2-CHLORO-5-(TRIFLUOROMETHYL)-3-PYRIDINAMINE

Zink(II)-chloride-dihydrate (4.39 g, 19.5 mmol) is added to a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.00 g, 4.41 mmol) in a ethyl acetate (25 ml), and the resultant suspension is stirred for 2 h at 80° C.Example 182-Chloro-3-amino-5-(trifluoromethyl)pyridine:Zink(ll)-chloride-dihydrate (4.39 g, 19.5 mmol) is added to a solution of 2-chloro- 3- nitro-5-(trifluoromethyl)pyridine (1.00 g, 4.41 mmol) in a ethyl acetate (25 ml), and the resultant suspension is stirred for 2 h at 80 °C. After cooling to room temperature, the reaction mixture is slowly added dropwise into an ice cooled saturated sodium hydrogen carbonate solution (100 ml). After warming to room temperature, the resultant suspension is filtered via a celite layer, and the residue is washed four times with ethyl acetate (50 ml each). The filtrate and the washing solution are combined and subsequently washed with a saturated sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and conenctrated to dryness. Yield: 0.78 g (90 percent).1-Trimethylsilyl-2-(2-ethylthio-4-trifluoromethylphenyl)ethyne (794 mg), 240 mg (1.19 mmol) of 6-Bromo-3-(ethylsulphanyl)pyridine-2-carboxylic acid (3 g, 11.5 mmol) was dissolved in 60 ml of dichloromethane and cooled to 0 C. With stirring, oxalyl chloride (14.5 g, 115 mmol) and one drop of dimethylformamide were added, then the mixture was stirred at room temperature for 30 min. After removing the solvent, the crude product 6-bromo-3-(ethylsulphanyl)pyridine-2-carbonyl chloride was further reacted directly. 2-Chloro-5-(trifluoromethyl)pyridin-3-amine (1.05 g, 5.38 mmol) was added at 0 C. to a suspension of sodium hydride (60% in mineral oil, 258 mg, 6.46 mmol) in tetrahydrofuran. The mixture was stirred for 30 min, then 6-bromo-3-(ethylsulphanyl)pyridine-2-carbonyl chloride (3 g, 10.75 mmol) was added in portions. After stirring for 12 h, the reaction was ended by adding 10 ml of ice-water. The product was isolated in the form of a precipitate by filtration. log P (neutral): 5.27; MH+: 442; 1H-NMR (400 MHz, D6-DMSO) delta ppm: 10.57 (s, 1H); 8.91 (s, 1H), 8.70 (s, 1H), 7.95-7.87 (m, 2H), 3.05-3.00 (m, 2H), 1.30-1.27 (m, 3H).N-[2-Chloro-5-(trifluoromethyl)pyridin-3-yl]-3-(ethylsulphanyl)imidazo[1, 2-a]pyridine-2-carboxamide (XXVI-1) 1.1 mg (9.37 mmol) of thionyl chloride were added dropwise to a solution of 298 mg (1.33 mmol) of 3-(ethylsulphanyl)imidazo[1, 2-a]pyridine-2-carboxylic acid in 10 ml of acetonitrile, and the mixture was heated under reflux for 3 h. The solvent was removed under reduced pressure and the residue was twice co-evaporated with toluene. The residue was dissolved in 3 ml of N, N-dimethylformamide. Separately, 263 mg (1.33 mmol) of [0276] [B] N- (2-Chloro-5- (trifluoromethyl) pyridin-3-yl) acetamide [0277] [0278] A mixture solution of 2-chloro-5- (trifluoromethyl) pyridin-3-amine (75 g, 381.6 mmol) and Ac2O (82.5 mg, 808.1 mmol) in pyridine (200 mL) was stirred at 80 for 16 h. After cooling to room temperature, it was diluted with EtOAc (500 mL), washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was first purified by silica gel flash chromatography (petroleum etherEtOAc 51) and then crystallization in petroleum ether (100 mL) to afford the title compound (65 g, mixture of mono-and bis-Ac protected product, 73yield) as white solids. MS239.0 [M+H] +.N- (2-Methyl-5- (trifluoromethyl)pyridin-3-yl) acetamide[0280][0281]To a mixture of N- (2-chloro-5- (trifluoromethyl) pyridin-3-yl) acetamide and N-acetyl-N- (2-methyl-5- (trifluoromethyl) pyridin-3-yl) acetamide (35 g 146.7 mmol) K2CO3(62.2 g 450 mmol) methyl boroxine (50in ether 70 g 278.8 mmol) and X-phos (14.4 g 43mmol) in MeCN (250 mL) and water (150 mL) was added Pd (OAc)2(3.4 g 15.1 mmol) And the resulting reaction mixture was stirred at 100 for 16 h. After cooling to room temperature The reaction was diluted with EtOAc (300 mL) washed with water (300 mL) and brine (300 mL) . The organic layer was dried over anhy. Na2SO4 filtered and concentrated in vacuo to give a crude product which was then purified by silica gel flash chromatography (petroleum etherEtOAc51) to afford the title compound (20 g 57yield) as a gray solid. MS 219.0 [M+H]+.1H NMR (400MHz CHCl3-d1) delta 8.62 (s 1H) 8.54 (s 1H) 7.11 (br 1H) 2.60 (s 3H) 2.28 (s 3H) .[0276] [B] N- (2-Chloro-5- (trifluoromethyl) pyridin-3-yl) acetamide [0277] [0278] A mixture solution of 2-chloro-5- (trifluoromethyl) pyridin-3-amine (75 g, 381.6 mmol) and Ac2O (82.5 mg, 808.1 mmol) in pyridine (200 mL) was stirred at 80 for 16 h. After cooling to room temperature, it was diluted with EtOAc (500 mL), washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was first purified by silica gel flash chromatography (petroleum etherEtOAc 51) and then crystallization in petroleum ether (100 mL) to afford the title compound (65 g, mixture of mono-and bis-Ac protected product, 73yield) as white solids. MS239.0 [M+H] +.

Molecular Weight:196.56
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Exact Mass:196.0015103
Monoisotopic Mass:196.0015103
Topological Polar Surface Area:38.9
Heavy Atom Count:12
Complexity:161
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes