Methyl vinyl ketone → (R,E)-6-(3-Hydroxypyrrolidin-1-yl)-5-(3-oxobut-1-en-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73735Notes

Reaction equation

HRID 73735 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[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].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:50][C:51](=[O:54])[CH:52]=[CH2:53]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2](/[CH:53]=[CH:52]/[C:51](=[O:54])[CH3:50])=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1

Participants

6

Reactant 3

HCID 6570Methyl vinyl ketone2×HCID 80271Tri-o-tolylphosphineHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 86702596(R,E)-6-(3-Hydroxypyrrolidin-1-yl)-5-(3-oxobut-1-en-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent

Conditions

Temperature
130 °C

Procedure

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 250 mg, 0.560 mmol), Pd(OAc)2 (3.77 mg, 0.017 mmol), tri-o-tolylphosphine (20.46 mg, 0.067 mmol), but-3-en-2-one (55.1 μL, 0.672 mmol) and TEA (102 μL, 0.728 mmol) were added to a MW vial, which was sealed and purged with argon. DMF (1.87 mL) was added and the RM was stirred at 130° C. for 6 h. Additional but-3-en-2-one (22.96 μL, 0.280 mmol) was then added and mixture was stirred at 130° C. for 16 h. The RM was poured into water (25 mL) and extracted with DCM (3×20 mL). The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1) from 40% to 75% EtOAc-EtOH+0.1% NH4OH (9:1)). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was azeotroped with xylene and triturated in cyclohexane to yield the title compound as a yellow solid. UPLC-MS (Condition 1) tR=2.39 min, m/z=436.0 [M+H]+, m/z=434.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.91 (m, 1H) 1.91-2.00 (m, 1H) 2.35 (s, 3H) 3.43 (d, J=11.25 Hz, 1H) 3.59-3.67 (m, 1H) 3.78-3.88 (m, 2H) 4.34 (br. s, 1H) 4.99 (d, J=3.18 Hz, 1H) 6.61 (d, J=15.89 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.81-7.93 (m, J=16.14, 9.29 Hz, 3H) 8.29 (d, J=2.20 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.21 (s, 1H).

Workup

  1. customwas sealed
  2. custompurged with argon
  3. additionDMF (1.87 mL) was added
  4. stirringmixture was stirred at 130° C. for 16 h
  5. extractionextracted with DCM (3×20 mL)
  6. dry with materialThe combined extracts were dried over MgSO4
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give the crude product which
  9. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1) from 40% to 75% EtOAc-EtOH+0.1% NH4OH (9:1))
  10. additionFractions containing pure product
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give a residue which
  13. customwas azeotroped with xylene
  14. customtriturated in cyclohexane

Sources & evidence

ORD record
ord-db16f23ba19146fc9d681efcb902536c
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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