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【结 构 式】 
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【分子编号】39829 【品名】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 【CA登记号】 |
【 分 子 式 】C25H23N3O8S 【 分 子 量 】525.53904 【元素组成】C 57.14% H 4.41% N 8% O 24.36% S 6.1% |
合成路线1
该中间体在本合成路线中的序号：(XV)3) By reaction of 4-methoxybenzylamine (I) with methyl isothiocyanate (B) in ether to yield N-(4-methoxybenzyl)-N'-methylthiourea (III), which is then methylated with MeI in refluxing methanol affording N-(4-methoxybenzyl)-N',S-dimethylisothiourea (IV). Finally, this compound is treated first with methylamine in refluxing methanol and then with H2SO4.
| 【1】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【2】 Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates. Tetrahedron Lett 1973, 46, 4645-48. |
| 【3】 Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin. Tetrahedron Lett 1973, 46, 4649-52. |
| 【4】 Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (A) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (I) | 39815 | 1,3,5-tribenzyl-1,3,5-triazinane | 2547-66-2 | C24H27N3 | 详情 | 详情 |
| (II) | 39816 | diethyl (benzylamino)methylphosphonate | C12H20NO3P | 详情 | 详情 | |
| (III) | 39817 | diethyl aminomethylphosphonate | C5H14NO3P | 详情 | 详情 | |
| (IV) | 39818 | diethyl [[(E)-benzylidene]amino]methylphosphonate | 50917-73-2 | C12H18NO3P | 详情 | 详情 |
| (V) | 39819 | 1-[[(chlorocarbonyl)oxy]methyl]-4-methoxybenzene | C9H9ClO3 | 详情 | 详情 | |
| (VI) | 39820 | 4-methoxybenzyl 2-(diethoxyphosphoryl)-2-[[(E)-benzylidene]amino]acetate | C21H26NO6P | 详情 | 详情 | |
| (VII) | 39821 | 4-methoxybenzyl 2-amino-2-(diethoxyphosphoryl)acetate | C14H22NO6P | 详情 | 详情 | |
| (VIII) | 39822 | O-ethyl thioformate | C3H6OS | 详情 | 详情 | |
| (IX) | 39823 | 4-methoxybenzyl 2-(diethoxyphosphoryl)-2-(thioformylamino)acetate | C15H22NO6PS | 详情 | 详情 | |
| (X) | 39824 | 3-chloro-2-oxopropyl acetate | 40235-68-5 | C5H7ClO3 | 详情 | 详情 |
| (XI) | 39825 | 4-methoxybenzyl 5-[(acetoxy)methyl]-6H-1,3-thiazine-4-carboxylate | C16H17NO5S | 详情 | 详情 | |
| (XII) | 39826 | 2-azidoacetyl chloride | C2H2ClN3O | 详情 | 详情 | |
| (XIII) | 39827 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-azido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H18N4O6S | 详情 | 详情 | |
| (XIV) | 39828 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H20N2O6S | 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 | |
| (C) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)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 |