Sodium hydride → (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxy-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

HRID 1028630Notes

Reaction equation

HRID 1028630 reaction equation
[H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[C:38]([OH:46])[C:37]=1[O:47][CH3:48].[NH4+].[Cl-]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=3[C:36]3[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[C:38]([OH:46])[C:37]=3[O:47][CH3:48])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 23583229(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-oneHCID 866034362'-(Bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol

Product 1

HCID 11650409(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxy-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Sodium hydride (60% dispersion in mineral oil, 14.7 mg, 0.368 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (57.7 mg, 0.184 mmol) in dry THF (2 mL) at room temperature. After 30 min a solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (62.0 mg, 0.123 mmol) in dry THF (2 mL) was added by cannula and the reaction mixture was stirred overnight. Saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.25 (20% EtOAc in hexanes). LCMS calc.=654.2; found=654.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.86 (m, 1H), 7.73-7.63 (m, 4H) 7.44 (m, 1H), 6.55 (d, J=7.6 Hz, 0.5H), 6.52 (d, J=7.7 Hz, 0.5H), 5.71 (br s, 1H), 5.60 (d, J=8.0 Hz, 0.5H), 5.54 (d, J=8.0 Hz, 0.5H), 4.87 (d, J=16.0 Hz, 0.5H), 4.72 (d, J=16.1 Hz, 0.5H), 4.23 (d, J=16.1 Hz, 0.5H), 3.98 (d, J=15.9 Hz, 0.5H), 3.93-3.85 (m, 0.5H), 3.77-3.71 (m, 0.5H), 3.51 (s, 1.5H), 3.47 (s, 1.5H), 3.25-3.17 (m, 1H), 1.26-1.18 (m, 6H), 0.58 (d, J=6.5 Hz, 1.5H), 0.38 (d, J=6.6 Hz, 1.5H).

Workup

  1. extractionthe mixture was extracted with EtOAc (3×20 mL)
  2. dry with materialThe combined extracts were dried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. customto give the crude product
  5. customThis was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-7adf1e642318471195d7e0aef78bc717
Source dataset
uspto-grants-2014_05
Patent number
US08735435B2

Reaction notes

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