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D. 4-Amino-3-methyl-2-trifluoromethylbenzonitrile (841D) A solution of the mixed product from example 841C (7.53 g, 26.5 mmol) was dissolved in 120 mL of concentrated HCl/EtOH (1:1) and was refluxed for 14 h. After cooling to rt, the solution was concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 (2*) and brine (1*), dried over MgSO4, filtered and concentrated in vacuo. The residue was chomatographed (silica gel), eluding with chloroform/methanol (98:2) to furnish compound 841D (4.62 g, 87%). MS (ES): m/z=201 [M+1]+.
18D. 4-Amino-3-methyl-2-trifluoromethylbenzonitrile A solution of the mixed product from 18C (7.53 g, 26.5 mmol) in 120 mL of concentrated HCl/EtOH (1:1) was refluxed for 14 h. After cooling to rt, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 (2*) and brine (1*), dried (MgSO4), filtered and concentrated. The residue was chromatographed (silica gel), eluding with chloroform/MeOH (98:2) to furnish the title compound (4.62 g, 87%). MS (ES) m/z 201 [M+1]+.
9
[ 573764-86-0 ]
[ 1182367-75-4 ]
Yield
Reaction Conditions
Operation in experiment
Example 31; 4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methyl-2-(trifluoromethyl)benzonitrile; Intermediate 31a; 4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile <strong>[573764-86-0]4-amino-3-methyl-2-(trifluoromethyl)benzonitrile</strong> (CAS 573764-86-0, 2.0 g, 9.99 mmol) was dissolved in fluoroboric acid, HBF4 solution (15 mL) at -10 C. (ice/MeOH). To the pre-cooled solution was added NaNO2(689 mg, 9.992 mmol) in 2 mL H2O drop by drop under constant stirring. The reaction mixture was allowed to stir for 15 min at -10 C. and filtered off. The white residue was washed with cold EtOH and cold ether to get the diazosalt as a white crystalline solid. The salt is dried over high vacuum for 4-5 h. to provide 1.9 g. The salt was heated up (>250 C.) and sublimed under reduced pressure to get the crude fluoro compound as an oil. The oil is chromatographed to get the pure 4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile as a clear oil (700 mg): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.68 (dd, J=5.0, 9.0 Hz, 1H), 7.33 (t, J=9 Hz, 1H), 2.43 (quin, J=2 Hz, 3H).
With triethylamine; In dichloromethane; at 20℃; for 3h;
Intermediate 46: 2-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]amino}-2- oxoethyl acetate; To a solution of <strong>[573764-86-0]4-amino-3-methyl-2-(trifluoromethyl)benzonitrile</strong> (commercially available, for example from Sunshine Chemlab, Downington, PA, USA, 500 mg, 2.50 mmol) and triethylamine (0.383 mL, 2.75 mmol) in dichloromethane (10 mL) was added 2-chloro-2-oxoethyl acetate (0.269 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was diluted with DCM (100ml) and water (50ml) and aqueous was extracted with DCM (100ml). The organics were combined, passed through a phase separator and concentrated to afford 710mg of the title compound as a pale yellow powder.MS ES-ve m/z 299 (M-H)1H NMR (400 MHz, METHANOLS) δ ppm 2.18 (s, 3 H) 2.41 (q, J=2.12 Hz, 3 H) 4.78 (s, 2 H) 7.81 (d, J=8.33 Hz, 1 H) 7.92 (d, J=8.33 Hz, 1 H)
4-bromo-3-methyl-2-(trifluoromethyl)benzonitrileOf); 3e 3f; To a solution of 4-amino-3-methyl-2-(trifluoromethyl) benzonitrile (3e) (0.8 g, 4.0 mmol) in water (2 mL), cooled to 0C, 48% aqueous HBr (10 mL, 18.5 mmol) was added followed by NaN02 (0.33 g, 4.8 mmol) taken in water (2 mL) and stirred for 10 min. To the reaction mixture a solution of CuBr (2.7 g, 18.8 mmol) in HBr (10 mL) was added at 0C and slowly warmed to room temperature and then heated to 50C for 1 h. The reaction mixture was brought to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (2 x 20 mL), dried over Na2S04 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to provide the bromo 3f (0.6 g, 60%) as a tan colored solid.TLC: 10% EtOAc/Hexane Rf: (0.6)1H NMR (500MHz, CDC13, δ in ppm): 7.88 (d, J= 9.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 2.62 (s, 3H).
4-amino-3-methyl-2-(trifluoromethyl) benzonitrile; N-(4-cyano-2-methyl-3-(trifluoromethyl) phenyl) pivalamide (3d) (1.5 g,5.28 mmol) was taken in EtOH/HCl (30 mL, 1 : 1) and heated to 80C for 12 h. The reaction was slowly brought to room temperature and poured into ice cold water (30 mL) during which white solid precipitated which was filtered. The solid was washed with hexane (3 x 20 mL) and dried under vacuum to provide the amine 3e (0.9 g,90%) as a white solid. TLC: 40% EtOAc/Hexane (Rf: 0.3)1H NMR (200MHz, DMS0-< δ in ppm): 7.51 (d, J= 8.2 Hz, 1H), 6.91 (d, J= 8.6 Hz, 1H), 6.45 (br s, 2H), 2.15-2.12 (m, 3H).Mass (ESI): 198.9 [M+-]
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