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【结 构 式】 
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【分子编号】26347 【品名】3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride 【CA登记号】98-16-8 |
【 分 子 式 】C7H6F3N 【 分 子 量 】161.1265896 【元素组成】C 52.18% H 3.75% F 35.37% N 8.69% |
合成路线1
该中间体在本合成路线中的序号：(V)Two different ways to obtain talniflumate were developed: The first method is by reacting the previously salified niflumic acid (II) with 3-bromophthalide (I). The second way is by condensation of salified 2-halonicotinic acid (III) with 3-bromophthalide (I) to give the corresponding phthalidyl ester (IV), which is then treated with 3-trifluoromethylaniline (V).
| 【1】 Boned, J.; Los, M.; Piccinali, C.; Acidos anilino nicotinico y N-arilantranilicos convenientemente sustituidos. VII Latinoamerican Congress Pharmacology 1978. |
| 【2】 GB 381578 . |
| 【3】 US 879749 . |
| 【4】 Procedimiento para la obtencion de nuevos esterees de acidos fenil- y piridin-3-carboxilicos sustituidos. ES 474566 . |
| 【5】 Phthalidyl 2-(3'-trifluoromethylanilino)pyridine-3-caboxylalate and process for its preparation. AR 209858; GB 1553171 . |
| 【6】 Nouveaux esters d'acides phényl- et pyridine-3-carboxylique et procédé premettant leur préparation. BE 0858864 . |
| 【7】 Torriani, H.; Talniflumate. Drugs Fut 1979, 4, 6, 448. |
| 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) | 24560 | 3-Bromophthalide; 3-Bromo-2-benzofuran-1(3H)-one | 6940-49-4 | C8H5BrO2 | 详情 | 详情 |
| (II) | 33257 | sodium 2-[3-(trifluoromethyl)anilino]nicotinate | C13H8F3N2NaO2 | 详情 | 详情 | |
| (III) | 33255 | sodium 2-chloronicotinate | C6H3ClNNaO2 | 详情 | 详情 | |
| (IV) | 33256 | 3-oxo-1,3-dihydro-2-benzofuran-1-yl 2-chloronicotinate | C14H8ClNO4 | 详情 | 详情 | |
| (V) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)In a different procedure, 2-chloronicotinic acid (III) was chlorinated to (IV) by means of boiling thionyl chloride. Condensation of acid chloride (IV) with 2-morpholinoethanol (V) gave rise to the morpholinoethyl chloronicotinate (VI). Finally, displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) in the presence of zinc oxide and iodine furnished the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VI) | 56318 | 2-(4-morpholinyl)ethyl 2-chloronicotinate | C12H15ClN2O3 | 详情 | 详情 | |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Alternatively, acid chloride (IV), prepared from 2-chloronicotinic acid (III), was treated with methanol and triethylamine to afford the methyl ester (VIII). Displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) yielded methyl niflumate (IX). Finally, transesterification of methyl ester (IX) with 2-morpholinoethanol (V) in the presence of sodium metal gave rise to the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (VIII) | 56319 | methyl 2-chloronicotinate | C7H6ClNO2 | 详情 | 详情 | |
| (IX) | 56320 | methyl 2-[3-(trifluoromethyl)anilino]nicotinate | C14H11F3N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)A synthesis of [14C]-labeled SR-57746A has been described: The iodination of [14C6]-benzene (I) with nitric acid/I2 gives iodobenzene (II), which is treated with sodium trifluoroacetate and CuI yielding trifluoromethylbenzene (III). The nitration of (III) with sodium nitrate affords 3-(trifluoromethyl)nitrobenzene (IV), which is reduced with Fe/HCl to the corresponding aniline (V). The reaction of (V) with tert-butyl nitrite and CuBr2 provides 3-(trifluoromethyl)bromobenzene (VI), which is treated with Mg in THF affording the corresponding Grignard reagent (VII). The condensation of (VII) with piperidone (VIII) gives the piperidol (IX), which is finally dehydrated in acidic medium. In order to aviod radioactive contamination during the purification of compounds iodobenzene (II) and trifluoromethylbenzene (III) by liquid chromatography, a safer route using less volatile compounds has been developed: The nitration of [14C6]-benzene (I) with nitric acid gives nitrobenzene (X), which is iodinated with IPy2BF4/CF3SO3H yielding 3-iodonitrobenzene (XI). Finally, this compound is trifluoromethylated with CF3SiMe3, CuI and KF to provide 3-(trifluoromethyl)nitrobenzene (IV) already reported.
| 【1】 Robic, N.; Noel, J.P.; Synthesis of [trifluoromethyl-[C-14(6)]-phenyl] SR 57746A. J Label Compd Radiopharm 1999, 42, 2, 109. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (I) | 45201 | benzene | C6H6 | 详情 | 详情 | |
| (II) | 26344 | 1-Iodobenzene | 591-50-4 | C6H5I | 详情 | 详情 |
| (II) | 45202 | 1-iodobenzene | C6H5I | 详情 | 详情 | |
| (III) | 26345 | 1-(Trifluoromethyl)benzene | 98-08-8 | C7H5F3 | 详情 | 详情 |
| (III) | 45203 | 1-(trifluoromethyl)benzene | C7H5F3 | 详情 | 详情 | |
| (IV) | 26346 | 1-nitro-3-(trifluoromethyl)benzene | 98-46-4 | C7H4F3NO2 | 详情 | 详情 |
| (IV) | 45204 | 1-nitro-3-(trifluoromethyl)benzene | C7H4F3NO2 | 详情 | 详情 | |
| (V) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (V) | 45205 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline | C7H6F3N | 详情 | 详情 | |
| (VI) | 26348 | 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride | 401-78-5 | C7H4BrF3 | 详情 | 详情 |
| (VI) | 45206 | 1-bromo-3-(trifluoromethyl)benzene | C7H4BrF3 | 详情 | 详情 | |
| (VII) | 12028 | Bromo[3-(trifluoromethyl)phenyl]magnesium | 402-26-6 | C7H4BrF3Mg | 详情 | 详情 |
| (VII) | 45207 | bromo[3-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (VIII) | 26349 | 1-[2-(2-naphthyl)ethyl]-4-piperidinone | C17H19NO | 详情 | 详情 | |
| (IX) | 26350 | 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H24F3NO | 详情 | 详情 | |
| (IX) | 45208 | 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H24F3NO | 详情 | 详情 | |
| (X) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (X) | 45209 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (XI) | 26352 | 3-Iodonitrobenzene; 1-iodo-3-nitrobenzene | 645-00-1 | C6H4INO2 | 详情 | 详情 |
| (XI) | 45210 | 1-iodo-3-nitrobenzene | C6H4INO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)3-(Trifluoromethyl)aniline (I) was protected as the tert-butyl carbamate (II) by treatment with Boc2O at 80 C. Lithiation of (II) with sec-butyllithium at -78 C, followed by condensation with diethyl oxalate afforded keto ester (III). Subsequent acid hydrolysis of the Boc group of (III) with concomitant cyclization gave rise to 6-(trifluoromethyl)isatin (IV). Addition of Grignard reagent (V) to (IV) produced the 3-hydroxy-3-aryloxindole (VI). Conversion of (VI) to the corresponding 3-fluoro oxindole was then effected by treatment with diethylaminosulfur trifluoride at low temperature. Finally, optical resolution by means of chiral HPLC furnished the title (S)-enantiomer.
| 【1】 Hewawasam, P.; et al.; The synthesis and characterization of BMS-204352 (MaxiPost) and related 3-fluorooxindoles as openers of maxi-K potassium channels. Bioorg Med Chem Lett 2002, 12, 7, 1023. |
| 【2】 Starrett, J.E. Jr.; Hewawasam, P.; Ortiz, A.A.; et al.; Synthesis, pharmacokinetic analysis and MCAO stroke activity of the maxi-K opener BMS-204352. Pottasium Channels: Struct Funct Ther Util (March 11 2000, Tahoe City) 2000, Abst 315. |
| 【3】 Martín, L.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; BMS-204352. Drugs Fut 2001, 26, 1, 9. |
| 【4】 Hewawasam, P.; Meanwell, N.A.; Gribkoff, V.K. (Bristol-Myers Squibb Co.); 3-Substd. oxindole derivs. as potassium channel modulators. CA 2176183; EP 0747354; JP 1996333336; US 5565483; US 5602169 . |
| 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) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (II) | 39335 | tert-butyl 3-(trifluoromethyl)phenylcarbamate | C12H14F3NO2 | 详情 | 详情 | |
| (III) | 39336 | ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate | C16H18F3NO5 | 详情 | 详情 | |
| (IV) | 39337 | 6-(trifluoromethyl)-1H-indole-2,3-dione | C9H4F3NO2 | 详情 | 详情 | |
| (V) | 39338 | bromo(5-chloro-2-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (VI) | 39339 | 3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C16H11ClF3NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The reaction of 3-(trifluoromethyl)aniline (I) with Boc2O gives the carbamate (II), which is condensed with 14C labeled diethyl oxalate (III) by means of BuLi to yield the ketoester (IV). The cyclization of (IV) by means of refluxing aq. HCl affords the labeled 6-(trifluoromethyl)isatin (V), which is condensed with 5-chloro-2-methoxyphenylmagnesium bromide (VI) to provide the hydroxyketone (VII). The fluorination of (VII) with DAST gives the target compound as a racemic mixture (VIII), which is finally submitted to optical resolution by chiral HPLC.
| 【1】 Dischino, D.D.; Gribkoff, V.K.; Hewawasam, P.; Luke, G.M.; Rinehart, J.K.; Spears, T.L.; Starrett, J.E. Jr.; Synthesis of 3H and 14C labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, MaxiPost(TM). An agent for post-stroke neuroprotection. J Label Compd Radiopharm 2003, 46, 2, 139. |
| 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) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (II) | 39335 | tert-butyl 3-(trifluoromethyl)phenylcarbamate | C12H14F3NO2 | 详情 | 详情 | |
| (III) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (III) | 64193 | allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate | C82H151N2O18PSi | 详情 | 详情 | |
| (IV) | 39336 | ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate | C16H18F3NO5 | 详情 | 详情 | |
| (IV) | 64197 | ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate | C16H18F3NO5 | 详情 | 详情 | |
| (V) | 39337 | 6-(trifluoromethyl)-1H-indole-2,3-dione | C9H4F3NO2 | 详情 | 详情 | |
| (V) | 64198 | 6-(trifluoromethyl)-1H-indole-2,3-dione | C9H4F3NO2 | 详情 | 详情 | |
| (VI) | 39338 | bromo(5-chloro-2-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (VII) | 39339 | 3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C16H11ClF3NO3 | 详情 | 详情 | |
| (VII) | 64199 | 3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C16H11ClF3NO3 | 详情 | 详情 | |
| (VIII) | 43889 | 3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C16H10ClF4NO2 | 详情 | 详情 | |
| (VIII) | 64200 | 3-(5-Chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-2,3-dihydro-1H-indol-2-one | C16H10ClF4NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The intermediate anthranilamide (IV) is prepared by two alternative methods. Acylation of 3-(trifluoromethyl)aniline (I) with 2-nitrobenzoyl chloride (II) yields benzamide (III). The nitro group of (III) is then reduced to the corresponding amine (IV) by catalytic hydrogenation over Pd/C (1). Alternatively, 3-(trifluoromethyl)aniline (I) is condensed with isatoic anhydride (V) to furnish directly anthranilamide (IV) (2). Finally, reductive alkylation of (IV) with pyridine-4-carbaldehyde (VI) employing NaBH3CN gives rise to the target pyridylmethyl amine.
| 【1】 Manley, P.W.; Furet, P.; Bold, G.; Bruggen, J.; Mestan, J.; Meyer, T.; Schnell, C.R.; Wood, J.; Anthranilic acid amides: A novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem 2002, 45, 26, 5687. |
| 【2】 Seidelmann, D.; Huth, A.; Manley, P.W.; Thierauch, K.-H.; Krüger, M.; Bold, G.; Haberey, M.; Furet, P.; Altmann, K.-H.; Mestan, J.; Menrad, A.; Ferrari, S.; Wood, J.M.; Hofmann, F. (Novartis AG; Schering AG); N-Aryl(thio)anthranilic acid amide derivs., their preparation and their use as VEGF receptor tyrosine kinase inhibitors. EP 1129075; JP 2002529453; US 6448277; WO 0027820 . |
| 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) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (II) | 21099 | o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride | 610-14-0 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 64309 | 2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide | C14H9F3N2O3 | 详情 | 详情 | |
| (IV) | 64310 | 2-amino-N-[3-(trifluoromethyl)phenyl]benzamide | C14H11F3N2O | 详情 | 详情 | |
| (V) | 29797 | 2H-3,1-benzoxazine-2,4(1H)-dione；Isatoic anhydride;4H-3,1-Benzoxazine-2,4(1H)-dione；1,2-Dihydro-4H-3,1-benzoxazine-2,4-dione;1H-benzo[d][1,3]oxazine-2,4-dione | 118-48-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |