Water → 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)amino)propan-2-ol

HRID 1399845Notes

Reaction equation

HRID 1399845 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([OH:22])[CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:5]=[CH:4][CH:3]=1.O.[CH3:24][N:25]1[C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[CH2:11][CH:10]([OH:22])[CH2:9][NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]3[N:27]=[CH:26][N:25]([CH3:24])[C:29]=3[CH:30]=2)[N:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 594746911-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)-1H-benzo[D]imidazoleHCID 867292551-((6-bromopyridin-2-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

Product 1

HCID 867292561-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)amino)propan-2-olYield 8.1%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

To a stirred mixture of 1-((6-bromopyridin-2-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (130 mg, 0.36 mmol) in dioxane:H2O (15 mL, 2:1) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (102 mg, 0.396 mmol), Cs2CO3 (351 mg, 1.08 mmol) and then Pd(dppf)Cl2 (10 mg). The mixture was degassed with N2 4 times and stirred at 25° C. for 16 hours. The reaction mixture was quenched with water (20 mL), extracted with EA (20 mL×3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title compound (12 mg, 8%). 1HNMR (CH3OD, 400 MHz) δ: 8.05 (s, 1H), 7.88-7.87 (m, 2H), 7.83-7.80 (m, 1H), 7.50 (t, J=8.0, 1H), 7.13-7.11 (m, 4H), 7.01-7.00 (m, 1H), 6.40 (d, J=4.0, 1H), 5.00 (s, 1H), 4.45 (br, 1H), 4.11-4.13 (m, 1H), 3.82-3.61 (m, 6H), 3.52-3.45 (m, 1H), 2.91 (s, 3H), 2.81-2.63 (m, 3H). LCMS (m/z): 414.2 [M+H]

Workup

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

Sources & evidence

ORD record
ord-e32525cfb5814d899dee289046c9dafb
Source dataset
uspto-grants-2014_12
Patent number
US08906900B2

Reaction notes

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