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【结 构 式】 
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【分子编号】14316 【品名】ethyl 4-[2-(benzhydryloxy)-2-oxoethyl]-2,3,5-trifluorobenzoate 【CA登记号】 |
【 分 子 式 】C24H19F3O4 【 分 子 量 】428.4076696 【元素组成】C 67.29% H 4.47% F 13.3% O 14.94% |
合成路线1
该中间体在本合成路线中的序号：(III)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 |
合成路线2
该中间体在本合成路线中的序号：(V)A new synthesis for T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with SOCl2 and ethanol gives ethyl 2,3,4,5-tetrafluorobenzoate (II), which is condensed with di-tert-butyl malonate (III) by means of NaH in DMF and decarboxylated with HCl/trifluoroacetic acid to 4-(carboxymethyl)-2,3,5-trifluorobenzoic acid ethyl ester (IV). Esterification of (IV) with diphenyldiazomethane in ether affords the corresponding ester (V), which is methylenated with bis(dimethylamino)methane (VI) and acetic anhydride in DMSO to give 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoic acid ethyl ester (VII). The cyclopropanation of (VII) with trimethylsulfoxonium iodide and potassium tert-butoxide [(CH3)2SO=CH2] yields the cyclopropane compound (VIII), which is selectively hydrolyzed with trifluoroacetic acid to 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoic acid ethyl ester (IX). The decarboxylative amination of (IX) with ethyl chloroformate, sodium azide and benzyl alcohol gives 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid ethyl ester (X), which is saponified with NaOH in dioxane/ethanol to the corresponding acid (XI). The condensation of (XI) with the magnesium salt of malonic acid mono-tert-butyl ester (XII) by means of carbonyldiimidazole (Im2CO) in THF affords the benzoylacetic ester (XIII), which is treated first with dimethylformamide dimethylacetal (XIV) in refluxing benzene and then with 2-amino-1-propanol (XV) to yield 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)-2-propenoic acid ethyl ester (XVI). The cyclization of (XVI) by means of K2CO3 in hot DMF gives the pyridobenzoxazine (XVII), which is saponified with NaOH in ethanol/dioxane to the corresponding free acid (XVIII). Finally, the amino group of (XVIII) is deprotected by hydrogenation with H2 over Pd/C
| 【1】 Fukuoka, Y.; Nitta, J.; Todo, Y.; Nishida, N.; Saikawa, I.; Narita, H.; Miyajima, M.; Yamashiro, Y.; Pyridonecarboxylic acids as antibacterial agents. VIII. Synthesis and structure-activity relationship of 7-(1-aminocyclopropyl)-4-oxo-1,8-naphthyridine-3-carboxylic acids and 7-(1-aminocyclopropyl)-4-oxoquinoline-3-carboxylic acids. Chem Pharm Bull 1994, 42, 10, 2063. |
| 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) | 14328 | 2,3,4,5-tetrafluorobenzoic acid | 1201-31-6 | C7H2F4O2 | 详情 | 详情 |
| (II) | 14313 | diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate | C27H35N5O7 | 详情 | 详情 | |
| (III) | 14346 | di(tert-butyl) malonate; Di-tert-butyl malonate | 541-16-2 | C11H20O4 | 详情 | 详情 |
| (IV) | 14315 | 2-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]acetic acid | C11H9F3O4 | 详情 | 详情 | |
| (V) | 14316 | ethyl 4-[2-(benzhydryloxy)-2-oxoethyl]-2,3,5-trifluorobenzoate | C24H19F3O4 | 详情 | 详情 | |
| (VI) | 14349 | N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine | 51-80-9 | C5H14N2 | 详情 | 详情 |
| (VII) | 14318 | ethyl 4-[1-[(benzhydryloxy)carbonyl]vinyl]-2,3,5-trifluorobenzoate | C25H19F3O4 | 详情 | 详情 | |
| (VIII) | 14319 | ethyl 4-[1-[(benzhydryloxy)carbonyl]cyclopropyl]-2,3,5-trifluorobenzoate | C26H21F3O4 | 详情 | 详情 | |
| (IX) | 14320 | 1-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]cyclopropanecarboxylic acid | C13H11F3O4 | 详情 | 详情 | |
| (X) | 14353 | benzyl N-[1-(4-acetyl-2,3,6-trifluorophenyl)cyclopropyl]carbamate | C19H16F3NO3 | 详情 | 详情 | |
| (XI) | 14322 | 4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoic acid | C18H14F3NO4 | 详情 | 详情 | |
| (XII) | 14355 | Bis(malonic acid monoethyl ester) magnesium salt | C10H14MgO8 | 详情 | 详情 | |
| (XIII) | 14323 | ethyl 3-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorophenyl]-3-oxopropanoate | C22H20F3NO5 | 详情 | 详情 | |
| (XIV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XV) | 14358 | 2-amino-1-propanol; DL-Alaninol | 6168-72-5 | C3H9NO | 详情 | 详情 |
| (XVI) | 14359 | ethyl (E)-2-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoyl]-3-[(2-hydroxy-1-methylethyl)amino]-2-propenoate | C26H27F3N2O6 | 详情 | 详情 | |
| (XVII) | 14360 | ethyl 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 | |
| (XVIII) | 14361 | 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 |