- A Cilastatin ding Gai the crystal and its preparation method and application
-
The invention discloses a cilastatin calcium crystal, a preparation method and an application thereof. Under X-ray powder diffraction, the cilastatin calcium crystal has main characteristic peaks at positions with 2[theta] being 5.2+/-0.1 degree, 10.3+/-0.1 degree, 15.9+/-0.1 degree, 18.9+/-0.1 degree, 20.7+/-0.1 degree and 22.4+/-0.1 degree. The preparation method of the cilastatin calcium crystal includes following steps: (1) adding calcium chloride to an aqueous solution containing cilastatin or/and cilastatin salt; (2) regulating the pH value to 5-9 with an inorganic acid or an inorganic alkali; (3) adding an organic solvent which is mix-dissolvable with water to the system to perform stir-crystallization; and (4) filtering and drying an obtained crystal. By means of the cilastatin calcium crystal provided in the invention, cilastatin sodium being higher than 99.0% in HPLC purity can be conveniently prepared. The preparation method is simple in operation, is high in yield, is easy to carry out in large scale, and can provide an effective approach for preparing the cilastatin sodium being high in purity and stable in quality industrially in large scale.
- -
-
Paragraph 0090-0092
(2017/08/25)
-
- Refining method of cilastatin
-
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.
- -
-
-
- Preparation method of cilastatin sodium active pharmaceutical ingredient
-
The invention provides a preparation method of a cilastatin sodium active pharmaceutical ingredient. The preparation method comprises the following steps: (1) mixing alkali and reaction solvent, adding a compound (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropylformacyl)-2-heptenoic acid shown in Formula (V), then adding cysteine hydrochloride, reacting to obtain a reaction solution containing a compound cilastatin shown in Formula (VI); (2) purifying the reaction solution obtained in the step (1) through macroporous adsorption resin to obtain the compound cilastatin shown in Formula (VI); and (3) mixing sodium hydroxide and water, adding the cilastatin obtained in the step (2), regulating the pH value, and drying to obtain the compound cilastatin sodium shown in Formula (I). The preparation method is quick, efficient and suitable for industrial production; and the obtained cilastatin sodium active pharmaceutical ingredient is low in impurity content.
- -
-
Paragraph 0087; 0088; 0092; 0093; 0097; 0098; 0102-0163
(2017/06/02)
-
- PROCESS FOR THE PREPARATION OF CILASTATIN SODIUM
-
The present invention relates to an improved process for the preparation of Cilastatin Sodium of formula (I), having mesityl oxide content less than 2000 ppm and more than 1 ppm. (Formula I) (I)
- -
-
Page/Page column 4
(2012/10/08)
-
- An improved process for the preparation of cilastatin acid
-
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.
- -
-
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF CILASTATIN SODIUM
-
The present invention relates to an improved process for the preparation of Cilastatin Sodium of formula (I), having mesityl oxide content less than 2000 ppm and more than 1 ppm. (Formula I) (I)
- -
-
Page/Page column 11
(2011/07/30)
-
- Process for the Preparation of Cilastatin and Sodium Salt
-
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.
- -
-
Page/Page column 4
(2009/06/27)
-
- Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
-
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.
- -
-
Page/Page column 7
(2008/12/05)
-
- A new approach to the synthesis of cilastatin, an inhibitor of renal dipeptidase
-
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.
-
p. 167 - 171
(2007/10/02)
-
- Inhibition of the Mammalian β-Lactamase Renal Dipeptidase (Dehydropeptidase-I) by (Z)-2-(Acylamino)-3-substituted-propenoic Acids
-
The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract.A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo.Many of the compounds were prepared in one step from an α-keto acid and a primary amide.The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl.With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 μM and a range of pharmacokinetic properties.By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer.The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.
- Graham, Donald W.,Ashton, Wallace T.,Barash, Louis,Brown, Jeannette E.,Brown, Ronald D.,et al.
-
p. 1074 - 1090
(2007/10/02)
-