Preparation method of bilastine

A bilastine and compound technology, applied in the preparation field of bilastine, can solve the problems of complicated operation, harsh operation conditions, expensive raw materials and the like, and achieve the effects of simple preparation process, low overall cost and high total yield

Active Publication Date: 2014-12-03
BEIJING COLLAB PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In summary, the existing methods for synthesizing bilastine have harsh operating conditions, high toxicity, expensive raw materials, cumbersome operations, and low total reaction yields

Method used

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  • Preparation method of bilastine

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preparation example Construction

[0040] The present invention provides a method for preparing bilastine, including:

[0041] 1) Convert the compound with the structure of formula (II) into the compound with the structure of formula (III),

[0042]

[0043] Wherein, R is a C1-C4 alkyl group;

[0044] 2) Hydrolyze the compound having the structure of formula (III) to obtain bilastine.

[0045] According to the present invention, the compound with the structure of formula (II) is converted into the compound with the structure of formula (III) in the present invention. Specifically, the present invention preferably combines the compound with the structure of formula (II) and the methylating reagent under alkaline conditions. The following reaction yields a compound with the structure of formula (III), the methylating reagent is preferably dimethyl sulfate or methyl iodide; the base of the reaction is preferably sodium alkoxide, potassium tert-butoxide, sodium hydride, LiHMDS or two Lithium isopropylamide, more preferabl...

Embodiment 1

[0065] Preparation of methyl 2-[4-(2-hydroxyethylphenyl)]acetate (compound of structure (VI))

[0066] At 0°C, in a nitrogen atmosphere, to a tetrahydrofuran (260 mL) solution in which 20.0 g of a compound of formula (VII) (wherein R is a methyl) dissolved in 30 minutes, 100 mL of 0.1N borane tetrahydrofuran solution was added dropwise. After finishing, warm to room temperature and stir for 2h, quench with 130mL 2N hydrochloric acid aqueous solution, concentrate under reduced pressure, add 500mL dichloromethane and 250mL 2N hydrochloric acid aqueous solution, separate the liquids, extract the aqueous phase with 250mL*2 dichloromethane, combine the organic phases. Water was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 16.2 g of colorless oily methyl 2-[4-(2-hydroxyethylphenyl)]acetate with a yield of 87.2.

[0067] The methyl 2-[4-(2-hydroxyethylphenyl)]acetate prepared in Example 1 was detected by high performance liquid chromatography, ...

Embodiment 2

[0070] Preparation of methyl 2-[4-(2-p-toluenesulfonyloxyethylphenyl)]acetate (compound of structure (IV))

[0071] At room temperature, 135.0mL of triethylamine, 63.1g of the compound prepared in Example 1, 67.9g of p-toluenesulfonyl chloride, and 600mL of dry dichloromethane solution were added to the reaction flask and stirred for 2 hours. After the reaction, 300mL*3 Washed with purified water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 97.9 g of yellow oily 2-[4-(2-p-toluenesulfonyloxyethylphenyl)]acetate methyl ester with a yield of 80.2 %.

[0072] The methyl 2-[4-(2-p-toluenesulfonyloxyethylphenyl)]acetate prepared in Example 2 was detected by high performance liquid chromatography, and the result showed that its purity was 97.4%;

[0073] The methyl 2-[4-(2-p-toluenesulfonyloxyethylphenyl)]acetate prepared in Example 2 was detected by nuclear magnetism, and the results showed that 1 HNMR(CDCl 3 , 500MHz, TMS,)δ: 2.43(S,3H...

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Abstract

The invention provides a preparation method of bilastine. The preparation method of bilastine comprises the following steps: converting a compound with a structure shown as a formula (II) to a compound with a structure shown as a formula (III), and then hydrolyzing the compound with the structure shown as the formula (III) to obtain bilastine. A preparation method of the compound with the structure shown as the formula (II) is relatively simple; a method for converting the compound with the structure shown as the formula (II) to the compound with the structure shown as the formula (III) is also relatively simple; accordingly, the preparation method of bilastine is relatively low in cost and relatively high in total yield.

Description

Technical field [0001] The invention relates to the field of chemical synthesis, 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. Compared with the first-generation histamine H1 receptor antagonist, it has lower central nervous system sedation and side effects such as drowsiness and fatigue after taking the drug. Small, it is a promising drug for the treatment of allergic rhinitis and urticaria. Its structure is shown in formula (I). [0003] [0004] At present, there are many reports on the preparation method of bilastine, such as: [0005] Spain Chemicals and Pharmaceuticals Manufacturing Co., Ltd. reported in patents CN1105716C and ES2151442 the methods for preparing bilastine and intermediates. The reaction process is shown in synthetic route 1. [0006] [0007] Synthetic Route 1 [0008] This route uses butyl lithium or format reagent, w...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 修利伟杜立民王宁谈敦潮邹德超赵大龙王珂
Owner BEIJING COLLAB PHARMA
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