تفاعل #159054

معادلة التفاعل

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

المردود 53.0%

المذيبات

dioxane

DCM

ظروف التفاعل

المعالجة

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

الإجراء التجريبي

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%).

المصدر