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【结 构 式】 
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【分子编号】39835 【品名】(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 【CA登记号】 |
【 分 子 式 】C17H18N2O7S2 【 分 子 量 】426.4712 【元素组成】C 47.88% H 4.25% N 6.57% O 26.26% S 15.04% |
合成路线1
该中间体在本合成路线中的序号：(XX)The reaction of the Schift base (XV) phenyllithium and CH3SCl (D) in DMF gives the corresponding methylthio derivative (XVI), which is debenzylated with 2,4-DNPH p-toluenesulfonate in ethanol yielding p-methoxybenzyl-7beta-amino-7alpha-thiomethyl-3-acetoxymethyl-3-cephem-4-carboxylate (XVII). The acylation of (XVII) with 2-thienylacetyl chloride (E) / pyridine in CH2Cl2 provided the corresponding 2-thienylacetamido derivative (XVIII), which by methanolysis in the presence of thallium trinitrate gives the 7alpha-methoxy derivative (XIX). The p-methoxybenzyl ester of (XIX) is cleaved with TFA-anisole affording 7alpha-methoxycephalothin-(7alpha-methoxy-7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid) (XX), which is deacetylated with citrus acetyl enzyme yielding the corresponding hydroxymethyl compound (XXI). Finally, this compound is treated with chlorosulfonyl isocyanate in THF or acetonitrile.
| 【1】 Ratcliffe, R.W.; Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin. Tetrahedron Lett 1973, 46, 4653-56. |
| 【2】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【3】 Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488 . |
| 【4】 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 |
| (D) | 39830 | methanesulfenyl chloride | 5813-48-9 | CH3ClS | 详情 | 详情 |
| (XV) | 39829 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-[[(E)-(4-nitrophenyl)methylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C25H23N3O8S | 详情 | 详情 | |
| (XVI) | 39831 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-(methylsulfanyl)-7-[[(E)-(4-nitrophenyl)methylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H25N3O8S2 | 详情 | 详情 | |
| (XVII) | 39832 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-amino-7-(methylsulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C19H22N2O6S2 | 详情 | 详情 | |
| (XVIII) | 39833 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-(methylsulfanyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C25H26N2O7S3 | 详情 | 详情 | |
| (XIX) | 39834 | 4-methoxybenzyl (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 | C25H26N2O8S2 | 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 | |
| (XXI) | 39836 | (6R,7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H16N2O6S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)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 |