A kind of glutaminyl cyclase inhibitor containing 4-imidazolyl
A glutaminyl cyclase and imidazole-based technology, applied in the field of medicinal chemistry, can solve the problems of single pharmacophore structure and limited molecular activity, and achieve the effect of high QC inhibitory activity and expanding structural diversity
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Embodiment 1
[0035] The synthesis of N-([1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1-amine, its synthetic route is as follows:
[0036]
[0037] 1), the preparation of 2-(bromomethyl)-1,1'-biphenyl:
[0038] 2-Bromomethylbromobenzene (7.53 mmol, 1 equiv), phenylboronic acid (9.04 mmol, 1.2 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Dichloromethane complex (0.45mmol, 0.06 equivalent) was placed in a 50ml round bottom flask, and 10ml of dioxane and 10ml of 2mol / L K 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 79%.
[0039] 2), the preparation of N-([1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1-amine:
[0040] Dissolve 2-(bromomethyl)-1,1'-biphenyl (1.35mmol...
Embodiment 2
[0042] N-(3',4,4',5'-tetramethoxy-[1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1 -The synthesis of amine, its synthetic route is as follows:
[0043]
[0044] 1), the preparation of 2-(bromomethyl)-3',4,4',5'-tetramethoxy-1,1'-biphenyl:
[0045] 2-Bromomethyl-4-methoxybromobenzene (6.49mmol, 1 equivalent), 3,4,5-trimethoxyphenylboronic acid (7.78mmol, 1.2 equivalents) and [1,1'-bis(di Phenylphosphine) ferrocene] dichloropalladium (II) dichloromethane complex (0.39mmol, 0.06 equivalents) is placed in a 50ml round bottom flask, and 10ml of dioxane and 10ml of 2mol / L K 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 63%.
[0046] 2), N-(3',4,4',5'-tetramethoxy-[1,1'-biphenyl]-2-methyl)-2-...
Embodiment 3
[0049] N-((4'-cyclopropyl-4-fluoro-[1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1-amine (9 ), its synthetic route is as follows:
[0050]
[0051] 1), the preparation of 2-(bromomethyl)-4'-cyclopropyl-4-fluoro-1,1'-biphenyl:
[0052] 2-Bromomethyl-4-fluorobromobenzene (6.41 mmol, 1 equivalent), p-cyclopropylphenylboronic acid (7.69 mmol, 1.2 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (II) dichloromethane complex (0.38mmol, 0.06 equivalent) is placed in the 50ml round bottom flask, adds the dioxane of 10ml and the 2mol / L K of 10ml respectively 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 75%.
[0053] 2), N-(4'-cyclopropyl-4-fluoro-[1,1'-biphenyl]-2...
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