Ammonia → 6-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

HRID 525681Notes

Reaction equation

HRID 525681 reaction equation
Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N.CO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.CCO.O.COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:35]2[NH:34][N:33]=[CH:37][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1

Participants

12

Reactant 6

HCID 222AmmoniaHCID 887MethanolHCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 89906571HCID 89906571, compound

Product 1

HCID 1180451586-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

Reagents, catalysts & solvents 5

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 26.1, 113 mg, 0.25 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69.5 mg, 0.25 mmol), Pd(PPh3)2Cl2 (0.018 g, 0.025 mmol), Na2CO3 (0.106 g, 1.000 mmol), DME (1.061 mL), water (0.303 mL) and EtOH (0.152 mL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 0.105 g, 0.150 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc). The resulting intermediate was treated with a mixture of TFA (0.963 mL, 12.50 mmol) and DCM (2.5 mL) and for stirred for 2 h at RT. The solvent was evaporated off under reduced pressure and the residue was basified with a solution of NH3 7 M in MeOH (2 mL, 14 mmol). The solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column DEAP, isocratic 28% in 9 min) to afford the title compound as a yellow solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=438.2 [M+H]+, m/z=436.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.38-3.61 (m, 4H) 4.61 (br. s, 1H) 6.47 (s, 1H) 7.68 (d, J=8.56 Hz, 2H) 7.83 (br. s, 1H) 7.93 (d, J=8.80 Hz, 2H) 8.15 (br. s, 1H) 8.71 (br. s, 1H) 10.36 (s, 1H) 12.83-13.15 (m, 1H).

Workup

  1. customwas sealed
  2. customevacuated/purged with argon
  3. customsubjected to MW irradiation at 125° C. for 20 min
  4. additionThe RM was diluted with DME (2 mL)
  5. filtrationthe supernatant was filtered
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a residue which
  8. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc)
  9. customThe solvent was evaporated off under reduced pressure
  10. customThe solvent was evaporated off under reduced pressure
  11. customto give a crude product which
  12. customwas purified by preparative SFC (Column DEAP, isocratic 28% in 9 min)

Sources & evidence

ORD record
ord-0a8433310ecb4b40966ca24616ea829c
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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