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Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine

A technology of methyl propionate and haloethyl, applied in the field of pharmaceutical synthesis, can solve the problems of difficult industrial production, difficult operation and high cost, and achieve the effects of stable raw material properties, easy availability of raw materials and low cost

Inactive Publication Date: 2014-01-29
王蕾
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] To sum up, this route has high cost, difficult operation, heavy pollution, and it is difficult to realize industrial production

Method used

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  • Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Synthesis of 2-(4-haloethyl)phenyl-2-methyl propionate

[0061] a. In dichloromethane, 2,2-dimethylphenylacetate and chloroacetyl chloride undergo acylation reaction under the action of aluminum trichloride. The acylation reaction conditions are: temperature is 5°C; time is 3 hours , generating 2-(4-haloacetyl)phenyl-2-methylpropionate,

[0062] b, 2-(4-haloacetyl) phenyl-2-methyl propionate undergoes a Kisner-Wolf-Huang Minglong reduction reaction, reducing the carbonyl to generate 2-(4-haloethyl) phenyl- 2-methyl propionate; the reduction reaction conditions are as follows: the solvent is polyethylene glycol, the reaction temperature is 180° C.; the reaction time is 3 hours.

Embodiment 2

[0063] Example 2 Synthesis of 2-(4-haloethyl)phenyl-2-methyl propionate

[0064] a. In tetrahydrofuran, 2,2-dimethylphenylacetate and bromoacetyl bromide undergo acylation reaction under the action of aluminum trichloride. The acylation reaction conditions are: temperature is 0°C; time is 24 hours, and 2-(4-Haloacetyl)phenyl-2-methylpropionate,

[0065] b, 2-(4-haloacetyl) phenyl-2-methyl propionate undergoes a Kisner-Wolf-Huang Minglong reduction reaction, reducing the carbonyl to generate 2-(4-haloethyl) phenyl- 2-methyl propionate; the reduction reaction conditions are: the solvent is polyethylene glycol, the reaction temperature is 100°C; the reaction time is 8 hours.

Embodiment 3

[0066] Example 3 Synthesis of 2-(4-haloethyl)phenyl-2-methylpropionate

[0067] a. In nitromethane, 2,2-dimethylphenylacetate and chloroacetyl bromide undergo acylation reaction under the action of aluminum trichloride. The acylation reaction conditions are: temperature is 100°C; time is 1 hour , generating 2-(4-haloacetyl)phenyl-2-methylpropionate,

[0068] b, 2-(4-haloacetyl) phenyl-2-methyl propionate undergoes a Kisner-Wolf-Huang Minglong reduction reaction, reducing the carbonyl to generate 2-(4-haloethyl) phenyl- 2-methyl propionate; the reduction reaction conditions are as follows: the solvent is polyethylene glycol, the reaction temperature is 200° C.; the reaction time is 1 hour.

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Abstract

The invention discloses a preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and a synthesis method of bilastine, which comprises the following steps of: carrying out acylation reaction on 2, 2-dimethyl phenylacetate and halogen acetyl halides under the action of catalyst, to generate 2-(4-halogen acetyl) phenyl-2-methyl propionic ester; carrying out kishner-wolff-huang reduction reaction on the 2-(4-halogen acetyl) phenyl-2-methyl propionic ester, to reduce the carbonyl so as to generate the 2-(4-haloethyl) phenyl-2-methyl propionic ester; having condensation reaction with 1-ethoxy ethyl-2-pyridine-4-group benzimidazole by taking the 2-(4-haloethyl) phenyl-2-methyl propionic ester as a midbody to obtain esterified bilastine; and hydrolyzing, to generate the bilastine. The novel synthesis method of the bilastine provided by the invention can easily obtain raw materials, and is simple to operate, lower in cost, environment-friendly, and completely suitable for the industrial production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of 2-(4-haloethyl)phenyl-2-methylpropionate and a method for synthesizing bilastine. Background technique [0002] Bilastine, the second-generation histamine H developed for Spanish FAES pharmaceutical company 1 Receptor antagonist, approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria. This product is safe, without the sedative effect and cardiotoxicity of commonly used antihistamines. [0003] Chemical Structure: [0004] [0005] CAS: 202189-78-4. [0006] WO2009102155 reports the synthesis method of bilastine, and its synthesis route is as follows: [0007] [0008] In this method, the synthesis of the key intermediate 2-(4-hydroxyethylphenyl)-2-methylpropionate ethyl ester (compound 3) is based on p-bromophenethyl alcohol (compound 1) and 1-methoxy- 1-(Trimethylsilyloxy)-2-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/65C07C67/14C07D401/04
Inventor 王蕾李科王倩刘为峰
Owner 王蕾
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