Water → HCID 73051160, compound

HRID 537279Notes

Reaction equation

HRID 537279 reaction equation
[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1

Participants

6

Reactant 4

HCID 962WaterHCID 13901-MethylimidazoleHCID 86710001HCID 86710001, compoundHCID 178418339Butyllithium

Product 1

HCID 73051160HCID 73051160, compoundYield 10%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent3×

Conditions

Temperature
-78 °C

Procedure

1-Methyl-1H-imidazole (104 mg, 1.267 mmol) in dry ether (5 mL) was added to butyllithium (2.5M in hexanes) (519 μl, 1.298 mmol) in dry ether (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-methyl 1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (200 mg, 0.415 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 45 minutes at −78° C., then allowed to warm to room temperature over 2 hours. Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (3×20 mL), the combined organic phases were washed with brine (20 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-60% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone (22 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.52 min, m+H=532.0; 1H NMR (400 MHz, CDCl3): δ 7.61-7.58 (2H, m), 7.46-7.40 (2H, m), 7.31 (1H, s), 7.29-7.27 (2H, m), 7.18 (1H, d, J=0.9 Hz), 7.17-7.12 (2H, m), 6.99 (1H, br. s), 6.50 (1H, d, J=2.2 Hz), 5.53 (1H, dd, J=12.2, 2.2 Hz), 4.45 (1H, d, J=16.7 Hz), 3.88-3.84 (4H, m), 2.92-2.78 (2H, m), 2.60 (1H, d, J=12.2 Hz), 2.50-2.37 (5H, m).

Workup

  1. stirringthe reaction mixture was stirred for 45 minutes at −78° C.
  2. temperatureto warm to room temperature over 2 hours
  3. stirringthe reaction mixture was stirred at room temperature for 10 minutes
  4. extractionThe aqueous phase was extracted with ethyl acetate (3×20 mL)
  5. washthe combined organic phases were washed with brine (20 mL)
  6. dry with materialdried (magnesium sulfate), and solvent
  7. customremoved
  8. customto give a yellow oil
  9. customThe crude product was purified by chromatography on silica gel (gradient: 0-60% ethyl acetate in isohexane)

Sources & evidence

ORD record
ord-d13657522ad343ed97540a7df055ff55
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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