A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.

Nitriles P 0350Mild and Efficient DBU-Catalyzed Amidation of Cyanoacetates. -This method can be applied to prepare complex cyanoacetamides of type (V) which display potent immunosuppressant activity. -(PRICE, K. E.; LARRIVEE-ABOUSSAFY, C.; LILLIE, B. M.; MCLAUGHLIN, R. W.; MUSTAKIS, J.; HETTENBACH, K. W.; HAWKINS, J. M.; VAIDYANATHAN*, R.; Org. Lett. 11 (2009) 9, 2003-2006; Chem. Res. Dev., Pfizer Inc., Groton, CT 06340, USA; Eng.) -Jannicke 36-053

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