Cilastatin sodium, Cilastatino, MK-791, L-642957, -Drug Synthesis Database

【结构式】

【药物名称】Cilastatin sodium, Cilastatino, MK-791, L-642957

【化学名称】[R-[R*,S*(Z)]]-7-[(2-Amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid monosodium salt

【CA登记号】81129-83-1, 82009-34-5 (free acid)

【分子式】C₁₆H₂₅N₂NaO₅S

【分子量】380.44185

【开发单位】Merck & Co. (Originator)

【药理作用】Carbapenems

合成路线1 合成路线2

合成路线1

The alkylation of ethyl 1,3-dithiane-2-carboxylate (I) with 1,5-dibromopentane (II) by means of NaH in DMF gives ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate (III), which is treated with NBS in acetonitrile water to open the dithiane ring yielding ethyl 7-bromo-2-oxoheptanoate (IV). Hydrolysis of the ester group of (IV) with 50% HBr affords 7-bromo-2-oxoheptanoic acid (V), which is condensed with 2,2-dimethylcyclopropanecarboxamide (VI) in refluxing toluene giving 7-bromo-2-(2,2-dimethycyclopropanecarboxamido)-2-octenoic acid (VII). Finally, this compound is condensed with L-cysteine (VIII) by means of NaOH in water.

参考文献中间体

【1】 Graham, D.W.; Rogers, E.F.; Kahan, F.M. (Merck & Co., Inc.); 2-(Cyclopropanecarboxamido)-alkenoic acids, their esters and salts, and antibacterial compositions comprising the same a thiennamycin-type compound. EP 0048301 .
【2】 Castaner, J.; Serradell, M.N.; Cilastatin. Drugs Fut 1984, 9, 5, 320.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	30559	ethyl 1,3-dithiane-2-carboxylate	20462-00-4	C₇H₁₂O₂S₂	详情	详情
(II)	30560	1,5-dibromopentane	111-24-0	C₅H₁₀Br₂	详情	详情
(III)	30561	ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate		C₁₂H₂₁BrO₂S₂	详情	详情
(IV)	30562	ethyl 7-bromo-2-oxoheptanoate		C₉H₁₅BrO₃	详情	详情
(V)	30563	7-bromo-2-oxoheptanoic acid		C₇H₁₁BrO₃	详情	详情
(VI)	30564	2,2-dimethylcyclopropanecarboxamide		C₆H₁₁NO	详情	详情
(VII)	30565	(Z)-7-bromo-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid		C₁₃H₂₀BrNO₃	详情	详情
(VIII)	14643	L-cysteine; (R)-2-Amino-3-mercaptopropionic acid	52-90-4	C₃H₇NO₂S	详情	详情

合成路线2

The condensation of 7-chloro-2-oxoheptanoic acid ethyl ester (I) with (S)-2,2-dimethylcyclopropanecarboxamide (II) by means of TsOH in refluxing toluene gives (S)-7-chloro-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (III), which is hydrolyzed in aq. NaOH to yield the corresponding carboxylic acid (IV). Finally, this compound is condensed with (R)-cysteine (V) by means of NaOH in water to afford the target Cilastatino.

参考文献中间体

【1】 Tyagi, O.D.; Kumar, Y.; Srivastava, T.K. (Ranbaxy Laboratories Ltd.); Process for the preparation of cilastatin. WO 03018544 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	61845	propyl 7-chloro-2-oxoheptanoate		C₁₀H₁₇ClO₃	详情	详情
(II)	61846	(1S)-2,2-dimethylcyclopropanecarboxamide		C₆H₁₁NO	详情	详情
(III)	61847	propyl (Z)-7-chloro-2-({[(1S)-2,2-dimethylcyclopropyl]carbonyl}amino)-2-heptenoate		C₁₆H₂₆ClNO₃	详情	详情
(IV)	61848	(Z)-7-chloro-2-({[(1S)-2,2-dimethylcyclopropyl]carbonyl}amino)-2-heptenoic acid		C₁₃H₂₀ClNO₃	详情	详情
(V)	14643	L-cysteine; (R)-2-Amino-3-mercaptopropionic acid	52-90-4	C₃H₇NO₂S	详情	详情

Extended Information