To a solution of 3-tert-butyldimethylsilylmorphine (1 eq.) and the oxycodone-linker oxime from step 1 (1 eq.) in an anhydrous solvent such as THF (approximately 0.1 M) is added 2 equivalents of diethyl azodicarboxylate (DEAD) and 2 equivalents of triphenylphosphine. The resulting mixture is stirred at ambient temperature until the 3 -ten-butyldimethylsilylmorphine and/or the oxycodone-linker oxime is consumed, as monitored by TLC or HPLC. The resulting mixture is then subjected to an aqueous work up, and the product is purified by silica gel column chromatography or preparatory HPLC to provide the protected hybrid morphine-oxycodone compound.
