Ammonium Chloride → HCID 121317073, compound

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).

1. stirringThe reaction mixture was stirred for 1 hour at room temperature
2. extractionthe mixture was extracted with ethyl acetate
3. washThe combined organic phases were washed with brine
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure Ammonia in methanol (7M, 2 mL)
7. additionwas added
8. stirringthe reaction mixture was stirred at 55° C. in a sealed vial overnight
9. concentrationThe reaction mixture was concentrated under reduced pressure
10. customThe crude product was purified by flash chromatography on silica (heptane:ethyl acetate)
11. dissolutionThe product was dissolved in ethyl acetate
12. washwashed 5 times with satureted aqueous NaHCO3/water
13. customto remove thiourea byproducts
14. washThe combined organic phases were washed with brine
15. dry with materialdried over MgSO4
16. filtrationfiltered
17. concentrationconcentrated under reduced pressure

ORD record

ord-5bf905621b1144d2a13259de17c0e6a5

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346797B1