5-Chloro-4-(trifluoromethyl)-2-pyridinamine

Synthesis of Compound A.6. To a solution of 2-amino-4-trifluoropyridine (2.00 g, 0.0123 mol) in DMF (4 mL, 0.05 mol) was added a solution of 1, 3-dichloro-5, 5-dimethylhydantoin (1.4 g, 0.0074 mol) in DMF (4 mL) dropwise. The reaction was stirred at RT for 2 hr, whereupon the reaction mixture was diluted with ether (80 mL) and washed with water (10 mL). The organic phase was dried and concentrated to give the crude product, which was purified on combiflash (0-20percent EtOAc/Hexanes) to give compound A.6 as light yellow oil. (65percent yield); To a solution of 2-amino-4-trifluoropyridine (2.00 g, 0.0123 mol) in DMF (4 mL, 0.05 mol) was added a solution of 1, 3-dichloro-5, 5-dimethylhydantoin (1.4 g, 0.0074 mol) in DMF (4 mL) dropwise. The reaction was stirred at RT for 2 hr, whereupon the reaction mixture was diluted with ether (80 mL) and washed with water (10 mL). The organic phase was dried and concentrated to give the crude product, which was purified on combiflash (0-20percent EtOAc/Hexanes) to give compound A.6 as light yellow oil. (65percent yield); To a solution of 2-amino^l- trifluoromethyl-pyridine (2.00 g, 0.0123 mol) in DMF (4 mL, 0.05 mol) was added a solution of 1, 3-dichloro-5, 5- dimethylhydantoin (1.4 g, 0.0074 mol) in DMF (4 mL) dropwise. The reaction was stirred at room temperature for 2 hr, whereupon the reaction mixture was diluted with ether (80 mL) and washed with water (10 mL). The organic phase was dried and concentrated to give the crude product, which was purified on combiflash (0-20percent EtOAc/Hexanes) to give compound G.5 as light yellow oil. (65percent yield); No. I.5-451: 5-Ethylcarbonyloxy-4-methyl-1-(5-chloro-4-trifluoromethylpyridin-2-yl)-1, 5-dihydro-2H-pyrrol-2-one 5-Hydroxy-4-methyl-2, 5-dihydrofuran-2-one (300 mg, 2.63 mmol, 1.0 equiv) and Synthesis of Compound S.7. To a solution of S.6 (205 mg, 0.64 mmol) in methylene chloride (4 mL) at rt was added oxalyl chloride (160 muL, 0.0019 mol) followed by the addition of DMF (50 muL) and stirred at RT for 1 hr. Separately a solution of A.6 (132 mg, 0.000672 mol), acetonitrile (2 ml) and pyridine (520 muL, 0.0065 mol) was stirred at RT followed by the addition of chlorotrimethylsilane (100 muL, 0.0008 mol). The acid chloride was concentrated under reduced pressure to a tan solid and redissolved in acetonitrile (2 mL). To the acid chloride solution was added the activated aniline. After 3 hr, the reaction mixture was diluted with ethyl acetate (75 mL) and washed with dilute citric acid (50 mL), aqueous sodium bicarbonate (50 mL) and water. The organic layer was dried over sodium sulfate and concentrated to a residue which was purified by to give compound S.7. MS m/z: 498.95 [M+1]+.To a solution of S.6 (205 mg, 0.64 mmol) in methylene chloride (4 mL) at RT was added oxalyl chloride (160 muL, 0.0019 mol) followed by the addition of DMF (50 muL) and stirred at RT for 1 hr. Separately a solution of A.6 (132 mg, 0.000672 mol), acetonitrile (2 ml) and pyridine (520 muL, 0.0065 mol) was stirred at RT followed by the addition of chlorotrimethylsilane (100 muL, 0.0008 mol). The acid chloride was concentrated under reduced pressure to a tan solid and redissolved in acetonitrile (2 mL). To the acid chloride solution was added the activated aniline. After 3 hr, the reaction mixture was diluted with ethyl acetate (75 mL) and washed with dilute citric acid (50 mL), aqueous sodium bicarbonate (50 mL) and water. The organic layer was dried over sodium sulfate and concentrated to a residue which was purified by to give compound S.7. LCMS m/z: 498.95 [M+1]+.Synthesis of Compound A.7. A 20 mL vial was charged with compound A.5 (191.8 mg, 0.0006561 mol), methylene chloride (3.0 mL), a 2.0 M solution of oxalyl chloride in methylene chloride (390 muL) and DMF (10.0 muL, 0.000129 mol). The reaction mixture was stirred for 15 minutes at RT, then concentrated in vacuo and the resultant residue was taken up in acetonitrile (3.0 mL). To this solution was added a solution of compound A.6 (129 mg, 0.000656 mol) and pyridine (0.5 mL, 0.006 mol) in acetonitrile (1.5 mL). The reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue was purified by combiflash (0-30% EtOAc/CH2Cl2) to give compound A.7 in 49% yield. MS: m/z 471 [M+1]+.A 20 mL vial was charged with compound A.5 (191.8 mg, 0.0006561 mol), methylene chloride (3.0 mL), a 2.0 M solution of oxalyl chloride in methylene chloride (390 muL) and DMF (10.0 muL, 0.000129 mol). The reaction mixture was stirred for 15 minutes at rt, then concentrated in vacuo and the resultant residue was taken up in acetonitrile (3.0 mL). To this solution was added a solution of compound A.6 (129 mg, 0.000656 mol) and pyridine (0.5 mL, 0.006 mol) in acetonitrile (1.5 mL). The reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue was purified by combiflash (0-30% EtOAc/CH2Cl2) to give compound A.7 in 49% yield. LCMS: m/z 471 [M+1]+.A 20 mL vial was charged with compound G.4 (191.8 mg, 0.65 mmol), CH2Cl2 (3.0 mL), a 2.0 M solution of oxalyl chloride in CH2Cl2 (390 muL), and DMF (10.0 muL, 0.129 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then concentrated in vacuo and the resultant residue was taken up in acetonitrile (3.0 mL). To this solution was added a solution of compound G.5 (129 mg, 0.65 mmol) and pyridine (0.5 mL, 0.006 mol) in acetonitrile (1.5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 0-30% EtOAc/CH2Cl2) to give compound G.6 in 49% yield. LCMS: m/z = All [M+l].Synthesis of Compound A.6. To a solution of 2-amino-4-trifluoropyridine (2.00 g, 0.0123 mol) in DMF (4 mL, 0.05 mol) was added a solution of 1, 3-dichloro-5, 5-dimethylhydantoin (1.4 g, 0.0074 mol) in DMF (4 mL) dropwise. The reaction was stirred at RT for 2 hr, whereupon the reaction mixture was diluted with ether (80 mL) and washed with water (10 mL). The organic phase was dried and concentrated to give the crude product, which was purified on combiflash (0-20% EtOAc/Hexanes) to give compound A.6 as light yellow oil. (65% yield); 1H NMR: (DMSO-d6) delta 8.16 (s, 1H), 6.87 (s, 1H), 6.76 (brs, 1H); MS: m/z 197 [M+1]+.To a solution of 2-amino-4-trifluoropyridine (2.00 g, 0.0123 mol) in DMF (4 mL, 0.05 mol) was added a solution of 1, 3-dichloro-5, 5-dimethylhydantoin (1.4 g, 0.0074 mol) in DMF (4 mL) dropwise. The reaction was stirred at RT for 2 hr, whereupon the reaction mixture was diluted with ether (80 mL) and washed with water (10 mL). The organic phase was dried and concentrated to give the crude product, which was purified on combiflash (0-20% EtOAc/Hexanes) to give compound A.6 as light yellow oil. (65% yield); 1H NMR: (DMSO-d6) delta 8.16 (s, 1 H), 6.87 (s, 1 H), 6.76 (brs, 1 H); LCMS: m/z 197 [M+1]+.To a solution of 2-amino^l- trifluoromethyl-pyridine (2.00 g, 0.0123 mol) in DMF (4 mL, 0.05 mol) was added a solution of 1, 3-dichloro-5, 5- dimethylhydantoin (1.4 g, 0.0074 mol) in DMF (4 mL) dropwise. The reaction was stirred at room temperature for 2 hr, whereupon the reaction mixture was diluted with ether (80 mL) and washed with water (10 mL). The organic phase was dried and concentrated to give the crude product, which was purified on combiflash (0-20% EtOAc/Hexanes) to give compound G.5 as light yellow oil. (65% yield); 1H NMR: (DMSO-d6) delta 8.16 (s, 1H), 6.87 (s, 1H), 6.76 (brs, 1H); LCMS: m/z 197 [M+l].

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