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Preparation process of cadotril

A technology of thiomethyl and oxo substitution, applied in organic chemistry and other fields, can solve the problems of difficult removal of DCU and impractical industrial production

Active Publication Date: 2009-09-09
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this route, the poisonous reagent formaldehyde is used; in addition, the condensation reagent DCC is used. Although the by-product DCU can be removed by column chromatography in the laboratory, DCU is difficult to remove in industrial production, so it is not practical for industrial production.

Method used

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  • Preparation process of cadotril
  • Preparation process of cadotril
  • Preparation process of cadotril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of 2-chloromethylphenylpropionyl chloride

[0036] I is halogenated with sulfoxide halide

[0037] Add 1.4ml (19.2mmol) thionyl chloride and 3 drops of DMF to a 25ml three-necked reaction flask, stir for 5 minutes, cool in an ice bath, add 1.0g (5.6mmol) 2-benzyl-3-hydroxypropionic acid, and keep The temperature was reacted for 30 minutes, and the temperature was raised to 60° C. for 1 hour. Thin layer chromatography judged that the reaction was complete, and the solution was evaporated to dryness under reduced pressure to obtain 1.0 g of a colorless oil.

[0038] II is halogenated with phosphorus halide

[0039] Add 2.0g (11.2mmol) of 2-benzyl-3-hydroxypropionic acid into a 50ml three-necked reaction flask equipped with a drying tube, then add 20ml of dichloroethane and stir to dissolve, cool to -10°C in an ice bath, and then add 3.5 gPCl 5 , maintained the temperature for 30 minutes, then raised the temperature to 60°C for 20 minutes, and the reaction w...

Embodiment 2

[0043] Preparation of 2-bromomethylphenylpropionyl bromide

[0044] Add 2.0g (11.2mmol) 2-benzyl-3-hydroxypropionic acid in 125ml three-necked reaction flask, add 10ml dichloromethane and 1% pyridine, stir to dissolve. Cool in an ice bath to -5°C, add 5.84 g (28 mmol) of thionyl bromide dropwise, maintain the temperature for 50 minutes, and evaporate the solution to dryness under reduced pressure to obtain 1.8 g of a colorless oil. MS(EI): 306(M + )

[0045] II Add 2.0g (4.5mmol) of 2-benzyl-3-hydroxypropionic acid into a 25ml three-necked reaction flask, add 10ml of dichloroethane, and stir to dissolve. After cooling in an ice bath to -10°C, add 4.5 g of boron tribromide, maintain the temperature for 30 minutes, and raise the temperature to 60°C for 20 minutes. Thin layer chromatography judged that the reaction was complete, and the solution was evaporated to dryness under reduced pressure to obtain a colorless oil 2.2g.

[0046] III Add 2.0g (4.5mmol) 2-benzyl-3-hydroxyp...

Embodiment 3

[0048] Preparation of N-(2-chloromethyl-1-oxo-3-phenylpropyl)glycine benzyl ester

[0049] Add 33.6g (166.8mmol) glycine benzyl ester hydrochloride and 15ml dichloromethane in a 100ml three-necked flask, add 40.0ml pyridine after cooling to 0°C in an ice bath, stir for 10 minutes, add dropwise 10ml to dissolve 22.8g (105.6mmol ) 2-chloromethylphenylpropionyl chloride. After 2 hours of reaction, the reaction was complete, washed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, stirred and crystallized with 200ml of petroleum ether to obtain 33.2g of solid (92.3% yield).

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Abstract

The invention discloses a method for preparing cadotril. The method uses 2-benzyl-3-hydroxypropionic acid as a raw material to prepare cadotril through halogenation, amidation and substitution. The raw materials and reagents used in the route are all The method is cheap and easy to obtain, has less three wastes, is simple to operate, has few reaction steps and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of acetorphan (4). Background technique [0002] Cardotril (acetorphan, acetorphan, 4), the chemical name is N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl) glycine benzyl ester, developed by Bioprojet, in 1993 It was first launched in France under the trade name Tiorfan in 1999 and subsequently in other markets for the treatment of acute diarrhea in adults. In 2001, it was approved for marketing for children with diarrhea indications. [0003] [0004] The synthetic route of Cadotril reported in document US5786494 starts from benzyl chloride, and is obtained through alkylation, monohydrolysis, Mannich reaction, and Michael addition: [0005] [0006] In this route, the poisonous reagent formaldehyde is used; in addition, the condensation reagent DCC is used. Although the by-product DCU can be removed by column chromatography in the laboratory, DCU is d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C327/06
Inventor 侯建赵惠清王国平何康永陈旭东
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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