Efficient synthesis of bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7-diones and its application to the synthesis of GnRH antagonists.

Treatment of various 2-methyl oxazolines or thiazolines with chlorocarbonyl isocyanate gives the corresponding bicyclic oxazolino- or thiazolino[3,2-c]pyrimidin-5,7-dione derivatives in very good yield. This reaction has been applied to the rapid syntheses of human gonadotropin-releasing hormone (hGnRH) receptor antagonists for SAR study, resulting in 13e with binding affinity in the low nanomolar range (4.5 nM).