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Method for synthesizing Vilanterol intermediate in mixed solvent

A technology of mixed solvents and intermediates, applied in the field of drug synthesis, can solve the problems of poor selectivity and achieve the effects of improving selectivity, simplifying the difficulty of post-processing, and simple post-processing

Active Publication Date: 2019-04-05
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Analyzing the reason therein, it is not difficult to find that adding sodium borohydride in the acetic acid solvent first generates sodium triacetoxy borohydride, although the sodium triacetoxy borohydride that generates is less active than sodium borohydride, it is still active in protic solvents. Has high reactivity, resulting in poor selectivity of the reaction

Method used

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  • Method for synthesizing Vilanterol intermediate in mixed solvent
  • Method for synthesizing Vilanterol intermediate in mixed solvent
  • Method for synthesizing Vilanterol intermediate in mixed solvent

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Add 5-bromoacetyl-2-hydroxybenzaldehyde (200g) into a 5L three-necked flask, add 1,2-dichloroethane (1.5L), propionic acid (500mL), start stirring, and cool down to 5-10°C , within half an hour, add sodium borohydride (21.8g) in small amounts in batches. After the addition is complete, the liquid phase is controlled in the middle, and the remaining raw materials are less than 1%. Add 1L of water to the reaction system, stir at 0-5°C for 1 hour, and filter , washed with 500mL of water and dried to obtain 185g of white solid with a yield of 92% and a purity of 98%, of which over-reduction products accounted for 1.2%.

Embodiment 2

[0024] Add 5-bromoacetyl-2-hydroxybenzaldehyde (200g) into a 5L three-necked flask, add propionic acid (500mL), tetrahydrofuran (1.5L), start stirring, cool down to 5-10°C, within half an hour, a small amount of . Add sodium borohydride (21.8g) in batches. After the addition is complete, the liquid phase is controlled in the middle, and the remaining raw materials are less than 1%. Add 1L of water to the reaction system, stir at 0-5°C for 1 hour, filter, wash with 500mL of water, and dry. 190 g of white solid was obtained with a yield of 94% and a purity of 97.3%, of which over-reduced products accounted for 1.9%.

Embodiment 3

[0026] Add 5-bromoacetyl-2-hydroxybenzaldehyde (200g) into a 5L three-necked flask, add methanol (650mL), 1,2-dichloroethane (1.35L), start stirring, cool down to 5-10°C, Within half an hour, add sodium borohydride (21.8g) in small amounts in batches. After the addition is complete, the liquid phase is controlled in the middle, and the remaining raw materials are less than 1%. Add 1L of water to the reaction system, stir at 0-5°C for 1 hour, and filter. Washed with 500mL of water and dried to obtain 181g of white solid with a yield of 90% and a purity of 98%. Among them, over-reduction products accounted for 1.3%.

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Abstract

The invention discloses a method for synthesizing a Vilanterol intermediate in a mixed solvent, and belongs to the field of drug synthesis. According to the method, 5-bromoacetyl-2-hydroxybenzaldehydeis reduced by sodium borohydride in the mixed solvent to obtain 2-bromo-1-[4-hydroxy-3-(hydroxymethyl) phenyl] ethyl-1-ketone. Reaction selectivity and yield are improved, post-treatment is simple, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to a method for synthesizing vilanterol intermediate 2-bromo-1-[4-hydroxyl-3-(hydroxymethyl)phenyl]ethan-1-one in a mixed solvent. Background technique [0002] Bronchial asthma is a typical chronic respiratory disease with a high incidence and a wide distribution worldwide. It is estimated that by 2025, the number of patients worldwide will increase to 400 million. At present, the average incidence rate of asthma in my country is 2.1%, about 30 million people, and it is increasing year by year. In the European Union, the annual cost of asthma treatment is about 40 billion euros. In the United States, the annual direct economic cost of asthma is approximately $29.5 billion. The pathogenesis of asthma is complicated, and the traditional treatment methods have long treatment cycle, slow effect and high mortality rate, which not only cause the loss of labor force, decrease the quality of l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/64C07C49/84
CPCC07C45/64C07C49/84
Inventor 郑庚修汪崇文高令峰张启龙卢伟阳
Owner ANHUI DEXINJIA BIOPHARM
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