5-Aminopyridine-2-carboxamide

A 18 ml vial was loaded with a mixture of 30percent HGeneral procedure: The appropriate nitro compound was dissolved in an ethanol/water mixture (5:1) (about 2-3M), and concentrated hydrochloric acid (0.5-1 eq.) and iron powder (3-8 eq.) were added. The reaction mixture was heated at 80 to 100° C. until the reaction had gone to completion (about 1 to 6 h). The hot reaction mixture was filtered through kieselguhr. The filtercake was washed with methanol and the filtrate was concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient); According to General Method 9A, the crude product (about 23.8 mmol) 5-nitropyridine-2-carboxamide was reacted. The product obtained was purified by means of normal phase chromatography (eluent: dichloromethane/ methanol (9:1) with 1.5percent concentrated ammonia). Yield:1.40 g (42percent of theory) LC/MS [Method 5]: Rt=0.50 mm; MS (ESIpos):mlz=138 (M+H), ‘H-NMR (400 MHz, DMSO-d5): ö [ppm]=7.89 (d, 1H), 7.70 (d, 1H), 7.64 (bs, 1H), 7.11 (bs, 1H), 6.95 (dd, 1H), 5.90 (s, 2H).A) To a solution of 2, 4-dichloro-6-fluoro-benzoyl chloride (2.5 g, 11.0 mmol) and DIEA (4.8 mL, 27 mmol) in 1 -methyl -pyrrolidin-2 -one (25 mL) at 0 C was added a solution of 5-aminopyridine-2- carboxamide (1.51 g, 11.0 mmol) in dichloromethane (12.5 mL) dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with water (20 mL) and the resulting suspension was filtered to provide 5-[(2, 4-dichloro-6-fluoro-benzoyl)amino]pyridine-2- carboxamide (1.2 g, 33%). ESI-MS m/z calc. 326.99, found 328.1 (M+l)+; retention time (Method B): 1.16 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 11.34 (s, 1H), 8.88 - 8.82 (m, 1H), 8.29 (dd, J = 8.5, 2.5 Hz, 1H), 8.12 - 8.01 (m, 2H), 7.76 (dq, J = 4.2, 2.0 Hz, 2H), 7.58 (s, 1H) ppm.A solution of To a flask charged with 2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride was dissolved in THF (2 mL) and cooled to 0 C. DIEA (138 mu, 0.792 mmol) and 5-aminopyridine-2- carboxamide (40 mg, 0.29 mmol) were added and the resulting suspension was stirred at 0 C for 30 minutes and then allowed to warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic later was separated, dried by passing through a phase separation cartridge and concentrated in vacuo. Silica gel chromatography (0- 100% ethyl acetate/petroleum ether) provided 5-[[2-chloro-3-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (85 mg, 64%). ESI-MS m/z calc. 499.06, found 500.0 (M+l)+;497.9 (M-l)-; retention time (Method E): 3.01 minutes (5 minute run). NMR (400 MHz, DMSO-d6) delta 11.25 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 8.6, 2.5 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.56 (s, 1H), 7.49 (t, J = 9.0 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.98 (ddd, J = 8.9, 2.8, 1.3 Hz, 1H), 6.84 (dd, J = 9.3, 3.9 Hz, 1H), 3.77 (s, 3H) ppm.To a solution of 3-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]benzoic acid (100 mg, 0.241 mmol) in dichloromethane (3 mL) and DMF (19 mu^, 0.24 mmol) at 0 C was added oxalyl chloride (21 mu, 0.24 mmol) dropwise under N2 atmosphere. The reaction mixture was allowed to warm to room temperature then stirred for 30 minutes. The solution was then added dropwise to a stirring solution of To a stirring slurry of General procedure: 4-(2-chloro-9H-purin-6-yl)morpholine (50 mg, 0.21 mmol), heteroaromatic amine (1.2 equiv), 2 mol % Pd(OAc)2, 3 mol % Xantphos, Cs2CO3(140 mg, 0.43 mmol) in dioxane (1.5 mL) was heated to 160 C in a microwave reactor for 40 min. The solvent was removed under reduced pressure and the crude material was purified by column chromatography on silica gel with CH2Cl2/CH3OH in a 15:1 (v/v)ratio as eluent, to afford product 3m-p.General procedure: [1058] A solution of the appropriate carboxylic acid or carboxylic acid hydrochloride (1 eq.) and the appropriate amine or amine hydrochloride (1.1-1.9 eq.) in pyridine (about 0.1 M) was heated to 60 C., and T3P (50% in ethyl acetate, 1.5-15 eq.) was added dropwise. Alternatively, T3P was added at RT and the mixture was then stirred at RT or heated to 50 to 90 C. Afier 1 to 20 h, the reaction mixture was cooled to RT and either purified directly by means of preparative HPLC (water-acetonitrile gradient or water- methanol gradient) or admixed with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous buffer solution (pH=5), with saturated aqueous sodium hydrogen- carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was then optionally purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).[1160] 50 mg (0.121 mmol) of 2-[4-(5-chloro-2-cyano- phenyl)-5-methoxy-2-oxopyridin-1 (2H)-yl] -3 -(5-methyl-i, 2, 4-oxadiazol-3-yl)propanoic acid (racemate) and 25 mg(0.181 mmol, 1.5 eq.) of [1144] 40 mg (0.098 mmol) of 2-[4-(5-chioro-2-cyano- phenyl)-5-methoxy-2-oxopyridin-i (2H)-yl] -3-(i , 3-oxazol- 2-yl)propanoic acid (racemate) and 20mg (0.147 mmol, 1.5 eq.) of

Molecular Weight:137.14
XLogP3:-0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:137.058911855
Monoisotopic Mass:137.058911855
Topological Polar Surface Area:82
Heavy Atom Count:10
Complexity:137
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes