Cesium carbonate → {1-[4-(Isoquinolin-6-ylamino)-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamic acid benzyl ester

HRID 45197

Reaction equation

HRID 45197 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH2:12]([O:19][C:20](=[O:40])[NH:21][CH:22]([C:25]1([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)[CH2:23][CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:19][C:20](=[O:40])[NH:21][CH:22]([C:25]1([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:26][CH2:27][CH:28]([NH:31][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:29][CH2:30]1)[CH2:23][CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 3136816-BromoisoquinolineHCID 634876Binap, (A+-)-HCID 58380970{1-[4-Amino-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}carbamic acid benzyl ester

Product 1

HCID 67075630{1-[4-(Isoquinolin-6-ylamino)-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamic acid benzyl esterYield 28.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

In 1 mL of absolute toluene were dissolved 66.0 mg (0.32 mmol) of 6-bromo-isoquinoline, 151 mg (380 μmol) of {1-[4-amino-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamic acid benzyl ester (98), and 155 mg (476 μmol) of cesium carbonate. The solution was degassed twice, then 2.14 mg (9.5 μmol) of palladium acetate and 8.89 mg (14.3 μmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added and the reaction mixture was heated to 100° C. until complete conversion could be observed. The mixture was evaporated, then redissolved in 50 mL of dichloromethane and washed twice with 50 mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate, filtered, concentrated and purified by silica gel chromatography (dichloromethane:methanol) to give 48 mg of the pure desired product. Rt=1.38 min (Method 19). Detected mass: 524.4 (M+H+).

Workup

  1. customThe solution was degassed twice
  2. customThe mixture was evaporated
  3. dissolutionredissolved in 50 mL of dichloromethane
  4. washwashed twice with 50 mL of saturated aqueous sodium bicarbonate solution
  5. dry with materialThe organic phase was dried over magnesium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified by silica gel chromatography (dichloromethane:methanol)

Sources & evidence

ORD record
ord-c82a7faf1ea04e85bdff193acf86afb6
Source dataset
uspto-grants-2013_09
Patent number
US08541449B2

Linked notes

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