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【结 构 式】 
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【分子编号】15696 【品名】4-chloro-3-oxobutanoyl chloride 【CA登记号】 |
【 分 子 式 】C4H4Cl2O2 【 分 子 量 】154.97996 【元素组成】C 31% H 2.6% Cl 45.75% O 20.65% |
合成路线1
该中间体在本合成路线中的序号：(A)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.
| 【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
该中间体在本合成路线中的序号：(XXV)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 |