Synthesizing method of vilanterol intermediate

Abstract

The invention discloses a synthesizing method of a vilanterol intermediate and belongs to the field of drug synthesis. According to the synthesizing method of the vilanterol intermediate, 4-hydroxymandelic acid serving as the raw material is prepared through electrophilic substitution reaction into 3-hydroxymethyl-4-hydroxymandelic acid. The prepared new vilanterol intermediate is simple in raw material acquisition and operation, and when applied to synthesizing vilanterol, can greatly shortens the synthetic route and reduce the production cost, thereby being applicable to industrial production.

Description

technical field

[0001] The invention belongs to the field of drug synthesis, and relates to a method for synthesizing the intermediate 3-hydroxymethyl-4-hydroxymandelic acid of the anti-asthma drug vilanterol. Background technique

[0002] Vilanterol is a long-acting beta drug developed by GlaxoSmithKline (GSK) 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. Vilanterol has a molecular weight of 486.4 and a molecular formula of C 24 h 33 Cl 2 NO 5 , CAS: 503068-34-6, Chinese name: Chemical name: (R)-4-[2-[[6-[(2,6-dichlorobenzyl)oxy]-ethoxy]ethyl ]amino]-1-hydroxyethyl]-2-hydroxyethyl]-2-hydroxymethylphenol, the chemical structural formula is as follows:

[0003]

[0004] The world patent WO2003024439 relates to a method for synthesizing vilanterol, the specific synthe...

Examples

Embodiment 1

[0018] Add 4-hydroxymandelic acid (16.8g), paraformaldehyde (9g) into the there-necked flask, add glacial acetic acid (85mL), FeCl 3 (0.8g), reacted at 80°C for 4h, the reaction in TLC was completed, cooled to room temperature, concentrated the solvent in vacuo, added water (100mL) to the residue, stirred for half an hour, filtered to obtain a solid, and the crude product was recrystallized from ethanol to obtain 13.5 g of 4-hydroxy-3-formylmandelic acid, yield 68%, purity 98%.

[0019] Note: 4-Hydroxymandelic acid was purchased from Jiangxi Keyuan Biopharmaceutical Co., Ltd., and the purity of the raw material was 98%.

Embodiment 2

[0021] Add 4-hydroxymandelic acid (50.4g), paraformaldehyde (27g) in the there-necked flask, add trifluoroacetic acid (250mL), ZnCl 2 (2g), reacted at 70°C for 4h, the reaction in TLC was completed, cooled to room temperature, concentrated the solvent in vacuo, added water (200mL) to the residue, stirred for half an hour, filtered to obtain a solid, and the crude product was recrystallized from ethanol to obtain 4 -Hydroxy-3-formylmandelic acid 41g, yield 70%, purity 98%.

technical field

[0001] The invention belongs to the field of drug synthesis, and relates to a method for synthesizing the intermediate 3-hydroxymethyl-4-hydroxymandelic acid of the anti-asthma drug vilanterol. Background technique

[0002] Vilanterol is a long-acting beta drug developed by GlaxoSmithKline (GSK) 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. Vilanterol has a molecular weight of 486.4 and a molecular formula of C 24 h 33 Cl 2 NO 5 , CAS: 503068-34-6, Chinese name: Chemical name: (R)-4-[2-[[6-[(2,6-dichlorobenzyl)oxy]-ethoxy]ethyl ]amino]-1-hydroxyethyl]-2-hydroxyethyl]-2-hydroxymethylphenol, the chemical structural formula is as follows:

[0003]

[0004] The world patent WO2003024439 relates to a method for synthesizing vilanterol, the specific synthe...

Examples

Embodiment 1

[0018] Add 4-hydroxymandelic acid (16.8g), paraformaldehyde (9g) into the there-necked flask, add glacial acetic acid (85mL), FeCl 3 (0.8g), reacted at 80°C for 4h, the reaction in TLC was completed, cooled to room temperature, concentrated the solvent in vacuo, added water (100mL) to the residue, stirred for half an hour, filtered to obtain a solid, and the crude product was recrystallized from ethanol to obtain 13.5 g of 4-hydroxy-3-formylmandelic acid, yield 68%, purity 98%.

[0019] Note: 4-Hydroxymandelic acid was purchased from Jiangxi Keyuan Biopharmaceutical Co., Ltd., and the purity of the raw material was 98%.

Embodiment 2

[0021] Add 4-hydroxymandelic acid (50.4g), paraformaldehyde (27g) in the there-necked flask, add trifluoroacetic acid (250mL), ZnCl 2 (2g), reacted at 70°C for 4h, the reaction in TLC was completed, cooled to room temperature, concentrated the solvent in vacuo, added water (200mL) to the residue, stirred for half an hour, filtered to obtain a solid, and the crude product was recrystallized from ethanol to obtain 4 -Hydroxy-3-formylmandelic acid 41g, yield 70%, purity 98%.

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