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Method for preparing clopidogrel intermediate alpha-bromo (2-chloro) methyl phenylacetate by recycling aqueous solution method

A technology of methyl phenylacetate and clopidogrel, which is applied in the field of organic synthesis technology and drug synthesis technology, can solve the problems of low yield and environmental protection, and achieve simple treatment, reduce the pressure of environmental pollution, and mild reaction conditions Effect

Pending Publication Date: 2020-08-07
ZHEJIANG LIAOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is also the use of HBr as a bromine source, but a large amount of organic solvents are used, and there are certain requirements for the concentration of HBr, the yield is not high, and it is not environmentally friendly

Method used

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  • Method for preparing clopidogrel intermediate alpha-bromo (2-chloro) methyl phenylacetate by recycling aqueous solution method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 100g (0.58mol) of 2-chlorophenylacetic acid, 119.4g (1.16mol) of sodium bromide, 116g of 50% sulfuric acid solution, 300mL of dichloromethane, and 300mL of water into a 1.0L three-necked reaction flask, and stir at room temperature. Control the internal temperature at 10-15°C, slowly add 394g of 30% hydrogen peroxide dropwise, and the dropping temperature does not exceed 20°C. After the dropwise addition, the temperature was raised to 30° C., and the reaction was continued for 36 hours. After the reaction was completed, the liquids were separated, and the aqueous layer was used for the next reaction. The organic layer was washed with saturated aqueous sodium thiosulfate solution and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure at 35°C to obtain 117.2 g of light yellow crystalline solid with a yield of 81%. Add the solid to 80 mL of methanol solution containing concentrated sulfuric acid (containing 0.046 mol of sulfu...

Embodiment 2

[0023] Embodiment 2 (application scheme):

[0024] 100g (0.58mol) of 2-chlorophenylacetic acid, 71g (0.69mol) of sodium bromide, 116g of 50% sulfuric acid solution, 300mL of dichloromethane, and 300mL of mechanically applied aqueous solution (the content of bromide ion is about 0.18g / mL) were added to In a 1.0L three-necked reaction flask, stir at room temperature. Control the internal temperature at 10-15°C, slowly add 394g of 30% hydrogen peroxide dropwise, and the dropping temperature does not exceed 20°C. After the dropwise addition, the temperature was raised to 30° C., and the reaction was continued for 36 hours. After the reaction was completed, the liquids were separated, and the aqueous layer was used for the next reaction. The organic layer was washed with saturated aqueous sodium thiosulfate solution and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure at 35°C to obtain 120.1 g of light yellow crystalline solid with a y...

Embodiment 3

[0025] Embodiment 3 (application scheme):

[0026] 100g (0.58mol) of 2-chlorophenylacetic acid, 71g (0.69mol) of sodium bromide, 116g of 50% sulfuric acid solution, 300mL of dichloromethane, and 300mL of mechanically applied aqueous solution (the content of bromide ion is 0.20g / mL) were added to 1.0 L three-necked reaction flask, stirring at room temperature. Control the internal temperature at 10-15°C, slowly add 394g of 30% hydrogen peroxide dropwise, and the dropping temperature does not exceed 20°C. After the dropwise addition, the temperature was raised to 30° C., and the reaction was continued for 36 hours. After the reaction was completed, the liquids were separated, and the aqueous layer was used for the next reaction. The organic layer was washed with saturated aqueous sodium thiosulfate solution and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure at 35°C to obtain 115.7 g of light yellow crystalline solid with a yield o...

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Abstract

The invention provides a method for preparing clopidogrel intermediate alpha-bromo (2-chloro) methyl phenylacetate by recycling an aqueous solution method. According to the method, o-chlorophenylacetic acid is adopted as a main raw material, an organic solvent and water in an appropriate proportion are optimized to serve as a bromination mixed solvent, a two-phase reaction mode is adopted in the reaction process, a bromine-containing wastewater solution can be reused without complex treatment, a target product is prepared through bromination and esterification reactions, and the yield reaches78% or above; the method provided by the invention is based on a technical scheme of recycling an aqueous solution containing a bromination reagent. In the process production process, the input amountof a new bromination reagent is reduced to a great extent, the bromine atom utilization rate of the bromination reagent is increased, the problems of wastewater treatment and discharge are reduced, the pressure of environmental pollution is reduced, meanwhile, the reaction conditions are relatively mild, treatment is simple, and industrial production is facilitated.

Description

technical field [0001] The present invention relates to a kind of bromine-containing wastewater generated in the production process of clopidogrel as raw material to brominate 2-chlorophenylacetic acid to synthesize α-bromo(2-chloro)phenylacetic acid methyl ester. Organic synthesis technology and pharmaceutical synthesis technology field. Background technique [0002] Clopidogrel Hydrogen Sulfate Tablets, also known as (S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)methyl acetate Ester bisulfate, the drug can be used to prevent and treat myocardial infarction, ischemic cerebral thrombosis, vasculitis obliterans and complications caused by atherosclerosis and thromboembolism. α-Bromo (2-chloro) methyl phenylacetate is a key intermediate in the synthesis of clopidogrel drugs, and its activity is higher than that of α-chloro (2-chloro) methyl phenylacetate, which greatly improves the condensation yield (as follows shown in the formula). In industrial produc...

Claims

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Application Information

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IPC IPC(8): C07C69/65C07C67/08
CPCC07C67/08C07C51/363C07C69/65C07C57/58
Inventor 何灵敏王锦涛
Owner ZHEJIANG LIAOYUAN PHARM CO LTD
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