Improved preparation method of bepotastine besilate

Abstract

The invention relates to an improved preparation method of bepotastine besilate.The improved preparation method of bepotastine besilate includes the following steps that firstly, 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine and a resolving agent are reacted, and S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalaninate is obtained; secondly, S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalaninate is added with acid to be extracted, and S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine is obtained; thirdly, S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine and ethyl 4-bromobutyrate are subjected to a coupling reaction, a hydrolysis reaction and a salt-forming reaction in sequence in acetonitrile, and bepotastine besilate is obtained.According to the technical scheme, the yield is greatly increased, the process time is shortened, and the obtained product is high in purity, safe and stable.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to an improved preparation method of bepotastine besilate by adopting a chemical resolution method and a "one-pot cooking" method. Background technique [0002] Bepotastine, chemical name (+)-4-[[(S)-p-chloro-α-2-pyridylbenzyl]oxy]-1-piperidine butanoic acid, English name Bepotastine, English chemical name (+ )-4-[[(S)p-Chloro-alpha-2-pyridylbenzyl]oxy]-1-piperidinebutyricacid, bepotastine is clinically marketed as active ingredient bepotastine, bepotyric acid Tastatin is a histamine H1 receptor antagonist jointly developed by Japan's Tanabe Seiyaku Company and Japan's Ube Industries Company. It was first launched in Japan in 1998 and is used clinically to treat allergic rhinitis, conjunctivitis, etc. The structural formula of bepotastine besilate as follows: [0003] [0004] Bepotastine was first publicly reported as a racemate of a pair of enantiomers in t...

AI Technical Summary

Problems solved by technology

[0006] Due to the need to prepare intermediate compounds with complex structures in this route, the preparation method is complicated and the cost is high, which seriously limits the application of this method

[0007] The process route disclosed by CN1242013A is to use a resolving agent to resolve 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine to obtain S-2-[(4-chlorobenzene base)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt, followed by reaction with ethyl 4-bromobutyrate to give S-4-[(4-chloro Phenyl) (2-pyridyl methoxy) piperidino base] ethyl butyrate, then obtain bepotastine benzenesulfonate through hydrolysis and salt-forming reaction, wherein, the last three-step continuous coupling reaction, hydrolysis reaction Different solvents are used for the salt-forming reaction, crystallization and drying are required respectively, the overall process takes a long time, the operation is cumbersome, and the yield is also low

Due to the introduction of a chiral ester protecting group, the yield of the resolution has been greatly improved, but the raw material 4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidine In the synthesis, the old method is still used, and the process of forming ether is complicated. At the same time, due to the use of expensive chiral alcohol reagents, the cost is greatly increased, which is not conducive to industrialization.

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