Dimethylformamide → N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-methylpyrrolidin-2-yl)benzamide

HRID 468776

Reaction equation

HRID 468776 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:4][CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1.[C:53](=[O:56])([O-])[O-].[K+].[K+].[NH2:59][C:60]1[CH:61]=[CH:62][C:63]([CH3:82])=[C:64]([C:66]2[CH:75]=[C:74]3[C:69]([CH:70]=[C:71]([NH:76][C:77]([CH:79]4[CH2:81][CH2:80]4)=[O:78])[N:72]=[CH:73]3)=[CH:68][CH:67]=2)[CH:65]=1.CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:79]1([C:77]([NH:76][C:71]2[N:72]=[CH:73][C:74]3[C:69]([CH:70]=2)=[CH:68][CH:67]=[C:66]([C:64]2[CH:65]=[C:60]([NH:59][C:53](=[O:56])[C:2]4[CH:7]=[CH:6][C:5]([CH:8]5[CH2:12][CH2:11][CH2:10][N:9]5[CH3:13])=[CH:4][CH:3]=4)[CH:61]=[CH:62][C:63]=2[CH3:82])[CH:75]=3)=[O:78])[CH2:80][CH2:81]1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 2848972-(4-Bromophenyl)-1-methylpyrrolidineHCID 67974803N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamideHCID 71317487Phosphine, 1,1'-(1,3-propanediyl)bis[1,1-dicyclohexyl-, tetrafluoroborate(1-) (1:2)

Product 1

HCID 71115021N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-methylpyrrolidin-2-yl)benzamideYield 8.3%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Procedure

A flask containing a mixture of 2-(4-bromophenyl)-1-methylpyrrolidine (58.8 mg, 0.245 mmol), palladium acetate (8.9 mg, 0.040 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (35.5 mg, 0.0582 mmol), potassium carbonate (79.0 mg, 0.572 mmol), and N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (89.0 mg, 0.280 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was evacuated purged with nitrogen five times, and then evacuated and purged three times with CO gas. The reaction was stirred under a CO gas balloon, at 100° C., for 15 hours. The reaction mixture was poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) followed by purification via reverse phase HPLC and lyophilized to yield 10.3 mg (8%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-methylpyrrolidin-2-yl)benzamide. LCMS (ESI): RT=4.125, M+H=505.3, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.20 (s, 1H), 9.20 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.92 (t, J=8.2 Hz, 3H), 7.79 (s, 1H), 7.77-7.67 (m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.3 Hz, 1H), 2.26 (s, 3H), 2.21-2.13 (m, 1H), 2.10 (m, 4H), 1.79 (m, 4H), 1.71-1.50 (m, 2H), 0.85 (m, 4H).

Workup

  1. additionA flask containing
  2. customwas evacuated
  3. custompurged with nitrogen five times
  4. customevacuated
  5. custompurged three times with CO gas
  6. additionThe reaction mixture was poured into ethyl acetate
  7. washwashed with saturated aqueous sodium bicarbonate and brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane)
  12. customfollowed by purification via reverse phase HPLC

Sources & evidence

ORD record
ord-81693201e5ff42cbaad433c274c22d25
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Linked notes

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