1,2-Dimethoxyethane → [1-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 417616Notes

Reaction equation

HRID 417616 reaction equation
COC(=O)[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:29][O:30][C:31](=[O:70])[NH:32][CH:33]([C:37]([N:39]1[CH:44]([C:45]2[NH:46][C:47]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[C:55](B5OC(C)(C)C(C)(C)O5)[CH:56]=4)[CH:51]=3)=[CH:48][N:49]=2)[CH:43]2[CH2:69][CH:40]1[CH2:41][CH2:42]2)=[O:38])[CH:34]([CH3:36])[CH3:35].[C:71]([O-:74])([OH:73])=O.[Na+].[CH3:76]OCCOC>O>[CH3:29][O:30][C:31](=[O:70])[NH:32][CH:33]([C:37]([N:39]1[CH:44]([C:45]2[NH:46][C:47]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[C:55]([C:24]5[CH:23]=[CH:22][C:21]([C:18]6[NH:17][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:71]([O:74][CH3:76])=[O:73])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=6)=[CH:26][CH:25]=5)[CH:56]=4)[CH:51]=3)=[CH:48][N:49]=2)[CH:43]2[CH2:69][CH:40]1[CH2:41][CH2:42]2)=[O:38])[CH:34]([CH3:35])[CH3:36]

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 516892Sodium BicarbonateHCID 66620141Methyl (1-(2-(4-(4-bromophenyl)-1H-imidazol-2-YL)pyrrolidin-1-YL)-3-methyl-1-oxobutan-2-YL)carbamateHCID 66620723[2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]carbamic acid methyl ester

Product 1

HCID 66621232[1-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl esterYield 44%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.251 g), [2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]carbamic acid methyl ester (0.301 g), and NaHCO3 (0.162 g) were dissolved in a mixture of 1,2-dimethoxyethane (9 mL) and water (3 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0254 g) was added. The reaction mixture was stirred at 80° C. for 21 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and extracted twice with water (10 mL) and once with brine (10 mL). The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-5% MeOH:DCM. The fractions containing product were combined and the solvent was removed under reduced pressure. Oil was dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [1-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.187 g, 44%) as a white solid.

Workup

  1. customThe solution was degassed with nitrogen, and Pd(PPh3)4 (0.0254 g)
  2. additionwas added
  3. customevaporated under vacuum
  4. dissolutionSolid was dissolved in DCM (20 mL)
  5. extractionextracted twice with water (10 mL) and once with brine (10 mL)
  6. additionThe fractions containing product
  7. customthe solvent was removed under reduced pressure
  8. dissolutionOil was dissolved in DMF
  9. custompurified by reverse phase HPLC (5-70% acetonitrile:water)

Sources & evidence

ORD record
ord-cdca9ea8d3dd4b58a6fb110fd4671ebe
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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