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)(thiazol-2-yl)methanone

HRID 537272Notes

Reaction equation

HRID 537272 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[S:29][CH:30]=[CH:31][N:32]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:33]([C:36]2[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1>CN1CCCC1>[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[S:29][CH:30]=[CH:31][N:32]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1

Participants

4

Reactant 2

HCID 31268PyrrolidineHCID 72550068(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

Product 1

HCID 72550508(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)(thiazol-2-yl)methanoneYield 52.9%

Reagents, catalysts & solvents 1

HCID 84541-MethylpyrrolidineSolvent

Conditions

Temperature
100 °C

Procedure

A solution of pyrrolidine (0.046 mL, 0.557 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)(thiazol-2-yl)methanone (0.1 g, 0.186 mmol) in N-methylpyrrolidine (2 mL) was stirred at 50° C. in a sealed vial for 6 hours, then allowed to stand at room temperature for 72 hours. The reaction mixture was then stirred at 100° C. for an additional 5 hours, cooled to room temperature, and purified directly by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 50-70% 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)(thiazol-2-yl)methanone as a pale yellow solid (58 mg). LCMS (Method F, ES-API): RT 2.81 min, m+H=590.0; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.1 Hz), 7.62 (d, 1H, J=3.1 Hz), 7.54-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.28 (s, 1H), 7.219-7.12 (m, 2H), 6.50-6.45 (m, 3H), 5.46 (dd, 1H, J=12.1, 2.0 Hz), 4.21 (d, 1H, J=16.8 Hz), 3.86-3.80 (m, 1H), 3.35-3.30 (m, 4H), 2.92-2.81 (m, 2H), 2.64 (d, 1H, J=12.2 Hz), 2.52-2.36 (m, 2H), 2.07-2.01 (m, 4H).

Workup

  1. temperaturecooled to room temperature
  2. custompurified directly by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 50-70% acetonitrile in water)

Sources & evidence

ORD record
ord-bd41a90ea272496e918859699582de50
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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