Hydrochloric Acid → Ethyl 6-(tert-butoxycarbonyl(2,6-difluorophenyl)amino)-2-(2,4-difluorophenyl)nicotinate

HRID 2390948Notes

Reaction equation

HRID 2390948 reaction equation
Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O>[C:32]([O:31][C:30]([N:29]([C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[F:21])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:3]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 21062879Ethyl 6-chloro-2-(2,4-difluorophenyl)pyridine-3-carboxylateHCID 21939655N-Boc-2,6-difluoroaniline

Product 1

HCID 21062880Ethyl 6-(tert-butoxycarbonyl(2,6-difluorophenyl)amino)-2-(2,4-difluorophenyl)nicotinate

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
57.5 °C

Procedure

A mixture of Compound 5 (100.82 g, 0.33 mol, 1.0 equiv.), Compound 7 (101.05 g, 0.44 mol, 1.30 eq), and cesium carbonate (177.12 g, 0.54 mol, 1.60 eq) was suspended in DMSO (250 mL, 2.5 volumes) and stirred vigorously at 55-60° C. for 48 hours (completeness of reaction determined by HPLC). The mixture was cooled to 20-30° C. and the base was quenched by careful and slow addition of a 1 N HCl (aq) solution (540 mL, 1.60 eq), keeping the internal temperature of the reaction mixture below 30° C. Upon cooling, a precipitate formed and was filtered and washed with water (2×250 mL, 2×2.5 volumes). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. The reflux was maintained for 30-60 minutes, and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then heated again to reflux, and reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C. The resulting solids were then filtered and washed with water (2×250 mL, 2×2.5 volumes), followed by absolute ethanol (250 mL, 2.5 volumes), and then transferred to a vacuum oven and dried at 50-60° C. The title Compound, 8, was obtained as a white crystalline solid. (1H NMR, 500 MHz; CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.19 (q, 1H), 6.96 (t, 2H), 6.81 (t, 1H), 6.74 (t, 1H), 4.25 (q, 2H), 1.50 (s, 9H), 1.20 (t, 3H).

Workup

  1. custom(completeness of reaction determined by HPLC)
  2. temperatureThe mixture was cooled to 20-30° C.
  3. customthe base was quenched by careful and
  4. customthe internal temperature of the reaction mixture below 30° C
  5. temperatureUpon cooling
  6. customa precipitate formed
  7. filtrationwas filtered
  8. washwashed with water (2×250 mL, 2×2.5 volumes)
  9. temperatureheated to reflux
  10. temperatureThe reflux was maintained for 30-60 minutes
  11. additionwater (200 mL, 2 volumes) was added to the mixture
  12. temperatureThe resulting mixture was then heated again
  13. temperatureto reflux
  14. temperaturereflux
  15. temperaturewas maintained for 30 minutes, at which point the suspension
  16. temperaturewas cooled to 10° C
  17. filtrationThe resulting solids were then filtered
  18. washwashed with water (2×250 mL, 2×2.5 volumes)
  19. customdried at 50-60° C

Sources & evidence

ORD record
ord-0ed799059822447e8abd891cb8a13839
Source dataset
uspto-grants-2012_09
Patent number
US08273896B2

Reaction notes

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