Cesium carbonate → 8-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one

HRID 1045940Notes

Reaction equation

HRID 1045940 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]2.[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25](I)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]4[C:11]=3[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]4)[C:24]([C:28]([F:30])([F:29])[F:31])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 162026268-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-oneHCID 56951658N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine

Product 1

HCID 446088838-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-2-methyl-3,4-dihydroisoquinolin-1-oneYield 34%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 3283Diethyl EtherSolventHCID 312751,4-DioxaneSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

A suspension of 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (23.06 mg, 0.13 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol, Ex. 2.02), palladium(II) acetate (1.469 mg, 6.54 μmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7.57 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) in dioxane (1 ml) was stirred at 80° C. overnight under nitrogen. The same reactants were dissolved in DMA (1 mL) and sealed into a microwave tube. Argon was bubbled through the reaction mixture then the reaction was heated to 150° C. over a period of 30 minutes in a microwave reactor. The crudes were combined, poured onto a silica gel column and purified by flash chromatography eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness. Trituration with a few drops of MeCN gave a solid which was taken up into Et2O, collected by filtration and dried to afford the title compound (19 mg, 33.7%) as a white solid. 1H NMR spectrum (500 MHz, CDCl3): 2.16 (s, 3H), 2.90-2.99 (m, 2H), 3.14 (s, 3H), 3.51-3.58 (m, 2H), 3.79 (s, 3H), 5.94 (s, 1H), 6.42 (s, 1H), 6.90 (d, 1H), 7.20 (dd, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 8.26 (s, 1H), 11.13 (s, 1H); Mass spectrum: ESI+ MH+ 431.

Workup

  1. customsealed into a microwave tube
  2. customArgon was bubbled through the reaction mixture
  3. temperaturethe reaction was heated to 150° C. over a period of 30 minutes in a microwave reactor
  4. additionpoured onto a silica gel column
  5. custompurified by flash chromatography
  6. washeluting with 0 to 5% MeOH in EtOAc/DCM (1:1)
  7. customThe solvent was evaporated to dryness
  8. customTrituration with a few drops of MeCN gave a solid which
  9. filtrationcollected by filtration
  10. customdried

Sources & evidence

ORD record
ord-f6c76679b92b4561a3a5e59a6bb609c6
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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