p-Toluenesulfonic acid → Anacetrapib metabolite M1

HRID 1028625

Reaction equation

HRID 1028625 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.[F:24][C:25]1[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][C:28]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[CH2:44]I)=[C:27]([O:46]C2CCCCO2)[CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[NH4+].[Cl-].O.CO>[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]([CH2:44][C:35]3[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:34]=3[C:28]3[CH:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[C:25]([F:24])=[CH:26][C:27]=3[OH:46])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1

Participants

9

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 24758Sodium hydrideHCID 23583229(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-oneHCID 667166702-{[4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran

Product 1

HCID 11527411Anacetrapib metabolite M1

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 25517Ammonium ChlorideSolvent

Procedure

Sodium hydride (60% dispersion in mineral oil, 1.9 mg, 0.0485 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one in dry DMF (1 mL) and the reaction was stirred for 30 min, A solution of 2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran (16.9 mg, 0.324 mmol) in dry DMF (1 mL) was added by cannula and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NH4Cl (10 mL) and water (5 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. A solution of the crude product and p-toluenesulfonic acid (0.6 mg, 0.00324 mmol) in MeOH (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-35% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (20% EtOAc in hexanes). LCMS calc.=624.2; found=624.3 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.86 (s, 1H), 7.67 (m, 4H), 7.42 (d, J=7.1 Hz, 0.5H), 7.41 (d, J=7.1 Hz, 0.5H), 6.95 (d, J=7.3 Hz, 0.5H), 6.94 (d, J=7.3 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.68 (d, J=5.6 Hz, 0.5H), 5.66 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.1 Hz, 0.5H), 4.93 (d, J=15.8 Hz, 0.5H), 4.88 (d, J=15.8 Hz, 0.5H), 4.18 (d, J=15.8 Hz, 0.5H), 4.00 (d, J=15.8 Hz, 0.5H), 3.87-3.83 (m, 0.5H), 3.77-3.71 (m, 0.5H), 3.22-3.14 (m, 1H), 1.77 (br s, 1H), 1.27-1.17 (m, 6H), 0.57 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H).

Workup

  1. stirringthe reaction was stirred at room temperature overnight
  2. extractionextracted with EtOAc (3×20 mL)
  3. dry with materialThe combined extracts were dried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. customto give the crude product
  6. concentrationThe reaction mixture was concentrated in vacuo
  7. customto give the crude product
  8. customThis was purified by flash chromatography (Si, 12×160 mm, 0-35% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-97fb3d9a45954e31b0e0c8f045044e5b
Source dataset
uspto-grants-2014_05
Patent number
US08735435B2

Linked notes

Loading…