Process for synthesizing doripenem lateral chain

Abstract

The invention discloses a process for synthesizing a doripenem lateral chain. According to the process disclosed by the invention, L-hydroxyproline is taken as a starting raw material, and the doripenem lateral chain is obtained through the following steps of: amino protection, carboxyl protection, hydroxyl activation, reduction reaction, acetyl vulcanization reaction and condensation reaction. The process provided by the invention has the advantages of simple and easily-obtained raw materials, no high-temperature and high-pressure reactions and no super-low-temperature reactions; the 'three wastes' generated in the production process mainly comprise waste liquid and the wastewater in the waste liquid is neutralized by appropriate acid and alkali and then is discharged after achieving the discharging standard; and the organic solvents in the waste liquid comprises dichloromethane, dichloromethane and alcohols and can be recycled to be reutilized so that the pollution on the environment is small.

Description

technical field [0001] The present invention relates to a synthesis process of a key intermediate of carbapenem antibiotics, in particular to a synthesis process of the side chain of doripenem, i.e. (2S, 4S)-4-acetylthio-2-[[N -A synthesis process of aminosulfonyl-N-(tert-butoxycarbonyl)amino]methyl]pyrrolidine-1-carboxylic acid p-nitrobenzyl ester. Background technique [0002] Doripenem (S-4661) is a new broad-spectrum carbapenem antibiotic developed by Shionogi Company in Japan. It has the characteristics of broad antibacterial spectrum and stability to most β-lactamases. At present, this product obtained the drug production license in Japan on July 25, 2005, and went on the market in Japan in September 2005 under the trade name of Finibax. On October 15, 2007, the FDA approved Johnson & Johnson's doripenem (Doribax) injection for the treatment of complicated intra-abdominal infections and complicated urinary tract infections such as pyelonephritis. [0003] Its structu...

AI Technical Summary

Problems solved by technology

[0012] Among them, route 1 is too complicated, using trityl sodium sulfide as configuration inversion agent, which is more expensive, and the removal is cumbersome, and the introduction of the 2-sulfamoylamino group needs four steps to be realized, which is not suitable for industrial production

[0013] The first few steps of route 2 have relatively strict temperature requirements (-20~30°C); phase transfer catalysts-tetra-n-butylammonium bromide and sodium borohydride should be used to reduce the ester group, which is expensive; the highly toxic reagent ethyl chloroformate is used Esters, not suitable for industrial production

[0014] Route 3 still needs to prepare two special intermediates, which increases the cost, and the gain outweighs the gain

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