Triethylamine → (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2-(3,3-difluoroazetidin-1-yl)-5-(5-isopropyl-2-methoxypyridin-3-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

HRID 531280Notes

Reaction equation

HRID 531280 reaction equation
[F:1][C:2]([F:43])([F:42])[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]([C:26]4[C:27]([O:35][CH3:36])=[N:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=4)=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:45][C:46]1([F:50])[CH2:49][NH:48][CH2:47]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:43])([F:42])[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]([C:26]4[C:27]([O:35][CH3:36])=[N:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:48]4[CH2:49][C:46]([F:50])([F:45])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 90009173(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one2×

Product 1

HCID 118021465(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2-(3,3-difluoroazetidin-1-yl)-5-(5-isopropyl-2-methoxypyridin-3-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneYield 55.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 17, 80 mg, 0.126 mmol) in 1 mL THF was added to 1 dram vial that contained 3,3-difluoroazetidine hydrochloride (11.8 mg, 0.126 mmol). Triethylamine (0.071 mL, 0.506 mmol) was added, the vial was capped and the reaction mixture heated to 60° C. for 3 hours. The mixture was cooled to ambient temperature and stirred overnight. Diluted the mixture with ethyl acetate (2 mL) and washed with H2O (3×1 mL), brine (1×1 mL), dried over MgSO4, filtered and concentrated in vacuo. Purified the residue by RP HPLC (Waters Sunfire C18 column; 19×100 mm; 5 μM; CH3CN/H2O (0.1% TFA); 20-90% gradient; 20 mL/minutes; 12 minutes run) and the corresponding fractions that contained product were lyophilized to afford 45 mg of a white powder as the titled compound. LCMS (M+H)+: 646.3. 1H NMR (500 MHz, CDCl3): δ: 0.73 (d, 3H, J=7.5 Hz), 1.28 (d, 6H, J=6.9 Hz), 2.95 (septet, 1H, J=7.5 Hz), 3.95 (s, 3H), 4.04 (d, 1H, J=7.5 Hz), 4.54-4.59 (m, 4H), 4.64 (d, 1H, J=7.5 Hz), 5.65 (d, 1H, J=8.5 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.73 (s, 2H), 7.90 (s, 1H), 8.13 (d, 1H, J=2.4 Hz), 8.23 (s, 1H). RTA IC50: 5 nM

Workup

  1. customthe vial was capped
  2. temperatureThe mixture was cooled to ambient temperature
  3. washwashed with H2O (3×1 mL), brine (1×1 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurified the residue by RP HPLC (Waters Sunfire C18 column; 19×100 mm; 5 μM; CH3CN/H2O (0.1% TFA); 20-90% gradient; 20 mL/minutes; 12 minutes run)

Sources & evidence

ORD record
ord-425c4057209844f7865218c3176301d1
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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