Sodium Sulfate → (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde

HRID 920609Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](OC)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1

Participants

Conditions

Temperature: -78 °C

Procedure

A solution of (R)-methyl 1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (2.12 g, 3.96 mmol) was dissolved in dry dichloromethane and cooled to −78° C. under nitrogen. A solution of diisobutylaluminium hydride (1.0 M in dichloromethane, 16 mmol, 16 mL) was added dropwise maintaining the reaction temperature at <−70° C. and the reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was treated with water (6 mL), stirred at −78° C. for 5 minutes then warmed to >0° C. over 15 minutes. Solid sodium bicarbonate (5.5 g) was added and the mixture stirred vigorously for 5 minutes. Excess sodium sulfate was added (˜20 g) and the resultant mixture was stirred vigorously for a further 15 minutes. The solid materials were removed by filtration and rinsed with a little dichloromethane. The filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) followed by ethyl acetate to afford (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde as a white foam (0.62 g). 1H NMR (400 MHz, CDCl3): 9.48 (s, 1 H); 7.93 (d, J=8.2 Hz, 2 H); 7.84 (d, J=8.3 Hz, 2H); 7.39-7.40 (m, 3 H); 7.17 (t, J=8.5 Hz, 2 H); 6.52 (d, J=2.5 Hz, 1 H); 4.32 (d, J=12.3 Hz, 1 H); 3.90 (br s, 1 H); 3.14 (d, J=16.4 Hz, 1 H); 2.65-2.80 (m, 1H); 2.51-2.52 (m, 4 H) and (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol as a white solid (1.0 g). 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.2 Hz, 2 H); 7.83 (d, J=8.3 Hz, 2 H); 7.40-7.41 (m, 3 H); 7.14-7.15 (m, 2 H); 6.31 (d, J=2.4 Hz, 1 H); 4.11-4.12 (m, 1 H); 4.02 (dd, J=11.4, 5.9 Hz, 1 H); 3.78 (dd, J=11.5, 5.6 Hz, 1 H); 3.34 (dd, J=11.4, 8.1 Hz, 1 H); 3.13 (d, J=15.8 Hz, 1 H); 2.74-2.76 (m, 1 H); 2.59-2.60 (m, 1 H); 2.41 (d, J=15.5 Hz, 1 H); 2.24-2.25 (m, 2 H); 2.04 (s, 1 H).

Workup

temperaturemaintaining the reaction temperature at <−70° C.
stirringstirred at −78° C. for 5 minutes
temperaturethen warmed to >0° C. over 15 minutes
stirringthe mixture stirred vigorously for 5 minutes
customThe solid materials were removed by filtration
washrinsed with a little dichloromethane
concentrationThe filtrate was concentrated under reduced pressure
customthe residue purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume)

Sources & evidence

ORD record: ord-3e0479501c88446b8391c2ae988f96c3
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09273047B2

Reaction notes

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