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【结 构 式】 
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【分子编号】39805 【品名】(6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C9H11N3O5S 【 分 子 量 】273.26956 【元素组成】C 39.56% H 4.06% N 15.38% O 29.27% S 11.73% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)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 |
合成路线2
该中间体在本合成路线中的序号：(IV)Compound can be prepared by several related ways: 1) The reaction of diphenylmethyl (6R,7R)-3-hydroxymethyl-7-(2-thienylacetamido)ceph-3-em-4-carboxylate (I) with trichloroacetyl isocyanate (A) in anhydrous acetone gives the corresponding N-trichloroacetylcarbamate (II), which by reaction with PCl5 and pyridine in CH2Cl2 and then with p-toluenesulfonic acid affords diphenylmethyl 7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate p-toluenesulfonic acid salt (III). The hydrolysis of (III) with trifluoroacetic acid in anisole yields the corresponding acid (IV), which is finally condensed with 2-(2-furyl)-2-methoxyiminoacetic acid (V) by means of PCl5 and N,N-dimethylacetamide in acetonitrile containing triethylamine. 2) The elimination of the protecting groups of compound (II) can also be performed stepwise with isolation of the intermediate p-toluenesulfonic salt (VI). 3) The deprotected compound (III) can also be treated first with NaHCO3 and then condensed with the acetic acid (V) by means of dicyclohexylcarbodiimide in CH2Cl2 to give the diphenvimethyl ester (VII), which is finally hydrolyzed with trifluoroacetic acid.
| 【1】 Loren, J.G.; Castañer, J.; Cefuroxime. Drugs Fut 1978, 3, 4, 266. |
| 【2】 Cook, M.C.; et al. (Glaxo Group Ltd.); 7-Hydrocarbonoxyiminoacetamido-3-carbamoyloxy methylceph-3-em-4 carboxylic acids. US 3974153 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 39802 | 2,2,2-trichloroacetyl thiocyanate | C3Cl3NOS | 详情 | 详情 | |
| (I) | 39801 | benzhydryl (6R,7R)-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 | |
| (II) | 39803 | benzhydryl (6R,7R)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-3-[([[(2,2,2-trichloroacetyl)amino]carbonyl]oxy)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H24Cl3N3O7S2 | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 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 | |
| (V) | 39806 | 2-(2-furyl)-2-(methoxyimino)acetic acid | C7H7NO4 | 详情 | 详情 | |
| (VI) | 39807 | benzhydryl (6R,7R)-7-amino-8-oxo-3-[([[(2,2,2-trichloroacetyl)amino]carbonyl]oxy)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H20Cl3N3O6S | 详情 | 详情 | |
| (VII) | 39808 | benzhydryl (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-7-[[2-(2-furyl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H26N4O8S | 详情 | 详情 |