Methylamine → 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-N,4-dimethylpicolinamide

HRID 1502345Notes

Reaction equation

HRID 1502345 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:24])[CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1.[C:64](=[O:67])([O-])[O-].[K+].[K+].[CH3:70][NH2:71]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:5]2[C:4]([CH3:24])=[CH:3][C:2]([C:64]([NH:71][CH3:70])=[O:67])=[N:7][CH:6]=2)[CH:17]=3)=[O:20])[CH2:23][CH2:22]1

Participants

8

Reactant 4

HCID 6329MethylamineHCID 11430Potassium CarbonateHCID 71317487Phosphine, 1,1'-(1,3-propanediyl)bis[1,1-dicyclohexyl-, tetrafluoroborate(1-) (1:2)HCID 76401541N-(7-(6-chloro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

Product 1

HCID 711151395-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-N,4-dimethylpicolinamideYield 50%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-(7-(6-chloro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (50 mg, 0.1 mmol), palladium acetate (2 mg, 0.007 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (9 mg, 0.014 mmol), potassium carbonate (29 mg, 0.21 mmol), methylamine (2.0M solution in tetrahydrofuran, 0.74 mL), and N,N-dimethylformamide (1 mL) was purged with nitrogen and evacuated (3×), flushed with carbon monoxide and evacuated (2×), and then left under a carbon monoxide balloon and heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (25 mg, 50%). 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 9.21 (s, 1H), 8.79 (m, 1H), 8.54 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 2.85 (d, J=4.8 Hz, 3H), 2.41 (s, 3H), 2.14-2.03 (m, 1H), 0.92-0.78 (m, 4H). LCMS (Method E): RT=4.054 min, M+H+=361.1.

Workup

  1. customwas purged with nitrogen
  2. customevacuated (3×)
  3. customflushed with carbon monoxide
  4. customevacuated (2×)
  5. waitleft under a carbon monoxide balloon
  6. customThe cooled reaction mixture
  7. washwashed with water (100 mL)
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customto afford a residue that
  13. customwas purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min)

Sources & evidence

ORD record
ord-4a926aae7af74189965b1d2b4f099b34
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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