Diisopropylamine → 4-[2-(2,5-Dichloro-pyrimidin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1184717Notes

Reaction equation

HRID 1184717 reaction equation
[Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][N:15]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]([OH:36])[CH2:20][C:18]2[C:17]([Cl:21])=[CH:16][N:15]=[C:14]([Cl:13])[N:19]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 61028n-Butyl lithiumHCID 1514430tert-Butyl 4-formylpiperidine-1-carboxylateHCID 212786212,5-Dichloro-4-methylpyrimidine

Product 1

HCID 866749004-[2-(2,5-Dichloro-pyrimidin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

N-butyllithium (1.6 M in hexanes, 4.99 mL) is added drop wise to diisopropylamine (1.13 mL) in tetrahydrofuran (20 mL) at −50 to −60° C. under an argon atmosphere. The mixture is stirred for 30 min at this temperature, cooled to −70° C., and 2,5-dichloro-4-methyl-pyrimidine (1.00 g) is added. After 1 h a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.37 g) in tetrahydrofuran (10 mL) is added and the resulting mixture is stirred for another hour. The reaction is quenched with acetic acid solution (1% in ethanol, 10 mL) and the mixture is diluted with ethyl acetate. The organic phase is separated, washed with water and aqueous NaHCO3 solution, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→30:70) to give the title compound. LC (method 7): tR=1.40 min; Mass spectrum (ESI+): m/z=376 [M+H]+.

Workup

  1. stirringthe resulting mixture is stirred for another hour
  2. customThe reaction is quenched with acetic acid solution (1% in ethanol, 10 mL)
  3. additionthe mixture is diluted with ethyl acetate
  4. customThe organic phase is separated
  5. washwashed with water and aqueous NaHCO3 solution
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated in vacuo
  8. customThe residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→30:70)

Sources & evidence

ORD record
ord-b5fc272293fe4153bbf46a8c8d7de8ba
Source dataset
uspto-grants-2014_03
Patent number
US08669271B2

Reaction notes

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