A kind of preparation method of improved bepotastine besilate

Abstract

The present invention relates to an improved preparation method of bepotastine bepotastine, which comprises the following steps: the first step, combining 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine with Resolving agent reaction, obtain S-2-[(4-chlorophenyl) (4-piperidinyloxy) methyl] pyridine N-acetyl-L-phenylalanine salt, the second step, S ‑2‑[(4‑chlorophenyl) (4‑piperidinyloxy) methyl] pyridine N‑acetyl‑L‑phenylalanine salt plus acid extraction to obtain S‑2‑[(4‑chlorobenzene Base) (4-piperidinyloxy)methyl]pyridine, the third step, S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine sequentially in acetonitrile Coupling reaction with ethyl 4-bromobutyrate, hydrolysis reaction and salt-forming reaction to obtain bepotastine besilate. The technical scheme of the invention greatly improves the yield, shortens the process time, and the obtained product has high purity, safety and stability.

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 -piperidine butyric acid, bepotastine is clinically marketed with bepotastine besilate as the active ingredient. Sulbestatin is a histamine H1 receptor antagonist jointly developed by Japanese Tanabe Seiyaku Company and Japanese Ube Industries Company. The structural formula of stin is as follows: [0003] [0004] Bepotastine was first publicly reported as a racemate of a pair of enantiomers in the patent JP1990025465. Later studies found that the S-configuration of bepotastine was more effective than the R...

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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