The halogenomorphides and halogendcodides are formed when the secondary alcoholic hydroxyl group of morphine or codeine is replaced by a halogen atom. Although the compounds occupy a position of considerable importance in the development of the morphine structural theory, and are the source of the morphine and codeine isomers, there has been no direct proof of structure offered for any single member of the series.The related pair, -chloromorphide and -chlorocodide, are the principal products obtained when morphine and codeine, respectively, are treated with thionyl chloride or phosphorus pentachloride. The halogen atom has tacitly been assumed to take the place of the hydroxyl that is known to occupy the 6-position, although it has been shown (1,2,3) in recent years that replacement of a group at this point in the nucleus often involves an a,7-shift, as a result of which the new group may appear at position 8. In carrying out numerous kilogram-scale preparations, we have observed that the a compounds are not the only products of the reaction, but are accompanied by the ß-halogeno derivatives to the extent of 10% to 15% of the total yield. In the codeine series, a-and 0-chlorocodides were obtained in part in the form of a new molecular compound of constant properties, that could not be separated into the components by fractional crystallization, although a-and ß-chlorocodides themselves differ considerably in solubility. Separation through salts, a method previously employed successfully for similar molecular compounds in the 1 The work reported in this paper is part of a unification of effort by a number of agencies having responsibility for the solution of the problem of drug addiction.

The introduction of an acetyl group into the aromatic ring of morphine and codeine by the action of sulfoacetic acid, H0S02CH2C00H (1), was first described in a patent of Knoll and Co. (2). Later, Knorr (3) prepared various derivatives of acetocodeine, degraded it to aceto-0-methyhnorphimethine, and ultimately to acetomethylmorphol. More recently, Small and Mallonee (4) proved by way of the Beckmann rearrangement of aceto-6-acetylcodeine oxime, that the acetyl ("aceto") group occupies the 1 -position. It is convenient to retain the term "aceto" for this group to distinguish it from O-acetyl groups. SUMMARY Acetylation of dihydromorphine and dihydrocodeine with sulfoacetic acid is described. The same nuclear acetylated compounds are obtained by hydrogenation of 1-acetomorphine and 1-acetocodeine derivatives. In the acetocodeine series, stepwise reduction of the nuclear acetyl group to the 1-hydroxyethyl and ethyl group can be accomplished.1-Acetocodeine can be degraded to 1-aceto-a-methylmorphimethine, and this in turn converted to l-aceto-/3-methylmorphimethine, thus establishing the heretofore doubtful nature of the latter.Bethbsda 14, Md.

In the preceding communication (1) it was pointed out that the action of phosphorus pentachloride on dihydropseudocodeine and on dihydroallopseudocodeine resulted in the same 8-chlorodihydrocodide (I). This chloro compound is exceedingly resistant to reduction, but we find that prolonged treatment with sodium in boiling cyclohexanol results in loss of hydrogen chloride, with formation of a new desoxycodeine that we shall designate as desoxycodeine-D. The structure II that we propose for the compound represents it also as the desoxy derivative of the rare opium alkaloid neopine (2). The new desoxycodeine might be logically named desoxyneopine, but this leads to embarrassment in selecting a name for the morphine analog. nch3 I. 8-Chlorodihydrocodide NCHs 1The work reported in this paper is part of a unification of effort by a number of agencies having responsibility for the solution of the problem of drug addiction.

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.