Ammonium Chloride → HCID 121317073, compound

Participants

Reaction Steps

5-chloropicolinic acid (19 mg, 0.12 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (67.4 mg, 0.177 mmol) was dissolved DMF (1 mL). The reaction mixture was stirred for 5 minutes. Then (S)-6-(5-amino-2-fluorophenyl)-6-(difluoromethyl)-5,5-difluoropiperidine-2-thione (25 mg, 0.081 mmol) and DIPEA (N,N-di-isopropyl ethylamine) (52 mg, 0.07 ml, 0.4 mmol) were added. The reaction mixture was stirred for 1 hour at room temperature. Satureted aqueous NH4Cl was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure Ammonia in methanol (7M, 2 mL) was added and the reaction mixture was stirred at 55° C. in a sealed vial overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (heptane:ethyl acetate). The product was dissolved in ethyl acetate and washed 5 times with satureted aqueous NaHCO3/water to remove thiourea byproducts. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-chloropicolinamide. 1H NMR (DMSO-d6, 600 MHz): δ 10.78 (s, 1H), 8.79 (dt, J=2.4, 1.1 Hz, 1H), 8.20 (dd, J=8.4, 2.4 Hz, 1H), 8.16 (dd, J=8.4, 0.7 Hz, 1H), 7.96-7.90 (m, 1H), 7.88 (dd, J=6.8, 2.7 Hz, 1H), 7.20 (dd, J=11.6, 8.8 Hz, 1H), 6.74 (t, J=55.2 Hz, 1H), 6.38 (s, 2H), 2.51 (dt, J=3.7, 1.8 Hz, 2H), 2.19-1.98 (m, 2H).

Provenance & Evidence