Potassium Carbonate → 4-Chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile

HRID 922776Notes

Reaction equation

HRID 922776 reaction equation
Cl.[CH3:2][C@H:3]1[O:8][C@@H:7]([C:9]([F:12])([F:11])[F:10])[CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[CH:26][C:27]([C:31]#[N:32])=[N:28]2)=[CH:23][CH:22]=1>CC#N.O>[Cl:33][C:25]1[C:24]2[C:29](=[CH:30][C:21]([CH2:20][N:5]3[CH2:6][C@H:7]([C:9]([F:10])([F:12])[F:11])[O:8][C@H:3]([CH3:2])[CH2:4]3)=[CH:22][CH:23]=2)[N:28]=[C:27]([C:31]#[N:32])[CH:26]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 667895247-(Bromomethyl)-4-chloroquinoline-2-carbonitrileHCID 89545142(2R,6R)-2-Methyl-6-(trifluoromethyl)morpholine hydrochloride

Product 1

HCID 895549564-Chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrileYield 96%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

(2R,6R)-2-Methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6, 500 mg, 2.432 mmol) and K2CO3 (739 mg, 5.35 mmol) were combined in CH3CN (10 ml) at rt. To this was added 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 753 mg, 2.68 mmol) all at once as a solid then the mixture was heated to 60° C. overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were filtered through a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (50 g, 0-10% EtOAc/hexanes, 15 minute gradient) to afford 4-chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-7, 859, 96%) as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=8.7 Hz, 1H); 8.11 (s, 1H); 7.83 (dd, J=8.6, 1.6 Hz, 1H); 7.78 (s, 1H); 4.09-4.01 (m, 1H); 3.79 (m, 3H); 2.90 (d, J=10.9 Hz, 1H); 2.73 (d, J=11.4 Hz, 1H); 2.28-2.17 (m, 1H); 2.03-1.92 (m, 1H); 1.20 (d, J=6.2 Hz, 3H).

Workup

  1. temperatureThe mixture was cooled to rt
  2. extractionextracted with EtOAc (3×)
  3. filtrationThe combined organic layers were filtered through a pad of Celite
  4. washwashing with EtOAc
  5. concentrationthen concentrated
  6. customwas subjected to silica gel chromatography (50 g, 0-10% EtOAc/hexanes, 15 minute gradient)

Sources & evidence

ORD record
ord-086900025ee04ba99e2415c4057d2f91
Source dataset
uspto-grants-2016_03
Patent number
US09278960B2

Reaction notes

Loading…