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【结 构 式】

【分子编号】14324

【品名】ethyl (Z)-2-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate

【CA登记号】

【 分 子 式 】C26H27F3N2O6

【 分 子 量 】520.5054696

【元素组成】C 60% H 5.23% F 10.95% N 5.38% O 18.44%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XI)

Reaction of ethyl 2,3,4,5-tetrafluorobenzoate (I) with the anion of di-tert-butyl malonate followed by in situ decarboxylation with CF3CO2H affords ethyl 4-carboxymethyl-2,3,5-trifluorobenzoate (II), which is esterfied with diphenyldiazomethane to give ethyl 4-(diphenylmethoxycarbonylmethyl)-2,3,5-trifluorobenzoate (III). Compound (III) is treated with p-formaldehyde in the presence of sodium methoxide to give ethyl 4-[1-(diphenylmethoxycarbonyl)-2-hydroxyethyl]-2,3,5-trifluorobenzoate (IV), which is dehydrated with mesyl chloride and triethylamine to give ethyl 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoate (V). Cyclopropanation of (V) with trimethylsulfoxonium iodide affords ethyl 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoate (VII). Treatment of (VII) with ethyl chlorocarbonate and sodium azide followed by reaction with benzyl alcohol affords ethyl 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoate (VIII), which is hydrolyzed to 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid (IX) on treatment with NaOH. Reaction of (IX) with magnesium ethoxycarbonylacetate and 1,1'-carbonyldiimidazole yields ethyl 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoylacetate (X) , which is then sequentially reacted with N,N-dimethylformamide dimethylacetal and (S)-2-amino-1-propanol to give (S)-ethyl 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)acrylate (XI). Cyclization of (XI) with sodium hydride or with K2CO3 (2) affords (S)-ethyl 10-[1-(benzyloxycarbonylamino)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (XII), which is hydrolyzed on treatment with sodium hydroxide to give (S)-10-[1-(benzyloxycarbonylamino)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (XIII). Deprotection of (XIII) by hydrogenation over Pd in acetic acid, followed by treatment with hydrochloric acid, affords the monohydrochloride of T-3761 (XIV), which is finally converted to free T-3761 with potassium hydroxide.

1 Narita, H.; Todo, Y.; Nitta, J.; Takagi, H.; Iino, F.; Miyajima, M.; Fukuoka, Y.; Saikawa, I. (Toyama Chemical Co., Ltd.); Pyridonecarboxylic acid derivs. and their salts, process for their preparation as well as antibacterial agent containing them. CH 680793; DE 3913245; JP 1993043464; US 4990508 .
2 Takakura, I.; Yamakawa, T.; Kitayama, I.; Fujishima, T. (Toyama Chemical Co., Ltd.); Dissolution method for quinolonecarboxylic acids or their salts. JP 1990264724 .
3 Prous, J.; Mealy, N.; Castaner, J.; T-3761. Drugs Fut 1993, 18, 8, 717.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14341 L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol 2749-11-3 C3H9NO 详情 详情
(I) 14314 ethyl 2,3,4,5-tetrafluorobenzoate C9H6F4O2 详情 详情
(II) 14315 2-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]acetic acid C11H9F3O4 详情 详情
(III) 14316 ethyl 4-[2-(benzhydryloxy)-2-oxoethyl]-2,3,5-trifluorobenzoate C24H19F3O4 详情 详情
(IV) 14317 ethyl 4-[2-(benzhydryloxy)-1-(hydroxymethyl)-2-oxoethyl]-2,3,5-trifluorobenzoate C25H21F3O5 详情 详情
(V) 14318 ethyl 4-[1-[(benzhydryloxy)carbonyl]vinyl]-2,3,5-trifluorobenzoate C25H19F3O4 详情 详情
(VI) 14319 ethyl 4-[1-[(benzhydryloxy)carbonyl]cyclopropyl]-2,3,5-trifluorobenzoate C26H21F3O4 详情 详情
(VII) 14320 1-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]cyclopropanecarboxylic acid C13H11F3O4 详情 详情
(VIII) 14321 ethyl 4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoate C20H18F3NO4 详情 详情
(IX) 14322 4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoic acid C18H14F3NO4 详情 详情
(X) 14323 ethyl 3-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorophenyl]-3-oxopropanoate C22H20F3NO5 详情 详情
(XI) 14324 ethyl (Z)-2-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate C26H27F3N2O6 详情 详情
(XII) 14325 ethyl (3S)-10-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C26H25FN2O6 详情 详情
(XIII) 14326 (3S)-10-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid C24H21FN2O6 详情 详情
(XIV) 14327 (3S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid C16H15FN2O4 详情 详情
Extended Information