| 摘要 |
A preparation method of cilastatin ammonium salt is provided to reduce side reaction because the crystallization is carried out at a room temperature, to solve problems of production facilities by using a neutral absorbent resin, and to improve quality of cilastatin. A preparation method of cilastatin ammonium salt of chemical formula (1) comprises the steps of: reacting (b) (Z)-7-chloro-[[[(S)-2,2-dimethylcyclopropyl]carbonyl]amino]-2-heptanoic acid of chemical formula (2) or its salts with (c) cysteine of chemical formula (3) or its salts in (a) NaOH solution or potassium hydroxide solution by using water, at least one organic solvent mixable with water, or their solvent mixture as a solvent under nitrogen gas, and a catalyst at 50~80 ‹C for 3-15 hours to prepare cilastatin so that an equivalence ratio of (a):(b):(c) is 1:1:1~1:3:5; controlling the pH of the prepared cilastatin by using a strong acid to 1.0~5.0, adsorbing the cilastatin to a neutral adsorbent resin, washing it with water, eluting it with ammonium water, and concentrating it to prepare cilastatin ammonium salt; and dissolving the cilastatin ammonium salt in water, ammonia solution or a mixed solution of water and ammonia solution and stirring it in organic solvent at 5~50‹C for 2-5 hours to make crystals.
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