Dimethylformamide → 3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1lambda6-thiane-1,1-dione

HRID 1051675Notes

Reaction equation

HRID 1051675 reaction equation
[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH:41]1[CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43][CH2:42]1>C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:20]=[N:19][N:18]([CH:42]5[CH2:41][CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43]5)[CH:17]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:2][CH2:3]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 615632594-bromotetrahydro-2H-thiopyran-1,1-dioxideHCID 118075498(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

Product 1

HCID 1183060293-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1lambda6-thiane-1,1-dione

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL, round-bottom flask was charged with (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.200 g, 0.56 mmol), cesium carbonate (0.114 g, 0.35 mmol), N,N-dimethylformamide (5 mL), and 4-bromo-1λ6-thiane-1,1-dione (0.114 g, 0.53 mmol). The resulting mixture stirred at 100° C. for 4 h and was then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 25-50% ethyl acetate/petroleum). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded 3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ6-thiane-1,1-dione (0.122 g, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.76-0.82 (m, 1H), 0.92-1.02 (m, 2H), 1.13-1.22 (m, 4H), 1.42-1.50 (m, 1H), 1.95-2.08 (m, 3H), 2.08-2.13 (m, 1H), 2.14-2.37 (m, 3H), 2.68-2.77 (m, 1H), 3.11-3.19 (m, 2H), 3.37 (s, 1H), 3.53-3.60 (m, 1H), 4.66-4.72 (m, 1H), 4.74-4.81 (m, 1H), 6.79 (d, J=8.00 Hz, 2H), 6.98 (t, J=7.60 Hz, 1H), 7.23 (t, J=7.60 Hz, 2H), 7.62 (d, J=8.40 Hz, 1H), 7.83 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 506 [M+H]+.

Workup

  1. temperaturewas then cooled to room temperature
  2. washwashed with water (3×10 mL)
  3. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customThe residue was purified via column chromatography on silica gel (gradient elution with 25-50% ethyl acetate/petroleum)
  7. customThe product was further purified by preparative-HPLC with the following conditions (Waters I)
  8. custommobile phase, Water and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min)

Sources & evidence

ORD record
ord-85ae844a119745cb99f4b6703cd0d3d9
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

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