Pralatrexate preparation method

Abstract

The present invention discloses a practical synthesis process of a new anticancer drug pralatrexate. According to the present invention, 10-propargyl-10-methoxycarbonyl-4-deoxy-4-amino-10-deaza pteroic acid methyl ester is adopted as a starting raw material, a saponification reaction is performed to obtain 4-(2-carboxy-1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid, the 4-(2-carboxy-1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid is subjected to decarboxylation to obtain 4-(1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid, the 4-(1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid reacts with L-diethyl glutamate to obtain 10-propargyl-10-deaza aminopterin diethyl ester, and finally a saponification reaction is performed to obtain the target product pralatrexate, wherein the green, high yield and convenient synthesis of the pralatrexate is completed, the final product can achieve the level from several grams to tens of grams, the purity is more than or equal to 90%, and the good industrial application prospects are provided.

Description

technical field [0001] The invention relates to a preparation method of an anticancer drug pralatrexate, which belongs to the technical field of medicine. Background technique [0002] Pralatrexate (pralatrexate) is a new type of dihydrofolate reductase inhibitor, which was approved by the FDA in 2009 and became the first drug for the treatment of peripheral T-cell lymphoma. The trade name of pralatrexate is Folotyn, which is an orphan drug. Its price is very expensive, more than three times the price of common anticancer drugs, and the total cost within the course of treatment (3 to 5 months) reaches 126,000 US dollars. Therefore, there is an urgent need to develop new practical synthetic processes to effectively reduce the research and development costs of this drug, thereby reducing the economic burden on patients. [0003] In terms of foreign patents or literature, Joseph I.DeGraw et al took the lead in reporting the synthetic route of pralatrexate in 1993. They used me...

AI Technical Summary

Problems solved by technology

The reported yield of this pathway is very low, especially in the high-temperature decarboxylation step of dicarboxylic acid, the yield is only 29% (purity is only 82%), and the step intermediate product L-diethyl glutamate is reacted to obtain 10-propargyl The purification of base-10-deazaaminopterin diethyl ester also needs to be separated by column, and the resulting final product, pralatrexate, is at the milligram level, which is only suitable for the synthesis of trace products

[0004] Patents PCT Int.Appl.2012061469, PCT Int.Appl.2012021392, U.S.Pat.Appl.Publ.20110190305, U.S.Pat.Appl.Publ.20110111436, U.S.Pat.Appl.Publ.20100248249, etc. are used in conjunction with Joseph I.DeGraw, etc. With the same starting material, the method has similar disadvantages, such as the use of flammable and explosive substances such as KH or NaH, dry ice ultra-low temperature conditions, the removal of solvents requires high vacuum equipment, and the purification of intermediate product IV requires column separation. Finally, The products are also at the milligram level, and Carter’s condensing agent (BOP) is used in the selection of peptide coupling reagents. This reagent will produce carcinogenic hexamethylphosphoric triamide during the reaction process, which is harmful to the environment and operators. Potential threat, not conducive to large-scale industrial production

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