Preparation method of bilastine key intermediate

A bilastine and intermediate technology, applied in the field of pharmaceutical preparation, can solve the problems of difficult operation, difficult industrial production, large pollution and the like

Active Publication Date: 2015-01-14
江苏华阳制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This reaction mainly has the following deficiencies: (1) raw material 1-methoxy group-1 (trimethylsilyloxy group)-2-methyl-1-propene and catalyst bis(dibenzylidene acetone) palladium and three tertiary The price of butyl phosphine etc. is all extremely expensive, is not easy to buy, and is difficult to preserve; (2) this reaction requires extremely strict anh

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1: 2, the synthesis of ethyl 2-dimethylphenylacetate

[0028] Add 2,2-dimethylphenylacetic acid (500g, 3.1mol) and 2.5L dichloromethane solution into a 10L reaction flask, stir at room temperature, add thionyl chloride (750g, 6.3mol), and heat up to system reflux React for 15 hours in the state, then slowly add 400mL of absolute ethanol dropwise and stir for a period of time. After the reaction is detected by TLC, adjust the pH value to 9-10 with NaOH solution, separate the organic layer, wash twice with saturated sodium bicarbonate, and then wash with saturated chlorine After washing twice with sodium chloride, it was concentrated and dried to obtain ethyl 2,2-dimethylphenylacetate (560 g, 96%).

Embodiment 2

[0029] Embodiment 2: the synthesis of ethyl 2-(4-chloroacetyl) phenyl-2-methyl propionate

[0030] In a 5L reaction flask, add ethyl 2,2-dimethylphenylacetate (542g, 2.8mol), 2L dichloromethane solution, stir, add anhydrous aluminum chloride (600g, 4.5mol), and drop Add 500mL dichloromethane mixed solution containing chloroacetyl chloride (318.6g, 2.8mol), and then react for a period of time, stop the reaction after the completion of the TLC detection reaction, separate the organic layer, and use water and saturated sodium bicarbonate solution respectively for the organic layer , saturated sodium chloride solution, concentrated and dried to obtain ethyl 2-(4-chloroacetyl)phenyl-2-methylpropanoate (660 g, 87%).

Embodiment 3

[0031] Embodiment 3: the synthesis of ethyl 2-(4-bromoacetyl)phenyl-2-methylpropionate

[0032] According to the operation of Example 2, the chloroacetyl chloride in Example 2 was replaced with bromoacetyl bromide to obtain ethyl 2-(4-bromoacetyl)phenyl-2-methylpropionate (yellow liquid, 86%).

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Abstract

The invention discloses a preparation method of a bilastine key intermediate 2-(4-ethoxy)-phenyl-2-methyl propionate. The method comprises the following steps: carrying out carbonyl reducing reaction on 2-(4-haloacetyl)-phenyl-2-methyl propionate under the action of a catalyst; carrying out cyclization in an alkaline solution; and then carrying out reduction reaction under the action of a catalyst, so as to obtain 2-(4-ethoxy)-phenyl-2-methyl propionate. According to the method disclosed by the invention, the severe condition in the prior art is avoided, and the method is available in raw materials, simple in operation, low in cost, friendly to environment and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular to a preparation method of 2-(4-hydroxyethyl)phenyl-2-methylpropionate. Background technique [0002] Bilastine, a second-generation histamine H developed for Spanish FAES company 1 Receptor antagonists, approved in the European Union in 2010, were one of 15 new molecular entities approved globally that year. As a second-generation antihistamine, bilastine is mainly used for the treatment of allergic rhinitis, urticaria and chronic asthma. Compared with the first-generation antihistamine, it has a lower central nervous system sedative effect, and is lethargic and weak after taking it. And other side effects are small. [0003] The Chinese chemical name of bilastine is: 2-[4-(2-(4-(1-(2-ethoxyethyl)-benzimidazol-2-yl)piperidin-1-yl)ethyl Base) phenyl] -2-methyl propionic acid, its structural formula is as follows: [0004] [0005] cas: 202189-78-4. [0006] WIPO Internati...

Claims

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Application Information

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IPC IPC(8): C07C69/732C07C67/31
CPCC07C67/31C07C69/732C07D301/26C07D303/40
Inventor 徐峰胡丹丹黄辉蒋玉伟张孝清
Owner 江苏华阳制药有限公司
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