【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% |
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 |