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【结 构 式】 
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【分子编号】39828 【品名】4-methoxybenzyl (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 】C18H20N2O6S 【 分 子 量 】392.43268 【元素组成】C 55.09% H 5.14% N 7.14% O 24.46% S 8.17% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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：(XIV)The hydrolysis of p-methoxybenzyl-7-aminocephalosporanate (XIV) with trifluoroacetic acid gives the corresponding tree acid (XXII), which is treated with tert-butoxycarbonylazide (F) yielding the tert-butoxycarbonylamidocephalosporanic acid (XXIII). This compound is deacetylated by treatment with citrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chlorosulfonyl isocyanate gives the 3-carbamoyloxymethyl compound (XXV). The hydrolysis of (XXV) with TFA yields 3-carbamoyloxymethyl-7beta-amino-3-cephem-4-carboxylic acid (XXVI), which is esterified with diphenyldiazomethane in dioxane affording the benzhydryl ester (XXVII). The acylation of (XXVII) with 2-thienylcarbonyl chloride (E) in CH2Cl2 gives the acylated ester (XXVIII), which by methoxylation of (XXVIII) can also be performed through hydroxylation with phenyllithium and tert-butyl hypochlorite (G) in tert-butanol to the 7-hydroxy compound (XXXII), which is then methylated with diazomethane to (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.
| 【1】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【2】 Hazen, G.C. (Merck & Co., Inc.); Process for preparin cephalosporin compounds. DD 100957; ES 408969; US 3780033 . |
| 【3】 Christensen, B.G.; Firestone, R.A.; Process for preparing cephalosporin compounds. DD 100956; ES 408970; US 3775410 . |
| 【4】 Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Process for preparing penicillin and cephalosporin compounds. FR 2163144; GB 1401060; US 3843641 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (F) | 39837 | 2,2-dimethylpropanoyl azide | C5H9N3O | 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 | |
| (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 | |
| (XXIII) | 39838 | (6R,7R)-3-[(acetoxy)methyl]-7-[(2,2-dimethylpropanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H20N2O6S | 详情 | 详情 | |
| (XXIV) | 39839 | (6R,7R)-7-[(2,2-dimethylpropanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C13H18N2O5S | 详情 | 详情 | |
| (XXV) | 39840 | (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-7-[(2,2-dimethylpropanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H19N3O6S | 详情 | 详情 | |
| (XXVI) | 39805 | (6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C9H11N3O5S | 详情 | 详情 | |
| (XXVII) | 39804 | benzhydryl (6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H21N3O5S | 详情 | 详情 | |
| (XXVIII) | 39841 | benzhydryl (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H25N3O6S2 | 详情 | 详情 | |
| (XXX) | 39843 | benzhydryl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H27N3O7S2 | 详情 | 详情 | |
| (XXXII) | 39842 | benzhydryl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-hydroxy-7-[[(Z)-1-methoxy-2-(2-thienyl)ethylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H27N3O7S2 | 详情 | 详情 |