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

HRID 625611Notes

Reaction equation

HRID 625611 reaction equation
BrC1C=C2C(=CC=1)[N:8]=[C:7]([C:12]1[N:13]=[C:14]([C@@H:17]3[CH2:22][C@@H:21]4[C@@H:19]([CH2:20]4)[N:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:15][CH:16]=1)[CH:6]=[N:5]2.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[C:54](OC)=[CH:53][CH:52]=[CH:51][C:50]=2OC)CCCCC1.CC1(C)C(C)(C)OB(C2C=CC3[N:80]=[C:79]([C@@H:81]4[CH2:86][C@@H:85]5[C@@H:83]([CH2:84]5)[N:82]4[C:87]([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[O:88])[NH:78]C=3C=2)O1>C1COCC1.O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:90]([O:89][C:87]([N:82]1[C@H:81]([C:79]2[NH:78][C:53]3[CH:54]=[C:49]([C:44]4[CH:43]=[C:48]5[C:47](=[CH:46][CH:45]=4)[N:8]=[C:7]([C:12]4[NH:13][C:14]([C@@H:17]6[CH2:22][C@@H:21]7[C@@H:19]([CH2:20]7)[N:18]6[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:15][CH:16]=4)[CH:6]=[N:5]5)[CH:50]=[CH:51][C:52]=3[N:80]=2)[CH2:86][C@@H:85]2[C@H:83]1[CH2:84]2)=[O:88])([CH3:93])([CH3:92])[CH3:91]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 58498658(1R,3S,5R)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylateHCID 178452526HCID 178452526, compound

Product 1

HCID 66981900(1R,3S,5R)-tert-butyl 3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylateYield 164.2%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
110 °C

Procedure

Pd(OAc)2 (1.230 mg, 5.48 μmol) was added to a degassed suspension of (1R,3S,5R)-tert-butyl 3-(4-(6-bromoquinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (25 mg, 0.055 mmol), K2CO3 (22.71 mg, 0.164 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.50 mg, 10.96 μmol) and (1R,3S,5R)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (30.3 mg, 0.071 mmol) in THF (1 mL) and water (0.250 mL) and the mixture was stirred at 110° 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-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (12 mg, 0.018 mmol, 33% yield) as yellow solid. LC-MS retention time 1.90 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 9.38 (s, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.16-8.22 (m, 1H), 8.10-8.15 (m, 1H), 7.95 (s, 2H), 7.66-7.76 (m, 2H), 3.54-3.73 (m, 2H), 2.52-2.69 (m, 2H), 2.33-2.47 (m, 2H), 1.71-1.84 (m, 2H), 1.08-1.57 (m, 20H), 0.83-0.95 (m, 2H), 0.60-0.74 (m, 2H).

Workup

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

Sources & evidence

ORD record
ord-6e3d79571b464db5824840b023bb5c59
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

Loading…