Novel process for preparing doripenem

Abstract

The invention discloses a process for preparing (2S, 4S)-1-p-nitro benzyloxycarbonyl-2-(N-tert-butoxycarbonyl amine-N-sulfonyl amino) methyl-4-mercapto-pyrrolidine which is an important intermediate used during preparation of doripenem and further discloses a novel process for preparing the doripenem by carrying out reaction on the intermediate which is used as a starting raw material and (1R, 5S, 6S)-6-[(1R)-1-hydroxy ethyl]-2-diphenylphosphine oxide acyloxy-1-methyl-1-carbon substituted-2-penem-3-carboxylic acid p-nitro benzyl ester with diisopropylethylamine used as the alkaline and removing protecting groups by adopting Pd/C. in the method, the readily available raw materials are adopted, other reagents are adopted to replace the traditional volatile reagents and the recrystallization method is adopted to purify the important intermediate, the high yield is ensured and the process is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for preparing Doripenem (Doripenem) and its important intermediate (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-tert-butoxycarbonyl-N- Novel preparation process of doripenem from sulfamoyl)methyl-4-mercaptopyrrolidine. Background technique [0002] Doripenem (Compound Ⅰ), the chemical name is (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-aminosulfonamide Methylpyrrolidin-3-yl] mercapto-1-methyl-1-carbo-2-penem-3-carboxylic acid is a 1β-methyl carbapenem antibacterial product developed by Shionogi Company in Japan The drug, which was first marketed in Japan in 2005, can be used to treat serious infections of the brain, kidneys and lungs. The inhibitory activity of doripenem to gram-positive bacteria is higher than that of meropenem, the inhibitory activity to gram-negative bacteria is higher than that of imipenem, and it is also effective against imipenem-resistant bacteria. Re...

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Problems solved by technology

[0017] In the synthesis method reported in WO 2006 / 117763, compound IV obtained after the reaction of compound II and compound III is directly subjected to deprotection reaction without purification treatment, but because the synthesized compound IV contains a small amount of impurities, the final product doripenem is affected content, but the patent reported the method of recrystallization to obtain doripenem

[0018] WO 2007 / 029084 reported that compound Ⅴ Compound III was synthesized by using different reagents such as acetyl chloride, thionyl chloride, phosphorus oxychloride, etc., but the patent did not report the purification method of compound III, and the obtained compound III was an oil, which was directly used to react with compound II, The impurities in the oil affect the content of the final product doripenem

[0019] WO 2010 / 097686 reported the purification method of compound III, and reported several different methods for the synthesis and purification of doripenem, but the patent did not report compound V synthesis method

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