New synthesis technology of anti-cancer drug Raltitrexed

Abstract

The invention relates to a new synthesis technology of anti-cancer drug Raltitrexed. The technology comprises the following steps: 1) using L-glutamic acid as raw material to perform esterification with alcohol under the action of halogenating agent and obtain L-glutamic acid diester hydrochloride; 2) using 2-amino-5-methyl-benzoic acid as raw material to prepare 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline through cyclization, amination and bromination; 3) using 2-thienyl-propanedioic acid as raw material to prepare N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thenoyl]-L-glutamic acid diethyl ester through nitrification, esterification, reduction, amino protection, N-methylation and device-esterification; 4) using L-glutamic acid diester hydrochloride and N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thenoyl]-L-glutamic acid diethyl ester to prepare N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester through dehydrant condensation and deamination protection; and 5) using N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline to perform condensation under the catalysis of alkali, recycling preparative chromatography, purifying, and performing de-esterification to obtain Raltitrexed.

Description

technical field [0001] The invention relates to the field of chemically synthesized drugs, in particular to a new synthesis process of an anticancer drug raltitrexed. Background technique [0002] Colorectal cancer (CRC) is the second most common tumor in the world after lung cancer and is one of the leading causes of patient death. In the past 25 years, colorectal cancer has also become one of the two fastest growing malignant tumors in my country, with an increase of 100%. With the improvement of people's living standards and changes in eating habits, the incidence of colorectal cancer is increasing at a rate of 4.2% per year. It rose to 23.4 / 100,000 people in the early 1990s, and it has far exceeded this ratio. In Shanghai, which is more developed, the incidence rate of colorectal cancer is about 40 / 100,000, which is close to the level of western developed countries, and has risen from No. 6 to No. 2 in the ranking of tumor incidence. The number of patients suffering fr...

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Problems solved by technology

[0013] However, the former method needs to use reagents such as butyllithium, and the reaction conditions are harsh, the reaction time is long, and the production cost is high; the latter method has mild reaction conditions and is easy to operate, but in the N-methylation reaction process, it is difficult to control A single methylated product is obtained, and the separation of the monomethylated product is difficult, resulting in a very low yield

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