Improved preparation method of ampicillin

Abstract

The invention relates to the pharmaceutical field and provides a method for preparing ampicillin and a product obtained by the method. The method comprises the following steps: 1) mixing 6-APA and D-phenylglycine methyl ester or salt thereof in water and adding into ampicillin synthase at the temperature of 0 DEG C-30 DEG C, and reacting at the pH value of 5.5-7.5 and the temperature of 10 DEG C-30 DEG C; 2) adjusting the product obtained in the step 1) with acid till solution is clear, and keeping the pH value at 0.5-2.0 and the temperature at 10 DEG C-30 DEG C; 3) cooling the solution obtained in the step 2) to 12 DEG C-15 DEG C, then regulating the pH value to 3.00-3.50, further cooling to 5 DEG C-6 DEG C, and maintaining the pH value at 3.50; then, adjusting the pH value to 4.9-5.0, cooling to 1 DEG C-2 DEG C, and keeping so as to obtain ampicillin crystals. By adopting the method provided by the invention, the yield and quality of ampicillin products are greatly upgraded, the production efficiency is improved, and the medication safety of the ampicillin products is further ensured.

Description

technical field [0001] The invention relates to a preparation method of ampicillin, in particular to an improved enzymatic method for preparing ampicillin. Background technique [0002] Ampicillin, chemical name (2S,5R,6R)-3,3-dimethyl-6-[(R)-2-amino-2-phenethylamino]-7-oxo-4-thia- 1-Azabicyclo[3.2.0]heptane-carboxylic acid, its free acid contains 3 molecules of crystal water, it is a commonly used penicillin broad-spectrum β-lactam antibiotics. [0003] Ampicillin has a strong bactericidal effect and the ability to penetrate the cell wall, and is one of the most widely used oral penicillins at present. The preparation of ampicillin includes chemical synthesis and enzymatic preparation. The chemical method has relatively harsh reaction conditions, complex reaction steps, and relatively large environmental pollution. The enzymatic synthesis method can significantly reduce the reaction steps, and the reaction conditions are mild, so it is one of the important ways to produce...

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Problems solved by technology

[0004] "Research on Enzymatic Synthesis of Ampicillin and Medium System" (Pan Shengbin, School of Science, Zhejiang University, Master's Degree Thesis, 20070901) reported the enzymatic synthesis of ampicillin under different medium systems, mainly introducing organic systems and two The method for synthesizing ampicillin under the system, due to the requirements for environmental protection, the enzymatic synthesis of ampicillin in the organic system medium has the problem of environmental pollution; while the aqueous phase system is relatively in line with environmental protection requirements, but the method described in the article is in The yield of the enzyme-catalyzed synthesis of ampicillin under the study of the aqueous phase system is not very high, even under the best reaction conditions, the yield is only 65.6%, and the organic solvent is added in the aqueous phase medium, the ratio of the substrate concentration Inappropriate (such as 1:2), the amount of D-phenylglycine methyl ester hydrochloride is relatively large, not the most economical and not the most suitable for large-scale production, and practice has proved that the more side chains introduced, the worse the quality of the product, and the side chains The inability of the chain to react is the impurity in the product; the prior art documents add organic solvents in order to improve the reaction efficiency, compared with the complete water phase reaction, it is not conducive to economic and environmental protection, low toxicity, and reduced allergens; and how to improve the pure water phase system The lower ampicillin production rate still needs further research, and at the same time, improving the quality of ampicillin products and ensuring drug safety are also further goals in the field of drug research and development.

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