Water → (S)-isopropyl 4-acetyl-3-methyl-7-(1-(pyrazin-2-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

HRID 1485761Notes

Reaction equation

HRID 1485761 reaction equation
[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].O.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[N:45][CH:44]=[CH:43][N:42]=3)[CH:39]=2)OC1(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]4[CH:46]=[N:45][CH:44]=[CH:43][N:42]=4)[CH:39]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 118079263HCID 118079263, compoundHCID 1231652252-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methylpyrazine

Product 1

HCID 118079254(S)-isopropyl 4-acetyl-3-methyl-7-(1-(pyrazin-2-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylateYield 38%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A 100-mL round-bottom flask was charged with isopropyl (3S)-4-acetyl-7-bromo-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (60 mg, 0.17 mmol), bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol), water (8 mL), 1,4-dioxane (20 mL), cesium carbonate (165 mg, 0.50 mmol), and 2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methylpyrazine (60 mg, 0.21 mmol). The resulting mixture stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was passed through a short pad of celite and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (1#waters2767): Column, Xbridge Phenyl 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B: CH3CN (15% CH3CN up to 60% in 8 min); Detector, UV220&254 nm to afford (S)-isopropyl 4-acetyl-3-methyl-7-(1-(pyrazin-2-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (27.7 mg, 38%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.10 (d, J=6.60 Hz, 3H), 1.27-1.37 (m, 6H), 2.22 (s, 3H), 3.35-3.50 (m, 1H), 4.05-4.17 (m, 1H), 4.95-5.10 (m, 2H), 5.58 (s, 2H), 7.39 (br s, 2H), 7.91 (s, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 8.56 (d, J=2.70 Hz, 1H), 8.59-8.62 (m, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.

Workup

  1. temperatureAfter cooling to room temperature
  2. concentrationconcentrated under vacuum
  3. customThe residue was purified by Prep-HPLC with the following conditions (1#waters2767)
  4. waitmobile phase, Phase A: water (0.05% NH4HCO3), Phase B: CH3CN (15% CH3CN up to 60% in 8 min)

Sources & evidence

ORD record
ord-6bcb6b6d4e234f7a82096355714dcd7f
Source dataset
uspto-grants-2016_08
Patent number
US09422281B2

Reaction notes

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