5-Fluoro-2-pyridinecarboxamide

The solution of 5-fluoropicolinoyl chloride (2.30 g, 14.4 mmol, 1.00 equiv) in THF (40 mL) was added dropwise to a stirred saturated solution of ammonium hydroxide (40 mL)at 0°C. The resulting mixture was stirred at 10 °C for 30 min. The solvent was evaporated under reduced pressure. The residue was diluted with dichloromethane (30 mL), washed with brine (2 x 30 mL), dried (NaThe solution of 5-fluoropicolinoyl chloride (2.30 g, 14.4 mmol, 1.00 equiv) in THF (40 mL) was added dropwise to a stirred saturated solution of ammonium hydroxide (40 mL) at 0°C. The resulting mixture was stirred at 10 °C for 30 mm. The solvent was evaporated under reduced pressure. The residue was diluted with dichloromethane (30 mL), washed with brine (2 x 30 mL), dried (Na2504), filtered, and solvent was evaporated under reduced pressure giving 1.82 g(7 1percent) of 5-fluoropicolinamide as a yellow solid: MS (ES, m/z): 140.9 (M + 1).General procedure: A microwave tube was loaded with intermediate 14 (195 mg, 0.493 mmol), 5-methoxy- 2-pyrazinecarboxamide (91 mg, 0.592 mmol), Cul (103 mg, 0.543 mmol) and K3PO4 (209 mg, 0.987 mmol) in dioxane (5.1 mL). The vial was degassed by bubbling nitrogen for a few minutes. Then, trans -N, A/-dimethylcyclohexane-l, 2-diamine (84 mg, 0.592 mmol) was added and, after stirring for 2 min at r.t., the mixture was heated for 16 h at 100 C. The mixture was then poured into 7 N NH3 in MeOH and stirred for 1 h. Next, water and DCM were added and the org. layer was separated. The aq. layer was extracted twice with DCM. The org. layer was separated, dried (MgS04), filtered and concentrated in vacuo providing a crude which was purified by Prep SFC (Stationary phase: Chiralcel Diacel OD 20x250 mm; Mobile phase: C02, EtOH+0.4% iPrNH2) to yield two fractions, each of them individually further purified by flash column chromatography (silica; DCM/(7 N NH3 in MeOH) 100/0 to 90/10). After removal of the solvent the desired compounds were obtained as white crystals (Compound 1 : 52 mg, 22%. Compound 2: 58 mg, 25%).General procedure: A microwave tube was loaded with intermediate 14 (195 mg, 0.493 mmol), 5-methoxy- 2-pyrazinecarboxamide (91 mg, 0.592 mmol), Cul (103 mg, 0.543 mmol) and K3PO4 (209 mg, 0.987 mmol) in dioxane (5.1 mL). The vial was degassed by bubbling nitrogen for a few minutes. Then, trans -N, A/-dimethylcyclohexane-l, 2-diamine (84 mg, 0.592 mmol) was added and, after stirring for 2 min at r.t., the mixture was heated for 16 h at 100 C. The mixture was then poured into 7 N NH3 in MeOH and stirred for 1 h. Next, water and DCM were added and the org. layer was separated. The aq. layer was extracted twice with DCM. The org. layer was separated, dried (MgS04), filtered and concentrated in vacuo providing a crude which was purified by Prep SFC (Stationary phase: Chiralcel Diacel OD 20x250 mm; Mobile phase: C02, EtOH+0.4% iPrNH2) to yield two fractions, each of them individually further purified by flash column chromatography (silica; DCM/(7 N NH3 in MeOH) 100/0 to 90/10). After removal of the solvent the desired compounds were obtained as white crystals (Compound 1 : 52 mg, 22%. Compound 2: 58 mg, 25%).A microwave tube was loaded with intermediate 60a (70 mg, 0.18 mmol), Step C: Preparation of ('R -2-('('R -l, l-dimethylethylsulfinamido -2-('2-fluoro-5- fluoropicolinamide phenyl -N-('4-methoxybenzyl -N-methylpropane- 1 -sulfonamide (6a) To a reactor (R-l) equipped with a temperature probe, nitrogen inlet and agitator was charged To a reactor Ri) equipped with a temperature probe, nitrogen inlet and agitator was charged 5.-fluoro2-pydinecarboxamide (1.049g. 7.49 rnmol), K2C03 (2.82g. 20.42 mrnol), trans-JV, N ?.-dimethylcyc1ohexane I , 2diamine (2.147 mL, 13.61 mmol). copper(I) iodide (1.296g. 6.81 mmol), toluene (8.5 mL) and 4a (37 wt% in toluene, lOg, 6.81 mmol). Agitation was begun and the reaction was warmed to 8090C. When the reaction was deemed complete, the reaction was cooled to 20 to 30C. in a separate reactor (R2) equipped with an agitator was charged a 5% sodium chloride solution, The aqueous layer was separated andthe organic layer was washed with 5% sodium chloride solution until the aqueous layer was clear. The organic layer was then concentrated to provide 6a (3.09 g, 5.08 rnmol). 'H NMR (CDCi3, 500 MFIz) 10, 79 (s, 1H), 8, 74 (d, J 2.9 Hz, 1H), 8.24 (dd, J 4.2, 8.5Hz, 2H), 7.98 (dt, , 1 2.8, 5.5 Hz, IH). 7.92 (dq, , 1 2.4, 8.8 Hz, 1H). 7.17-7.23 (m, 2H), 6.906.95 (m.2H), 558 (s, 1H), 4.00-4.10 (in, 2H), 3.81-3.90 (m, 2H), 3.74 (s, 3H), 2.56 (s, 3H), 1.94 (s, 3H), 1.20 (s, 9H); MS (m/z): [M ± fJfi+ calcd for C28H35F2N.O5S2, 609.20; found. 609.10.

Molecular Weight:140.11
XLogP3:0.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:140.03859095
Monoisotopic Mass:140.03859095
Topological Polar Surface Area:56
Heavy Atom Count:10
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes