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 1774146Notes

Reaction equation

HRID 1774146 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. temperaturewas 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-b51e266879c548439dcb7b4f25f0ff4d
Source dataset
uspto-grants-2016_02
Patent number
US09259470B2

Reaction notes

Loading…