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【结 构 式】

【分子编号】20860

【品名】2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid

【CA登记号】64486-18-6

【 分 子 式 】C8H8ClN3O4S

【 分 子 量 】277.68804

【元素组成】C 34.6% H 2.9% Cl 12.77% N 15.13% O 23.05% S 11.55%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VI)

The methylation of ethyl 3-oxo-2-hydroxyiminobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 3-oxo-2-methoxyiminobutyrate (II), which is brominated with Br2 in CHCl3 to afford ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate (III). The cyclization of (III) with thiourea (A) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (IV), which is acylated with chloroacetyl chloride in dimethylacetamide to yield ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (V). The hydrolysis of (V) with KOH in ethanol-water gives the corresponding free acid (VI), which is treated with PCl5 in methylene chloride to obtain the acyl chloride (VII). The condensation of tert-butyl 7-aminocephalosporanate (VIII) with (VII) by means of pyridine in methylene chloride gives tert-butyl 7-[alpha-methoxyimino-(2-chloroacetamidothiazol-4-yl)acetamido]cephalosporanate (IX), which is desacylated with thiourea and triethylbenzylammonium bromide in THF-ethanol yielding tert-butyl 7-[alpha-methoxyimino-alpha-(2-aminothiazol-4-yl)acetamido]cephalosporanate (X), which is hydrolyzed with trifluoroacetic acid to afford the free cephalosporanic acid (Xl). Finally, this compound is condensed with 1-methyl-5-mercaptotetrazol (XII) by means of NaHCO3 and triethylbenzylammoniurn bromide in water.

1 Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17.
2 Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 .
3 Ochiai, M.; et al. (Takeda Chemical Industries, Ltd.); Thiazolylacetamido cephasloporin type compounds. DE 2556736; ES 464772; FR 2294690; GB 1536283; NL 7514811; US 4098888 .
4 Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(I) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(II) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(III) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(IV) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(V) 20859 ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate C10H12ClN3O4S 详情 详情
(VI) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(VII) 32659 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride 75532-64-8 C8H7Cl2N3O3S 详情 详情
(VIII) 32660 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H20N2O5S 详情 详情
(IX) 32661 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H26ClN5O8S2 详情 详情
(X) 32662 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C20H25N5O7S2 详情 详情
(XI) 29686 (6R,7R)-3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H17N5O7S2 详情 详情
(XII) 28420 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide 13183-79-4 C2H4N4S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VI)

The condensation of (VII) or the free acid (VI) by means of pyridine or isobutyl chloroformate, respectively, with 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIII) gives 7-[alpha-(2-chloroacetylamidothiazol-4-yl)-alpha-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIV), which is finally desacylated with thiourea (A) and benzyltriethylammonium bromide as before.

1 Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17.
2 Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 .
3 Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(VII) 32659 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride 75532-64-8 C8H7Cl2N3O3S 详情 详情
(XIII) 32663 (6R,7R)-7-amino-3-[[(1-methyl-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 24209-38-9 C10H12N6O3S2 详情 详情
(XIV) 32664 (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-[[(1-methyl-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 C18H18ClN9O6S3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(VIII)

The methylation of ethyl 2-(hydroxyimino)-3-oxobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 2-(methoxyimino)-3-oxobutyrate (II), which is brominated with Br2 in CHCl3 yielding ethyl 4-bromo-2-(methoxyimino)-3-oxobutyrate (III). The cyclization of (III) with thiourea (IV) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate (V), which is acylated with chloroacetyl chloride (VI) in DMA to give the corresponding N-chloroacetyl derivative (VII). The hydrolysis of (VII) with KOH in ethanol-water affords 2-(2-chloroacetamidothiazol-4-yl)-2-(methoxyimino)acetic acid (VIII), which is condensed with desacetoxycephalosporanic acid (IX) by means of N-hydroxysuccinimide (NOHS) and dicyclohexylcarbodiimide (DCC) in THF yielding 7beta-[2-(2-chloroacetamidothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]desacetoxycephalosporanic acid (X). The deprotection of (X) with sodium acetate in THF gives the free acid (XI), which is finally esterified with pivaloyloxymethyl bromide (XII) by means of NaHCO3 in ethyl acetate-DMSO.

1 Ochiai, M.; Morimoto, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Cephalosporin derivatives, process for their preparation and medicines containing them. DE 2715385 .
2 Nakao, H.; Sugawara, S. (Sankyo Co., Ltd.); Cephalosporin derivatives for oral administration. DE 3020625 .
3 Prous, J.; Castaner, J.; CEFETAMET PIVOXIL < Prop INNM >. Drugs Fut 1989, 14, 5, 420.
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) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(II) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(III) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 20859 ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate C10H12ClN3O4S 详情 详情
(VIII) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(IX) 20861 (6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ADCA 22252-43-3 C8H10N2O3S 详情 详情
(X) 20862 (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H16ClN5O6S2 详情 详情
(XI) 20863 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H15N5O5S2 详情 详情
(XII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
Extended Information