Sodium hydride → 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy)-6-chloro-5-fluoropyrimidine

HRID 1677977Notes

Reaction equation

HRID 1677977 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[C:32]([F:33])=[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[C:32]([F:33])=[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 112866754,6-Dichloro-5-fluoropyrimidineHCID 59671236(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol

Product 1

HCID 866187254-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy)-6-chloro-5-fluoropyrimidineYield 83.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a stirred suspension of sodium hydride (37.4 mg, 0.93 mmol) in THF (5.00 mL) was added a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (285 mg, 0.79 mmol) in THF (2.50 mL) at 0° C. under an atmosphere of Argon, and the mixture was stirred for 15 minutes. To this cooled suspension was added a solution of 4,6-dichloro-5-fluoropyrimidine (120 mg, 0.72 mmol) in THF (2.50 mL) at 0° C., and the resulting mixture was stirred for 19 h at 23° C. After quenching by addition of saturated NH4Cl solution (50.0 mL), the mixture was extracted with ethyl acetate (3×70.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 5 to 7% ethyl acetate in hexanes to afford the title compound (295 mg, 79%). 1H-NMR (400 MHz, CDCl3) δ: 8.32 (s, 1H), 5.67-5.61 (m, 1m), 4.41-4.37 (m, 1H), 3.73 (dd, 1H, 1=9.8, 7.1 Hz), 3.59 (dd, 1H, 1=9.8, 6.6 Hz), 2.33-2.25 (m, 1H), 2.10-1.96 (m, 2H), 1.90 (ddd, 1H, 1=13.8, 7.7, 1.8 Hz), 1.55 (s, 18H), 0.89 (s, 6H), 0.88 (s, 6H).

Workup

  1. stirringthe resulting mixture was stirred for 19 h at 23° C
  2. customAfter quenching by addition of saturated NH4Cl solution (50.0 mL)
  3. extractionthe mixture was extracted with ethyl acetate (3×70.0 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated under vacuum
  7. customThe residue was purified via silica gel column chromatography
  8. washeluting with a gradient of 5 to 7% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-8be5896ca0ca485ea1d8457db5186152
Source dataset
uspto-grants-2011_08
Patent number
US08008307B2

Reaction notes

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