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With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In 1,4-dioxane; water; at 0 - 120℃; for 0.25h;Microwave irradiation; |
Intermediate 37a and 37b: 2-(2H-1,2,3-Triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-Triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) To a solution of 2H-1,2,3-triazole (CAS number 288-36-8; 1.0 g, 10.86 mmol) in DMF (4 ml) at 0-10 C. was added cesium carbonate (4.71 g, 14.49 mmol), copper (I) iodide (68 mg, 0.36 mmol), trans-1-N,2-N-dimethylcyclohexane-1,2-diamine (200 mg, 1.44 mmol) and 2-iodo-5-(trifluoromethyl)benzoic acid (CAS number 702641-04-1; 2.28 g, 7.24 mmol). The reaction was subjected to microwave irradiation at 120 C. for 15 minutes and was then partitioned between ethyl acetate (2×100 ml) and water (50 ml). The aqueous layer was acidified with HCl (aq, 2M) to give pH 2 and the organics were extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a; also commercially available CAS number 1384066-81-2). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b). Intermediate 37a 1H NMR (400 MHz, DMSO) delta ppm 8.07-8.08 (m, 3H), 8.20 (s, 2H), 13.57 (bs, 1H) MS ES+: 258 Intermediate 37b 1H NMR (400 MHz, DMSO) delta ppm 7.90-7.97 (m, 2H), 8.16-8.21 (m, 2H), 8.65 (s, 1H), 13.65 (bs, 1H) MS ES+: 258 Intermediate 39a and 39b: 2,3-Difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a) and 2,3-Difluoro-6-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 39b) Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 0.75 g, 10.86 mmol) and 2,3-difluoro-6-iodobenzoic acid (CAS number 333780-75-9; 1.54 g, 5.43 mmol) in 1,4-dioxane (10 ml) and water (0.2 ml). The crude solid was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 2,3-difluoro-6-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 39b). Intermediate 39a 1H NMR (400 MHz, DMSO) delta ppm 7.73-7.79 (m, 2H), 8.16 (s, 2H), 14.05 (bs, 1H) MS ES+: 226 Intermediate 39b 1H NMR (400 MHz, DMSO) delta ppm 7.60-7.63 (m, 1H), 7.79-7.86 (m, 1H), 7.96 (s, 1H), 8.61 (s, 1H), 14.17 (bs, 1H) MS ES+: 226 |
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