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

HRID 537270Notes

Reaction equation

HRID 537270 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1

Participants

4

Reactant 2

HCID 8083MorpholineHCID 73053203(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

Product 1

HCID 72550066(R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneYield 83.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (80 mg, 0.14 mmol) and morpholine (150 μL, 1.73 mmol) in acetonitrile (2.5 mL) was heated at 100° C. for 70 minutes in a microwave reactor. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (gradient: 30-60% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a colourless glass (70 mg). LCMS (Method D, ESI): RT 4.94 min, m+H=601.0; 1H NMR (400 MHz, CDCl3): δ 8.63 (ddd, J=4.8, 1.7, 0.9 Hz, 1 H); 8.44 (d, J=2.5 Hz, 1 H); 7.84-7.85 (m, 2 H); 7.66 (dd, J=9.1, 2.5 Hz, 1 H); 7.44-7.45 (m, 3 H); 7.29 (s, 1 H); 7.16 (t, J=8.5 Hz, 2 H); 6.49-6.50 (m, 2 H); 5.49 (dd, J=12.1, 2.1 Hz, 1 H); 4.28 (d, J=16.9 Hz, 1 H); 3.80 (t, J=4.8 Hz, 5H); 3.63 (t, J=4.8 Hz, 4H); 2.83-2.85 (m, 2 H); 2.71 (d, J=12.1 Hz, 1 H); 2.47-2.50 (m, 2 H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customthe residue purified by column chromatography on silica gel (gradient: 30-60% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-96b88dc3cf10434f8b76969557954b90
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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