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【结 构 式】 
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【分子编号】39849 【品名】benzhydryl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C23H22N2O5S 【 分 子 量 】438.50416 【元素组成】C 63% H 5.06% N 6.39% O 18.24% S 7.31% |
合成路线1
该中间体在本合成路线中的序号：(XXXVI)The acylation and methoxylation of 7-aminocephalosporanic acid (XXII) to (XX) can also be performed as follows: The acid (XXII) is esterified with diphenyldiazomethane in dioxane giving the ester (XXXVI), which is treated with NaNO2 and p-toluenesulfonic acid in CH2Cl2 yielding benzhydryl 7-diazocephalosporanate (XXXVII). The reaction of this compound with BrN3 in CH2Cl2-acetonitrile affords benzhydryl 7alpha-bromo-7beta-azidocephalosporanate (XXXVIII), which by hydrolysis with MeOH and AgBF4 is converted into the corresponding 7beta-methoxy compound (XXXIX). Hydrogenation of the azido group of (XXXIX) with H2 over PtO2 in dioxane gives 7alpha-methoxy-7beta-aminocephalosporanate (XL), which is acylated with 2-thienylcarbonyl chloride (E) in CH2Cl2 affording benzhydryl-7alpha-methoxy-7beta-(2-thienylacetamido)cephalosporanate (XLI). Finally, this compound is hydrolyzed to (XX) with trifluoroacetic acid.
| 【1】 Christensen, B.G.; et al.; In 7-Stellung substituierte Cephalosphoransaureester und Verfahren zu ihrer Herstellung. DE 2143331 . |
| 【2】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【3】 Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Antibiotics and processes for their production. DE 2203653; FR 2161866; GB 1350772 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (XX) | 39835 | (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N2O7S2 | 详情 | 详情 | |
| (XXII) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (XXXVI) | 39849 | benzhydryl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H22N2O5S | 详情 | 详情 | |
| (XXXVII) | 39850 | C23H21N3O5S | 详情 | 详情 | ||
| (XXXVIII) | 39851 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-azido-7-bromo-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H19BrN4O5S | 详情 | 详情 | |
| (XXXIX) | 39852 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-azido-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H22N4O6S | 详情 | 详情 | |
| (XL) | 39853 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H24N2O6S | 详情 | 详情 | |
| (XLI) | 39854 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H28N2O7S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)7-Aminocephalosporanic acid (I) was esterified with diphenyldiazomethane to produce the benzhydryl ester (II). Diazotization of (II) with isopropyl nitrite in the presence of trifluoroacetic acid, followed by treatment of the resulting diazo compound with propylene oxide and a catalytic amount of rhodium (II) octanoate, gave the corresponding 7-oxocephalosporanate (III). Wittig reaction of ketone (III) with the ylide resulting from 2-picolyltriphenylphosphonium chloride (IV) and NaNH2 in cold THF yielded olefin (V). Cephem double-bond isomerization upon treatment with triethylamine produced the 2-cephem derivative (VI) as the major compound, which was separated from the unreacted 3-cephem by flash chromatography. Acid hydrolysis of acetate ester (VI) gave rise to the corresponding alcohol (VII), which was further oxidized to aldehyde (VIII) by using pyridinium dichromate. Condensation of aldehyde (VIII) with the Wittig reagent (III) produced adduct (IX).
| 【1】 Adam, G.; Doppalapudi, V.R.; Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; New cephalosporin-derived beta-lactamase inhibitors. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F403. |
| 【2】 Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; Doppalapudi, V.R.; Adam, G.C. (Research Corporation Technologies, Inc.); beta-Lactamase inhibiting cpds.. WO 0063213 . |
| 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) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (II) | 39849 | benzhydryl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H22N2O5S | 详情 | 详情 | |
| (III) | 47065 | benzhydryl (6R)-3-[(acetoxy)methyl]-7,8-dioxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H19NO6S | 详情 | 详情 | |
| (IV) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (V) | 47066 | benzhydryl (6R)-3-[(acetoxy)methyl]-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H24N2O5S | 详情 | 详情 | |
| (VI) | 47067 | benzhydryl (2R,6R)-3-[(acetoxy)methyl]-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C29H24N2O5S | 详情 | 详情 | |
| (VII) | 47068 | benzhydryl (2R,6R)-3-(hydroxymethyl)-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C27H22N2O4S | 详情 | 详情 | |
| (VIII) | 47069 | benzhydryl (2R,6R)-3-formyl-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C27H20N2O4S | 详情 | 详情 | |
| (IX) | 47070 | benzhydryl (2R,6R)-8-oxo-3-[(E)-2-(2-pyridinyl)ethenyl]-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C33H25N3O3S | 详情 | 详情 |