【结 构 式】 |
【分子编号】15674 【品名】3-[(acetoxy)methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 【CA登记号】51098-29-4 |
【 分 子 式 】C16H16N2O6S2 【 分 子 量 】396.44492 【元素组成】C 48.47% H 4.07% N 7.07% O 24.21% S 16.18% |
合成路线1
该中间体在本合成路线中的序号:(III)1) The acylation of 7-aminocephalosporanic acid (I) with 2-thienylacetyl chloride (II) gives the acylated compound (III), which is treated with wheat bran enzyme to obtain 3-(hydroxymethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (IV). The esterification of (IV) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (V), which is treated with carbonyldiimidazole (CDI) in THF to yield the imidazolecarbonyl ester (VI). The reaction of (VI) with dimethylamine in ethyl acetate/water gives the dimethylcarbamoyl derivative (VII) as a mixture of the 3- and 2-cephem derivatives, which is oxidized with m-chloroperbenzoic acid to the corresponding S-oxides and separated by column chromatography to give pure 3-cephem derivative (VIII). Elimination of the oxide group of (VIII) with PCl3 in DMF affords 3-(dimethylcarbamoyloxymethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid diphenyl ester (IX), which is treated with PCl5 and pyridine to obtain compound (X) with a free amino group. The acylation of (X) with 2-[2-(tritylamino)thiazol-4-yl]-2(Z)-(trityloxyimino)acetic acid (XI) by means of dicyclohexylcarbodiimide (DCC) gives the fully protected cephem derivative (XII), which is deprotected with trifluoroacetic acid and anisole to yield 7-[2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-(N,N-dimethylcarbamoyloxymethyl)-3-cephem-4-carboxylic acid sodium salt (XIII). Finally, this compound is esterified with 1-(isopropoxycarbonyloxy)ethyl iodide (XIV) in DMF.
【1】 Fromtling, R.A.; Castaner, J.; E-1101. Drugs Fut 1995, 20, 8, 766. |
【2】 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. |
【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 |
---|---|---|---|---|---|---|
(I) | 15672 | 7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA | C10H12N2O5S | 详情 | 详情 | |
(II) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
(III) | 15674 | 3-[(acetoxy)methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 51098-29-4 | C16H16N2O6S2 | 详情 | 详情 |
(IV) | 15675 | 3-(hydroxymethyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H14N2O5S2 | 详情 | 详情 | |
(V) | 15676 | benzhydryl 3-(hydroxymethyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H24N2O5S2 | 详情 | 详情 | |
(VI) | 15677 | benzhydryl 3-[[(1H-imidazol-1-ylcarbonyl)oxy]methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H26N4O6S2 | 详情 | 详情 | |
(VII) | 15678 | benzhydryl 3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H29N3O6S2 | 详情 | 详情 | |
(VIII) | 15679 | benzhydryl 3-([[(dimethylamino)carbonyl]oxy]methyl)-5,8-dioxo-7-[[2-(2-thienyl)acetyl]amino]-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H29N3O7S2 | 详情 | 详情 | |
(IX) | 15678 | benzhydryl 3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H29N3O6S2 | 详情 | 详情 | |
(X) | 15681 | benzhydryl 7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H25N3O5S | 详情 | 详情 | |
(XI) | 15682 | 2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-[(benzhydryloxy)imino]acetic acid | C31H25N3O3S | 详情 | 详情 | |
(XII) | 15683 | benzhydryl 7-([2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-[(benzhydryloxy)imino]acetyl]amino)-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C55H48N6O7S2 | 详情 | 详情 | |
(XIII) | 15684 | 7-[2-(2-Aminothiazol-4-yl)-3(Z)-(hydroxyimino)acetamido]-2-(N,N-dimethylcarbamoyloxy)-3-cephem-4-carboxylic acid sodium salt | C16H17N6NaO7S2 | 详情 | 详情 | |
(XIV) | 15685 | 1-iodoethyl isopropyl carbonate | C6H11IO3 | 详情 | 详情 |