THE STRUCTURE OF ACETOCODEINE¹

Abstract

It was observed by Knoll and Co. about 1905 (1) that codeine reacts with warm "sulfoacetic acid" (a solution of concentrated sulfuric acid in acetic anhydride) in such manner that the alcoholic hydroxyl group is acetylated, and, in addition, the codeine molecule undergoes substitution by a second acetyl group. In contrast to the acetyl group at the hydroxyl, the second acetyl has ketonic properties, and cannot be removed by hydrolysis, whence Knorr (2) believed that the new group was substituted in the aromatic ring of codeine, at the same position as the bromine atom or the nitro group of bromocodeine or nitrocodeine respectively. This view was supported by the fact that acetocodeine, like bromocodeine, does not undergo nitration, an indication that the preferred nitration position is already occupied. Knorr assumed, on grounds not stated, that these derivatives all carried the substituent at the 1 position. Later investigators (6) considered that substitution in the morphine or codeine molecule may take place at the 2 position, a belief that was perhaps based on the probable ortho-orienting influence of the morphine phenolic hydroxyl at position 3. Schopf and Pfeifer (3), however, have suggested that bromination of dihydrocodeinone takes place at position 1. Direct proof of the position of bromination was offered by Small and Turnbull (4), through identification of the degradation product of bromocodeine (and consequently of bromomorphine) with synthetic l-bromo-3,4dimethoxyphenanthrene.