Preparation method for epinastine intermediate

A technology of epilastine and an intermediate, which is applied in the field of preparation of epilastine intermediate N-[2-phenyl]-2-chloroacetamide, can solve the problem that sodium borohydride is expensive, restricts industrial production, and It is not conducive to problems such as industrial production, and achieves the effects of stable and controllable quality, avoiding the introduction of toxic substances and high-boiling solvents, and simplifying the post-processing process.

Inactive Publication Date: 2015-11-18
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthesis method is cumbersome, the product yield is low, and sodium borohydride is expensive, which greatly limits its industrial production
[0007]

Method used

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  • Preparation method for epinastine intermediate
  • Preparation method for epinastine intermediate
  • Preparation method for epinastine intermediate

Examples

Experimental program
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Embodiment 1

[0025] Dissolve 20 g (0.109 mol) of the raw material 2-aminobenzophenone in 200 mL of dichloromethane, add 9.63 g (0.122 mol) of pyridine, cool down to 0°C, and slowly add 13.17 g (0.117 mol) of chloroacetyl chloride dropwise, After maintaining the reaction at 0°C for 30 min, continue to react at room temperature for 1.5 h, and detect the end point of the reaction by TLC [V (ethyl acetate): V (petroleum ether) = 10:1]. Wash the organic phase with water and dry, filter, retain the filtrate, add 23.21g (0.355mol) of Zn powder, keep the reaction temperature at 0°C, feed HCl gas for 1h while stirring, filter the zinc mud, concentrate the filtrate under reduced pressure, add water to precipitate the solid, pump After filtration and drying, 25.9 g of white solid was obtained, which was Intermediate I, with a yield of 98.6% and a purity of 99.1% by HPLC.

Embodiment 2

[0027] Dissolve 20 g (0.109 mol) of the raw material 2-aminobenzophenone in 200 mL of dichloromethane, add 9.22 g (0.117 mol) of pyridine, cool down to 0°C, and slowly add 12.60 g (0.112 mol) of chloroacetyl chloride dropwise, After maintaining the reaction at 0°C for 30 minutes, continue to react at room temperature for 2 hours, and detect the end point of the reaction by TLC [V (ethyl acetate): V (petroleum ether) = 10:1]. Wash the organic phase with water and dry it, filter it, and evaporate the solvent to dryness to obtain intermediate II. Dissolve it in 200 mL of ether, add 9.95 g (0.152 mol) of Zn powder, keep the reaction temperature at 10°C, and inject HCl gas for 2 h while stirring , filtered the zinc mud, concentrated the filtrate under reduced pressure, added water to precipitate the solid, filtered it with suction, and dried it to obtain 22.5 g of a white solid, namely Intermediate I, with a yield of 85.3% and a purity of 90.5% by HPLC.

Embodiment 3

[0029] Dissolve 20 g (0.109 mol) of the raw material 2-aminobenzophenone in 200 mL of dichloromethane, add 9.63 g (0.122 mol) of pyridine, cool down to 0°C, and slowly add 12.60 g (0.112 mol) of chloroacetyl chloride dropwise, After maintaining the reaction at 0°C for 30 minutes, continue to react at room temperature for 2 hours, and detect the end point of the reaction by TLC [V (ethyl acetate): V (petroleum ether) = 10:1]. Wash the organic phase with water and dry it, filter it, and evaporate the solvent to dryness to obtain intermediate II, which is dissolved in 200 mL of tetrahydrofuran, and 29.84 g (0.456 mol) of Zn powder is added. The reaction temperature is maintained at -10 ° C, and HCl gas is introduced under stirring After 1 hour, the zinc mud was filtered, the filtrate was concentrated under reduced pressure, the solid was precipitated by adding water, suction filtered, and dried to obtain 25.08 g of a white solid, namely Intermediate I, with a yield of 95.2% and a ...

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Abstract

The present invention discloses a new method for preparing an epinastine intermediate N-[2-(phenyl methyl) phenyl]-2-chloroacetamide. The method comprises the following steps of: by taking 2-aminobenzophenone as a starting raw material, firstly performing acylation and then performing reduction;, and introducing HCl gas to carry out selective reduction reaction for reducing carbonyl into methylene in the presence of Zn powder. The preparation method has the advantages of avoiding introduction of a solvent with a high boiling point and a toxic agent; and the method is simple in operation, mild in reaction condition, short in reaction time, low in cost, small in pollution, relatively high in product yield and product purity, and is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an epinastine intermediate N-[2-(phenylmethyl)phenyl]-2-chloroacetamide. Background technique [0002] The chemical name of Epinastine is 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine(Ⅲ). This product is an antihistamine, histamine H 1 receptor antagonists. Clinically, it is mainly used to treat diseases such as allergic rhinitis, dermatitis, eczema, urticaria and bronchial asthma. It has strong action, remarkable curative effect and good safety. The drug was developed by Boehringer Ingelheim and Sankyo Corporation of Japan, and was launched in Japan under the trade name of Alesion in 1994, becoming the second-generation antihistamine. N-[2-(phenylmethyl)phenyl]-2-chloroacetamide (I) is an important intermediate in the synthesis of epinastine. [0003] [0004] The methods for preparing N-[2-(phenylmethyl)phenyl]-2-chloroac...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/07
Inventor 郑庚修刘悦刘庆东付凯马志佳杨柳
Owner UNIV OF JINAN
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