【结 构 式】 |
【分子编号】12264 【品名】ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate 【CA登记号】 |
【 分 子 式 】C16H16F3NO4 【 分 子 量 】343.3025896 【元素组成】C 55.98% H 4.7% F 16.6% N 4.08% O 18.64% |
合成路线1
该中间体在本合成路线中的序号:(X)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:(XIV)The anhydrization of pyridine-2,3-dicarboxylic acid (I) with acetic anhydride gives the corresponding anhydride (II), which by treatment with benzylamine (III) is converted into the benzylimide (IV). The hydrogenation of (IV) with H2 over Pd/C yields 8-benzyl-2,8-diazabicyclo[4.3.0]nonane-7,9-dione (V), which is further hydrogenated with LiAlH4, affording (?-cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VI) (1). The optical resolution of (VI) by separation of the cis-(R,R)-isomer as crystalline L-(+)-tartrate and further purification of the cis-(S,S)-isomer (VII) as the D-(-)-tartrate affords enantiomerically pure (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VII). The debenzylation of (VII) by hydrogenolysis with H2 over Pd/C gives (S,S)-2,8-diazabicyclo[4.3.0]nonane (VIII), which is condensed with 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) in basic medium and finally salified with HCl. The 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) has been obtained as follows: The reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride (X) with malonic acid monoethyl ester monopotassium salt (XI) by means of triethylamine gives 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetic acid ethyl ester (XII), which is condensed with triethyl orthoformate yielding the corresponding ethoxymethylene derivative (XIII). The reaction of (XIII) with cyclopropylamine affords the cyclopropylaminomethylene derivative (XIV), which is finally cyclized to (IX) by means of NaF in DMF.
【1】 Martel, A.M.; Leeson, P.A.; Castañer, J.; Bay-12-8039. Drugs Fut 1997, 22, 2, 109. |
【2】 Petersen, U.; Bremm, K.-D.; Dalhoff, A.; Endermann, R.; Heilmann, W.; Krebs, A.; Schenke, T.; Synthesis and in vitro activity of BAY 12-8039, a new 8-methoxy-quinolone. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst. F1.. |
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) | 17246 | 2,3-pyridinedicarboxylic acid; Quinolinic Acid | 89-00-9 | C7H5NO4 | 详情 | 详情 |
(II) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
(III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
(IV) | 17249 | 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione | C14H10N2O2 | 详情 | 详情 | |
(V) | 17250 | 6-benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-dione | C14H16N2O2 | 详情 | 详情 | |
(VI) | 17251 | 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine | C14H20N2 | 详情 | 详情 | |
(VII) | 17252 | (4aS,7aS)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine | C14H20N2 | 详情 | 详情 | |
(VIII) | 17253 | (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine | C7H14N2 | 详情 | 详情 | |
(IX) | 12266 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 112811-72-0 | C14H11F2NO4 | 详情 | 详情 |
(X) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
(XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
(XII) | 12261 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 | |
(XIII) | 12262 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C15H15F3O5 | 详情 | 详情 | |
(XIV) | 12264 | ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C16H16F3NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)The condensation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (I) with 14C-labeled diethyl malonate (II) by means of MgCl2 and TEA gives the benzoylmalonate (III), which is monodecarboxylated with TsOH in refluxing water, yielding the benzoylacetate (IV). The reaction of (IV) with triethyl orthoformate and Ac2O at 140 C affords the benzoylacrylate (V), which is treated with cyclopropylamine (VI) in cyclohexane to provide ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (VII). The cyclization of (VII) by means of K2CO3 in hot N-methylpyrrolidone gives the quinolone carboxylate (VIII), which is hydrolyzed with NaOH in hot methanol, affording the carboxylic acid (IX). Finally, this compound is condensed with (S,S)-2,8-diazabicyclo[4.3.0]octane (X) by means of 1,4-diazabicyclo[2.2.2]octane (DABCO) in refluxing acetonitrile.
【1】 Seidel, D.; Conrad, M.; Brehmer, P.; Mohrs, K.; Petersen, U.; Synthesis of carbon-14 labelled moxifloxacin hydrochloride. J Label Compd Radiopharm 2000, 43, 8, 795. |
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) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
(II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
(II) | 45330 | diethyl malonate | C7H12O4 | 详情 | 详情 | |
(III) | 12260 | diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate | C15H15F3O6 | 详情 | 详情 | |
(III) | 45331 | diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate | C15H15F3O6 | 详情 | 详情 | |
(IV) | 12261 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 | |
(IV) | 45332 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 | |
(V) | 12262 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C15H15F3O5 | 详情 | 详情 | |
(V) | 45333 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C15H15F3O5 | 详情 | 详情 | |
(VI) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
(VII) | 12264 | ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C16H16F3NO4 | 详情 | 详情 | |
(VII) | 45334 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C16H16F3NO4 | 详情 | 详情 | |
(VIII) | 12265 | ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H15F2NO4 | 详情 | 详情 | |
(VIII) | 45335 | ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H15F2NO4 | 详情 | 详情 | |
(IX) | 12266 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 112811-72-0 | C14H11F2NO4 | 详情 | 详情 |
(IX) | 45336 | 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H11F2NO4 | 详情 | 详情 | |
(X) | 17253 | (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine | C7H14N2 | 详情 | 详情 |