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Polymorphs of atorvastatin tert.-butylester and use as intermediates for the preparation of atorvastatin

A technology of atorvastatin tert-butyl ester and atorvastatin, which is applied to the polymorphic form of atorvastatin tert-butyl ester and its application field as an intermediate in the preparation of atorvastatin, which can Solve the problems of inability to provide high purity, inability to obtain crystalline form of atorvastatin tert-butyl ester, inability to obtain filterability and purity of atorvastatin hemi-calcium, etc.

Inactive Publication Date: 2009-09-23
新梅斯托卡尔卡托瓦纳兹德拉韦尔公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, these methods cannot provide high purity of atorvastatin tert-butyl ester (II) in a well defined crystalline form
[0014] The above shows that the methods of the prior art cannot obtain atorvastatin tert-butyl ester (II) in crystal form and thus cannot obtain high-purity atorvastatin tert-butyl ester (II) form
[0015] In addition, these prior art methods cannot obtain atorvastatin hemi-calcium with the filterability and purity required for the preparation of pharmaceutical formulations due to impurities that are difficult to remove.

Method used

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  • Polymorphs of atorvastatin tert.-butylester and use as intermediates for the preparation of atorvastatin
  • Polymorphs of atorvastatin tert.-butylester and use as intermediates for the preparation of atorvastatin
  • Polymorphs of atorvastatin tert.-butylester and use as intermediates for the preparation of atorvastatin

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preparation example Construction

[0066] In the preparation process of crystal form 1 and crystal form 2, the dimethyl ketone atorvastatin tert-butyl ester (I) used as a starting material can be in any form, for example, it can be a reaction solution, a filtrate, any crude , polymorphs, anhydrates, solvates, or hydrated forms, or mixtures thereof, and may be prepared according to any of the following methods known to the expert or described in the prior art.

[0067] The water-miscible solvent is preferably an organic solvent, especially acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, lower alcohols such as methanol, ethanol, propanol, isopropanol and butanol, or ethyl acetate. The solvent is most preferably acetonitrile. Furthermore, the acid is preferably HCl.

[0068] It is also preferred that during the preparation of Form 1 and Form 2 of atorvastatin tert-butyl ester (II), the aqueous solution of water miscible solvent and acid is 10:1, more preferably 6:1 and most preferably 4 : 1 volume ratio appl...

Embodiment 1

[0089] To 1.32g (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (4.8mmol, 1.2 equivalents) in To a solution in a 9:1 mixture of heptane and toluene (30 mL), 0.49 g of 2-methylbutyric acid (0.52 mL, 4.8 mmol, 1.2 equivalents) and 1.66 g of 4-fluoro-α-[2-methyl -1-oxypropyl]-γ-oxy-N,β-diphenylbenzenebutyramide (4.0 mmol). The heterogeneous mixture was stirred at reflux for 22 h under argon atmosphere. The resulting yellow solution was cooled to room temperature, diluted with 30 mL tert-butyl methyl ether and washed sequentially with 50 mL 1M NaOH, 30 mL 1M HCl, and finally brine. Evaporation of the solvent gave a light brown viscous residue which was dissolved in 12 mL of acetonitrile, 2.2 mL of water and 0.6 mL of 1M HCl. The resulting clear solution was stirred overnight, during which time a precipitate appeared. 10 mL of water was added followed by 20 mL of acetonitrile, the latter being preferred for reducing the semi-solid precipitate to...

Embodiment 2

[0092] To 1.32g (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (4.8mmol) in 9:1 To a solution in a mixture of heptane and toluene (30 mL), 0.245 g of 2-methylbutanoic acid (0.26 mL, 2.4 mmol) and 1.66 g of 4-fluoro-α-[2-methyl-1-oxypropane were added successively base]-γ-oxyl-N,β-diphenylbenzenebutyramide (4.0 mmol). The heterogeneous mixture was stirred at reflux for 48 h under argon atmosphere. The resulting yellow solution was cooled to room temperature, diluted with 30 mL tert-butyl methyl ether and washed sequentially with 50 mL 1M NaOH, 30 mL 1M HCl, and finally brine. Evaporation of the solvent gave an orange sticky residue which was dissolved in 12 mL of acetonitrile, 2.2 mL of water and 0.6 mL of 1M HCl. The resulting mixture was heated and stirred at 45-49° C. for 5.5 h until the intermediate of general formula (I) was almost completely consumed according to HPLC analysis. The mixture was cooled and stirring was continued at 20-2...

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Abstract

The invention relates to crystalline forms 2 of atorvastatin tert.-butyl ester (Formula (II)), processes for their preparation and their conversion to highly pure atorvastatin hemi calcium in non-crystalline, in particular amorphous form.

Description

[0001] This application is submitted on April 8, 2005 with the application number 200580012246.X and the title "polymorphic form of atorvastatin tert-butyl ester and its application as an intermediate in the preparation of atorvastatin". A divisional application of a patent application. technical field [0002] The present invention relates to [R-(R * , R * )]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- New crystal forms 1 and 2 of tert-butyl pyrrole-1-heptanoate. [0003] [0004] The present invention also relates to (4R-cis)-6-{2-[2-(4-fluorobenzene) of the general formula (I), hereinafter referred to as dimethyl ketone atorvastatin tert-butyl ester (I). Base)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3 - A process for the preparation of these crystalline forms starting from tert-butyl dioxane-4-acetate. [0005] [0006] More specifically, the present invention relates to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34A61K31/40A61P3/06A61P9/10
CPCC07D207/34A61P3/06A61P9/10
Inventor 安东·斯蒂马克罗克·祖佩特马丽亚·格尔齐曼马泰·斯莫尔克杰雷娜塔·杰克塞
Owner 新梅斯托卡尔卡托瓦纳兹德拉韦尔公司
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