Use of oripavine as a starting material for buprenorphine
Inventors
Mannino, Anthony • Hoefgin, Erik R. • Hill, Lloyd P. • Buehler, Henry J.
Assignees
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Publication Number
US-8993764-B2
Publication Date
2015-03-31
Expiration Date
Abstract
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.
Core Innovation
The document describes a method for producing norbuprenorphine in which oripavine according to Formula I is reacted with methyl vinyl ketone to form a compound according to Formula II, and the compound according to Formula II is then hydrogenated to form a compound according to Formula III. These transformations proceed through a defined sequence from Formula I to Formula II to Formula III.
Next, a t-butyl group is added to the compound according to Formula III to form a compound according to Formula X, and the nitrogen of the compound according to Formula X is then demethylated to form norbuprenorphine, Formula VIII. The route therefore specifies structural progression from oripavine to Formula II, to Formula III, to Formula X, and finally to Formula VIII (norbuprenorphine).
The document also optionally converts norbuprenorphine to buprenorphine by adding a cyclopropylmethyl group. One independent embodiment specifies that the reaction yield of the compound according to Formula II is at least 85%.
Claims Coverage
The independent claims cover a multi-step synthesis route to norbuprenorphine. Across the independent claims, the inventive features include reaction of oripavine with methyl vinyl ketone, hydrogenation to the next intermediate, installation of a t-butyl group, and nitrogen demethylation to norbuprenorphine; one independent claim additionally requires a yield threshold for the Formula II intermediate.
Oripavine to methyl vinyl ketone adduct intermediate formation
Reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II.
Hydrogenation to next intermediate
Hydrogenating the compound according to Formula II to form a compound according to Formula III.
t-Butyl group installation
Adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X.
Nitrogen demethylation to norbuprenorphine
Demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.
Yield threshold for Formula II formation
Reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II, wherein the reaction has a yield of the compound of Formula II of at least 85%.
The independent claims define a structured pathway converting oripavine to norbuprenorphine through methyl vinyl ketone reaction, hydrogenation, t-butyl group addition, and nitrogen demethylation. One independent claim further requires the Formula II formation to have a yield of at least 85%.
Stated Advantages
Avoids an O-demethylation step required when using thebaine, because oripavine lacks the O-3 methyl group.
Documented Applications
Producing norbuprenorphine via conversion of oripavine.
Optional conversion of norbuprenorphine to buprenorphine by adding a cyclopropylmethyl group.
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