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【结 构 式】

【分子编号】15691

【品名】4-bromo-3-oxobutanoyl bromide

【CA登记号】

【 分 子 式 】C4H4Br2O2

【 分 子 量 】243.88256

【元素组成】C 19.7% H 1.65% Br 65.53% O 13.12%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XX)

2) The condensation of 7-(formamido)-3-(hydroxymethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (XV) with trichloromethyl chloroformate and dimethylamine in THF gives the corresponding dimethylcarbamoyloxy derivative (XVI), which is hydrolyzed with trifluoroacetic acid and anisole to the corresponding acid (as Na salt) (XVII). The esterification of (XVII) with 1-(isopropoxycarbonyloxy)ethyl iodide (XIV) in DMF as before affords the corresponding ester (XVIII), which is deformylated with HCl in methanol/THF to the 7-amino derivative (XIX). The acylation of (XIX) with 4-bromo-3-oxobutyryl bromide (XX) (obtained from diketene (XXI) with Br2) by means of bis(trimethylsilyl)acetamide in dichloromethane affords the 7-(4-bromo-3-oxobutyramido)-derivative (XXII), which is treated with NaNO2 and acetic acid to obtain the hydroxyimino compound (XXIII). Finally, this compound is cyclized with thiourea in dimethylacetamide. 3) The 7-amino cephem derivative (XIX) can also be acylated with 4-chloro-3-oxobutyryl chloride (XXV) (obtained from diketene (XXI) with Cl2) to yield the 7-(4-chloro-3-oxobutyramido)-derivative (XXVI), which is treated with amyl nitrite and acetyl chloride to afford the hydroxyimino compound (XXVII). Finally, this compound is cyclized with thiourea as before.

1 Negi, S.; et al.; Studies on orally active cephalosporins. I. Synthesis and structure-activity relationships of new 3-substituted carbamoyloxymethyl cephalosporins. J Antibiot 1994, 47, 12, 1507-25.
2 Fromtling, R.A.; Castaner, J.; E-1101. Drugs Fut 1995, 20, 8, 766.
3 Negi, S.; Yamanaka, M.; Katsu, K.; Sugiyama, I.; Komatu, Y.; Kamata, A.; Tsuruoka, A.; Machida, Y. (Eisai Co., Ltd.); 7-Acyl-3-(substd. carbamoyloxy)cephem cpds., use thereof and process for their preparation. EP 0484966; EP 0761671; JP 1992178392; JP 1992282388; JP 1993311173; JP 1993311174; JP 1994092969; JP 1998067784; US 5559225; US 5587473; US 5604217 .
4 Negi, S.; Yamanaka, M.; Sugiyama, I.; et al.; E1101, a new oral cephalosporin: I. Synthesis and structure-activity relations of 3-substituted carbamoyloxymethyl cephems. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 894.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
42918 Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene 503-38-8 C2Cl4O2 详情 详情
(XIV) 15685 1-iodoethyl isopropyl carbonate C6H11IO3 详情 详情
(XV) 15686 benzhydryl 7-(formylamino)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H20N2O5S 详情 详情
(XVI) 64676 diphenylmethyl 3-({[(dimethylamino)carbonyl]oxy}methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C25H25N3O6S 详情 详情
(XVII) 15687 7-(Formamido)-3-(N,N-dimethylcarbamoyloxy)-3-cephem-4-carboxylic acid sodium salt C12H14N3NaO6S 详情 详情
(XVIII) 15689 1-[(isopropoxycarbonyl)oxy]ethyl 3-([[(dimethylamino)carbonyl]oxy]methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C18H25N3O9S 详情 详情
(XIX) 15690 1-[(isopropoxycarbonyl)oxy]ethyl 7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C17H25N3O8S 详情 详情
(XX) 15691 4-bromo-3-oxobutanoyl bromide C4H4Br2O2 详情 详情
(XXI) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(XXII) 15693 1-[(isopropoxycarbonyl)oxy]ethyl 7-[(4-bromo-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28BrN3O10S 详情 详情
(XXIII) 64677 1-({[(1-methylethyl)oxy]carbonyl}oxy)ethyl 7-{[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino}-3-({[(dimethylamino)carbonyl]oxy}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27BrN4O11S 详情 详情
(XXIV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XXV) 15696 4-chloro-3-oxobutanoyl chloride C4H4Cl2O2 详情 详情
(XXVI) 15697 1-[(isopropoxycarbonyl)oxy]ethyl 7-[(4-chloro-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28ClN3O10S 详情 详情
(XXVII) 15698 1-[(isopropoxycarbonyl)oxy]ethyl 7-[[4-chloro-2-(hydroxyimino)-3-oxobutanoyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27ClN4O11S 详情 详情
Extended Information