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Method for preparation of glycopyrronium bromide

A technology of glycopyrronium bromide and compound, applied in the field of preparation of glycopyrronium bromide, can solve the problems of inability to guarantee safe production of glycopyrronium bromide, extremely high equipment and environmental requirements, unsuitable for industrialized production, etc., and achieves easy industrialized production , low-cost, easy-to-control effects

Inactive Publication Date: 2012-08-08
CUREGEN JIANGSU PHARMA
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  • Claims
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AI Technical Summary

Problems solved by technology

[0021] The title of the literature published by Dongting Pharmaceutical Factory in Pharmaceutical Industry, 3, 1979, p 10-12 - Stomach Changninger Reaction, Transesterification Process Improvement, using methyl acetophenone as the starting material, and cyclopentadiene and The key intermediate of glycopyrronium bromide is prepared by methylmagnesium bromide through Grignard reaction, catalytic hydrogenation and transesterification with 1-methyl-3-pyrrolidinol. Although this method recognizes the deficiencies in the above production process, Without technological innovation, its shortcomings are obvious, and it is impossible to guarantee safe production and obtain qualified clinical pharmaceutical grade glycopyrronium bromide
[0022] The synthesis of glycopyrronium bromide in the above several synthetic routes all has the disadvantages of extremely low yield and difficult operation.
High requirements on equipment and environment, not suitable for industrial production

Method used

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  • Method for preparation of glycopyrronium bromide
  • Method for preparation of glycopyrronium bromide
  • Method for preparation of glycopyrronium bromide

Examples

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Embodiment

[0044] a) Add 440g of α-cyclopentylmandelic acid and 6L of toluene to a 10L dry reaction kettle, under stirring at room temperature, add 360g of 4-chloro-2,6-dimethoxytriazine, and stir for 20min to obtain formula (II ) active intermediate solution

[0045] b) In the above solution, add 200g of 1-methyl-3-pyrrolidinol in 300ml of isopropanol solution, heat to 60°C within 1h, and keep stirring for 5 hours

[0046] c) Cool the above solution to -20°C, add 210g of methyl bromide dropwise, keep stirring for 2h, then raise the temperature to 60°C and keep stirring for 20min, cool to room temperature, let stand for 5h, filter, wash the solid with a small amount of isopropanol, 70-80°C Vacuum drying yielded 361 g of glycopyrronium bromide. The yield is 89.5% based on α-cyclopentylmandelic acid, and the melting point is 195°C to 198°C.

[0047]

[0048] 1 H-NMR (600MHz, CDCl 3 / TMS,ppm):

[0049]δ1.07~1.09(m, 1H); δ1.28~1.31(m, 1H); δ1.37~1.43(m, 1H); δ1.45~1.53(m, 1H); δ1.57~...

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Abstract

The invention belongs to the field of chemical synthesis, relates to a method for preparation of glycopyrronium bromide, and especially relates to enriched high-purity (3R, 2'S,) and (3S, 2'R,) glycopyrronium bromide and a preparation method of a novel intermediate involved in the synthesis method of glycopyrronium bromide. The method provided by the invention overcomes the defect that the prior art has a low yield and can produce large pollution, can realize preparation of glycopyrronium bromide shown in the formula I, has a high yield, produces low environmental pollution and is convenient for purification. Glycopyrronium bromide obtained by the method has a melting point of 195 to 198 DEG C.

Description

1. Technical field [0001] The invention belongs to the field of chemical synthesis, and more specifically relates to a preparation method of glycopyrronium bromide. 2. Background technology [0002] Glycopyrronium bromide was researched and developed by SHIONOGI INC of the United States, and its glycopyrronium bromide tablet was first launched in the United States in 1982; in the same year, its glycopyrronium bromide injection was developed and launched in the United States by BAXTER HEALTHCARE CORPANESTHESIAAND CRITICAL CAR in the United States. In October 2010, the State Drug Administration approved the domestic production of "glycopyrronium bromide raw materials and tablets" of Hunan Dongting Pharmaceutical Co., Ltd., and the approval number is: Guoyao Zhunzi H43020556. Since the product was launched on the market, countless patients have been treated for gastrointestinal diseases and used for preoperative administration of anesthesia. In order to meet the needs of clini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12
Inventor 徐奎
Owner CUREGEN JIANGSU PHARMA
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