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Preparation method for 2-halogenated phenyl-2-(2-thiophene diethylamino) acetic ester and salt thereof

A technology of halogenated phenylglycine ester and thiopheneethylamino, applied in the field of pharmacy, can solve the problems of difficult recovery and purification, expensive acetonitrile, low yield and the like, and achieves the effects of long reaction time, mild and easily controllable reaction conditions, and high price.

Inactive Publication Date: 2012-07-11
HUBEI CHENGTIAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] For the substitution reaction prepared by the double-substituted key secondary amine intermediate (Y=2-Cl), reports are mostly carried out in acetonitrile, but a long time reflux reaction is required (US2007191609A1 or CN101333223A), and acetonitrile is relatively expensive, highly toxic, and difficult to recover and purify Disaster
This substitution reaction is also reported in water (CN101519401A) or without solvent (WO2007144729A1), but the yield is low

Method used

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  • Preparation method for 2-halogenated phenyl-2-(2-thiophene diethylamino) acetic ester and salt thereof
  • Preparation method for 2-halogenated phenyl-2-(2-thiophene diethylamino) acetic ester and salt thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0022] At room temperature, add 105.0 g (1.25 mol) of anhydrous sodium bicarbonate to 100.0 g (0.50 mol, 98.6 ee%) of S-2-chlorophenylglycine methyl ester, 2-(2-thiophene) ethanol p-toluenesulfonic acid In the mixed solution of 155.3 g (0.55 mol) of ester and 500 mL of isopropanol, stir while adding. After the addition, the temperature was gradually raised to reflux, and the reaction was incubated for 10.0 h, and the reaction was detected by TLC. The solvent was removed by concentration under reduced pressure, and the residue was dispersed in 600 mL of dichloromethane and transferred to 600 mL of ice water. The organic layer was separated, the aqueous layer was extracted with dichloromethane (150 mL×2), the combined organic phases were washed with water (300 mL×2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under normal pressure to recover dichloromethane, and the residue was dried under reduced pressure to obtain a light red oil....

Embodiment 2

[0025] Isobutanol is used instead of isopropanol as the reaction solvent, the reaction temperature is controlled at an internal temperature of 80-85° C., and other operations are the same as in Example 1. 126.2 g of white solid was obtained, the yield was 81.7%, 98.7ee%, and the HPLC content was 98.7%.

Embodiment 3

[0027] Using tert-butanol instead of isopropanol as the reaction solvent, the reaction temperature is controlled at an internal temperature of 80-85° C., and other operations are the same as in Example 1. 127.4 g of white solid was obtained, the yield was 82.4%, 99.1ee%, and the HPLC content was 99.0%.

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Abstract

The invention discloses a preparation method for 2-halogenated phenyl-2-(2-thiophene diethylamino) acetic ester and salt thereof. According to the method, in an alcohol solvent, inorganic base or organic base is adopted as a deacid reagent, halogenated benzene glycine ester and active ester of 2-halogenated ethyl thiophene or 2-(2-thiophene) alcohol are subjected to substitution reaction, or 2-thiophene ethylamine and active ester of Alpha-halogenated aromatic acetate or Alpha-hydroxy aromatic acetate are subjected to substitution reaction so as to prepare 2-halogenated phenyl-2-(2-thiophene diethylamino) acetic ester. According to the method, the conditions are moderate and easy to control, a solvent is cheap, low in toxicity, environment-friendly, and easy to recover and purify. Due to the adoption of the method, 2-(2-chlorophynyl) -2- (2-thiophene diethylamino) acetic ester and salt thereof can be prepared successfully in a large scale so as to lay a foundation for industrial production of clopidogrel and medical salt thereof.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a preparation method of 2-halophenyl-2-(2-thienylethylamino) acetate and salts thereof, wherein 2-(2-chlorophenyl)-2-(2- Thiophene ethyl amino) methyl acetate is a key intermediate for the synthesis of clopidogrel bisulfate. Background technique [0002] Clopidogrel Hydrogen Sulfate (Clopidogrel Hydrogen Sulfate, 1), the chemical name is (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H ) methyl acetate was developed in 1986 by the French company Sanofi (Sanofi) and first listed in the United States in 1998. my country has approved the import of its tablets since 2001. The trade name is The safety and effectiveness of clopidogrel are significantly better than antithrombotic drugs Aspirin or Ticlopidine, and its side effects are low. It is a new generation of antithrombotic drugs widely used in the world. It is clinically used to prevent myocardial Infarction, stroke, or for the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20
Inventor 罗光明鄢来平郑德彬
Owner HUBEI CHENGTIAN PHARMA