Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps

摘要

A process for the preparation of a compound of formula (V), or salt thereof, comprises O-and N-demethylation of a compound of formula (I) followed by reaction of the product with an aldehyde RCHO to produce an intermediate containing an iminium ion which is reduced to give a compound of formula (I). X is O, CH2 or is a diC1-6alkoxy group and R is a cyclopropyl or vinyl group. Where X is a diC1-6alkoxy group, this may be removed to yield a compound of formula (V) wherein X is O. In particular, the compound of formula (V) is naltrexone or naloxone and the starting material of formula (I) is oxycodone. The O- and N-demethylation may be carried out with an aryl or alkyl chloroformate, especially a-chloroethylchloroformate, followed by hydrolysis of the resulting intermediate, e.g. with lithium tri-sec-butylborohydride or the O-demethylation may be carried out with BBr3. The reduction of the iminium-containing intermediate may be carried out with sodium triacetylborohydride or sodium cyanoborohydride. EMI ID=1.1 HE=131 WI=83 LX=755 LY=1426 TI=CF