1,2-DIAMINO-4-(TRIFLUOROMETHOXY)BENZENE

A solution of 2-nitro-4-trifluoromethoxy-phenylamine 1 (25.0 g, 0.112 mol) in EtOH (200 ml) was added to solution of stannous chloride dihydrate (82.0 g, 0.363 mol) in cone HCl (330 ml) . The resulting suspension was stirred for 0.5 h at 70-80°C, cooled at 0-5°C, and basified to pH=ll-12 by 40percent NaOH solution, and the product extracted with ether (2EXAMPLE 61; 1 -(7H-Pyrro lor2, 3-dlpyrimidin-4-yl)-4-(5-(trifluoromethoxy)-lH-benzordlimidazo 1-2- vDpiperidin-4-amine6 IA. 4-(trifluoromethoxy)benzene- 1 , 2-diamine 2-Nitro-4-(trifluoromethoxy)aniline (2.000 g, 9.00 mmol) and palladium (0.096 g, 0.90 mmol) were dissolved in ethanol (25 mL) and stirred under a balloon of hydrogen for 48 hours. The reaction was filtered and evaporated to dryness to afford 4-(trifluoromethoxy)- benzene-l, 2-diamine (1.392 g, 7.24 mmol, 92 percent) as a black oil; m/z (ESI+) (M+H)+ = ; HPLC tR = 1.53 min. IH NMR (400.132 MHz, CDC13) δ 3.41 (4H, vbrs), 6.60 - 6.58 (2H, m), 6.67 (IH, d).2-nitro-4-trifluoromethoxy-phenylamine Compound 16a (0.5 g, 2.25 mmol) was dissolved into EtOH (30 mL) and Raney Ni (~ 0.5 g, prewashed with EtOH) was added. The mixture was shaken in a Parr shaker under HExample 23Weigh 16 g of 4-trifluoromethoxy-2-chloroaniline into the autoclave, add 100 ml of 1, 4-dioxane and 37 g of 25% ammonia water in order.Prepare the reaction mixture, close the lid of the autoclave, replace the air with nitrogen, stir and heat up the temperature, control the 190 C, pressure 2.0MPa for 5h.Then cooled to room temperature, the reaction solution was added with water to precipitate a yellow solid, filtered, washed with water, and dried to obtain 13 g of Into a 1L autoclave, 120.0 g of 4-trifluoromethoxy-2-bromoaniline and 2.4 g of copper bromide (content 97%), 252.8g of deionized water, 150g of liquid ammonia was passed in, the molar ratio of NH3 to 4-trifluoromethoxy-2-bromoaniline was 20: 1, and the reaction was performed at 150 C for 12h.Subsequently, the autoclave is cooled, depressurized, disassembled, and the ammonia hydrolysis solution is taken out.The ammonolyzed aqueous layer was extracted three times with toluene to obtain an extracted oil layer. After the extracted oil layer and the ammonolyzed oil layer were combined, the solvent was distilled off, and the product was recrystallized in methanol to obtain the product [0371] Compounds 41a and 100a: To a stirred solution of 4-(trifluoromethoxy)benzene- 1, 2-diamine (0.5 g, 2.60 mmol) in acetonitrile (10 mL) was added 2-oxopropanal (0.5 mL) and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 30-40% EtOAc in hexane) to afford a mixture of 2-methyl-7- (0652) (trifluoromethoxy)quinoxaline and 2-methyl-6-(trifluoromethoxy)quinoxaline (41a and 100a, respectively; 0.5 g, 84%) as a pale yellow solid. (0653) [0372] MS (ESI) m/e |M+H]+/Rt/%: 228.95/1.79/89.5%[0373] Compounds 41 and 100: To a mixture of Comp-41a and Comp-lOOa mixture (0.3 g, 1.31 mmol) and Comp-3b (0.29 g, 1.31 mmol) was added i-BuOk (1 mL, 1M in THF) and the reaction mixture was heated at 50 C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with w'ater and extracted with EtOAc (50 mL X 2). The organic layer was washed with water, brine, separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford a mixture of regioisomers (E)-2-(2-(2, 5- dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-7-(trifluoromethoxy)quinoxaline and (E)-2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)-1H-pyrrol-3-yl)vinyl)-6- (0655) (trifluoromethoxy)quinoxaline (41 and 100, respectively; 0.09 g, 17%) as a yellow solid. (0656) [0374] HPLC purity : 98.19% (0657) [0375] MS (ESI) m/e [M+H]+/Rt/%: 431.20/1.69/97.8% (0658) [0376] 1H NMR (400 MHz, DMSO-d6, 2: l mixture of isomers) delta 1.73 (d, J=l 1.25 Hz, 2H), 2.01 - 2.11 (m, 2H), 2.14-2.17 (m, 2H), 2.23 (s, 3H), 2.29 (s, 3H), 2.44 (s, 3H), 2.91 (d, J=10.27 Hz, 2H), 3.92 - 4.02 (m, 1H), 6.24 (s, 1H), 6.85 (d, J=15.65 Hz, 1H), 7.62 - 7.78 (m, 1H), 7.85 (s, 1H), 7.91 - 7.98 (m, 1H), 8.04 - 8.13 (m, 1H), 9.24 & 9.28 (s, 0.56H & 0.34H).A mixture of 3-isothiocyanato-N-methyl-3-[3-(trifluoromethyl)phenyl]propanamide (0.3 g, 1 mmol) (from step 3) and 4-(trifluoromethoxy)benzene-l, 2-diamine (0.2 g, 1 mmol) in dichloromethane (100 mL) was stirred at ambient temperature. After 4 h, the reaction mixture was concentrated to afford the crude product (0.50 g) as yellow gum. It was purified by flash column using 230-400 silica gel, the product fraction was eluted using 40 % ethyl acetate in hexane to afford 3-({[2-amino-5- (trifluoromethoxy)phenyl]carbamothioyl} amino)-N-methyl-3 - [3 - (trifluoromethyl)phenyl]propanamide (0.4 g) as an off-white solid. MS: m/z 481 (M+l).

Molecular Weight:192.14
XLogP3:1.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:192.05104734
Monoisotopic Mass:192.05104734
Topological Polar Surface Area:61.3
Heavy Atom Count:13
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes