반응 #159054

반응 방정식

HATU

ethyl acetate

HCl

3-(6-{4′-[2-(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

2-Methoxycarbonylamino-3-methyl-butyric acid

4-methylmorpholine

→

(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

수율 53.0%

용매

dioxane

DCM

반응 조건

후처리

1. 1
   농축The reaction mixture was concentrated
2. 2
   기타dried overnight under vacuum
3. 3
   workup.DISSOLUTIONThe residue was dissolved in DMF (1 mL) and to this solution
4. 4
   기타Reaction mixture
5. 5
   workup.STIRRINGwas stirred at 0° C. for 50 minutes
6. 6
   세척washed with dilute sodium bicarbonate solution
7. 7
   건조The organic layer was dried (MgSO4)
8. 8
   농축concentrated
9. 9
   기타purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA)

실험 절차

4N HCl in dioxane (2 mL) was added to 3-(6-{4′-[2-(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%).

출처