- Cilastatin sodium intermediate preparation method
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The invention belongs to the technical field of medicines, and particularly provides a cilastatin sodium intermediate preparation method, which comprises: simply preparing a (Z)-7-X-2((2s)-2,2-dimethylcyclopropaneformamido)-2-heptenoic acid crude product through a one-pot method by using 7-X-2-oxoheptanoic acid ethyl ester and (s)-2,2-dimethylcyclopropaneformamide as raw materials sequentially under the action of a catalyst, concentrated hydrochloric acid and hydrogen chloride gas, and re-crystallizing to prepare a (Z)-7-X-2((2s)-2,2-dimethylcyclopropaneformamido)-2-heptenoic acid refined product. According to the invention, the method has advantages of short synthetic route, simple operation and high product purity, and is suitableness for industrial production.
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- Refining method of cilastatin
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The invention provides a refining method of cilastatin. The method comprises the steps of carrying out impurity removal and concentration on a solution containing [R-[R*,S*(Z)]]-7-[(2-amino-2-carboxyethyl)-thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid. The method is high in production efficiency, a few in impurities, simple and convenient to operate and suitable for industrialized production and further, the obtained [R-[R*,S*(Z)]]-7-[(2-amino-2-carboxyethyl)-thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid has the purity which can be up to 99.9 percent and the yield which can reach 96 percent or above.
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- Purification method of ethyl 7-chloro-2-oxoheptanoate
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The invention provides a purification method of ethyl 7-chloro-2-oxoheptanoate, wherein the purification method comprises the steps: firstly, carrying out a reaction of ethyl 7-chloro-2-oxoheptanoate oil crude product and a hydrosulphite solution, and separating to obtain a sulfite solid of ethyl 7-chloro-2-oxoheptanoate; then, dissolving the sulfite solid of ethyl 7-chloro-2-oxoheptanoate in water, adding an acid or alkali at a certain temperature, and decomposing the sulfite of ethyl 7-chloro-2-oxoheptanoate into ethyl 7-chloro-2-oxoheptanoate; and finally, extracting with an organic solvent immiscible with water, to obtain ethyl 7-chloro-2-oxoheptanoate having the purity improved. The method is simple in operation and suitable for industrialized production, and ensures the purity of a subsequent product and final product cilastatin sodium.
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- A process for the preparation of Cilastatin sodium
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The invention belongs to the field of pharmaceutical synthesis, and provides a preparation method of cilastatin sodium, and the method comprises the following steps: performing condensation, alkaline hydrolysis, and thioetherification of raw materials of 7-oxyhalogen alkyl heptylate and (s)-2,2-dimethylcyclopropane methanamide, adjusting the pH value of the thioetherified solution, washing by a nonpolar solvent, performing isomerization, purification by a neutral macroporous adsorption resin, and salt formation so as to obtain the cilastatin sodium solid. The invention reduces the generation of impurities, improves the isomerization efficiency, simplifies the preparation process, and effectively improves the yield and purity of cilastatin sodium.
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Paragraph 0007; 0024; 0025
(2017/02/17)
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- An improved process for the preparation of cilastatin acid
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The present invention relates to an improved process for the preparation of Cilastatin Sodium of formula (I). The present invention also provides an isolation technique for Cilastatin acid from the reaction mixture.
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Page/Page column 5
(2012/02/04)
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- Process for the Preparation of Cilastatin and Sodium Salt
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The present invention relates to an improved process for the preparation of Cilastatin Sodium of formula (I). The present invention also provides an isolation technique for Cilastatin acid from the reaction mixture.
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Page/Page column 3
(2009/06/27)
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- Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
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Provided is a novel preparation method of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid represented by the following formula (1), a key intermediate of cilastatin used as a supplement to imipenem. The novel preparation method of the invention produces a pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid, a key intermediate of cilastatin, by selective hydrolysis of E isomers.
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Page/Page column 6
(2008/12/05)
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- NOVEL PROCESS FOR THE PREPARATION OF CILASTATIN SODIUM SALT
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The present invention relates to a novel process for preparing cilastatin sodium salt used asa dehydropeptidase 1 inhibitor. The novel method of the present invention could prevent the formation of (E)-isomer from the preparation of intermediate for preparing cilastatin sodium, i.e., (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxarnido)-2-heptenoic acid metal salt and isolate the intermediate in situ providing simpler process with high yield and purity. Furthermore, it can provide with highly pure cilastatin sodium salt by isolating novel cilastatin amine salt and using by sodium hydroxide and cationic exchange resin. Accordingly, the method can be very useful in preparing cilastatin sodium salt with high yield and high purity.
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Page/Page column 12
(2010/10/20)
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- A new approach to the synthesis of cilastatin, an inhibitor of renal dipeptidase
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A convenient preoarative synthesis of cilastatin, an inhibitor of renal dipeptidase used in drugs with the antibiotic imipenem, has been elaborated.The key intermediate in this synthesis is 2-amino-7-chloroheptanoic acid prepared by oxidative cleavage of cycloheptanone followed by bromination of 7-chloroheptanoyl chloride with subsequent amination of the 2-bromo-7-chloroheptanoic acid thus formed.All of the stages of the new synthesis are easily performed, as is the isolation of the intermediate products, and they do not require any organometallic reagents. - Key words: cilastatin, (R)-cysteine, 7-chloroheptanoic acid, 2-amino-7-chloro-2-heptenoic acid, 2,2-dimethylcyclopropanecarbonyl chloride; oxidation, bromination, amination, cyclopropanation.
- Vinogradov, M. G.,Kaigorodova, L. N.,Chel'tsova-Bebutova, G. V.,Gorshkova, L. S.,Starostin, E. K.,et al.
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p. 167 - 171
(2007/10/02)
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