A preparation method of a meropenem intermediate

Abstract

A preparation method of a meropenem intermediate is disclosed. The method includes adding salicylamide and cyclohexanone into an organic solvent that is toluene; reacting the mixture under the function of a catalyst that is p-toluenesulfonic acid; then performing material centrifugation, rinsing and centrifugation until a product is dry to obtain white crystals; raising the temperature until the obtained material is dissolved; then adding an organic solvent that is toluene and a catalyst that is n-propylamine; then adding 2-chloropropionyl chloride dropwise and reacting the mixture until the reaction is finished; performing vacuum distillation to remove the toluene; performing centrifugation after crystallization; and after a centrifugation product is dry, discharging and drying. The moleratio of the salicylamide, the cyclohexanone, the p-toluenesulfonic acid, the n-propylamine and the 2-chloropropionyl chloride is 1:1.3-1.7:0.01-0.04:0.2-0.5:0.2-0.5. The salicylamide, the cyclohexanone and the 2-chloropropionyl chloride are adopted as raw materials, the p-toluenesulfonic acid and the n-propylamine are adopted as catalysts, the one-time product yield is 92.4% by reaction temperature control and material ratio control, and the mother liquor recovery rate is 5%.

Description

technical field [0001] The invention relates to the technical field of substance synthesis, in particular to a method for preparing a meropenem intermediate. Background technique [0002] Meropenem is another semi-synthetic carbapenem antibiotic for parenteral administration after imipenem-cilastatin was launched in the United States. Through its covalent bond and penicillin-binding proteins (PBPs) involved in cell wall synthesis, it inhibits the synthesis of bacterial cell walls, thereby playing an antibacterial role. It is sensitive to Gram-positive bacteria and Gram-negative bacteria, especially has strong antibacterial activity against Gram-negative bacteria. For example, the minimum inhibitory concentration (MIC) for about 90% of Enterobacter is 0.08-0.15mg / L, more than 90% of Pseudomonas aeruginosa strains are highly sensitive to it (MIC<4mg / L), and all Haemophilus Including ampicillin-resistant strains are highly sensitive to it (MIC 0.06-1mg / L). Neisseria gonor...

AI Technical Summary

Problems solved by technology

However, the yield and purity of meropenem prepared with bromopropionylspirobenzoxazine cyclohexane was low

At the same time, the raw material α-bromopropionyl bromide required for the preparation of bromopropionyl spirobenzoxazine cyclohexane is expensive, has a large odor, and is highly toxic. At the same time, the preparation needs to use complex and expensive magnetic Solid base catalyst, complex reaction process, high reaction risk system, complicated post-treatment, serious environmental pollution, and high cost; because the hydrogen chloride generated during acylation combines with free ammonia to form a salt, which reduces the speed of N-acylation reaction, Therefore, in the reaction process, an acid-binding agent is generally added to neutralize the generated hydrogen chloride. Pyridine is usually used as a catalyst. The acid-binding agent has a relatively stable structure, and it is in a transparent and colorless solution state, so it will not cause adverse effects on the reactants and the reaction solution; however, using pyridine as an acid-binding agent will cause serious odor problems

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