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The mixture of 500mg of 3-chlorobenzotrifuluoride and 3ml of tetrahydrofuran was cooled down to -50C and 2ml of 1.6M n-butyllithium hexan solution was added and stirred for 1 hour. The mixture was put into dry ice and diluted by an aqueous solution of 1N sodium hydroxide. After washing it with toluene, the water layer was made acidic by hydrochloric acid and extracted with ethyl acetate. The crude material obtained by removing the solvent was purified by reverse phase HPLC to the said compound. Yield 244mg H-NMR (DMSO-d6) δ 7.68 (1H, t), 7.80 (1H, d), 7.88 (1H, d). MS (ESI, m/z) 223 (M-H)-
1 described above from 3-chloro-benzotrifluoride via the intermediates 2-chloro-6-trifluoromethyl-benzoic acid (m.p. 120-123 C), 2-chloro-6-trifluoromethyl-aniline (an oil), and 2-chloro-6-trifluoromethyl-formanilide (m.p. 167-170 C).
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 60℃; for 92h;Inert atmosphere;
Borane-methyl sulfide complex (44.6 mL, 89.2 mmol, 2.0 M) was added dropwise to the solution of <strong>[2376-00-3]2-chloro-6-(trifluoromethyl)benzoic acid</strong> (5.0 g, 22.3 mmol) at 0 C under argon atmosphere. The resulting mixture was stirred at 60 C for 27 h. LCMS indicated the reactant was remained. Then, borane-methyl sulfide complex (33.5 mL, 66.9 mmol, 2.0 M) was added dropwise at 0 C. The resulting mixture was reacted at 60 C for 65 h. After cooling to room temperature, the reaction mixture was adjusted to about pH = 11 with 2.0 M sodium hydroxide solution, diluted with water (200 mL), extracted with diethyl ether (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the product (2-chloro-6-(trifluoromethyl)phenyl)methanol as a brown solid (6.23 g). LCMS: LC retention time 1.89 min. MS (ESI) m/z 193 [M-17]+.
The mixture of <strong>[2376-00-3]2-chloro-6-(trifluoromethyl)benzoic acid</strong> (i-la) (1.5 g, 6.70 mol) and (COCl)2 (1.1 ml, 13.4 mol) in DCM (20 ml) and DMF (5drops) was stirred at room temperature for 2h.Then MeOH (0.41 ml, 13.4 mol) was added dropwise and the reaction mixture was stirred at room temperature for another 30min.The result solution was diluted with H20 (50 ml) and the aqueous layer was extracted with DCM(50ml><2). The combined organic layers were washed with brine (50 ml x 1), dried over anhydrous Na2S04 and concentrated to get the desired product i-lb as a pale yellow oil. LCMS (ESI) calc'd for C9H6C1F302 [M+H] +: 239, found: 239.
A mixture of <strong>[2376-00-3]2-chloro-6-(trifluoromethyl)benzoic acid</strong> (i-la) (1.5 g, 6.70 mmol) and (COCl)2 (1.1 ml, 12.8 mmol) in DCM (20 ml) and DMF (5 drops) were stirred at room temperature for 2h. MeOH (0.41 ml, 13.4 mmol) was added dropwise and the reaction mixture was stirred at room temperature for another 30min.The resultant solution was diluted with H20 (50 ml) and the aqueous layer was extracted with DCM (50ml x 2). The combined organic layers were washed with brine (50 ml x 1), dried over anhydrous Na2S04 and concentrated to obtain the title compound i-lb as a pale yellow oil. LCMS (ESI) calc'd for C9H6C1F302 [M+H] +: 239, found: 239.
The mixture of <strong>[2376-00-3]2-chloro-6-(trifluoromethyl)benzoic acid</strong> (B-2) (0.46 g, 2.07 mol) and (COCl)2 (0.32 mL, 3.76 mol) in DCM (10 mL) and DMF (5drops) was stirred at room temperature for lh. The solvent was removed and the residue was dissolved in DCM (10 mL). To the mixture of 3-iodo-lH-indazole-4-carbaldehyde (B-l) (0.51 g, 1.88 mol), DMAP (23 mg,0.19 mol) and Et3N (0.52 mL, 3.76 mol) in DCM (10 mL) was added the aboved DCM solution dropwise and the reaction mixture was stirred at room temperature overnight. The result solution was diluted with H20 (50 mL) and the aqueous layer was extracted with DCM (30 mLx3). The combined organic layers were washed with brine (30 mLx l),dried over anhydrous Na2S04 and concentrated. The residue was chromatographed on silica gel(PE:EA 8: 1 to 4: 1) to get the desired product B-3 as a white solid. LCMS (ESI) calc'd for Ci6H7ClF3lN202 [M+H]+: 479, found: 479.
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