Dimethyl Sulfoxide → (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

HRID 1508508Notes

Reaction equation

HRID 1508508 reaction equation
[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+].CS(C)=O>CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:35]4[CH2:36][C:33]([F:37])([F:32])[CH2:34]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 516892Sodium BicarbonateHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 57576268(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

Product 1

HCID 86704600(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

A reaction vessel was charged with (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (50 mg, 0.097 mmol), 3,3-difluoroazetidine hydrochloride (125 mg, 0.966 mmol) and sodium bicarbonate (162 mg, 1.932 mmol). DMSO (2 mL) was added. The reaction was heated to 150° C. under an atmosphere of N2. After 16 hours, the reaction was cooled to r.t., diluted with EtOAc (40 mL), and washed with water and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 80% EtOAc/hexanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one contaminated with a minor impurity. This material was used in subsequent reactions without further purification. LCMS=575.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.78 (s, 2H), 7.63 (d, J=8.7 Hz, 1H), 6.24 (d, J=8.7 Hz, 1H), 5.75 (d, J=8.4 Hz, 1H), 4.87 (d, J=17.1 Hz, 1H), 4.23-4.40 (m, 6H), 0.79 (d, J=7.6 Hz, 3H).

Workup

  1. temperaturethe reaction was cooled to r.t.
  2. washwashed with water and brine (10 mL each)
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification of the residue by flash chromatography on silica gel with 0 to 80% EtOAc/hexanes

Sources & evidence

ORD record
ord-f806013c689c4891922dec211e408132
Source dataset
uspto-grants-2015_12
Patent number
US09221834B2

Reaction notes

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