Diisopropylamine → 3-Hydroxy-3-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid tert-butyl ester

HRID 1455255Notes

Reaction equation

HRID 1455255 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1.[NH4+].[Cl-]>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH:29]([OH:30])[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)([CH3:20])([CH3:19])[CH3:18]

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 10908tert-Butyl acetateHCID 25517Ammonium ChlorideHCID 154070082-Methylsulfanylpyrimidine-4-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 574380943-Hydroxy-3-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid tert-butyl esterYield 82.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a cold (0° C.) solution of diisopropylamine (5.7 mL, 40.5 mmol) in THF (130 mL) is added dropwise n-butyllithium (16.2 mL of a 2.5 M solution in hexanes, 40.5 mmol). The mixture is stirred for 45 min at 0° C., then the solution is cooled to −78° C. tert-Butyl acetate (5.5 mL, 40.5 mmol) is added dropwise to the reaction mixture. After stirring 40 min at −78° C., a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (5.0 g, 32.4 mmol) is added dropwise. After 30 min at −78° C., the solution is poured into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% EtOAc/hexanes, followed by 20% EtOAc/hexanes) to afford 7.2 g (82% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 5.00 (dd, J=8.4, 3.6 Hz, 1H), 2.93 (dd, J=16.5, 3.6 Hz, 1H), 2.70 (dd, J=16.5, 7.8 Hz, 1H), 2.58 (s, 3H), 1.46 (s, 9H); ESI+ MS: m/z (rel intensity) 271.1 (85, M++H).

Workup

  1. additionis added dropwise to the reaction mixture
  2. stirringAfter stirring 40 min at −78° C.
  3. waitAfter 30 min at −78° C.
  4. extractionThe aqueous phase is extracted with EtOAc
  5. dry with materialThe organic phase is dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude residue is purified over silica (5% EtOAc/hexanes, followed by 20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-a8c3b87abff949e48736639d2de7386b
Source dataset
uspto-grants-2009_01
Patent number
US07482356B2

Reaction notes

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