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【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information