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【结 构 式】 
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【分子编号】31133 【品名】benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C34H33N5O8S2 【 分 子 量 】703.79692 【元素组成】C 58.02% H 4.73% N 9.95% O 18.19% S 9.11% |
合成路线1
该中间体在本合成路线中的序号：(X)The reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (I), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (II), which by reaction with PCl5 is converted into the corresponding chloromethyl derivative (III). The reaction of (III) with triphenyl phosphine and NaI in DMF yields the phosphonium iodide (IV), which by a Wittig condensation with formaldehyde in methylene chloride affords benzhydryl-7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-vinyl-3-cephem-4-carboxylate (V). The cleavage of (V) with PCl-pyridine in methylene chloride gives benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (VI), which is condensed with 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (VII) [prepared from 2-formamidothiazol-4-yl)oxoacetic acid (VIII) and tert-butyl aminooxyacetate (IX)] yielding benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido-3-vinyl-3-cephem-4-carboxylate (X). The hydrolysis of (X) with HCl in methanol affords the 2-amino derivative (XI), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.
| 【1】 Takaya, T.; Tagasuki, H.; Masugi, T.; Yamanaka, H.; Kawabata, K. (Fujisawa Pharmaceutical Co., Ltd.); Starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. EP 0030630; EP 0123024; EP 0244637; JP 6279452; US 4409214; US 4423213 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; FR-17,027. Drugs Fut 1983, 8, 8, 682. |
| 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) | 31127 | sodium (6R,7R)-7-[(5-amino-5-carboxypentanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H18N3NaO7S | 详情 | 详情 | |
| (II) | 31128 | benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C47H43N3O8S | 详情 | 详情 | |
| (III) | 31129 | benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C47H42ClN3O7S | 详情 | 详情 | |
| (IV) | 31130 | ([(6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-2-[(benzhydryloxy)carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl)(triphenyl)phosphonium | C65H57N3O7PS | 详情 | 详情 | |
| (V) | 31131 | benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C48H43N3O7S | 详情 | 详情 | |
| (VI) | 22001 | benzhydryl (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H20N2O3S | 详情 | 详情 | |
| (VII) | 24084 | 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid | C12H15N3O6S | 详情 | 详情 | |
| (VIII) | 24090 | tert-butyl 2-(aminooxy)acetate | C6H13NO3 | 详情 | 详情 | |
| (IX) | 31132 | 2-[2-(formylamino)-1,3-thiazol-4-yl]-2-oxoacetic acid | C6H4N2O4S | 详情 | 详情 | |
| (X) | 31133 | benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H33N5O8S2 | 详情 | 详情 | |
| (XI) | 31134 | benzhydryl (6R,7R)-7-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C33H33N5O7S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (I), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (II), which by reaction with PCl5 under stronger conditions than before gives benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate (XII), which is condensed with (VII) by means of POCl3 in DMF as before, yielding the chloromethyl compound (XIII). The reaction of (XIII) with triphenyiphosphine and NaI affords the phosphonium salt (XIV), which is finally submitted to a Wittig condensation with formaldehyde giving (X). The hydrolysis of (X) with HCl in methanol affords the 2-amino derivative (XI), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.
| 【1】 Takaya, T.; Tagasuki, H.; Masugi, T.; Yamanaka, H.; Kawabata, K. (Fujisawa Pharmaceutical Co., Ltd.); Starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. EP 0030630; EP 0123024; EP 0244637; JP 6279452; US 4409214; US 4423213 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; FR-17,027. Drugs Fut 1983, 8, 8, 682. |
| 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) | 31127 | sodium (6R,7R)-7-[(5-amino-5-carboxypentanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H18N3NaO7S | 详情 | 详情 | |
| (II) | 31128 | benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C47H43N3O8S | 详情 | 详情 | |
| (VII) | 24084 | 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid | C12H15N3O6S | 详情 | 详情 | |
| (X) | 31133 | benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H33N5O8S2 | 详情 | 详情 | |
| (XI) | 31134 | benzhydryl (6R,7R)-7-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C33H33N5O7S2 | 详情 | 详情 | |
| (XII) | 31135 | benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H19ClN2O3S | 详情 | 详情 | |
| (XIII) | 31136 | benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C33H32ClN5O8S2 | 详情 | 详情 | |
| (XIV) | 31137 | [[(6R,7R)-2-[(benzhydryloxy)carbonyl]-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium | C51H47N5O8PS2 | 详情 | 详情 |