des derives d'acide 6-cyano syn 3,5-dihydroxy hexanoique
EP1323717A1 (fr) 2001-12-27 2003-07-02 Dsm N.V. Procédé de Préparation de Dérivés de l'acide 2-(1,3-dioxane-4-yl substitué en 6) acétique
EP1375493A1 (fr) 2002-06-17 2004-01-02 Dsm N.V. Procédé de fabrication d'un ester d'acide acétique de dioxane
IE20060197A1 (en) 2005-03-14 2006-10-18 Pfizer Science & Tech Ltd Preparation of an atorvastatin intermediate
WO2007034909A1 (fr) * 2005-09-22 2007-03-29 Kaneka Corporation Procédé pour la production d'un dérivé de l'acide (3r,5r)-7-amino-3,5-dihydroxyheptanoïque
SI2614057T1 (sl) 2010-09-09 2016-03-31 Dsm Sinochem Pharmaceuticals Netherlands B.V. Soli estrov 7-amino-3,5-dihidroksi heptanojske kisline
WO2017022846A1 (fr) 2015-08-05 2017-02-09 株式会社エーピーアイ コーポレーション Procédé de production de pitavastatine calcique
CN108191813B (zh) * 2017-12-20 2020-01-17 帕潘纳(北京)科技有限公司 一种缩酮的制备方法
CN109232353A (zh) * 2018-10-09 2019-01-18 河南师范大学 一种阿托伐他汀钙缩合物的制备方法
CN109232354A (zh) * 2018-10-09 2019-01-18 河南师范大学 一种高纯度阿托伐他汀钙原料药的制备方法
CN110940764B (zh) * 2019-12-31 2022-06-28 湖南九典制药股份有限公司 一种他汀类药物光学异构体的分离方法

Family Cites Families (7)

* 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
US5103024A (en) * 1990-10-17 1992-04-07 Warner-Lambert Company Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5155251A (en) * 1991-10-11 1992-10-13 Warner-Lambert Company Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
US5278313A (en) * 1992-03-27 1994-01-11 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
JP3652394B2 (ja) * 1995-01-27 2005-05-25 高砂香料工業株式会社 Ｎ−置換−７−アミノ−５−ヒドロキシ−３−オキソヘプタン酸誘導体およびその製造法
TR199900191T2 (xx) * 1996-07-29 1999-04-21 Warner-Lambert Company (S)-3,4-Dihidroksibutirik asitin korumal� esterlerinin sentezi i�in geli�tirilmi� proses.
HUP0103659A3 (en) * 1998-04-30 2003-01-28 Kaneka Corp Process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0068221A1 *

Also Published As

Publication number Publication date
AU4600200A (en) 2000-11-21
CN1349522A (zh) 2002-05-15
WO2000068221A1 (fr) 2000-11-16
CZ20013965A3 (cs) 2002-04-17
PL351145A1 (en) 2003-03-24
JP2002544207A (ja) 2002-12-24
SK15842001A3 (sk) 2002-04-04
HRP20010846A2 (en) 2003-02-28
CA2373077A1 (fr) 2000-11-16
HU9901526D0 (en) 1999-07-28
HU227840B1 (en) 2012-05-02
KR20020033617A (ko) 2002-05-07
HK1046271A1 (zh) 2003-01-03
RU2001133066A (ru) 2004-02-27
HUP9901526A2 (hu) 2001-04-28

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