Cesium carbonate → 7-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine

HRID 468728Notes

Reaction equation

HRID 468728 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=1.O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 2568102-Bromo-6-methoxypyridineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 574102447-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine

Product 1

HCID 679767437-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amineYield 105.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6344DichloromethaneSolvent

Procedure

To 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (151.4 mg, 0.6001 mmol) and 2-bromo-6-methoxypyridine (110.0 uL, 0.8951 mmol) was added 1,4-dioxane (4.0 mL, 51 mmol). Nitrogen gas was bubbled through this mixture while stirring for 10 minutes, and then palladium (II) acetate (14.5 mg, 0.0646 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.1 mg, 0.0987 mmol), and cesium carbonate (397.6 mg, 1.220 mmol) were added. The reaction mixture was stirred in a sealed vial at 100° C. for 90 minutes. The reaction mixture was diluted with dichloromethane, filtered through celite, and evaporated in vacuo. The crude residue was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 227.4 mg of the title compound as 80% pure material. 52.4 mg of this material was purified via reverse phase HPLC and lyophilized to yield 17.9 mg of 7-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine. LCMS (ESI): RT (min)=5.057, M+H=360.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.11 (s, 1H), 8.58 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.38 (q, J=6.3 Hz, 1H), 7.15 (t, J=8.5 Hz, 2H), 6.82 (d, J=7.8 Hz, 1H), 6.28 (d, J=7.8 Hz, 1H), 4.01 (s, 3H), 2.26 (s, 3H).

Workup

  1. customNitrogen gas was bubbled through this mixture
  2. stirringThe reaction mixture was stirred in a sealed vial at 100° C. for 90 minutes
  3. filtrationfiltered through celite
  4. customevaporated in vacuo
  5. customThe crude residue was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-e202b4c471f64583a184bbb0e6de62c1
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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