Improved preparation method of bepotastine besilate

A technology of bepotastine besylate and benzenesulfonic acid, which is applied in the field of drug synthesis, can solve the problems of complex preparation method, high cost, limited application and the like, and achieve the effects of shortening process time, improving yield and shortening process time.

Active Publication Date: 2016-06-15
SHIJIAZHUANG GERUI PHARMA CO LTD
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  • Abstract
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  • Claims
  • Application Information

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.

Method used

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  • Improved preparation method of bepotastine besilate
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  • Improved preparation method of bepotastine besilate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Step (1): Preparation of S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt

[0057] Dissolve 4.542kg of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine in 182L of ethyl acetate, stir and heat up to 65°C, stir to dissolve, then add 1.522kg of N-acetyl- L-phenylalanine, react for 1 hour. Cool to 20°C, crystallize for 6h, filter, and redissolve the filter cake in 130L ethyl acetate at 80°C, cool to 20°C for 6h, filter to obtain S-2-[(4-chlorophenyl)(4- Piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt 3.061kg, yield 80% (optical purity 99%).

[0058] Step (2): Preparation of S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine

[0059] Dissolve 2.856Kg of S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt in 14.3L of water, add 2.2L of 5N hydrochloric acid solution, add 5.6L ethyl acetate to extract twice, discard the organic phase, add 4.5L 5N NaOH solution to the water phase, extrac...

Embodiment 2

[0085] Step (1): Preparation of S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt

[0086] Dissolve 4.542kg of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine in 182L of ethyl acetate, stir and heat up to 50°C, stir to dissolve, then add 1.522kg of N-acetyl- L-phenylalanine, react for 1 hour. Cool to 20°C, crystallize for 6h, filter, and redissolve the filter cake in 130L ethyl acetate at 80°C, cool to 20°C for 6h, filter to obtain S-2-[(4-chlorophenyl)(4- Piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt 2.831kg, yield 74% (scientific purity 99%).

[0087] (2) and (3) are the same as in Embodiment 1.

Embodiment 3

[0089] Step (1): Preparation of S-2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt

[0090] Dissolve 4.542kg of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine in 182L of ethyl acetate, stir and heat up to 77°C, stir to dissolve, then add 1.522kg of N-acetyl- L-phenylalanine, react for 1 hour. Cool to 20°C, crystallize for 6h, filter, and redissolve the filter cake in 130L ethyl acetate at 80°C, cool to 20°C for 6h, filter to obtain S-2-[(4-chlorophenyl)(4- Piperidinyloxy)methyl]pyridine N-acetyl-L-phenylalanine salt 3.085kg, yield 81% (optical purity 99%).

[0091] (2) and (3) are the same as in Embodiment 1.

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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...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 张兴军张梓楠成新红
Owner SHIJIAZHUANG GERUI PHARMA CO LTD
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