Lithium diisopropylamide → 2-(4-Fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic acid methyl ester

HRID 1838859Notes

Reaction equation

HRID 1838859 reaction equation
C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)[CH:29]([C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)[OH:30]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 2733233Methyl 2-(4-fluorophenyl)acetateHCID 154070082-Methylsulfanylpyrimidine-4-carbaldehyde

Product 1

HCID 129914022-(4-Fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic acid methyl esterYield 76%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a cold (−78° C.) solution of lithium diisopropylamide (21.4 mL of 2M solution in THF, 42.8 mmol) in THF (70 mL) is added dropwise a solution of methyl 4-fluorophenyl-acetate (6.0 g, 35.7 mmol) in THF ( 30 mL). The solution is stirred for 1 hour at −78° C. after which a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1, (6.0 g, 39.3 mmol) in THF (30 mL) is added dropwise to the reaction mixture. Stirring is continued for 45 minutes at −78° C. then the reaction is quenched by pouring the reaction solution into aqueous saturated NH4Cl. The aqueous phase is extracted with ethyl acetate. The organic phases combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue is purified over silica (33% EtOAc/hexanes) to afford 8.7 g (76%) of the desired product as a mixture (1:1) of diastereomers. 1H NMR (300 MHz, CDCl3) δ 8.52 (dd, J=4.5, 1.5 Hz, 2H), 7.21-7.15 (m, 4H), 6.99 (t, J=9.0 Hz, 2H), 5.38 (d, J=5.4 Hz, 1H), 3.83 (d, J=5.4 Hz, 1H), 3.67 (s, 3H); ESI/MS: 276.1 (M+H).

Workup

  1. additionis added dropwise to the reaction mixture
  2. customthe reaction is quenched
  3. additionby pouring the reaction solution into aqueous saturated NH4Cl
  4. extractionThe aqueous phase is extracted with ethyl acetate
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude residue is purified over silica (33% EtOAc/hexanes)

Sources & evidence

ORD record
ord-9862f8e44a964a258f4f1a5b556333bb
Source dataset
uspto-grants-2004_01
Patent number
US06677337B2

Reaction notes

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