Cefotiam hydrochloride, SCE-963, CGP-14221/E, Abbott-48999, Pansporin, Halospor, -Drug Synthesis Database

【结构式】

【药物名称】Cefotiam hydrochloride, SCE-963, CGP-14221/E, Abbott-48999, Pansporin, Halospor

【化学名称】7beta-[2-(2-Imino-4-thiazolin-4-yl)acetamido]-3-[1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid dihydrochloride
　　　　　　(6R,7R)-7-[2-(2-Amino-4-thiazolyl)acetamido]-3-[[[1-[2-(dimethylamino)ethyl]-1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride

【CA登记号】66309-69-1, 61622-34-2 (free acid)

【分子式】C₁₈H₂₅Cl₂N₉O₄S₃

【分子量】598.55585

【开发单位】Novartis (Originator), Takeda (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1 合成路线2

合成路线1

The reaction of 7-beta-(D-5-phthalimido-5-carboxylvaleramido)-3-hydroxy-methyl-3-cephem-4-carboxylic acid (I) with diketene in CH2Cl2 gives the 3-(3-oxobutyryloxy)methyl derivative (II), which is treated with triethylamine-N,N-dimethylaniline, dimethyldichlososilane and PCl5 to obtain 7-beta-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (III).The acylation of (III) with 4-chloro-3-oxobutyryl chloride (A) and triethylamine in CH2Cl2 affords the amide (IV), which is condensed with thiourea (B) by means of NaHCO3 in acetone yielding the thiazole derivative (V). Finally, this compound is condensed with 5-mercapto-1-[2-(N,N-dimethylamino)ethyl-1H-tetrazole (VI) by means of NaHCO3 in hot water.

参考文献中间体

【1】 Tsushima, S.; et al. (Takeda Chemical Industries, Ltd.); Novel 3-acyloxymethyl-cephem compounds useful as intermediates for preparing cephalosporin antibiotics. DE 2607064; ES 459261; FR 2301528; GB 1544103; US 4245088 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Roberts, P.J.; Cefotiam. Drugs Fut 1979, 4, 6, 400.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(A)	15696	4-chloro-3-oxobutanoyl chloride		C₄H₄Cl₂O₂	详情	详情
(I)	33220	(6R,7R)-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₂₂H₂₁N₃O₉S	详情	详情
(II)	33221	(6R,7R)-3-[(acetoacetoxy)methyl]-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₂₆H₂₅N₃O₁₁S	详情	详情
(III)	15748	(6R,7R)-3-[(acetoacetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₂H₁₄N₂O₆S	详情	详情
(IV)	33222	(6R,7R)-3-[(acetoacetoxy)methyl]-7-[(4-chloro-3-oxobutanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₆H₁₇ClN₂O₈S	详情	详情
(V)	33223	(6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₇H₁₈N₄O₇S₂	详情	详情
(VI)	33224	1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide	61607-68-9	C₅H₁₁N₅S	详情	详情

合成路线2

The condensation of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (VII) with the mercaptane (VI) by means of NaHCO3 in hot water gives 7-beta-amino-3-[1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (VIII), which is then condensed with 2-aminothiazol-4-ylacetic acid (IX) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in THF. The free amino group of (VIII) is acylated with Cl2 and diketene giving the 4-chloro-3-oxobutyramido derivative (X), which is finally cyclized with thiourea (B) by means of NaHCO3 in acetone.

参考文献中间体

【1】 Numata, M.; et al. (Takeda Chemical Industries, Ltd.); 7-Alpha-(2-aminothiazole)acetamidocephalosporins. DE 2461478; FR 2255077; GB 1491018; NL 7416609; US 4080498; US 4421912; US 4517361 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Roberts, P.J.; Cefotiam. Drugs Fut 1979, 4, 6, 400.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VI)	33224	1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide	61607-68-9	C₅H₁₁N₅S	详情	详情
(VII)	33225	(6R,7R)-7-(acetoacetamido)-3-[(acetoxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₆N₂O₇S	详情	详情
(VIII)	33226	(6R,7R)-7-amino-3-[([1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₃H₁₉N₇O₃S₂	详情	详情
(IX)	33228	2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid		C₅H₆N₂O₂S	详情	详情
(X)	33227	(6R,7R)-7-[(4-chloro-3-oxobutanoyl)amino]-3-[([1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₇H₂₂ClN₇O₅S₂	详情	详情

Extended Information