82009-34-5

Usage

Synthesis

Cilastatin, (Z)-7-[(2-amino-2-carboethoxyethyl)thio]-2-[[2,2-dimethylcyclopropyl) carbonyl] amino]-2-heptenoic acid (32.1.3.6), is synthesized from the ethyl ester of 1,3-dithian-2-carboxylic acid (which is ethyl glyoxylate, protected at the aldehyde group with 1,3-propanedithiol), which is alkylated by 1,5-dibromopentane in the presence of sodium amide, forming the ethyl ester of 7-bromo-2-[2-(1,3-dithiano)]hepthanoic acid (32.1.3.2). Oxidative hydrolysis of this product with N-bromosuccinimide in a mixture of acetonitrile–water solvents leads to the formation of the ethyl ester of 7-bromo-α-ketoheptanoic acid (32.1.3.3). Acidic hydrolysis of this product using hydrogen bromide in acetic acid gives 7-bromo-α-ketoheptanoic acid (32.1.3.4). This is reacted with 2,2-dimethylcyclopropancarboxylic acid amide to form the corresponding enamide, (Z)-7-bromo-2-(2, 2-dimethylcycloprotancarboxamido)-2-heptenoic acid (32.1.3.5). The resulting product is used for S-alkylation of L-cysteine, which results in the production of the desired cilastatin (32.1.3.6).

InChI:InChI=1/C16H26N2O5S/c1-16(2)8-10(16)13(19)18-12(15(22)23)6-4-3-5-7-24-9-11(17)14(20)21/h6,10-11H,3-5,7-9,17H2,1-2H3,(H,18,19)(H,20,21)(H,22,23)/b12-6-/t10-,11+/m1/s1

Upstream product

• 52-90-4 L-Cysteine 
• 78834-80-7 (Z)-7-bromo-2 ((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid 
• 111-24-0 1,5-dibromo-pentane 
• 75885-59-5 2,2-dimethylcyclopropane-1-carboxylic acid 
• 14590-53-5 (+)-1S-2,2-dimethylcyclopropane-carboxylic acid 
• 877674-77-6 (Z)-7-chloro-2 ((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid 
• 166037-21-4 (E)-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid 
• 78834-75-0 ethyl-7-Chloro-2-oxoheptanoate 
• 52-89-1 l-cysteine hydrochloride 
• 75885-58-4 (S)-2,2-dimethylcyclopropanecarboxamide 
• 107871-21-6 (+)-N-<<(2,2-dimethylcyclopropyl)carbonyl>oxy>succinimide 
• 107871-16-9 2-(5-Bromo-pentyl)-[1,3]dithiane-2-carboxylic acid ethyl ester 
• 107871-17-0 ethyl 7-bromo-2-oxoheptenoate 
• 107872-93-5 7-bromo-2-oxoheptanoic acid 

Relevant academic research and scientific papers

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.

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.

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.

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.

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)

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)

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.

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.

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.