Synthetic method of mirabegron intermediate

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve the problems of cumbersome post-processing steps, unfriendly environment, difficult recycling, etc., and achieve the effect of facilitating large-scale industrial production, high feasibility of industrial operation, and reducing production costs

Inactive Publication Date: 2016-07-27
UNIV OF JINAN
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

The post-processing steps of this route are cumbersome and generate a lot of waste, and the cost is high and there are many by-products
In the second step of amide reduction, expensive borane-tetrahydrofuran solution and 1,3-dimethylimidazolidinone are used, and the recovery

Method used

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  • Synthetic method of mirabegron intermediate
  • Synthetic method of mirabegron intermediate
  • Synthetic method of mirabegron intermediate

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Embodiment 1

[0028] Preparation of intermediate (I): Add R-mandelic acid (12.17g, 80mmol, 1eq), triethylamine (23.28mL, 168mmol, 2.1eq) and dichloromethane (100mL ). Under ice bath, slowly add pivaloyl chloride (19.29g, 160mmol, 2.0eq) dropwise, keep the temperature of the reaction system not exceeding 5°C, after the dropwise addition is completed, rise to room temperature, add water (15mL) and slowly raise the temperature to 60°C for reaction After 3h, the reaction was completed and cooled to room temperature to obtain the mixed anhydride intermediate (I).

[0029] Preparation of intermediate (II): at room temperature, slowly add 4-nitrophenethylamine (12.61g, 76mmol, 0.95eq) dropwise to the dichloromethane / water solution of the above-mentioned mixed anhydride intermediate (I), dropwise After the addition was completed, the reaction was carried out at room temperature for 2h. After the reaction is completed, wash with 1 mol / L dilute hydrochloric acid (20 mL), separate layers, concentrat...

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Abstract

The invention discloses a synthetic method of a mirabegron intermediate (R)-2-(4-nitrobenzene ethyl amino)-1-phenyl ethanol hydrochloride (M-02) and belongs to the field of drug synthesis. The method comprises steps as follows: (1) R-mandelic acid and pivaloyl chloride produce a mixed anhydride intermediate (I); (2) the mixed anhydride intermediate (I) and 4-nitrobenzene ethylamine are subjected to an acrylation reaction to produce an intermediate (II); (3) a mirabegron intermediate (M-01) is obtained through hydrolysis of the intermediate (II); (4) an amido bond of the intermediate (M-01) is reduced and the mirabegron intermediate (M-02) is obtained. The reaction condition is mild, the yield is high, few impurities exist, the production cost is low, and the method is suitable for mass industrial production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis and relates to a synthesis method of mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride. Background technique [0002] In recent years, Overactive Bladder (OAB) has become a major disease that plagues people and seriously affects the quality of life of patients. Increased nocturia. In June 2012, the US FDA approved mirabegron (mirabegron, trade name Myrbetriq) for the treatment of overactive bladder in adults, with the following structural formula: [0003] . [0004] European patents (EP1440969, EP1559427) involve a synthesis of mirabegron and its intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride (M-02) Synthetic method, described method synthetic route is as follows: [0005] [0006] [0007] . [0008] In the first step of this route, the condensation of Mirabegron intermediate (R)-2-hydroxyl-N-(4-nitrophenethyl)-2-phenyla...

Claims

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Application Information

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IPC IPC(8): C07C215/30C07C213/02C07C213/08
CPCC07C213/02C07C213/08C07C231/02C07C231/12C07C215/30C07C235/34
Inventor 战付旭张启龙郑庚修
Owner UNIV OF JINAN
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