Sodium Carbonate → [5-Fluoro-8-(5-hydroxy-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-((1R,2R)-2-phenyl-cyclopropyl)-methanone

HRID 1773991Notes

Reaction equation

HRID 1773991 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:8][CH2:7]2.[OH:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:5]1[CH:4]=[CH:3][C:2]([C:29]2[CH:30]=[C:25]([OH:24])[CH:26]=[CH:27][C:28]=2[O:34][CH3:35])=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:10]2

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 447548315-Hydroxy-2-methoxyphenylboronic acidHCID 89648804(8-Bromo-5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-((1R,2R)-2-phenyl-cyclopropyl)-methanone

Product 1

HCID 118353176[5-Fluoro-8-(5-hydroxy-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-((1R,2R)-2-phenyl-cyclopropyl)-methanone

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 70394911MeOH toluene waterSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture under N2 of (8-bromo-5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-((1R,2R)-2-phenyl-cyclopropyl)-methanone (289 mg, 0.76 mmol, 1.00 eq.), 5-hydroxy-2-methoxyphenylboronic acid (131 mg, 0.76 mmol, 1.00 eq.) and sodium carbonate (324 mg, 3.05 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (15 mL), tetrakis(triphenylphosphine) palladium (0) (44 mg, 0.04 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 62 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (30 mL) and water (30 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×15 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 28 fractions of 40 mL, Heptane+10% AcOEt to Heptane+50% AcOEt) to yield the title product as a colorless oil.

Workup

  1. temperatureto cool to r.t.
  2. concentrationconcentrated in vacuo
  3. customThe residue was partitioned between AcOEt (30 mL) and water (30 mL)
  4. customThe layers were separated
  5. washphase was washed with sat. aq. NaCl soln
  6. dry with material(1×15 mL), dried over MgSO4
  7. filtrationfiltered through Celite
  8. concentrationThe filtrate was concentrated in vacuo
  9. customThe residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 28 fractions of 40 mL, Heptane+10% AcOEt to Heptane+50% AcOEt)

Sources & evidence

ORD record
ord-07f4c27486ff4833a849642952d7ad73
Source dataset
uspto-grants-2016_02
Patent number
US09255090B2

Reaction notes

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