Preparation method of vilanterol intermediate

A technology of an intermediate and hydroxymandelic acid, which is applied in the field of preparation of 3-hydroxymethyl-4-hydroxymandelic acid, an intermediate of anti-asthma drug vilanterol, can solve the problem of reducing the synthesis steps of vilanterol and reducing the production cost. and other problems, to achieve the effect of shortening the synthesis route, reducing the production cost and mild reaction conditions

Active Publication Date: 2019-04-26
ANHUI DEXINJIA BIOPHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] According to domestic and foreign literature reports, there is no synthetic route about 3-hydroxymethyl-4-hydroxymandelic acid at present, therefore, th

Method used

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  • Preparation method of vilanterol intermediate
  • Preparation method of vilanterol intermediate
  • Preparation method of vilanterol intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of 4-hydroxy-3-formylmandelic acid:

[0024] Add 4-hydroxymandelic acid (50.4g) and urotropine (46.2g) to a 500mL three-necked flask, add trifluoroacetic acid (250mL), heat up to 85°C for 4h, and control the reaction by TLC. Cool to room temperature. Concentrate the solvent in vacuo, add water (250mL) to the residue, extract with 150×2mL ethyl acetate, combine the organic phases, dry, filter, and concentrate to obtain the crude product, which is added to 150mL ethanol and refluxed for 1 hour, cooled to crystallize, filtered, and the filter cake Wash with 50 mL of ethanol and dry to obtain 43 g of white solid with a yield of 73%.

[0025] 3-Hydroxymethyl-4-hydroxymandelic acid

[0026] Add 4-hydroxy-3-formylmandelic acid (39.2g) into a 500mL three-necked flask, add methanol (200mL), cool down to 8°C, and add sodium borohydride (7.5g) in small amounts in batches within 30 minutes , the TLC control reaction is completed, the system is cooled to 0-5°C, water (...

Embodiment 2

[0028] Add 4-hydroxy-3-formylmandelic acid (20g), 10mL liquid caustic soda (mass fraction 40%), and chloroform (30g) into a 500mL three-necked flask, raise the temperature to 75°C and react for 3 hours, the liquid phase is controlled, no reaction , continue to heat up to 85 ° C for 2 hours, and no reaction is controlled in the liquid phase.

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Abstract

The invention discloses a preparation method of a vilanterol intermediate and belongs to the field of drug synthesis. The method is characterized in that 4-hydroxy-mandelic acid is taken as a raw material and is subjected to formylation reaction to obtain 4-hydroxy-3-formyl mandelic acid; an aldehyde group is reduced to obtain 3-hydroxymethyl-4-hydroxyphenylglycolic acid. The invention provides anovel intermediate of vilanterol; the raw material of the intermediate is easy to obtain; synthesis reaction conditions are mild and the operation is simple; in addition, by using the intermediate tosynthesize the vilanterol, a synthetic route is greatly shortened, and the production cost is reduced; the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of an anti-asthmatic drug vilanterol intermediate 3-hydroxymethyl-4-hydroxymandelic acid. Background technique [0002] Vilanterol trifenatate (Vilanterol trifenatate) is a long-acting beta 2 receptor agonist. Its compound preparation with fluticasone furoate and its compound preparation with umeclidinium bromide were approved by FDA in May and December 2013, respectively, for the treatment of obstructive pulmonary disease and asthma. The molecular weight of vilanterol is 486.4, the molecular formula is C24H33Cl2NO5, CAS: 503068-34-6, the Chinese name is: chemical name: (R)-4-[2-[[6-[(2,6-dichlorobenzyl )oxyl]-ethoxyl]ethyl]amino]-1-hydroxyethyl]-2-hydroxyethyl]-2-hydroxymethylphenol, the chemical structural formula is as shown: [0003] [0004] The world patent WO2003024439 relates to a method for synthesizing vilanterol, the specific synthetic route is as...

Claims

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Application Information

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IPC IPC(8): C07C59/52C07C51/367C07C59/74C07C51/373
CPCC07C51/367C07C51/373C07C59/74C07C59/52
Inventor 许坤林建华李学坤张启龙王红磊
Owner ANHUI DEXINJIA BIOPHARM
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