Diisopropylethylamine → cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate

HRID 1969605Notes

Reaction equation

HRID 1969605 reaction equation
[CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=O)[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:80])=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=[S:80])[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 87949Lawesson's reagentHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 131730520cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate

Product 1

HCID 131730519cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylateYield 90%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (5.62 g, 10.6 mmol, prepared using O from 4-methylnicotonic acid, M, H from Example #5, Step C, HATU and DIEA) and Lawesson's reagent (3.0 g, 7.4 mmol) in 1,4-dioxane (100 mL). The reaction was heated at about 80° C. for about 1 h, cooled to ambient temperature, and concd under reduced pressure. The crude product was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (3×100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.65 min; MS m/z: 544 (M+H)+. A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (2.6 g, 4.8 mmol) and mercury (II) trifluoroacetate (2.1 g, 4.8 mmol) in 1,4-dioxane (72 mL) and stirred at ambient temperature for about 1 h. The reaction mixture was filtered through a pad of Celite®. The Celite® pad was rinsed with DCM (30 mL) and EtOAc (30 mL). The filtrate was concd under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium thiosulfate (10 mL), and saturated aqueous NaHCO3 (25 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl-4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.57 min; MS m/z: 510 (M+H)+.

Workup

  1. customprepared
  2. temperaturecooled to ambient temperature
  3. washwashed with saturated aqueous NaHCO3 (3×100 mL)
  4. customThe organic layer was separated
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. customThe material was purified by silica gel chromatography
  8. washeluting with a gradient of 0-5% MeOH in DCM

Sources & evidence

ORD record
ord-f5b41924fb6c4749a1a27ef9211200b0
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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