1,2-Dimethoxyethane → 6-((2-Hydroxyethyl)(methyl)amino)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923989Notes

Reaction equation

HRID 923989 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].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=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

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 899068275-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 1181952516-((2-Hydroxyethyl)(methyl)amino)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1, 59 mg, 0.136 mmol), pyrimidin-5-ylboronic acid (33.7 mg, 0.272 mmol), Pd(PPh3)2Cl2 (9.54 mg, 0.014 mmol) and Na2CO3 (57.6 mg, 0.544 mmol) were added to a MW vial and treated with a mixture of DME (576 μL), water (165 μL) and EtOH (82 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min, diluted with DME (3 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 56.6 mg, 0.082 mmol). The RM was 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 DEAP, from 10% to 15% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.92 min, m/z=434.3 [M+H]+, m/z=432.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H) 3.44-3.52 (m, 2H) 3.53-3.60 (m, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.82-7.90 (m, 2H) 8.15 (d, J=2.38 Hz, 1H) 8.77 (d, J=2.38 Hz, 1H) 8.97 (s, 2H) 9.19 (s, 1H) 10.23 (s, 1H).

Workup

  1. customThe vial was sealed
  2. customevacuated/purged with argon
  3. customsubjected to MW irradiation at 125° C. for 20 min
  4. additiondiluted with DME (3 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 preparative SFC (Column DEAP, from 10% to 15% in 10 min)

Sources & evidence

ORD record
ord-0355288d50d347bba3cc9c63104f76b8
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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