Diisopropylamine → 3-(5-Chloro-pyrimidin-4-yl)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

HRID 2202788Notes

Reaction equation

HRID 2202788 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1>C1COCC1.C(OCC)(=O)C.O>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([C:31]1[C:30]([Cl:29])=[CH:35][N:34]=[CH:33][N:32]=1)([OH:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

8

Reactant 4

HCID 7912DiisopropylamineHCID 2794767tert-Butyl 3-oxo-8-azabicyclo(3.2.1)octane-8-carboxylateHCID 126003845-ChloropyrimidineHCID 178418339Butyllithium

Product 1

HCID 674659213-(5-Chloro-pyrimidin-4-yl)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterYield 13.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

n-Butyl lithium (2.5 M, 1.2 mL, 3.00 mmol) was added dropwise to a solution of diisopropylamine (0.406 mL, 3.0 mmol) in THF (5 mL) at 0° C. under nitrogen and stirred for 30 minutes. The mixture was then added to a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) and 5-chloropyrimidine (0.343 g, 3.0 mmol) in THF (1.5 mL) and stirred at 0° C. for 1 hour. Water and ethyl acetate were added, the organics separated, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-30% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 340.3 [M+H]+. R.T.=3.70 min (Analytical Method 3).

Workup

  1. stirringstirred at 0° C. for 1 hour
  2. dry with materialthe organics separated, dried over sodium sulphate
  3. filtrationfiltered
  4. customthe solvent removed by evaporation under vacuum
  5. customThe residue was purified by flash chromatography on silica eluting with 20-30% ethyl acetate/cyclohexane
  6. additionThe fractions containing the desired product
  7. concentrationwere concentrated under vacuum

Sources & evidence

ORD record
ord-6671ca24b2ef4e3dbaa93b620d4bde02
Source dataset
uspto-grants-2016_06
Patent number
US09365564B2

Reaction notes

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