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

HRID 2204562Notes

Reaction equation

HRID 2204562 reaction equation
Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].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>C(Cl)Cl>[CH3:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][CH:32]1[C:37](=[O:38])[NH:22][CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[CH:13][N:12]([S:2]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=3)(=[O:3])=[O:4])[C:16]2=[N:17][CH:18]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 450431571-(tert-Butoxycarbonyl)-4-methylpiperidine-3-carboxylic acidHCID 67068339(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

Product 1

HCID 58009799tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylateYield 95.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (29.6 g, 87.0 mmol, Step F), 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (21.2 g, 87.0 mmol, Step G) and HATU (33.2 g, 87.0 mmol) in DCM (400 mL) was added DIEA (46.0 mL, 263 mmol). After stirring for about 18 h at ambient temperature, the reaction mixture was washed with aqueous saturated NaHCO3 (400 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (330 g column) eluting with a gradient of 50-100% EtOAc in heptane to give tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 95%) as a tan foam: LC/MS (Table 2, Method a) Rt=2.38 min; MS m/z: 528 (M+H)+.

Workup

  1. washthe reaction mixture was washed with aqueous saturated NaHCO3 (400 mL)
  2. customThe organic layer was separated
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel chromatography (330 g column)
  7. washeluting with a gradient of 50-100% EtOAc in heptane

Sources & evidence

ORD record
ord-c121f5b2ed8f47b5a3b98ccf7e9153c1
Source dataset
uspto-grants-2016_06
Patent number
US09365579B2

Reaction notes

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