Pyrrolidine → (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

HRID 537276Notes

Reaction equation

HRID 537276 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:34]([C:37]2[CH:42]=[CH:41][C:40](F)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1>CN1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:41][CH:42]=2)(=[O:35])=[O:36])[CH2:21][CH2:20]4)=[CH:11][CH:12]=1

Participants

4

Reactant 2

HCID 31268PyrrolidineHCID 72548922(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

Product 1

HCID 72550949(R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneYield 34.1%

Reagents, catalysts & solvents 1

HCID 84541-MethylpyrrolidineSolvent

Procedure

A solution of pyrrolidine (0.065 mL, 0.783 mmol) and (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (183 mg, 0.261 mmol) in N-methylpyrrolidine (2 mL) was stirred in a sealed vial at 100° C. for 22 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as an off-white solid (52 mg). LCMS (Method F, ES-API): RT 2.78 min, m+H=584.3; 1H NMR (400 MHz, CDCl3): δ 8.63-8.62 (1H, m), 7.89 (1H, dt, J=8.0, 1.2 Hz), 7.81 (1H, td, J=7.5, 1.8 Hz), 7.51-7.47 (2H, m), 7.46-7.41 (3H, m), 7.28 (1H, s), 7.18-7.12 (2H, m), 6.48-6.45 (3H, m), 5.41 (1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.9 Hz), 3.80-3.76 (1H, m), 3.33-3.30 (4H, m), 2.88 (1H, d, J=16.9 Hz), 2.85-2.76 (1H, m), 2.61 (1H, d, J=12.1 Hz), 2.45-2.35 (2H, m), 2.07-2.01 (4H, m).

Workup

  1. customThe cooled reaction mixture
  2. customwas then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water)

Sources & evidence

ORD record
ord-539137feccdc4eef9c15953bf915c3c3
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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