Potassium Phosphate, Tribasic → tert-Butyl 4-(4-cyclopropyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

HRID 2088884Notes

Reaction equation

HRID 2088884 reaction equation
Br[C:2]1[N:3]=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:2]2[N:3]=[C:4]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:5]([CH2:7][CH2:8][O:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[CH:6]=2)[CH2:31][CH2:30]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 67265112tert-Butyl 4-(4-bromo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

Product 1

HCID 67968740tert-Butyl 4-(4-cyclopropyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylateYield 37%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolvent

Procedure

Add tert-butyl 4-(4-bromo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.82 g, 3.97 mmol), cyclopropylboronic acid (0.44 g, 1.3 eq), tricyclohexylphosphine (0.11 g, 0.1 eq), and potassium phosphate (2.95 g, 3.5 eq) in toluene (18 mL) and water (0.9 mL). Degas with nitrogen for 5 minutes. Add palladium acetate (0.045 g, 0.05 eq) and heat at 90° C. overnight. Stop heating after 12 hrs. Dilute with water then extract with ethyl acetate three times. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 0-20-50% ethyl acetate/hexanes, then with 1-3-5-7% methanol/dichloromethane, to give the title compound (0.61 g, 37%). MS (ES) m/z=420 [M]+.

Workup

  1. customDegas with nitrogen for 5 minutes
  2. temperatureStop heating after 12 hrs
  3. extractionthen extract with ethyl acetate three times
  4. dry with materialDry over anhydrous magnesium sulfate
  5. concentrationconcentrate in vacuo
  6. customPurify by silica gel chromatography
  7. washeluting with 0-20-50% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-b0276ffa2b1b4c7791fab89acf5d0a82
Source dataset
uspto-grants-2013_05
Patent number
US08436002B2

Reaction notes

Loading…