Preparation method of bilastine

A bilastine, molar ratio technology, applied in the field of medicine, can solve the problems of expensive raw materials, reduced industrial production efficiency, low purity and yield, etc., to achieve mild reaction conditions, improve product purity, and good catalytic effect

Active Publication Date: 2020-03-24
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] In this reaction route, compound 2 and compound 7 cannot be purchased from the market, so the reaction route is longer. In addition, in the synthesis process of bilastine, 20 hours of purification are required, which greatly prolongs the process time and reduces the industrial production efficiency.
[0020] In summary, in the prior art, the preparation of bilastine has problems such as expensive raw materials, high toxicity, easy to produce by-products, low purity and yield, and cumbersome process

Method used

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Examples

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Effect test

reference example

[0041] Reference example: Preparation of methyl α,α-dimethyl-4-(2-bromoethyl)phenylacetate (Compound II)

[0042] According to the literature [Kong Hao, Geng Haiming, Mei Yudan, etc. Synthesis of bilastine [J]. Chinese Journal of Pharmaceutical Industry, 2015, 46(7): 677-679.] Compound II was prepared:

[0043] Dissolve α,α-dimethyl-phenylacetate methyl ester (5.0g, 28mmol) and bromoacetyl bromide (7.4g, 36mmol) in dichloromethane (20mL), and drop the solution into trichloride at -30°C In a dichloromethane solution (50 mL) of aluminum (11.2 g, 84 mmol), the mixture was dropped and stirred at 0° C. overnight. Add dichloromethane (50ml) to dilute, the reaction solution is filtered through Celite, the filtrate is washed with saturated sodium chloride solution (30ml×2), dried with anhydrous sodium sulfate and filtered, the filtrate is concentrated to obtain a yellow oily α,α -Dimethyl-4-(2-bromoacetyl)phenylacetate methyl ester.

[0044] Add α,α-dimethyl-4-(2-bromoacetyl)phenylacetate ...

Embodiment 1

[0045] Example 1 Preparation of methyl α,α-dimethyl-4-[2-[4-carboxylic acid piperidinyl]ethyl]phenylacetate (Compound III)

[0046] Add 60 mL of N-methylpyrrolidone to a 500 mL reaction flask, add 5.68 g 4-piperidine carboxylic acid (compound I) while stirring, add 6.07 g potassium carbonate, 1.14 g potassium iodide, slowly add 11.41 g compound II, and again add 20 mL N- Methyl-2-pyrrolidone, the temperature was controlled at 40~50℃, the reaction was monitored by TLC after 3h, and the reaction was over after 3h. There was almost no compound II left, filtered, and the filtrate was added with 120mL of purified water at room temperature and stirred. A large amount of solid precipitated out. Continue stirring for 30min. Filter and vacuum dry the filter cake at 50°C for 2h to obtain 11.23g of methyl α,α-dimethyl-4-[2-[4-carboxylate piperidinyl]ethyl]phenylacetate, yield 84.2%, purity 98.6 %.

Embodiment 2

[0047] Example 2 Preparation of methyl α,α-dimethyl-4-[2-[4-carboxylate piperidinyl]ethyl]phenylacetate (Compound III)

[0048] Add 60 mL of N-methylpyrrolidone to the 500mL reaction flask, add 5.68g of compound I while stirring, add 7.18g of potassium carbonate, 1.14g of potassium iodide, slowly add 11.41g of compound II, and again add 20mL of N-methyl-2-pyrrolidone, control React at 40~50℃. After 3h, the reaction is monitored by TLC. There is almost no compound II left. Filter. Add 120mL of purified water to the filtrate at room temperature and stir. A large amount of solid precipitates. Continue stirring for 30min and filter. The filter cake is vacuum at 50℃. After drying for 2 hours, 11.95 g of methyl α,α-dimethyl-4-[2-[4-carboxylate piperidinyl]ethyl]phenylacetate was obtained, with a yield of 89.6% and a purity of 98.9%.

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Abstract

The invention belongs to the technical field of medicines, and discloses a preparation method of bilastine. 4-piperidinecarboxylic acid and methyl alpha,alpha-dimethyl-4-(2-bromoethyl)phenylacetate which are used as raw materials to prepare methyl alpha,alpha-dimethyl-4-[2-[4-formylpiperidyl]ethyl]phenylacetate, the methyl alpha,alpha-dimethyl-4-[2-[4-formylpiperidyl]ethyl]phenylacetate reacts with o-phenylenediamine to generate methyl alpha,alpha-dimethyl-4-[2-[4-[1H-2-benzimidazolyl]piperidin-1-yl]ethyl]phenylacetate, and chloroethyl ether is added into the obtained product to generate bilastine. The method for synthesizing bilastine by a three-step reaction has the advantages of simple route, easily available raw materials, mild reaction conditions, easiness in control, and suitablenessfor industrial production.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of bilastine. Background technique [0002] Bilastine is a second-generation histamine H1 receptor antagonist developed by FAES Pharmaceuticals in Spain. It was approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria. This product has good safety, without the sedation and cardiotoxicity of commonly used antihistamine drugs. Its chemical structure is as follows: [0003] [0004] WO2009102155 reports the synthesis method of bilastine, and its synthesis route is as follows: [0005] [0006] In this method, the key intermediate 2-(4-hydroxyethylphenyl)-2-methyl ethyl propionate is synthesized by p-bromophenethyl alcohol and 1-methoxy-1-(trimethylsilyl) (Oxy)-2-methyl-1-propene as raw material, prepared by condensation in the presence of catalyst bis(dibenzylideneacetone)palladium, tri-tert-butylphosphorus and zi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 王军岳淑娟武玉梅
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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