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

摘要

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.

主权项

1. A 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, comprising the steps of:
reacting a compound of formula (II) with methyl vinyl ketone, as illustrated in the following schematic:wherein the compound of formula (II) is combined with the methyl vinyl ketone in a solution that comprises an organic solvent, a mixture of organic solvents, or a mixture of water and an organic solvent, to provide a mixture of the compound of formula (III) and the compound of formula (IV);
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); reacting the anhydrous mixture of the compound of formula (III) and the compound of formula (IV) with a Grignard reagent, as illustrated in the following schematic:wherein the Grignard reagent is selected from the group consisting of t-butyl MgCl, t-butyl MgBr, and t-butyl MgI, to provide a mixture that comprises a compound of formula (V);
hydrogenating the compound of formula (V), as illustrated in the following schematic:to provide a mixture comprising a compound of formula (VI);
reacting the compound of formula (VI) with a source of cyanide in a first alcoholic solvent, as illustrated in the following schematic:wherein the first alcoholic solvent comprises one or more of a secondary alcohol and tertiary alcohol, and wherein the reaction optionally includes a first inorganic base, to provide a mixture that includes a compound of formula (VII); and
reacting the compound of formula (VII) with a second inorganic base in a second alcoholic solvent, as illustrated in the following schematic:wherein the second alcoholic solvent includes one or more of a secondary alcohol and tertiary alcohol, to provide a mixture that comprises a (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).