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

HRID 525667Notes

Reaction equation

HRID 525667 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]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[N:39](COCC[Si](C)(C)C)[N:38]=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O.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.CCO.O.COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:35]2[NH:39][N:38]=[CH:37][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O: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 3301EthylenediamineHCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 2724141Tetrabutylammonium FluorideHCID 447552015-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleHCID 899068275-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 1180449976-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 5

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-b5f791e03aed4955844253f38d583af9
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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