Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use

Abstract

The present invention relates to new compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate and its preparation process and application. The compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate in the chemical expression as shown is prepared through the reaction of compound diethyl 4-bromo benzoyl-L-glutamate and 3-butene-1-alcohol inside Nú¼N-dimethyl formamide solvent under the action of palladium acetate catalyst, weak alkali reagent, lithium halide and phase transfer catalyst in the protection of inert gas at 50-70 deg.c. The compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate is used in synthesizing diethyl 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate as the intermediate of Pemetrexed disodium. The present invention results in shortened Pemetrexed disodium synthesizing path and lowered production cost.

Description

(1) Technical field

[0001] The invention relates to a new compound 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl ester, its preparation method and application. (2) Background technology

[0002] Pemetrexed (also known as LY231514, trade name Alimta) is a new type of anti-folate anti-metabolite drug, the target of action includes a variety of enzymes in the synthesis of pyrimidine and purine, so it is also known as multi-targeted antifolate (multi2targeted antifolate) , MTA). It has shown a wide range of anti-tumor activities in vitro and clinical trials, and is a very potential anti-tumor drug.

[0003] Pemetrexed was successfully developed by Dr. Shi Quan, a Chinese scientist from Eli Lilly and the Department of Chemistry, Princeton University, after ten years of research. Since the 1990s, many patents and documents have introduced the chemical synthesis method of pemetrexed and its disodium salt, such as Taylor, E.C.; Kuhnt.D.; Shih, C.; etc.J. Med. Chem. 1992, 35, 4450...

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