Substituted aromatic ring phenylglycine fatty alcohol ester resolution method

Abstract

The invention discloses a substituted aromatic ring phenylglycine fatty alcohol ester resolution method which includes the steps: dissolving resolution agents in proper solvents by stirring; adding aldehyde or ketone accounting for 0.1-10% of the weight of a compound as shown in a formula I and serving as a catalyst; dropping mixed solution formed by dissolving the compound as shown in the formulaI in the proper solvents; performing reaction for 1-48 hours at the temperature of 20-50 DEG C; cooling the solution after complete reaction; performing suction filtration and drying to obtain S-(+)-substituted aromatic ring phenylglycine fatty alcohol ester salt. The method has the advantages that a technology is simple and convenient, a delta Rf value serves as a separation index for orthogonal experiments to rapidly screen resolution solvents, yield and an ee value serve as indexes for orthogonal experiments to rapidly screen resolution catalysts, the yield is high and reaches 93%, operation is simple and convenient, reaction time is short, reaction temperature is low, the solvents and the resolution agents are recycled and can be sufficiently used, and the method is environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and in particular relates to a resolution method for S-(+)- or R-(-) substituted aromatic ring phenylglycine fatty alcohol esters. Background technique [0002] Substituted phenylglycine and its derivatives are important intermediates of many target compounds or drugs. For example, 2-chlorophenylglycine, as an important intermediate of clopidogrel, has received extensive attention. The patent US5204469 respectively introduced two methods of splitting after esterification of 2-chlorophenylglycine and esterification after splitting. The splitting process is to use tartaric acid as a splitting agent, acetonitrile and butanone as solvents, and the temperature is about 60 ° C. Acetonitrile and methanol purification, yield 45.79%. The patent US20040073057 uses tartaric acid as a resolving agent, methanol as a solvent, a temperature of 25°C, a time of 96 hours, and ...

AI Technical Summary

Problems solved by technology

Patent US6635763 uses tartaric acid and other resolving agents to resolve (2-chlorophenyl) (6,7-dihydro-4-thiophene [3,2c] pyridine) acetonitrile, and the resolution yield is greater than 40%, but less than 48%

[0004] There are following disadvantages in the above splitting process: the racemization reaction is a high temperature or potential high pressure reaction, and the yield of the process is only 40-45%, the loss of raw materials is large, and the process is complicated, because the yield of the process is only 40-45%, which means Need to use a lot of solvents, which is potentially dangerous, use a lot of solvents and resolution reagents, and the screening of solvents and resolution reagents is complicated; it is not conducive to industrialization, and the reaction time is long

Although this method is an asymmetric transformation, the reaction time is long, the solvent usage is large, and there are three wastes discharged, which is not conducive to environmental protection

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