Cesium carbonate → 7-(5-fluoro-2-methylphenyl)-N-(1,1,1-trifluoropropan-2-yl)isoquinolin-3-amine

HRID 1502263Notes

Reaction equation

HRID 1502263 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]=2.Cl.[CH3:21][CH:22]([NH2:27])[C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.CC(C)([O-])C.[Na+]>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([NH:27][CH:22]([CH3:21])[C:23]([F:26])([F:25])[F:24])[N:3]=[CH:4]3)=[CH:9][CH:8]=2)[CH:17]=1

Participants

6

Reactant 5

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 18364314(RS)-2-Amino-1,1,1-trifluoropropane hydrochlorideHCID 23676156Sodium t-butoxideHCID 866749363-Chloro-7-(5-fluoro-2-methylphenyl)isoquinoline

Product 1

HCID 679750877-(5-fluoro-2-methylphenyl)-N-(1,1,1-trifluoropropan-2-yl)isoquinolin-3-amineYield 37.7%

Conditions

Temperature
90 °C

Procedure

A mixture of 3-chloro-7-(5-fluoro-2-methylphenyl)isoquinoline (41 mg, 0.15 mmol), 1-methyl-2,2,2-trifluoroethylamine, hydrochloride (36.5 mg, 0.244 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (8.4 mg, 0.016 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2-4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (13.7 mg, 0.0172 mmol), and cesium carbonate (148 mg, 0.454 mmol) in 1,4-dioxane (1.5 mL, 19 mmol) was purged with nitrogen and then heated at 90° C., for 2 hours. Sodium-tert-butoxide (49.2 mg, 0.512 mmol) was then added and the reaction mixture heated at 90° C. overnight. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 19.7 mg (37%) of 7-(5-fluoro-2-methylphenyl)-N-(1,1,1-trifluoropropan-2-yl)isoquinolin-3-amine. LCMS (ESI): RT (Min)=5.716, M+H=349.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.84 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.36 (dd, J=9.3, 5.9 Hz, 1H), 7.13 (dd, J=7.8, 5.1 Hz, 2H), 7.01 (d, J=9.1 Hz, 1H), 6.88 (s, 1H), 5.11-4.91 (m, 1H), 2.25 (s, 3H), 1.37 (d, J=6.9 Hz, 3H).

Workup

  1. customwas purged with nitrogen
  2. temperaturethe reaction mixture heated at 90° C. overnight
  3. customThe mixture was then partitioned between ethyl acetate and water
  4. washthe organic layer was washed with water and brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customThe crude product was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-fdf85c21f87a4816939a6f609a8b9418
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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