Cesium carbonate → 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)phenoxy)propan-2-ol

HRID 1051510Notes

Reaction equation

HRID 1051510 reaction equation
[CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3]1.Br[C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[O:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>O1CCOCC1.O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][N:19]1[CH2:18][CH:17]([OH:29])[CH2:16][O:15][C:14]1[CH:30]=[CH:31][CH:32]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH2:7]2)[CH:13]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 429098461-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-olHCID 707011991-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine

Product 1

HCID 867292811-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)phenoxy)propan-2-olYield 18.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred mixture of 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (30 mg, 0.219 mmol) in dioxane:H2O (6 mL, 2:1) was added 1-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (119 mg, 0.328 mmol), Cs2CO3 (213 mg, 0.657 mmol) and then Ruphos (2 mg) and Pd(Ruphos) (5 mg). The mixture was degassed by N2 4 times and stirred at 100° C. for 16 hours. The reaction mixture was then quenched with water (20 mL), extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to yield a residue which was purified by prep-HPLC to afford 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)phenoxy)propan-2-ol (17 mg, Yield 18.6%). 1H NMR (400 MHz, MeOD) δ=7.32 (s, 1H), 7.19-7.08 (m, 4H), 7.04 (d, J=5.8 Hz, 1H), 6.70-6.61 (m, 2H), 6.50-6.43 (m, 1H), 4.29-4.22 (m, 1H), 4.20 (s, 2H), 4.09-4.01 (m, 1H), 4.01-3.92 (m, 1H), 3.76 (s, 2H), 3.73 (s, 3H), 3.61 (t, J=5.8 Hz, 2H), 2.98-2.84 (m, 4H), 2.82-2.67 (m, 4H). LCMS (m/z): 419.2 (M+1).

Workup

  1. customThe mixture was degassed by N2 4 times
  2. customThe reaction mixture was then quenched with water (20 mL)
  3. extractionextracted with ethyl acetate (3×20 mL)
  4. washThe combined extracts were washed with brine (20 mL)
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationconcentrated
  7. customto yield a residue which
  8. customwas purified by prep-HPLC

Sources & evidence

ORD record
ord-35e40d939b1341d3ae11163b0dd9d932
Source dataset
uspto-grants-2016_07
Patent number
US09388173B2

Reaction notes

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