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

HRID 468776

反応式

HRID 468776 の反応式
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

参加物

7

反応物 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)

生成物 1

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

試薬・触媒・溶媒 1

HCID 167845palladium(II) acetate触媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-81693201e5ff42cbaad433c274c22d25
出典データセット
uspto-grants-2014_01
特許番号
US08623889B2

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