【结 构 式】 |
【分子编号】12258 【品名】2,4,5-Trifluoro-3-methoxybenzoic acid 【CA登记号】112811-65-1 |
【 分 子 式 】C8H5F3O3 【 分 子 量 】206.1211096 【元素组成】C 46.62% H 2.45% F 27.65% O 23.29% |
合成路线1
该中间体在本合成路线中的序号:(IV)The reaction of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (I) with CuCN and N-methyl-2-pyrrolidone at 150 C gives 2,4,5-trifluoro-3-methoxybenzonitrile (II), which by treatment with concentrated H2SO4 yields the benzamide (III). The hydrolysis of (III) with H2SO4 - water at 110 C affords 2,4,5-trifluoro-2-methoxybenzoic acid (IV), which by reaction with SOCl2 is converted into the acyl chloride (V). The condensation of (V) with diethyl malonate by means of magnesium ethoxide in toluene affords diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate (VI), which by treatment with p-toluenesulfonic acid in refluxing water gives ethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetate (VII). The condensation of (VII) with triethyl orthoformate in refluxing acetic anhydride yields 3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylic acid ethyl ester (VIII), which is treated with cyclopropylamine (IX) to afford the corresponding cyclopropylamino derivative (X). The cyclization of (X) by means of NaF in refluxing DMF gives 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XI), which is hydrolyzed with H2SO4 in acetic acid to yield the corresponding free acid (XII). Finally, this compound is condensed with 2-methylpiperazine (XIII) in hot DMSO.
【1】 Masuzawa, K.; Suzue, S.; Hirai, K.; Ishizaki, T. (Kyorin Pharmaceutical Co., Ltd.); 8-Alkyoxyquinolonecarboxylic acid and salts thereof excellent in the selective toxicity and process for preparing the same. EP 0230295; JP 1987252772; JP 1994080640; JP 1994092937; JP 1995304706; JP 1995304742; US 4980470 . |
【2】 Prous, J.; Castaner, J.; AM-1155. Drugs Fut 1993, 18, 3, 203. |
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) | 12255 | 3-Bromo-2,5,6-trifluorophenyl methyl ether; 1-Bromo-2,4,5-trifluoro-3-methoxybenzene | C7H4BrF3O | 详情 | 详情 | |
(II) | 12256 | 2,4,5-Trifluoro-3-methoxybenzonitrile | C8H4F3NO | 详情 | 详情 | |
(III) | 12257 | 2,4,5-Trifluoro-3-methoxybenzamide | C8H6F3NO2 | 详情 | 详情 | |
(IV) | 12258 | 2,4,5-Trifluoro-3-methoxybenzoic acid | 112811-65-1 | C8H5F3O3 | 详情 | 详情 |
(V) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
(VI) | 12260 | diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate | C15H15F3O6 | 详情 | 详情 | |
(VII) | 12261 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 | |
(VIII) | 12262 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C15H15F3O5 | 详情 | 详情 | |
(IX) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
(X) | 12264 | ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C16H16F3NO4 | 详情 | 详情 | |
(XI) | 12265 | ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H15F2NO4 | 详情 | 详情 | |
(XII) | 12266 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 112811-72-0 | C14H11F2NO4 | 详情 | 详情 |
(XIII) | 12267 | 2-Methylpiperazine | 109-07-9 | C5H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)The reaction of 2,4,5-trifluoro-3-methoxybenzoic acid (I) with SOCl2 in toluene gives the corresponding acyl chloride (II), which is condensed with 3-(dimethylamino)acrylic acid ethyl ester (III) by means of TEA to yield 3-(dimethylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylic acid ethyl ester (IV). The cyclization of (IV) with 2-fluorocyclopropylamine (V) by means of TEA and K2CO3 in DMF affords the quinolone-3-carboxylate (VI), which is hydrolyzed with HCl in HOAc to provide the carboxylic acid (VII). The reaction of (VII) with BF3/Et2O in diethyl ether gives the boronic ester (VIII), which is condensed with the spiropyrrolidine (IX) by means of TEA in ethanol. Finally, the boronic ester of (IX) is hydrolyzed with HCl to afford the target quinolone-3-carboxylic acid.
【1】 Kawakami, K.; et al.; DK-570k, a new 8-methoxyquinolone: Synthesis and biological evaluation of 7-[(3-amino-4-substituted)pyrrolidin-1-yl] derivatives. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-546. |
【2】 Suzuki, T.; Takahashi, H.; Hayakawa, I.; Takemura, M.; Ohtani, T.; Kawakami, K.; Itoh, M.; Miyauchi, R.; Sekiguchi, M. (Daiichi Pharmaceutical Co., Ltd.); Quinolonecarboxylic acid deriv.. WO 0172738 . |
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) | 12258 | 2,4,5-Trifluoro-3-methoxybenzoic acid | 112811-65-1 | C8H5F3O3 | 详情 | 详情 |
(II) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
(III) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
(IV) | 53193 | ethyl (Z)-3-(dimethylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | n/a | C15H16F3NO4 | 详情 | 详情 |
(V) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
(VI) | 53194 | ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C16H14F3NO4 | 详情 | 详情 |
(VII) | 53195 | 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | n/a | C14H10F3NO4 | 详情 | 详情 |
(VIII) | 53196 | 3-{[(difluoroboryl)oxy]carbonyl}-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4(1H)-quinolinone | n/a | C14H9BF5NO4 | 详情 | 详情 |
(IX) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
(X) | 53197 | tert-butyl (7S)-5-{3-{[(difluoroboryl)oxy]carbonyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl}-5-azaspiro[2.4]hept-7-ylcarbamate | n/a | C25H28BF4N3O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IV)
【1】 Masuzawa K. 1987.8-Alkoxyquinolone carboxlic acids and salts there of excellent in the selective toxicity and process of preparing the same. EP 0230259(本专利为Kyorin Pharmaceutical Co Ltd所有) |
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) | 12255 | 3-Bromo-2,5,6-trifluorophenyl methyl ether; 1-Bromo-2,4,5-trifluoro-3-methoxybenzene | C7H4BrF3O | 详情 | 详情 | |
(II) | 12256 | 2,4,5-Trifluoro-3-methoxybenzonitrile | C8H4F3NO | 详情 | 详情 | |
(III) | 12257 | 2,4,5-Trifluoro-3-methoxybenzamide | C8H6F3NO2 | 详情 | 详情 | |
(IV) | 12258 | 2,4,5-Trifluoro-3-methoxybenzoic acid | 112811-65-1 | C8H5F3O3 | 详情 | 详情 |
(V) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
(VI) | 12260 | diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate | C15H15F3O6 | 详情 | 详情 | |
(VII) | 12261 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 |