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A kind of synthetic method of bilastine intermediate

A technology of bilastine and a synthesis method, applied in the field of drug synthesis, can solve the problems of complex reaction epoxidation synthesis, difficulty in industrial scale-up, difficulty in purification and the like, and achieves low cost of raw materials, simple requirements for equipment and experimental conditions, and high application value. Effect

Active Publication Date: 2022-04-01
荆门医药工业技术研究院 +1
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Problems solved by technology

[0012] The synthetic method reaction epoxy synthesis is more complicated, the purification is more difficult, and the industrial scale-up is difficult

Method used

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  • A kind of synthetic method of bilastine intermediate
  • A kind of synthetic method of bilastine intermediate
  • A kind of synthetic method of bilastine intermediate

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Embodiment Construction

[0033] The present invention will be further described below in conjunction with specific embodiments. Of course, the embodiments described below are only a part of the present invention, not all embodiments.

[0034] Synthesis of intermediate compound B: In a 500ml three-neck flask, weigh phenethyl acetate (65.6g, 0.4mol), add 100ml of dichloromethane and stir. Cool down to 0°C, add anhydrous aluminum trichloride (51.1g, 0.48mol) and stir, add dropwise isobutyryl chloride (42.5g, 0.4mol), react for 1 hour, return to room temperature (25°C) and stir for 4 hours. After the reaction was completed, dilute hydrochloric acid was added to quench the reaction, dichloromethane was added to extract twice, the organic phases were combined, and the organic phases were washed once with water and saturated brine, evaporated to dryness and purified to obtain intermediate compound B (74.9g, y =80%).

[0035] 1HNMR (400Hz, CDCl 3 ( s, 3H), 1.21-1.22 (d, 6H).

[0036] Synthesis of intermed...

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Abstract

A method for synthesizing bilastine intermediates, including: S1, Friedel-Crafts reaction of phenethyl acetate with isobutyryl halide under the catalysis of Lewis acid to generate intermediate compound B; S2, intermediate compound B in alkaline Or hydrolytically remove the ester group under acidic conditions to obtain intermediate compound C; S3, intermediate compound C is subjected to hydroxyl protection reaction to benzyl or methoxybenzyl protecting group to obtain intermediate compound D; S4, intermediate compound D is bromine The bromo group generates intermediate compound E in the substitution reaction; S5, intermediate compound E undergoes a rearrangement reaction under the catalysis of a metal reagent to generate intermediate compound F; S6, intermediate compound F is hydrogenated or oxidatively deprotected to generate the target compound Bilas Stinging intermediate α,α-dimethyl-4-(2-hydroxyethyl)phenylacetic acid methyl ester. The method of the invention has low raw material cost, simple requirements for equipment and experimental conditions, can realize industrial production, and has high application value.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the synthesis of bilastine intermediate α,α-dimethyl-4-(2-hydroxyethyl)phenylacetic acid methyl ester. Background technique [0002] Bilastine, chemical name 2-[4-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethyl ]-phenyl]-2-methylpropionic acid, is the second generation of histamine H1 receptor antagonist developed by Spanish FAES pharmaceutical company, approved by the European Union in 2012 for the treatment of allergic rhinitis and chronic idiopathic urticaria . [0003] [0004] α,α-Dimethyl-4-(2-hydroxyethyl)phenylacetic acid methyl ester is an intermediate of bilastine, which is synthesized by reacting with another bilastine fragment 1. [0005] [0006] α,α-Dimethyl-4-(2-hydroxyethyl)phenylacetate methyl bilastine fragment 1 [0007] WO2009102155 reports the synthesis of ethyl α,α-dimethyl-4-(2-hydroxyethyl)phenylacetate, the method is as follows: [0...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/29C07C69/14C07C45/64C07C49/82C07C45/63C07C49/84C07C67/00C07C69/734C07C67/31C07C69/732
CPCC07C67/29C07C45/64C07C45/63C07C67/00C07C67/31C07C69/14C07C49/82C07C49/84C07C69/734C07C69/732Y02P20/55
Inventor 许方亮李立威陶再洲
Owner 荆门医药工业技术研究院
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