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Preparation method of bilastine intermediate

A preparation process and compound technology, applied in the field of preparation of bilastine intermediate 2-phenyl)-2-methylpropionic acid and its derivatives, can solve the problems of easy volatility, difficult industrial production, low yield, etc. problems, to achieve the effect of mild reaction conditions, no side reactions, and simple operation

Pending Publication Date: 2020-12-22
BEIJING VENTUREPHARM BIOTECH
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0005] Using ethyl 2-(4-bromophenyl)-2-methylpropionate as the starting material, hydrolyze under alkaline conditions of sodium hydroxide to obtain 2-(4-bromophenyl)-2-methylpropionate acid, then amidated with 2-amino-2-methyl-1-propanol, and cyclized to give 2-[1-(4-bromophenyl)-1-methylethyl]-4,5-dihydro -4,4-Dimethyloxazole, the reaction process of this route not only needs to strictly control the low-temperature reaction, but also uses a highly dangerous and flammable strong base n-butyllithium. There are many impurities in the reaction process, and the post-treatment is cumbersome. Low, not easy for industrial production; and because the boiling point of ethylene oxide is extremely low, only 11°C, it is extremely volatile, highly toxic, carcinogenic, irritating and sensitizing, will cause serious environmental pollution, and more obvious presentation Disadvantages of this route; phenylethyl alcohol obtained by alkylation and the toxic and irritating substance p-toluenesulfonyl chloride have made this route completely abandoned

Method used

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  • Preparation method of bilastine intermediate
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  • Preparation method of bilastine intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: Synthesis of 4-(1-(dimethylamino)-2-methyl-1-oxopropan-2-yl)styrene acetate

[0022] Dissolve 81.04g (0.3 mol) of 2-(4-bromophenyl)-N,N,2-trimethylpropanamide in 600ml of anhydrous tetrahydrofuran, cool down to -10°C, stir to dissolve, and replace with nitrogen for 3 times 1.01g (0.045 mol) of palladium acetate was added to the system in batches. After the addition, 68.87g (0.8 mol) of vinyl acetate was dissolved in 200ml of anhydrous tetrahydrofuran, and added dropwise to the reaction system. After the addition was completed, it rose to Continue to react at room temperature for 5 hours, TLC monitors that the raw material point basically disappears. After the reaction is completed, it is suction filtered, and the filtrate is washed with deionized water to separate the liquid. After drying, it is concentrated to obtain a light yellow oil with a yield of 92.51%, which is directly put into the next reaction.

Embodiment 2

[0023] Example 2: Synthesis of N, N, 2-trimethyl-2-(4-(2-oxoethyl)phenyl)propionamide

[0024] With 5.0 g of the compound in Example 1, use 1 mol / L sodium hydroxide solution as a solvent, stir at room temperature for 24 h, TLC monitors that the raw material point disappears, extract 3 times with 50 ml of dichloromethane, concentrate the organic phase, add 15 ml of petroleum ether and stir in an ice-water bath, Suction filtration gave 3.85 g of a waxy solid with a yield of 90.8%, and the product was stored at low temperature.

Embodiment 3

[0025] Example 3: Synthesis of 2-(4-(2-hydroxyethyl)phenyl)-N,N,2-trimethylpropionamide

[0026] Dissolve 12.0 g (0.05 mol) of the compound prepared according to Example 2 in ethanol, add 4.53 g (0.12 mol) of sodium borohydride in batches, stir at room temperature for 4 hours, slowly pour the reaction solution into 10% citric acid aqueous solution, add After completion, continue to stir for 30 minutes, spin off the ethanol in the system, then extract the reaction solution with dichloromethane, adjust the organic phase to neutrality with saturated aqueous sodium bicarbonate solution, then separate and dry, add ethyl acetate 4.8 g after the organic phase is concentrated ml and 15ml of petroleum ether were stirred and crystallized, and 10.6g of a light yellow solid was obtained by suction filtration, with a yield of 87.6%.

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a preparation method of a bilastine intermediate 2-(4-(2-hydroxyethyl) phenyl)-2-methyl propionic acid and derivatives thereof. The 2-(4-(2-hydroxyethyl) phenyl)-2-methyl propionic acid and the derivative thereof are obtained by taking a 4-halogenated phenyl-2-methyl propionic acid derivative as a raw material through the steps of alkylation, hydrolysis, reduction and the like, and the compound can be used for synthesizing bilastine.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of bilastine intermediate 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropionic acid and derivatives thereof. Background technique [0002] Bilastine (see formula below), chemical name 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzimidazol-2-yl]-piper Pyridin-1-yl}ethyl)-phenyl]-2-methyl-propionic acid, CAS No. 202189-78-4, the second generation of histamine H developed by Spanish FAES pharmaceutical company 1 Receptor antagonist, compared with the original drug, its drug has good safety, no sedative effect and cardiotoxicity of commonly used antihistamine drugs, etc. It was first launched in Ireland in 2011 for the treatment of allergic rhinitis and chronic idiopathic urticaria. [0003] [0004] 2-(2-(4-(2-(4-(1H-benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl)propan-2-yl)-4,4-di Methyl 4,5-dihydrooxazole is a key intermediate in the synthesis of bilastine. Its prepa...

Claims

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Application Information

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IPC IPC(8): C07C51/06C07C59/48C07C231/12C07C235/34C07C235/78
CPCC07C231/12C07C51/06C07C235/34C07C235/78C07C59/48
Inventor 李恩民姬东方赵国磊
Owner BEIJING VENTUREPHARM BIOTECH
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