Potassium Carbonate → (1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

HRID 1471148Notes

Reaction equation

HRID 1471148 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:32]=[N:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=5)[N:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:37]1[NH:41][C:40]([C@@H:42]2[CH2:47][C@@H:46]3[C@@H:44]([CH2:45]3)[N:43]2[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:39][CH:38]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:32]=[N:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:37]6[NH:41][C:40]([C@@H:42]7[CH2:47][C@@H:46]8[C@@H:44]([CH2:45]8)[N:43]7[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:39][CH:38]=6)[CH:29]=5)[N:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 58498724(1R,3S,5R)-tert-butyl 3-(4-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylateHCID 669821792-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronic acid

Product 1

HCID 66981769(1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylateYield 39.5%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

Pd(OAc)2 (2.67 mg, 0.012 mmol) was added to a degassed solution of 2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronic acid (56 mg, 0.119 mmol), (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (66.9 mg, 0.178 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (9.76 mg, 0.024 mmol) and K2CO3 (49.3 mg, 0.356 mmol) in THF (1 mL) and water (0.25 mL) and the mixture was stirred at 120° C. for 2 h. The reaction was diluted with MeOH, filtered and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield (1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (32 mg, 0.047 mmol) as yellow solid. LC-MS retention time 1.89 min; m/z 675 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=95% water/5% methanol/10 mM ammonium acetate. Solvent B=5% water/95% methanol/10 mM ammonium acetate. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 9.44 (s, 1H), 8.45 (br s, 1H), 8.39 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.64 (s, 1H), 4.69-4.78 (m, 1H), 4.49-4.57 (m, 1H), 3.56-3.70 (m, 2H), 2.50-2.73 (m, 2H), 2.31-2.47 (m, 2H), 1.67-1.86 (m, 2H), 1.31 (br s, 18H), 0.82-0.95 (m, 2H), 0.54-0.75 (m, 2H).

Workup

  1. filtrationfiltered
  2. custompurified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer)

Sources & evidence

ORD record
ord-3a229a58cab943d68a8c3ef35424b890
Source dataset
uspto-grants-2015_04
Patent number
US09006455B2

Reaction notes

Loading…