A kind of synthesis technique of raltitrexed key intermediate

Abstract

The invention relates to the technical field of medicine preparation, in particular to a synthesis process of a Raltitrexed key intermediate. According to the synthesis process of the Raltitrexed keyintermediate, forming an active intermediate (isocyanate) through glutamate diethyl ester, the active intermediate and N-methyl-(2-thienyl) tert-butyl carbamate are directly reacted, and a target product N-[5-[N-(t-butyloxycarboryl)-N-methyl amino]-2-thenoyl]-L-glutamate diethyl ester is prepared by two steps. The synthesis process avoids difficulties of potential risks of part of racemization ofa chiral center caused by amidation reaction, low yield, complicated operation and purification and the like. The synthesis process of the Raltitrexed key intermediate is simple to operate, short in line, environmentally friendly and high in yield.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis process of a key intermediate of raltitrexed. Background technique [0002] Raltitrexed, a quinazoline folate analogue, is a novel water-soluble inhibitor of thymidylate synthase, which can cause DNA fragmentation and cell death by inhibiting thymidylate synthase. Compared with 5-fluorouracil, raltitrexed has stronger selectivity, and can replace fluorouracil in the treatment of advanced colorectal cancer, and has become the first-line drug for the treatment of advanced colorectal cancer. [0003] Raltitrexed was developed and created by the British Zeneca Pharmaceutical Company. It was first launched in the UK in 1996. The trade name is Tomudex, and the chemical name is: N-[5-[N-methyl-N-(2-methyl-4-oxo Substitute-3,4-dihydroquinazoline-6-methyl)amino]thiophene-2-formyl]-L-glutamic acid, the structural formula is: [0004] [0005] About the synthet...

AI Technical Summary

Problems solved by technology

In this reaction route, in the process of introducing carboxyl functional groups, carbon insertion reaction is adopted. This reaction requires a large amount of dry ice or carbon dioxide gas. The reaction conditions are harsh and the reaction time is long, which is not conducive to controlling the reaction process and is not conducive to industrialization.

[0016] In view of the deficiencies in the synthesis process of key intermediates of raltitrexed reported above, such as: low reaction yield, difficult purification, harsh reaction conditions, complex process route, long preparation period, etc.

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