Synthesis method for Raltitrexed midbody

Abstract

The invention discloses a synthesis method for a Raltitrexed midbody. The method comprises the following steps of a, pumping N-(5-amino-2-thenolyl)-L-glutamate diethyl ester and methyl iodide same in mole into a high flux-microchannel reactor from two feeding injection ports; b, placing the reactor in constant temperature water bath at 35-45 DEG C, enabling the reaction solution to react through the high-flux-microchannel reactor at a velocity of 5-13 mL / min, collecting the reaction solution at the outlet, cooling the reaction solution to a room temperature, adding water and ethyl acetate firstly in the reaction solution, and using ethyl acetate to extract the reaction solution twice, and merging organic layers; after performing alkaline hydrolysis on the water layer with anhydrous sodium carbonate, extracting the alkaline hydrolyzed water phase with ethyl acetate, merging the organic layer which is extracted by the reaction solution and the organic layer after the water layer is alkaline hydrolyzed; and drying the organic layers with anhydrous magnesium sulfate, filtering the dried organic layers, decompressing to remove the solvent, and thus obtaining the Raltitrexed midbody. The synthesis method provided by the invention is scientific and rational, the product yield and purity are high, and the method is suitable for promotion and application.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a synthesis method of a raltitrexed intermediate (N-(5-methylamino-2-thiophenoyl)-L-glutamic acid diethyl ester). Background technique [0002] Raltitrexed is a thymus synthase inhibitor that belongs to the class of quinazoline folate analogues. It is mainly used for the treatment of advanced colon cancer, head and neck tumors, etc. In vivo, after being actively taken up by cells, raltitrexed is quickly metabolized into a series of polyglutamic acids by folate-based polyglutamic acid synthase, and these metabolites have a stronger inhibitory effect on thymus synthase than raltitrexed, thereby Inhibits the synthesis of cellular DNA, and can be retained in cells to exert an inhibitory effect for a long time. Its efficacy is similar to that of fluorouracil, but the incidence of side effects of raltitrexed is low, and patients are easy to accept. The synthetic method of raltitrex...

AI Technical Summary

Problems solved by technology

[0004] The object of the present invention is to improve the synthetic process method of raltitrexed intermediate (N-(5-methylamino-2-thiophenoyl)-L-glutamic acid diethyl ester), the improved method can Overcome the defects of large amount of organic solvent used in the existing synthesis method, long reaction time, many reaction by-products, low yield of a single methyl product and difficulty in subsequent separation and purification, thereby greatly increasing the yield of a single methylated product