3,3-Difluoroazetidine hydrochloride → 2-((6-(3-fluoroazetidin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile

HRID 1057024Notes

Reaction equation

HRID 1057024 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=2)[C:12]#[N:13])[CH:5]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1.Cl.[F:24][C:25]1(F)[CH2:28][NH:27][CH2:26]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>>[F:24][CH:25]1[CH2:28][N:27]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=3)[C:12]#[N:13])[CH:5]=[C:4]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:3]=2)[CH2:26]1

Participants

5

Reactant 4

HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 725507132-((6-chloro-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile

Product 1

HCID 725507172-((6-(3-fluoroazetidin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrileYield 6.8%

Conditions

Temperature
80 °C

Procedure

2-((6-Chloro-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile (50.0 mg, 0.159 mmol, 1.00 equiv), 3,3-difluoroazetidine hydrochloride (44.3 mg, 0.318 mmol, 2.00 equiv), sodium tert-butoxide (94.4 mg, 0.953 mmol, 6.00 equiv), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (7.56 mg, 0.0159 mmol, 0.100 equiv), and chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct (13.0 mg, 0.0159 mmol, 0.100 equiv) were added to a 2-dram vial. After purging the vial with nitrogen, dry tetrahydrofuran (1.50 mL) was added and the reaction mixture was left stirring at 80° C. for 14 h. The reaction mixture was then filtered over Celite washing with ethyl acetate (3×3 mL) and concentrated to dryness. Purification by reverse phase column chromatography (30:70 water/acetonitrile with 0.1% ammonium hydroxide) gave the desired product as a white solid (3.8 mg, 6.4% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.87 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.26 (s, 1H), 7.21 (dd, J=5.2, 2.0 Hz, 1H), 6.88 (s, 1H), 6.04 (s, 1H), 4.49-4.26 (m, 4H), 4.02-3.86 (m, 2H), 3.52-3.35 (m, 2H), 2.76-2.58 (m, 1H), 1.73-1.59 (m, 4H).

Workup

  1. customAfter purging the vial with nitrogen, dry tetrahydrofuran (1.50 mL)
  2. additionwas added
  3. waitthe reaction mixture was left
  4. filtrationThe reaction mixture was then filtered over Celite
  5. washwashing with ethyl acetate (3×3 mL)
  6. concentrationconcentrated to dryness
  7. customPurification by reverse phase column chromatography (30:70 water/acetonitrile with 0.1% ammonium hydroxide)

Sources & evidence

ORD record
ord-ae371235590c44f6b0b89d992e0e64c9
Source dataset
uspto-grants-2016_07
Patent number
US09399636B2

Reaction notes

Loading…