Sodium hydride → 4-Chloro-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)-2-(4-fluorobenzylthio)pyrimidine

HRID 1027861Notes

Reaction equation

HRID 1027861 reaction equation
Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].[CH3:20][C:21]1([CH3:29])[O:25][C@H:24]([C@H:26]([OH:28])[CH3:27])[CH2:23][O:22]1>O1CCCC1.CC1CCCO1>[Cl:8][C:6]1[CH:7]=[C:2]([O:28][C@@H:26]([C@@H:24]2[CH2:23][O:22][C:21]([CH3:29])([CH3:20])[O:25]2)[CH3:27])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:5]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 53628362(R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol2×HCID 866766784,6-Dichloro-2-(4-fluorobenzylthio)pyrimidine

Product 1

HCID 866766774-Chloro-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)-2-(4-fluorobenzylthio)pyrimidine

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8028TetrahydrofuranSolvent

Procedure

The sub-title product of step (ii) (85.7 g) and 60% sodium hydride (14.2 g) were suspended in tetrahydrofuran (1000 mL) and cooled in ice/water for 30 minutes. A solution of (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (Intermediate A) in 2-methyltetrahydrofuran (53% w/v) (104 mL) was added dropwise over 20 minutes and the reaction was stirred at 0° C. to room temperature for 20 hours. The reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The aqueous was re-extracted with ethyl acetate (2×500 mL) and the combined organics were dried and evaporated in vacuo. The crude material was purified by flash silica chromatography with gradient elution 0-30% ethyl acetate in isohexane using Isolera LS. Pure fractions were evaporated to dryness to afford to afford the sub-title product (94 g) as a yellow oil.

Workup

  1. customThe reaction was partitioned between water (500 mL) and ethyl acetate (500 mL)
  2. extractionThe aqueous was re-extracted with ethyl acetate (2×500 mL)
  3. customthe combined organics were dried
  4. customevaporated in vacuo
  5. customThe crude material was purified by flash silica chromatography with gradient elution 0-30% ethyl acetate in isohexane using Isolera LS
  6. customPure fractions were evaporated to dryness
  7. customto afford

Sources & evidence

ORD record
ord-2cbd2ee09b354bdf8d41396a53f685f9
Source dataset
uspto-grants-2014_05
Patent number
US08735413B2

Reaction notes

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