Ethylenediamine → 6-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Temperatur

75 °C

5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 19.1, 87 mg, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (130 mg, 0.401 mmol), Pd(PPh3)2Cl2 (14.06 mg, 0.020 mmol), Na2CO3 (85 mg, 0.801 mmol), DME (850 μL), water (243 μL) and EtOH (121 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 h. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 83 mg, 0.120 mmol, centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column NH2, from 8% to 13% in 10 min). The resulting intermediate was treated with ethylene diamine (33.7 μL, 0.499 mmol) and 1 M TBAF in THF (1.496 mL, 1.496 mmol) and stirred at 75° C. for 24 h. The solvent was evaporated off under reduced pressure to give a, diluted with EtOAc (30 mL), washed 3 times with sat. aq. NaHCO3, brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a. The crude product was purified by preparative SFC (Column DEAP, isocratic 23% in 9 min) to yield the title product as yellow wax. UPLC-MS (Condition 3) tR=0.92 min, m/z=422.2 [M+H]+, m/z=420.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.44 (t, J=5.87 Hz, 2H) 3.55 (q, J=5.46 Hz, 2H) 4.63 (br. s, 1H) 6.48 (d, J=2.20 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.70-7.84 (m, 1H) 7.84-7.91 (m, 2H) 8.15 (d, J=1.96 Hz, 1H) 8.71 (d, J=2.20 Hz, 1H) 10.26 (s, 1H).

1. customwas sealed
2. customevacuated/purged with argon
3. customsubjected to MW irradiation at 125° C. for 20 h
4. additionThe RM was diluted with DME (3 mL)
5. additiontreated with Si-Thiol (Silicycle, 1.44 mmol/g, 83 mg, 0.120 mmol
6. filtrationthe supernatant was filtered
7. customthe solvent was evaporated off under reduced pressure
8. customto give a residue which
9. customwas purified by preparative SFC (Column NH2, from 8% to 13% in 10 min)
10. customThe solvent was evaporated off under reduced pressure
11. customto give a,
12. washwashed 3 times with sat. aq. NaHCO3, brine
13. dry with materialdried over Na2SO4
14. customthe solvent was evaporated off under reduced pressure
15. customto give a
16. customThe crude product was purified by preparative SFC (Column DEAP, isocratic 23% in 9 min)

ORD-Eintrag

ord-b5f791e03aed4955844253f38d583af9

Quelldatensatz

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09340537B2