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

HRID 1969729Notes

Reaction equation

HRID 1969729 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][C@@H:33]([CH3:36])[C@@H: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>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](=[O:38])[NH:22][CH2:21][C:19]2[N:20]=[C:15]3[CH:14]=[CH:13][N:12]([S:2]([C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=4)(=[O:3])=[O:4])[C:16]3=[N:17][CH:18]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]

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 58557576(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acidHCID 67068339(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

Product 1

HCID 58557369(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylateYield 100.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (34.0 g, 100 mmol, Example #5, Step C), (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambient temperature for about 45 min. The reaction was washed with saturated aqueous NaHCO3 (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was purified by chromatography on silica gel (330 g) using 33-100% EtOAc in heptane to give (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (53 g, 100%) as a pale-yellow foam: LC/MS (Table 1, Method b) Rt=2.40 min; MS m/z: 528 (M+H)+.

Workup

  1. washThe reaction was washed with saturated aqueous NaHCO3 (300 mL)
  2. customThe organic layer was separated
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. customThe resulting residue was purified by chromatography on silica gel (330 g)

Sources & evidence

ORD record
ord-0e941f5579cc4299b048aba2394248c0
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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