Potassium bis(trimethylsilyl)amide → 1-[(1S)-1-(4-Chloro-3-fluorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-4-[2-(methylthio)-4-pyrimidinyl]-2(1H)-pyridinone

HRID 2365792Notes

Reaction equation

HRID 2365792 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=2)[CH:16]=[CH:15][N:14]=1.CS(O[C@H:31]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O>C1COCC1>[Si:34]([O:33][CH2:32][C@@H:31]([N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[CH:20][C:21]1=[O:25])[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35]

Participants

5

Reactant 3

HCID 3251421Potassium bis(trimethylsilyl)amideHCID 71726881Benzenemethanol, 4-chloro-alpha-((((1,1-dimethylethyl)dimethylsilyl)oxy)methyl)-3-fluoro-, 1-methanesulfonate, (alphaR)-HCID 717270054-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one

Product 1

HCID 866966481-[(1S)-1-(4-Chloro-3-fluorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-4-[2-(methylthio)-4-pyrimidinyl]-2(1H)-pyridinoneYield 63%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

1.0M KHMDS (5.09 mL, 5.09 mmol) as a solution in THF was added to a cold (0° C.) suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.93 g, 4.24 mmol) in THF (20 mL). The reaction mixture was stirred at 0° C. for 10 minutes before (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (2.44 g, 6.36 mmol) was added as a solution in THF (5 mL). The reaction was heated to reflux for 30 hours and then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate (200 mL) and washed with water. The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (4:1) to give (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (1.35 g, 63%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 7.43 (m, 2H), 7.34 (d, J=5.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.16 (m, 1H), 6.85 (m, 1H), 6.24 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 2.65 (s, 3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.03 (s, 3H); m/z (APCI-pos) M+1=506.1, 508.1.

Workup

  1. temperatureThe reaction was heated
  2. temperatureto reflux for 30 hours
  3. concentrationconcentrated
  4. washwashed with water
  5. customThe organics were dried
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified via column chromatography
  9. washeluting with hexanes/ethyl acetate (4:1)

Sources & evidence

ORD record
ord-8d30d188bed647e2af2ace84a4265292
Source dataset
uspto-grants-2014_04
Patent number
US08697715B2

Reaction notes

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