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Process for preparing nateglinide and intermediates thereof

A technology for nateglinide and cis-isomers, applied in the field of preparation of nateglinide and its intermediates, capable of solving problems such as contamination, unwanted cis-isomers, and adverse cross-reactions

Inactive Publication Date: 2008-04-30
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Esters function as protecting groups, limiting the number of unwanted cross-reactions
However, the final product of the process of U.S. Patent 4,816,484 may be contaminated with the methyl ester, since removal of the ester as a protecting group may be incomplete, leaving at least a small amount of the ester as an impurity in the final product
Additionally, crystallization from aqueous methanol may cause esterification of the product
[0015] A common problem in the preparation of nateglinide is the undesired presence of the corresponding cis-isomer during the preparation, which leads to contamination of the final product with the corresponding cis-isomer

Method used

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  • Process for preparing nateglinide and intermediates thereof
  • Process for preparing nateglinide and intermediates thereof
  • Process for preparing nateglinide and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Preparation of IPCHAC by chlorination in the presence of amide

[0103] Add N,N-dimethylformamide (0.1ml) and pure trans-4-isopropylcyclohexanecarboxylic acid (9.92g) to thionyl chloride (8.32g) at room temperature. The isomer content is less than 0.1%]. The mixture was stirred at room temperature for 2 hours, and the volatiles were removed under reduced pressure in a 40°C bath to obtain 10.39 g of the desired product trans-4-isopropylcyclohexane acid chloride with a purity of 97% and a colorless liquid. No cis isomer was detected by GC. Yield: 96%.

Embodiment 2

[0105] Preparation of IPCHAC by chlorination in ethyl acetate in the presence of amide

[0106] To a mixture of trans-4-isopropylcyclohexanecarboxylic acid (20.0g) in ethyl acetate (8ml) was added N,N-dimethylformamide (0.1g), and the mixture was heated to 40°C, Thionyl chloride (16.1 g) was gradually added within 1 hour. The mixture was stirred at 40°C for 1 hour, and volatiles were removed under reduced pressure in a 40°C bath to obtain 22.43 g of the desired product trans-4-isopropylcyclohexane acid chloride with a purity of 98% and a colorless liquid. No cis isomer was detected by GC. The yield was 99%.

Embodiment 3

[0108] Preparation of IPCHAC by chlorination in the presence of amide

[0109] To pure trans-4-isopropylcyclohexanecarboxylic acid (250 g) placed in a 2 liter reactor was added N,N-dimethylformamide (0.63 g). The mixture was cooled to 18°C, and thionyl chloride (189.8 g) was gradually added within 15 minutes. The mixture was stirred for 1 hour, maintaining the temperature at about 15°C to obtain a clear solution. A second portion of trans-4-isopropylcyclohexanecarboxylic acid (250g) was added to the reactor, followed by N,N-dimethylformamide (0.63g). Another portion of thionyl chloride (189.8g) was added dropwise within 15 minutes, and the mixture was stirred for 1 hour, keeping the temperature at about 15°C to obtain a clear solution of the crude product of the desired product, which was directly used to prepare nateglinide . No cis isomer was detected by GC.

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Abstract

Provided is a method for preparing an intermediate in the synthesis of nateglinide. Trans-4-isopropylcyclohexane acid chloride is formed by reacting 4-isopropylcyclohexanecarboxylic acid with thionyl chloride in the presence of an effective amount of an organic amide. Also provided is the acylation of a suitable salt of D-phenylalanine with trans-4-isopropylcyclohexane acid chloride in single-phase and two-phase systems and in water free of co-solvents to prepare Nagar Lennet's method.

Description

[0001] Cross reference of related applications [0002] According to 35 USC§ 119(c), this application requires the benefits of the following provisional applications: 60 / 393,495 filed on July 3, 2002; 60 / 396,904 filed on July 18, 2002; filed on September 25, 2002 60 / 413,622; 60 / 414,199 filed on September 26, 2002; 60 / 423,750 filed on November 5, 2002; 60 / 432,093 filed on December 10, 2002; 60 / 432,093 filed on December 12, 2002 / 432,962; 60 / 442,109 filed on January 23, 2003; 60 / 449,791 filed on February 24, 2003 and 60 / ____ filed on June 16, 2003 (pending case catalog number No.1662 / 1106) The contents of these applications are quoted as reference in this application. Technical field [0003] The present invention relates to a method for preparing nateglinide and its intermediates. Background technique [0004] Nateglinide, commonly known as (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine, has the following structure and properties: [0005] [0006] Chemical formula ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/02C07C231/24C07C233/63C07C51/60C07C61/08A61K31/16A61K31/198
CPCA61K31/16A61K31/198C07C51/60C07C231/24C07B2200/13C07C231/02C07C2101/14C07C2601/14C07C61/08C07C233/63
Inventor R·亚哈罗米E·夏皮罗B·-Z·多利茨基I·戈兹兰
Owner TEVA PHARMA IND LTD
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