ChemicalBook CAS DataBase List Cilastatin

Cilastatin synthesis

10synthesis methods

Product Name:Cilastatin
CAS Number:82009-34-5
Molecular formula:C16H26N2O5S
Molecular Weight:358.45

Cilastatin is a renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Dehydropeptidase is an enzyme found in the kidney and is responsible for degrading the antibiotic imipenem. Cilastatin can therefore be combined intravenously with imipenem in order to protect it from dehydropeptidase and prolong its antibacterial effect. Cilastatin itself does not have antibiotic activity although it has been proved to be active against a zinc-dependent beta-lactamase that usually confer antibiotic resistance to certain bacteria. Synthetic Description Reference: Graham, Donald W.; Ashton, Wallace T.; Barash, Louis; Brown, Jeannette E.; Brown, Ronald D.; Canning, Laura F.; Chen, Anna; Springer, James P.; Rogers, Edward F. Inhibition of the mammalian β-lactamase renal dipeptidase (dehydropeptidase-I) by Z-2-(acylamino)-3-substituted-propenoic acids. Journal of Medicinal Chemistry. Volume 30. Issue 6. Pages 1074-90. Journal. (1987). Synthetic Description Reference: Vinogradov, M. G.; Kaigorodova, L. N.; Chel'tsova-Bebutova, G. V.; Gorshkova, L. S.; Starostin, E. K.; Nikishin, G. I.; Ignatenko, A. V.; Shapiro, E. A. New approach to the synthesis of cilastatin, the inhibitor of renal dipeptidase. Izvestiya Akademii Nauk, Seriya Khimicheskaya. Issue 1. Pages 171-5. Journal. (1995). Synthetic Description Reference: Li, Quanliang; Zhai, Baokang. Process for preparation of cilastatin. Assignee Jiangxi Jindun Flavor Co., Ltd., Peop. Rep. China. CN 102875433. (2013). Synthetic Description Reference: Jayachandra, Suresh Babu; Yogesh, Ruchika; Morampudi, Raghuram; Khanduri, Chandra Has. Process for the preparation of cilastatin and its salts. Assignee Ranbaxy Laboratories Limited, India. WO 2011061609. (2011).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

Reference: Graham, Donald W.; Ashton, Wallace T.; Barash, Louis; Brown, Jeannette E.; Brown, Ronald D.; Canning, Laura F.; Chen, Anna; Springer, James P.; Rogers, Edward F. Inhibition of the mammalian β-lactamase renal dipeptidase (dehydropeptidase-I) by Z-2-(acylamino)-3-substituted-propenoic acids. Journal of Medicinal Chemistry. Volume 30. Issue 6. Pages 1074-90. Journal. (1987).

7-Chloro-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]-2-heptenoic acid

877674-77-6
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52-89-1 Synthesis

52-89-1
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$5.00/50mg

82009-34-5
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$39.00/10mg

Yield:82009-34-5 78%

Reaction Conditions:

Stage #1:(Z)-7-chloro-2 ((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid with sodium hydroxide in water at 5; for 0.166667 h;
Stage #2:l-cysteine hydrochloride in water at 45 - 50; for 0.166667 h;Temperature;

Steps:

4.1 (1) Preparation of the compound of formula (VI) cilastatin
At 5° C ,10.5 g of sodium hydroxide was added to 65 g of water,Stirring for 10min,10 g of the compound (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido) -2-heptenoic acid represented by the formula (V)Stirring for 10 min;At 45° C ,8 g of cysteine hydrochloride monohydrate was added, stirred for 10 min,The reaction begins at 50 ° C,(Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido) -2-heptenoic acid in the resulting reaction solution by HPLC was less than 5 % To complete the reaction;After cooling to 20° C ,To the solution was added 223 g of water,Stir,To the solution was slowly added 6M hydrochloric acid solution,Adjust the pH to 2. The obtained solution was added to the Φ45 * 4.0m macroporous adsorption resin column HZ-816, eluted with water, and the conductivity of the collected liquid was less than 100us / cm, and then the aqueous solution was eluted with an aqueous solution of ethanol. The ethanol and water The mass ratio was 15:85 and the elution temperature was 25 ° C. (Z) -7-chloro-2 - ((S) -2,2-dimethylcyclopropylcarboxyl) was added to the above raw material under reduced pressure to collect the material liquid having a conductivity of 100 μ / cm or more 2-heptenoic acid) to obtain the compound of formula (VI). After the addition of 200 g of acetone in the cilastatin, the seeds were incubated at -30 ° C for 6 h, filtered and dried The water content in the obtained cilastatin was less than 3%, and 7.8 g of the pale yellow cilastatin was obtained. The purity was 99.4% by HPLC and the yield was 78%.

References:

Shenzhen Haibin Pharmaceutical Co., Ltd.;Ren, Peng;Zhang, Ming;Ou, Peng;Zhao, Yong;Deng, Huasheng CN106518741, 2017, A Location in patent:Paragraph 0087; 0088; 0092; 0093; 0097; 0098; 0102-0163

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75885-58-4 Synthesis