Mallinckrodt, Inc.

Lloyd P Hill

Henry J Buehler

Anthony Mannino

Erik R Hoefgin

There is provided a method for the synthesis of norbuprenorphine, and ultimately buprenorphine, utilizing oripavine as the starting material. Conventional methods of producing buprenorphine utilize thebaine as the starting material, requiring an O-demethylation step, typically a low to moderate yield transformation. The present use of oripavine as a starting material does not require an O-demethylation step, since the oripavine molecule lacks an O-3 methyl group.

Use of oripavine as a starting material for buprenorphine

An improved process for the preparation of codeine from morphine comprises the steps of a) reacting morphine with a methylating agent in the presence of a hydrocarbon solvent at a temperature of 100 to 215&deg; C. under reflux conditions such that approximately 50% or more of the hydrocarbon solvent is returned to the reaction mixture to substantially avoid the formation of codeine methyl ether; and b) recovering codeine from the reaction mixture. The process may include step a) above followed by b) cooling the reaction mixture to approximately 85&deg; C. and adding water to terminate the reaction; c) raising the pH of the reaction mixture to approximately 11; d) separating the hydrocarbon solvent phase containing codeine and dimethylaniline; and e) adding a dilute mineral or organic acid and approximately 6 to 7 times the volume of water for each volume of hydrocarbon solvent to separate dimethylaniline and codeine.

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St. Louis, MO, United States of America

Lloyd P Hill