Environmentally-friendly synthesis process of Aztreonam main ring (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid

Abstract

The invention provides an environmentally-friendly synthesis process of Aztreonam main ring (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid. The synthesis process comprises: carrying out methyl esterification on L-threonine, carrying out ammonolysis on L-threonine methyl ester bisulfate, carrying out N-BOC (N-tert-butoxycarbonyl) protection on amino group of L-threoninamide, carrying out mesylation on N-BOC-L-threoninamide, carrying out sulfonylation on N-BOC-O-mesyl-L-threoninamide, carrying out cyclization reaction on sodium N-BOC-O-mesyl-L-threoninamide sulfonate, and de-protecting and acidifying sodium (3S-trans)-3-tert-butoxyformamido-4-methyl-2-oxo-1-azetidinyl sulfonate to obtain (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid. The synthesis process has the advantages that simple post-treatment, high yield, high utilization rate of wastes, low cost and low pollution; moreover raw materials can be obtained easily.

Description

technical field [0001] The invention relates to an environment-friendly synthesis process of the main ring (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid of the antibiotic medicine aztreonam. Background technique [0002] Aztreonam is the first synthetic monocyclic β-lactam antibiotic developed by Bristol-Myers Squibb Co. It has a good therapeutic effect on Gram-negative bacterial infections, such as pneumonia, Pleurisy, abdominal infection, biliary tract infection, bone and joint infection, etc., especially for urinary tract infection. And its cost largely depends on the production cost of its main ring. The existing methods for synthesizing the main ring mainly include: 1. Starting from L-threonine, through esterification, ammonolysis, Cbz (benzyloxyformyl) amino protection, hydroxyl protection, sulfonation, cyclization, and deprotection reactions The obtained (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid {Zhang Hong et al. Study on the synthesi...

AI Technical Summary

Problems solved by technology

[0004] Method 1: A large amount of thionyl chloride (80 grams of L-threonine, 165 ml of thionyl chloride) is used for esterification, which produces a large amount of hydrogen chloride and sulfur dioxide, which are toxic and harmful gases; Cbz (benzyloxyformyl) amino Protection, palladium-carbon catalytic hydrogenation deprotection is needed later, palladium-carbon catalyst is expensive, the production cost is high, the organic solvent used in the whole process is more, the amount is larger, post-processing is troublesome, and the total yield (45.2%)

[0005] Method 2: Catalyze with hydrogen chloride during esterification, which is inconvenient to operate and has poor catalytic effect; after sulfonation, quaternary ammonium salts are used for cyclization, quaternary ammonium salts are more expensive, and the production cost is high. There are many organic solvents used in the whole process , large amount, post-processing trouble, the total yield is very low (less than 9%)

[0006] Method 3: Although the synthesis steps are shorter (4 steps), the overall yield is lower (27%)