Potassium Phosphate, Tribasic → (R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

HRID 2209071Notes

Reaction equation

HRID 2209071 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH:23]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=N1)([CH3:25])C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:2]3[CH:28]=[CH:29][C:30]([N:26]4[CH2:23][CH2:25][O:8][CH2:6][CH2:5]4)=[CH:4][CH:3]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 467380211-(Propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 117842863(R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

Product 1

HCID 117843265(R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

Intermediate 2.64 (27 mg, 0.082 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.17 mmol), Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (1.8 mg, 0.0025 mmol) and K3PO4 (52 mg, 0.25 mmol) were taken up in 1,4-dioxane (0.9 mL) under Ar. Water (0.1 mL) was added and the resulting stirred mixture was heated to 100° C. After 1.25 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (2 mL), water (1 mL), and brine (1 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM) to afford (R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.25. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H23F2N6O2: 405.2; found 405.1. 1H NMR (400 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.85 (s, 1H), 7.59 (t, J=61.1 Hz, 1H), 7.48 (s, 1H), 6.12 (s, 1H), 5.71-5.61 (m, 1H), 4.63-4.46 (m, 1H), 3.63-3.50 (m, 1H), 3.37 (dd, J=9.7, 6.1 Hz, 1H), 2.99-2.87 (m, 1H), 2.55 (dd, J=17.2, 9.3 Hz, 1H), 2.45 (dd, J=17.2, 7.4 Hz, 1H), 1.56 (d, J=6.7 Hz, 6H), 1.47 (d, J=6.2 Hz, 3H).

Workup

  1. temperaturethe reaction mixture was cooled to r.t.
  2. customThe phases were separated
  3. extractionthe aqueous phase was extracted with EtOAc (4×1.5 mL)
  4. dry with materialThe combined organic phase was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM)

Sources & evidence

ORD record
ord-de5c8ac27a2d406cb113ad349a2a4cc7
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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