Potassium Carbonate → Tert-butyl 2-azabicyclo[2.2.1]heptane-2-carboxylate

HRID 2392381Notes

Reaction equation

[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2NC(C3C=CC(Br)=CC=3)=CN=2)[CH2:13][C:10]2([CH2:12]C2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C(C2NC3C=C(C4C=CC(B5OC(C)(C)C(C)(C)O5)=CC=4)C=CC=3N=2)C2CC1CC2)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:13][CH:14]1[CH2:15][CH2:12]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

Conditions

Temperature: 90 °C

Procedure

A mixture of 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (101 mg, 0.243 mmol, 1 eq.), 3-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (150 mg, 0.291 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (5%, 17 mg) and 2M potassium carbonate aqueous solution (5 eq., 0.73 mL) in 1.5 mL DME was heated to 90° C. under Are overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane) to give 3-(6-{4′42-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (53 mg, yield 26%). LCMS-ESI−: calc'd for C44H50N6O4: 726.91. Found: 727.2 (M+H+). (1-{6-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DH): 4N HCl in dioxane (2 mL) was added to 3-(6-{4′42-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (53 mg, 0.073 mmol) in 2 mL DCM and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (1 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2.1 eq., 26.6 mg), 4-methylmorpholine (6 eq., 0.048 mL), followed by HATU (2 eq., 56 mg). Reaction mixture was stirred at 0° C. for 50 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{6-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DH) (41.6 mg, 53%).

Workup

temperatureThe reaction mixture was cooled
washwashed with saturated sodium bicarbonate solution
dry with materialThe organic layer was dried (MgSO4)
concentrationconcentrated
custompurified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane)

Sources & evidence

ORD record: ord-94dfc393ec7649dcb8ec51d3cc31978f
Source dataset: uspto-grants-2012_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08273341B2

Reaction notes

Loading…