Cefmatilen hydrochloride hydrate, S-1090, -Drug Synthesis Database

【结构式】

【药物名称】Cefmatilen hydrochloride hydrate, S-1090

【化学名称】(-)-(6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-(1H-1,2,3-triazol-4-ylsulfanylmethylsulfanyl)-3-cephem-4-carboxylic acid monohydrochloride monohydrate

【CA登记号】154776-45-1, 154776-44-0 (anhydrous), 140128-74-1 (anhydrous free base)

【分子式】C₁₅H₁₇ClN₈O₆S₄

【分子量】569.06174

【开发单位】Shionogi (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1 合成路线2

合成路线1

1) The protection of the amino group of 2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetic acid ethyl ester (I) with di-tert-butyl dicarbonate, dimethylaminopyridine and NaOH gives 2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(hydroxyimino)acetic acid (II), which is then treated with triphenylmethyl chloride (Tr-Cl) and K2CO3 in DMF to afford 2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(triphenylmethoxyimino)acetic acid (III). The condensation of (III) with 7beta-amino-3-(methanesulfonyloxy)-3-cephem-4-carboxylic acid diphenylmethyl ester (IV) by means of phenylphosphoryl dichloride and N-methylmorpholine gives the 7beta-acetamido derivative (V), which is then condensed with 4-(acetylsulfanylmethylsulfanyl)-1-(triphenylmethyl)-1,2,3-triazole (VI) by means of NaOMe in THF/DMF/methanol to yield the fully protected compound (IX). Finally, this compound is deprotected by a treatment with AlCl3 anisole. The triazole (VI) can be obtained by reaction of the sodium salt of 1,2,3-triazole-4-thiol (VII) with thioacetic acid S-(chloromethyl)ester (VIII) in DMS followed by NH-protection with triphenylmethyl chloride.

参考文献中间体

【1】 Mealy, N.; Castaner, J.; S-1090. Drugs Fut 1996, 21, 3, 254.
【2】 Takahashi, H.; Ide, Y. (Shionogi & Co. Ltd.); Triazolylthiomethylthio cephalosporin hydrochloride, its crystalline hydrate and the production of the same. EP 0581552; JP 1994092970; US 5407929 .
【3】 Kubota, T.; Kume, M. (Shionogi & Co. Ltd.); Thioalkylthio cephalosporin derivs. EP 0467647; JP 1992234346; JP 1993059066; US 5214037 .
【4】 Kume, M.; Kubota, T.; Kimura, Y.; Nakashimizu, H.; Motokawa, K.; Nakano, M.; Orally active cephalosporins. II. Synthesis and structure-activity relationships of new 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-cephalosporins with 1,2,3-triazole in C-3 side chain. J Antibiot 1993, 46, 1, 177-92.

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)	15889	Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate	60845-81-0	C₇H₉N₃O₃S	详情	详情
(II)	15890	2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-(hydroxyimino)acetic acid		C₁₀H₁₃N₃O₅S	详情	详情
(III)	15891	2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetic acid		C₂₉H₂₇N₃O₅S	详情	详情
(IV)	15892	benzhydryl (6R,7R)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₃H₂₄N₂O₄S₂	详情	详情
(V)	15893	benzhydryl (6R,7R)-7-([2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₅₂H₄₉N₅O₈S₃	详情	详情
(VI)	15894	S-[[(1-trityl-1H-1,2,3-triazol-4-yl)sulfanyl]methyl] ethanethioate		C₂₄H₂₁N₃OS₂	详情	详情
(VII)	15895	sodium 1H-1,2,3-triazole-4-thiolate		C₂H₂N₃NaS	详情	详情
(VIII)	15896	S-(chloromethyl) ethanethioate		C₃H₅ClOS	详情	详情
(IX)	15897	benzhydryl (6R,7R)-7-([2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-3-([[(1-trityl-1H-1,2,3-triazol-4-yl)sulfanyl]methyl]sulfanyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₇₁H₆₀N₈O₇S₄	详情	详情

合成路线2

2) The condensation of 1,2,3-triazol-4-thiol (X) with bromochloromethane by means of NaH gives 4-(chloromethylsulfanyl)-1,2,3-triazole (XI) with is treated with NaI in hot acetone to afford 4-(iodomethylsulfanyl)-1,2,3-triazole (XII). The reaction of (XII) with the silver mercaptide of the 7beta-[2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(triphenylmethoxyimino)acetamido]-3-sulfanyl-3-cephem-4-carboxylic acid diphenylmethyl ester 1beta-oxide (XIII) in HMPT yields the condensation product (XV), which is then treated with PCl3 in DMF to eliminate the 1beta-oxide oxygen, affording the protected compound (XVI), which is deprotected with AlCl3 in anisole, as before.

参考文献中间体

【1】 Mealy, N.; Castaner, J.; S-1090. Drugs Fut 1996, 21, 3, 254.
【2】 Kubota, T.; Kume, M. (Shionogi & Co. Ltd.); Thioalkylthio cephalosporin derivs. EP 0467647; JP 1992234346; JP 1993059066; US 5214037 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	19740	bromo(chloro)methane	74-97-5	CH₂BrCl	详情	详情
(X)	15898	1H-1,2,3-triazole-4-thiol; 1H-1,2,3-triazol-4-ylhydrosulfide		C₂H₃N₃S	详情	详情
(XI)	15899	4-[(chloromethyl)sulfanyl]-1H-1,2,3-triazole; chloromethyl 1H-1,2,3-triazol-4-yl sulfide		C₃H₄ClN₃S	详情	详情
(XII)	15900	iodomethyl 1H-1,2,3-triazol-4-yl sulfide; 4-[(iodomethyl)sulfanyl]-1H-1,2,3-triazole		C₃H₄IN₃S	详情	详情
(XIII)	15901	7beta-[2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z) -(triphenylmethoxyimino)acetamido]-3-sulfanyl-3-cephem-4-carboxylic acid dibenzyl ester 1beta-oxide; (6R,7R)-7-[2-[2-(Tert-butoxycarbonylamino)thiazol-4-yl]-2-(triphenylmethoxyimino)acetamido]-3-sulfanyl-3-cephem-4-carboxylic acid dibenzyl ester 1-oxide silver salt		C₄₉H₄₂AgN₅O₈S₃	详情	详情
(XIV)	15902	benzhydryl (6R,7R)-7-([2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5,8-dioxo-3-sulfanyl-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₄₉H₄₃N₅O₈S₃	详情	详情
(XV)	15903	benzhydryl (6R,7R)-7-([2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5,8-dioxo-3-[[(1H-1,2,3-triazol-4-ylsulfanyl)methyl]sulfanyl]-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₅₂H₄₆N₈O₈S₄	详情	详情
(XVI)	15904	benzhydryl (6R,7R)-7-([2-[2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-3-[[(1H-1,2,3-triazol-4-ylsulfanyl)methyl]sulfanyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₅₂H₄₆N₈O₇S₄	详情	详情

Extended Information