Sodium hydride → 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine

HRID 2406265Notes

Reaction equation

HRID 2406265 reaction equation
[H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>C1COCC1>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:31]2[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 709434,6-DichloropyrimidineHCID 59671236(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol

Product 1

HCID 596712514-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidineYield 92.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A flame-dried 50 mL round bottom flask with was charged with sodium hydride (0.322 g, 0.008 mol) and tetrahydrofuran (20 mL, 0.3 mol) and the resulting suspension was cooled to 0° C. under an atmosphere of nitrogen. To the suspension was added dropwise a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (13) (1.45 g, 0.004 mol) in 0.5 mL THF at 0° C. The mixture was stirred at 0° C. for 10 minutes, at which point 4,6-dichloropyrimidine (0.659 g, 0.004 mol) was added, and the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched with via addition of saturated aqueous NH4Cl solution (25 mL) and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with tert-BuOMe (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (eluent—0-10% EtOAc in hexanes) to afford 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (1.75 g, 92% yield). LCMS: (FA) ES+ 473; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=0.7, 1H), 6.69 (d, J=0.8, 1H), 5.61-5.49 (m, 1H), 4.36 (dd, J=4.6, 6.8, 1H), 3.73 (dd, J=7.0, 10.0, 1H), 3.57 (dd, J=6.7, 9.9, 1H), 2.36-2.13 (m, 2H), 2.10-1.73 (m, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.08-0.00 (m, 12H).

Workup

  1. additionwas added
  2. temperatureto warm to room temperature
  3. customThe reaction was quenched with via addition of saturated aqueous NH4Cl solution (25 mL)
  4. customtransferred to a separatory funnel
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with tert-BuOMe (3×25 mL)
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried over anhydrous MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe resulting oil was purified by silica gel chromatography (eluent—0-10% EtOAc in hexanes)

Sources & evidence

ORD record
ord-af8a4d5a65e743d79512fc388f73721a
Source dataset
uspto-grants-2014_08
Patent number
US08809356B2

Reaction notes

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