Dimethylformamide → cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1lambda6-thian-3-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate

HRID 1485769Notes

Reaction equation

HRID 1485769 reaction equation
[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][NH:17][CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].CN(C)C=O.Br[CH:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:34]4[CH2:33][CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 615632594-bromotetrahydro-2H-thiopyran-1,1-dioxideHCID 118080491cyclobutyl (S)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

Product 1

HCID 118080516cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1lambda6-thian-3-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL round-bottom flask was charged with cyclobutyl (35)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.67 g, 4.71 mmol), N,N-dimethylformamide (10 mL), 4-bromo-1λ6-thiane-1,1-dione (1.0 g, 4.7 mmol), and cesium carbonate (3.08 g, 9.45 mmol). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether). The material was further purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 Sum, 19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% acetonitrile up to 100% in 10 min); Detector, UV 220&254 nm. This afforded cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ6-thian-3-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.01 g, 44%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.09 (d, J=6.60 Hz, 3H), 1.62-1.74 (m, 1H), 1.75-1.92 (m, 1H), 2.03-2.35 (m, 9H), 2.36-2.45 (m, 2H), 3.06-3.18 (m, 2H), 3.38-3.56 (m, 2H), 3.67 (t, J=13.20 Hz, 1H), 4.07-4.18 (m, 1H), 4.75-4.83 (m, 1H), 4.97-5.07 (m, 2H), 7.37 (s, 2H), 7.88 (s, 1H), 8.03 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 487 [M+H]

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionextracted with ethyl acetate (2×30 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether)
  8. customThe material was further purified by Prep-HPLC with the following conditions (Waters III)
  9. waitmobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% acetonitrile up to 100% in 10 min)

Sources & evidence

ORD record
ord-918f9ebb71b940c588b92f676791500c
Source dataset
uspto-grants-2016_08
Patent number
US09422281B2

Reaction notes

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