The preparation and synthetic utility of O‐substituted normethylmorphines

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Abstract
Previously described alkylation procedures on normethylmorphine in ethanol usually give low yields of N‐ and (phenolic) O,N‐alkylated products. While the O‐aikylation problem has been overcome for alkyl halides by doing the alkylations in dimethylformamide, reactive halides such as ethyl bromoacetate still give some O‐alkylation. Selective N‐acylation on normethylmorphine would present even more difficulty. We have developed syntheses of two phenolic O‐substituted normethylmorphines which allow selective reaction on nitrogen. 3,6‐Diacetylnormethylmorphine (normethylheroin) is prepared via the recently described trichloroethyl chloroformate method of Montzka et al. as applied to heroin. The reaction of N,N‐diethylcarbamoyl chloride on morphine gives 3‐(N,N‐diethylcarbamoyl)morphine, i.e. the phenolic hydroxyl is derivatized. Its 6‐acetyl derivatives is N‐demethylated by the von Braun (cyanogen bromide) method to give 3‐(N,N‐diethylcarbamoyl)normethylmorphine. Norheroin is monoalkylated in good yield on nitrogen with ethyl bromoacetate in dimethylformamide. It is similarly N‐acylated with chloroacetyl chloride in methylene chloride.