N-Methyl-2-aminopyridine-3-carboxamide

V-MethvI-2-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)nicotinamide; 2-Amino-./V-methylnicotinamide; To the mixture of 2-aminonicotinic acid (2.0 g, 14.5 mmol), methylamine hydrogen chloride (1.47 g, 1.5 eq), EDC (4.49 g, 1.5 eq), HOBt (2.35 g, 1.2 eq) in DMF (2OmL) was added DIEA (7.6 mL, 3.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCOExample 89; /V-MethvI-2-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)nicotinamide; 2-Amino-./V-methylnicotinamide; To the mixture of 2-aminonicotinic acid (2.0 g, 14.5 mmol), methylamine hydrogen chloride (1.47 g, 1.5 eq), EDC (4.49 g, 1.5 eq), HOBt (2.35 g, 1.2 eq) in DMF (2OmL) was added DIEA (7.6 mL, 3.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0%~20% MeOH/DCM) to obtain the desired product 2-amino-iV- methylnicotinamide (2.16 g, isolated yield -98%).Example 1, Step A, Method A and Method B; A 500 ml round bottomed flask was charged with methyl 2- aminopyridine 3-carboxamide 1 (4.5 g, 29.76 mmol) and 1 , 2-dichloroethane(150 ml). The resulting solution was cooled to -40 C while triphosgene (7 g, 23.59 mmol) was slowly added. Triethylamine (4.4 g, 43.48 mmol) was then added via a syringe dropwise at this temperature. The reaction mixture was stirred at -40 C for two hours before warming up gradually to room temperature and maintained at this temperature overnight. The suspension was treated with water (100 ml) and saturated sodium carbonate (100 ml) and separated. The aqueous solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated on rotavapor. The residue was dried under house vacuum to provide a deep tan solid (4.1 g). This material was mixed with phosphorus oxychloride (50 ml) in a 250 ml flask. The resulting suspension was refluxed for 4 hours. The excess phosphorus oxychloride was removed by distillation under reduced pressure. The residue was dissolved in methylene dichloride (200 ml) and poured into ice (50 g). The suspension was neutralized with saturated sodium carbonate solution and separated. The organic layer was dried over sodium sulfate, concentrated, and dried under vacuum to afford a black gel (1.4 g), which was used directly for the next reaction without purification.(2) Production of 3-methyl-2-[4-(3-piperidin-1-ylpropoxy)phenyl]pyrido[2, 3-d]-pyrimidin-4(3H)-one: 2-Amino-N-methylnicotinamide (105 mg, 0.69 mmol), 4-(3-piperidin-1-ylpropoxy)benzamide (171 mg, 0.69 mmol) and p-toluenesulfonic acid monohydrate (66 mg, 0.35 mmol) were suspended in toluene (2 mL), and stirred under reflux for 24 hours. After cooled to room temperature, DDQ (157 mg, 0.69 mmol) and THF (2 mL) were added thereto and stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate, then washed with aqueous 1 N sodium hydroxide solution and saturated saline water, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol = 3/1) to obtain the intended compound (52.5 mg, 20 %) as a colorless solid (m.p. 109-112C). 1H-NMR (400 MHz, CD3 OD) delta: 1.44-1.55 (2H, m), 1.63 (4H, quint., J=5.6 Hz), 2.00-2.07 (2H, m), 2.36-2.54 (4H, m), 2.56 (2H, t, J=7.7 Hz), 3.54 (3H, s), 4.12 (2H, t, J=5.9 Hz), 7.08 (2H, d, J=8.8 Hz), 7.54 (1H, dd, J=4.4, 8.1 Hz), 7.65 (2H, d, J=8.8 Hz), 8.64 (1H, dd, J=1.5, 8.1 Hz), 8.90 (1H, dd, J=1.5, 4.4 Hz)

Molecular Weight:151.17
XLogP3:1.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:151.074561919
Monoisotopic Mass:151.074561919
Topological Polar Surface Area:68
Heavy Atom Count:11
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes