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【结 构 式】

【分子编号】31128

【品名】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

【CA登记号】

【 分 子 式 】C47H43N3O8S

【 分 子 量 】809.93984

【元素组成】C 69.7% H 5.35% N 5.19% O 15.8% S 3.96%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

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.

参考文献 中间体
合成目标
【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：(II)

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.

参考文献 中间体
合成目标
【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
Extended Information