Potassium Phosphate, Tribasic → 2-(2,2-Difluoropropyl)-N-(4-methyl-3-(5-methylpyridin-2-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine

HRID 1505045Notes

Reaction equation

HRID 1505045 reaction equation
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[CH2:7]2.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:15][C:13]([F:16])([CH3:14])[CH2:12][N:6]1[CH2:5][CH2:4][C:3]2[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([CH3:17])=[C:19]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 574932814-Methyl-3-(5-methylpyridin-2-yl)anilineHCID 583179355-Bromo-2-(2,2-difluoropropyl)-1,2,3,4-tetrahydroisoquinoline

Product 1

HCID 583178822-(2,2-Difluoropropyl)-N-(4-methyl-3-(5-methylpyridin-2-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
96 °C

Procedure

To a reaction tube under argon containing 5-bromo-2-(2,2-difluoropropyl)-1,2,3,4-tetrahydroisoquinoline (29 mg, 0.1 mmol), 4-methyl-3-(5-methylpyridin-2-yl)aniline (20 mg, 0.1 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), xantphos (17 mg, 0.02 mmol), potassium phosphate (60 mg, 0.3 mmol) is added anhydrous dioxane (0.5 ml). The mixture is stirred at 96° C. under argon for 18 hours, cooled to room temperature and filtered through a celite pad. The filtrate is concentrated and preparative HPLC is used to isolate 2-(2,2-Difluoropropyl)-N-(4-methyl-3-(5-methylpyridin-2-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine as a white solid. LC-MS m/z: 408.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.48 (s, 1H), 7.52 (dd, 2H, J=1.6, 8 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.14 (d, 1H, J=8.0 Hz), 7.07-7.00 (m, 2H), 6.95 (dd, 1H, J=2.4, 8.0 Hz), 6.62 (d, 1H, J=6.8 Hz), 5.30 (s, 1H), 3.77 (s, 2H), 2.92 (t, 2H, J=6.0 Hz), 2.83 (t, 2H, J=13.6 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.36 (s, 3H), 2.27 (s, 3H), 1.66 (t, 3H, J=18.8 Hz).

Workup

  1. temperaturecooled to room temperature
  2. filtrationfiltered through a celite pad
  3. concentrationThe filtrate is concentrated

Sources & evidence

ORD record
ord-fe3133539b87479cbdd728c83d7e42f4
Source dataset
uspto-grants-2015_12
Patent number
US09216964B2

Reaction notes

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