WO2000068221A1 - Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof - Google Patents
Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof Download PDFInfo
- Publication number
- WO2000068221A1 WO2000068221A1 PCT/HU2000/000042 HU0000042W WO0068221A1 WO 2000068221 A1 WO2000068221 A1 WO 2000068221A1 HU 0000042 W HU0000042 W HU 0000042W WO 0068221 A1 WO0068221 A1 WO 0068221A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- dimethyl
- carboxylic acid
- formula
- process according
- Prior art date
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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
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- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00927612A EP1178980A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
AU46002/00A AU4600200A (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
KR1020017014104A KR20020033617A (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
CA002373077A CA2373077A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
SK1584-2001A SK15842001A3 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
HK02105736.6A HK1046271A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
PL00351145A PL351145A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
JP2000617201A JP2002544207A (en) | 1999-05-06 | 2000-05-05 | 2,2-Dimethyl-1,3-dioxane intermediate salt and method for producing the same |
HR20010846A HRP20010846A2 (en) | 1999-05-06 | 2001-11-16 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUP9901526 | 1999-05-06 | ||
HU9901526A HU227840B1 (en) | 1999-05-06 | 1999-05-06 | Intermediates of atorvastatin synthesis and process for producing them |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000068221A1 true WO2000068221A1 (en) | 2000-11-16 |
Family
ID=89998261
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU2000/000042 WO2000068221A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1178980A1 (en) |
JP (1) | JP2002544207A (en) |
KR (1) | KR20020033617A (en) |
CN (1) | CN1349522A (en) |
AU (1) | AU4600200A (en) |
CA (1) | CA2373077A1 (en) |
CZ (1) | CZ20013965A3 (en) |
HK (1) | HK1046271A1 (en) |
HR (1) | HRP20010846A2 (en) |
HU (1) | HU227840B1 (en) |
PL (1) | PL351145A1 (en) |
RU (1) | RU2001133066A (en) |
SK (1) | SK15842001A3 (en) |
WO (1) | WO2000068221A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002057274A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | A process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
WO2003106447A1 (en) * | 2002-06-17 | 2003-12-24 | Dsm Ip Assests B.V. | Process for the preparation of dioxane acetic acid esters |
US6870059B2 (en) | 2000-07-19 | 2005-03-22 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives |
US7157255B2 (en) | 2000-05-09 | 2007-01-02 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
EP1861364A1 (en) | 2005-03-14 | 2007-12-05 | Pfizer Science and Technology Ireland Limited | Preparation of an atorvastatin intermediate using a paal-knorr condensation |
US7692034B2 (en) | 2001-07-06 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives |
US7718812B2 (en) | 2001-12-27 | 2010-05-18 | Astrazeneca Uk Limited | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates |
WO2012032035A1 (en) | 2010-09-09 | 2012-03-15 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Salts of 7-amino-3,5-dihydroxyheptanoic acid esters |
CN109232354A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of high purity atorvastatin calcium raw material drug |
CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
US10676441B2 (en) | 2015-08-05 | 2020-06-09 | Api Corporation | Method for producing pitavastatin calcium |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007034909A1 (en) * | 2005-09-22 | 2007-03-29 | Kaneka Corporation | Process for production of (3r,5r)-7-amino-3,5-dihydroxyheptanoic acid derivative |
CN108191813B (en) * | 2017-12-20 | 2020-01-17 | 帕潘纳(北京)科技有限公司 | Preparation method of ketal |
CN110940764B (en) * | 2019-12-31 | 2022-06-28 | 湖南九典制药股份有限公司 | Separation method of statin optical isomer |
Citations (7)
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EP0330172A2 (en) * | 1988-02-22 | 1989-08-30 | Warner-Lambert Company | Improved process for trans-6-[2-(substituted-pyrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
WO1992006968A1 (en) * | 1990-10-17 | 1992-04-30 | 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 |
US5599954A (en) * | 1995-01-27 | 1997-02-04 | Takasago International Corporation | N-substituted-7-amino-5-hydroxy-3-oxoheptanoic acid derivatives and method for producing the same |
WO1998004543A1 (en) * | 1996-07-29 | 1998-02-05 | Warner-Lambert Company | Improved process for the synthesis of protected esters of (s)-3,4-dihydroxybutyric acid |
WO1999057109A1 (en) * | 1998-04-30 | 1999-11-11 | Kaneka Corporation | Process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives |
-
1999
- 1999-05-06 HU HU9901526A patent/HU227840B1/en not_active IP Right Cessation
-
2000
- 2000-05-05 PL PL00351145A patent/PL351145A1/en unknown
- 2000-05-05 SK SK1584-2001A patent/SK15842001A3/en unknown
- 2000-05-05 HK HK02105736.6A patent/HK1046271A1/en unknown
- 2000-05-05 CA CA002373077A patent/CA2373077A1/en not_active Abandoned
- 2000-05-05 EP EP00927612A patent/EP1178980A1/en not_active Withdrawn
- 2000-05-05 RU RU2001133066/04A patent/RU2001133066A/en unknown
- 2000-05-05 JP JP2000617201A patent/JP2002544207A/en active Pending
- 2000-05-05 AU AU46002/00A patent/AU4600200A/en not_active Abandoned
- 2000-05-05 CN CN00807159A patent/CN1349522A/en active Pending
- 2000-05-05 CZ CZ20013965A patent/CZ20013965A3/en unknown
- 2000-05-05 KR KR1020017014104A patent/KR20020033617A/en not_active Withdrawn
- 2000-05-05 WO PCT/HU2000/000042 patent/WO2000068221A1/en active Search and Examination
-
2001
- 2001-11-16 HR HR20010846A patent/HRP20010846A2/en not_active Application Discontinuation
Patent Citations (7)
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EP0330172A2 (en) * | 1988-02-22 | 1989-08-30 | Warner-Lambert Company | Improved process for trans-6-[2-(substituted-pyrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
WO1992006968A1 (en) * | 1990-10-17 | 1992-04-30 | 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 |
US5599954A (en) * | 1995-01-27 | 1997-02-04 | Takasago International Corporation | N-substituted-7-amino-5-hydroxy-3-oxoheptanoic acid derivatives and method for producing the same |
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Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7157255B2 (en) | 2000-05-09 | 2007-01-02 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7888083B2 (en) | 2000-05-09 | 2011-02-15 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7732171B2 (en) | 2000-05-09 | 2010-06-08 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7416865B2 (en) | 2000-05-09 | 2008-08-26 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7989643B2 (en) | 2000-07-19 | 2011-08-02 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives |
US6870059B2 (en) | 2000-07-19 | 2005-03-22 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives |
US7642363B2 (en) | 2000-07-19 | 2010-01-05 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives |
RU2269515C2 (en) * | 2001-01-19 | 2006-02-10 | Байокон Лимитид | Synthesis of atorvastatine and intermediate phenylboronate (variants) |
US6867306B2 (en) | 2001-01-19 | 2005-03-15 | Biocon Limited | Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
WO2002057274A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | A process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
US7692034B2 (en) | 2001-07-06 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives |
US7718812B2 (en) | 2001-12-27 | 2010-05-18 | Astrazeneca Uk Limited | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates |
EP1375493A1 (en) * | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
JP2005533065A (en) * | 2002-06-17 | 2005-11-04 | アストラゼネカ・ユーケイ・リミテッド | Process for producing dioxane acetates |
US7442811B2 (en) | 2002-06-17 | 2008-10-28 | Astrazeneca Uk Limited | Process for the preparation of dioxane acetic acid esters |
RU2315761C2 (en) * | 2002-06-17 | 2008-01-27 | АстраЗенека Ю-Кей Лимитед | Method for preparing dioxaneacetic acid esters |
WO2003106447A1 (en) * | 2002-06-17 | 2003-12-24 | Dsm Ip Assests B.V. | Process for the preparation of dioxane acetic acid esters |
EP1861364A1 (en) | 2005-03-14 | 2007-12-05 | Pfizer Science and Technology Ireland Limited | Preparation of an atorvastatin intermediate using a paal-knorr condensation |
WO2012032035A1 (en) | 2010-09-09 | 2012-03-15 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Salts of 7-amino-3,5-dihydroxyheptanoic acid esters |
US20130197243A1 (en) * | 2010-09-09 | 2013-08-01 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Salts of 7-amino-3,5-dihydroxyheptanoic acid esters |
US10676441B2 (en) | 2015-08-05 | 2020-06-09 | Api Corporation | Method for producing pitavastatin calcium |
US10815201B2 (en) | 2015-08-05 | 2020-10-27 | Api Corporation | Method for producing pitavastatin calcium |
CN109232354A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of high purity atorvastatin calcium raw material drug |
CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
Also Published As
Publication number | Publication date |
---|---|
AU4600200A (en) | 2000-11-21 |
CZ20013965A3 (en) | 2002-04-17 |
EP1178980A1 (en) | 2002-02-13 |
SK15842001A3 (en) | 2002-04-04 |
CA2373077A1 (en) | 2000-11-16 |
HUP9901526A2 (en) | 2001-04-28 |
HU9901526D0 (en) | 1999-07-28 |
HK1046271A1 (en) | 2003-01-03 |
HU227840B1 (en) | 2012-05-02 |
CN1349522A (en) | 2002-05-15 |
KR20020033617A (en) | 2002-05-07 |
JP2002544207A (en) | 2002-12-24 |
PL351145A1 (en) | 2003-03-24 |
RU2001133066A (en) | 2004-02-27 |
HRP20010846A2 (en) | 2003-02-28 |
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