N-methyl-2-pyrrolidone → t-Butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

HRID 1962278Notes

Reaction equation

HRID 1962278 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O-:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.F[C:48]1[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=1[F:58]>C(OCC)(=O)C>[Cl:21][C:20]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][C:17](=[O:22])[N:18]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=2[F:58])[CH:19]=1

Participants

5

Reactant 3

HCID 13387N-methyl-2-pyrrolidoneHCID 27827431,2-Difluoro-4-(methylsulfonyl)benzeneHCID 584679435-Chloro-4-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxypyridin-2-olate;tetrabutylazanium

Product 1

HCID 58467953t-Butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylateYield 73.3%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A two liter round bottom flask was charged with tetrabutylammonium 4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate (90 g, 158 mmol), NMP (500 mL), and 1,2-difluoro-4-(methylsulfonyl)benzene (30.3 g, 158 mmol). The mixture was heated to 80° C. under nitrogen for 12 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate (500 mL) and distilled water (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the residue was added 500 mL of 20% ethyl acetate in diethyl ether and the mixture was stirred for 12 hours at room temperature. The slurry was then cooled to 4° C. and stirring was continued for additional 1 hour. The solid was collected by filtration and dried under vacuum for 4 hours at 45° C. to yield t-butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (58 g, 70% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.85-7.89 (m, 1H), 7.61-7.64 (m, 1H), 7.32 (s, 1H), 6.02 (s, 1H), 4.57-4.63 (m, 1H), 3.59-3.69 (m, 2H), 3.44-3.55 (m, 2H), 3.11 (s, 3H), 1.83-2.05 (m, 4H), 1.48 (s, 9H); MS m/e 501.2 (M+H+).

Workup

  1. temperatureAfter cooling to room temperature
  2. distillationdistilled water (500 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. additionTo the residue was added 500 mL of 20% ethyl acetate in diethyl ether
  8. temperatureThe slurry was then cooled to 4° C.
  9. stirringstirring
  10. waitwas continued for additional 1 hour
  11. filtrationThe solid was collected by filtration
  12. customdried under vacuum for 4 hours at 45° C.

Sources & evidence

ORD record
ord-786883bbac834ad2a18f52baf20bb16e
Source dataset
uspto-grants-2013_04
Patent number
US08415367B2

Reaction notes

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