Acetic Acid → HCID 178522237, compound

Temperature

100 °C

Pyrrolidine (0.230 mL, 2.78 mmol) and K2CO3 (0.524 g, 3.79 mmol) were added to a solution of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 1 g, 2.53 mmol) in MeCN (5 mL) and the RM was stirred at 100° C. for 4 h. The product was filtered, suspended in MeCN and water, filtered and the filtrate was evaporated off under reduced pressure to give a residue. The residue (100 mg, 0.232 mmol) was suspended in dioxane (1 mL), treated with tributyl(1-ethoxyvinyl)stannane (101 mg, 0.279 mmol) and Pd(Ph3P)4 (26.9 mg, 0.023 mmol) and stirred at 110° C. for 2 h. The solvent was evaporated off under reduced pressure, the residue was dissolved in dioxane (2 mL), and filtered through a PS-Thiol cartridge. This solution was treated with HCl (4 N) and stirred at RT for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOH (2 mL), treated with NaOEt (0.5 mL from a solution of 100 mg sodium dissolved in 5 mL EtOH), stirred 30 min and the treated with diethyl oxalate (0.069 mL, 0.508 mmol). The RM was stirred for 4 h at 80° C. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. NH4Cl solution and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in acetic acid (2 mL, 34.9 mmol), treated with hydrazine hydrate (0.030 mL, 0.956 mmol) and stirred at RT for 2 h. the solvent was evaporated off under reduced pressure to give a residue which was treated with MeCN/n-hexane and extracted with MeCN. The MeCN phase was separated and the solvent was evaporated off under reduced pressure to give a residue, which was dissolved in THF (1 mL), treated with LiAlH4 (20 mg, 0.527 mmol) and stirred at RT for 4 h. Additional LiAlH4 (3 eq.) were added and the RM was stirred overnight at RT. The RM was treated with an aq. solution of Rochelle salt's, filtered and the filtrate was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC and lyophilized (water/MeCN) afforded the title product. UPLC-MS (Condition 3) tR=0.9 min, m/z=448.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.81 (br. s, 4H) 3.25 (br. s, 4H) 4.53 (s, 2H) 6.33 (s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.86 (d, J=9.03 Hz, 2H) 8.14 (s, 1H) 8.67 (s, 1H) 10.31 (br. s, 1H).

1. filtrationThe product was filtered
2. filtrationwater, filtered
3. customthe filtrate was evaporated off under reduced pressure
4. customto give a residue
5. stirringstirred at 110° C. for 2 h
6. customThe solvent was evaporated off under reduced pressure
7. dissolutionthe residue was dissolved in dioxane (2 mL)
8. filtrationfiltered through a PS-Thiol cartridge
9. additionThis solution was treated with HCl (4 N)
10. stirringstirred at RT for 4 h
11. customThe solvent was evaporated off under reduced pressure
12. dissolutionthe residue was dissolved in EtOH (2 mL)
13. additiontreated with NaOEt (0.5 mL from a solution of 100 mg sodium
14. dissolutiondissolved in 5 mL EtOH),
15. stirringstirred 30 min
16. stirringThe RM was stirred for 4 h at 80° C
17. customThe solvent was evaporated off under reduced pressure
18. additionthe residue was treated with sat. aq. NH4Cl solution
19. extractionextracted with DCM
20. washThe combined extracts were washed with brine
21. dry with materialdried over Na2SO4
22. customthe solvent was evaporated off under reduced pressure
23. customto give a residue which
24. stirringstirred at RT for 2 h. the solvent
25. customwas evaporated off under reduced pressure
26. customto give a residue which
27. extractionextracted with MeCN
28. customThe MeCN phase was separated
29. customthe solvent was evaporated off under reduced pressure
30. customto give a residue, which
31. stirringstirred at RT for 4 h
32. stirringthe RM was stirred overnight at RT
33. filtrationfiltered
34. customthe filtrate was evaporated off under reduced pressure
35. customto give a crude product which
36. customwas purified by preparative SFC

ORD record

ord-a60f04734bd14bd59da62f92901b4365

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09340537B2