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A kind of preparation method of vilanterol intermediate

An intermediate, the technology of hydroxymandelic acid, which is applied in the field of preparation of the anti-asthma drug Vilanterol intermediate 3-hydroxymethyl-4-hydroxymandelic acid, can solve the problem of reducing production costs and reducing the synthesis steps of Vilanterol And other issues

Active Publication Date: 2021-08-20
ANHUI DEXINJIA BIOPHARM
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  • 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, the synthesis of 3-hydroxymethyl-4-hydroxymandelic acid is very important, not only can reduce the Luo synthesis steps, but also greatly reduce production costs

Method used

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  • A kind of preparation method of vilanterol intermediate
  • A kind of preparation method of vilanterol intermediate
  • A kind of 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, belonging to the field of drug synthesis. The method uses 4-hydroxymandelic acid as a raw material to obtain 4-hydroxy-3-formylmandelic acid through formylation reaction, and then reduces the aldehyde group to obtain 3-hydroxymethyl-4-hydroxymandelic acid. The invention provides a new intermediate of vilanterol, the intermediate raw material is easy to get, the synthesis reaction conditions are mild, and the operation is simple, and the synthesis of vilanterol by the intermediate greatly shortens the synthetic route and reduces the production cost. cost, 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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Patent Type & Authority Patents(China)
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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