Diisopropylethylamine → (R)-di-tert-butyl 2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperazine-1,4-dicarboxylate

HRID 1972695Notes

Reaction equation

HRID 1972695 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:25]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[C@@H:29]12[N:32]([C:21]([C@H:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:23])[C@@H:25]([CH2:31][CH2:30]1)[CH2:26][O:27][CH2:28]2

Participants

8

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 26339502(2R)-1,4-bis((tert-butoxy)carbonyl)piperazine-2-carboxylic acidHCID 534011293-Oxa-8-azabicyclo(3.2.1)octane hydrochloride

Product 1

HCID 70655322(R)-di-tert-butyl 2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperazine-1,4-dicarboxylateYield 91.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 250-mL round-bottomed flask, a solution of (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.51 g, 4.57 mmol, ASW Medchem, New Brunswick, N.J.), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.684 g, 4.57 mmol, Advanced Chemblocks, Burlingame, Calif.), and Hünig's base (1.76 mL, 10.06 mmol) in 15 mL of DMF was stirred at 0° C. To this mixture was added HATU (1.912 g, 5.03 mmol, Oakwood Products, West Columbia, S.C.). The reaction was stirred for 3 h at room temperature. The mixture was then diluted with EtOAc (25 mL) and water (25 mL). The organic solution was then extracted with water (2×25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified via column chromatography (about 40 g silica gel, 5% to 80% of EtOAc in hexanes) to give (R)-di-tert-butyl 2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperazine-1,4-dicarboxylate (1.78 g) as a colorless oil.

Workup

  1. extractionThe organic solution was then extracted with water (2×25 mL) and brine (25 mL)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude material was purified via column chromatography (about 40 g silica gel, 5% to 80% of EtOAc in hexanes)

Sources & evidence

ORD record
ord-08197acff434442082a15087b0cd5225
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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