Synthesis of a Glucokinase Activator

Key words

glucokinase activators - amide bond formation - n-propanesulfonic anhydride

Significance

Glucokinase mediates glucose metabolism in the liver and insulin release in the pancreas. The target molecule selectively activates liver glucokinase with diminished risk of hypoglycemia. It is a lead for the treatment of type 2 diabetes. A major challenge in the synthesis depicted was the formation of amide I by the condensation of the racemization-prone carboxylic acid G with the weakly nucleophilic 6-aminonicotinic ester H. Best results were obtained using n-propane­sulfonic anhydride (T3P) as the condensing agent.

Comment

The N-alkylation of imidazole E was studied extensively to achieve high regioselectivity with minimal racemization. Best results were obtained using potassium phosphate as base and ethyl acetate as solvent, in which case the regio­selectivity was 96:4. The unwanted regioisomer and epimer was removed by crystallization of the salt prepared from (R)-α-methylbenzylamine. A further complication was the hydrolytic lability of the hard-won amide bond in I.