Process for the preparation of (S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol
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Publication Number
US-10287296-B2
Publication Date
2019-05-14
Expiration Date
Abstract
An invention includes a process for the preparation of (S)-2((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol.
Core Innovation
The invention describes a multi-step process for preparing (S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol (formula I) from a compound of formula (II) by reacting the compound of formula (II) with methyl vinyl ketone. A mixture of compounds of formula (III) and (IV) is provided, followed by azeotropically removing at least one of water and an alcoholic solvent to obtain an anhydrous mixture of the compounds of formula (III) and (IV).
The anhydrous mixture of compounds of formula (III) and (IV) is reacted with a Grignard reagent selected from t-butyl MgCl, t-butyl MgBr, and t-butyl MgI to provide a mixture comprising a compound of formula (V), and the compound of formula (V) is hydrogenated to provide a mixture comprising a compound of formula (VI). The compound of formula (VI) is reacted with a source of cyanide in a first alcoholic solvent comprising one or more of a secondary alcohol and tertiary alcohol, optionally including a first inorganic base, to provide a mixture comprising a compound of formula (VII).
Finally, the compound of formula (VII) is reacted with a second inorganic base in a second alcoholic solvent including one or more of a secondary alcohol and tertiary alcohol to provide a mixture comprising formula I. The process is described as a telescoped conversion without intermediate isolations and is framed as a synthesis strategy for preparing buprenorphine and buprenorphine hydrochloride from formula I, with reported compound distributions by HPLC.
Claims Coverage
The document describes one independent claim covering a multi-step process with six inventive features: methyl vinyl ketone reaction, azeotropic removal, Grignard reaction with selected t-butyl magnesium halides, hydrogenation, cyanide addition in a specified alcoholic solvent with optional inorganic base, and final base-mediated conversion.
Methyl vinyl ketone reaction of formula (II) to form III/IV
A process preparing formula I by reacting the compound of formula (II) with methyl vinyl ketone in a solution comprising an organic solvent, a mixture of organic solvents, or a mixture of water and an organic solvent to provide a mixture of a compound of formula (III) and a compound of formula (IV).
Azeotropic removal to form an anhydrous III/IV mixture
Azeotropically removing at least one of water and alcoholic solvent from the mixture of the compound of formula (III) and the compound of formula (IV) to provide an anhydrous mixture of the compound of formula (III) and the compound of formula (IV).
Grignard reaction of anhydrous III/IV using selected t-butyl magnesium halides
Reacting the anhydrous mixture of the compound of formula (III) and the compound of formula (IV) with a Grignard reagent selected from t-butyl MgCl, t-butyl MgBr, and t-butyl MgI to provide a mixture that comprises a compound of formula (V).
Hydrogenation of compound of formula (V) to form VI
Hydrogenating the compound of formula (V) to provide a mixture comprising a compound of formula (VI).
Cyanide addition to VI in a first alcoholic solvent with optional inorganic base
Reacting the compound of formula (VI) with a source of cyanide in a first alcoholic solvent comprising one or more of a secondary alcohol and tertiary alcohol, wherein the reaction optionally includes a first inorganic base, to provide a mixture that comprises a compound of formula (VII).
Final reaction of VII with second inorganic base in second alcoholic solvent to form formula I
Reacting the compound of formula (VII) with a second inorganic base in a second alcoholic solvent including one or more of a secondary alcohol and tertiary alcohol to provide a mixture that comprises formula I.
Claim coverage centers on a telescoped, multi-step process that builds from formula (II) to formula (I) through anhydrous III/IV formation, Grignard conversion to formula (V), hydrogenation to formula (VI), cyanide addition to formula (VII), and final base-mediated conversion in a second alcoholic solvent.
Stated Advantages
Fewer intermediate isolations.
Improved yield/purity via reduced β-isomer.
Telescoping without isolation.
Use of more environmentally/operationally favorable solvents.
Documented Applications
Conversion of formula (I) to buprenorphine and use of buprenorphine hydrochloride in a pharmaceutical composition for treatment of pain (moderate/severe).
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