Method for making tetrabenazine compounds

A method of preparing a TBZ compound having structure V,

• said method comprising:
• (a) reacting a nucleophilic alkenyl species with aldehyde compound VI
• and oxidizing of the resultant allylic alcohol to provide a first intermediate having structure VII;
• and
• (b) removing the Boc protecting group and inducing an amino cyclization reaction to provide a product TBZ compound having structure V,
• wherein with respect to structures V, VI, and VII;
• R2-R3 are independently hydrogen or an isotope thereof, a halogen atom, a C1-C20 aliphatic radical, a C2-C20 cycloaliphatic radical, or a C2-C20 aromatic radical;
• R11 is hydrogen or an isotope thereof, a C1-C20 aliphatic radical, a C2-C20 cycloaliphatic radical, or a C2-C20 aromatic radical;
• and Q1 is hydrogen or an isotope thereof.

A method of preparing an enantiomerically enriched TBZ compound comprising at least 95 mole percent enantiomer VIII,

• said method comprising:
• (a) reacting a nucleophilic alkenyl species with an aldehyde compound comprising at least 95 mole percent enantiomer IX
• and oxidizing the resultant allylic alcohol to provide a first intermediate having structure X;
• and
• (b) removing the Boc protecting group and inducing an amino cyclization reaction to provide a product TBZ compound having structure VIII,
• wherein with respect to structures VIII, IX, and X;
• R2-R3 are independently hydrogen or an isotope thereof, a halogen atom, a C1-C20 aliphatic radical, a C2-C20 cycloaliphatic radical, or a C2-C20 aromatic radical;
• R11 is hydrogen or an isotope thereof, a C1-C20 aliphatic radical, a C2-C20 cycloaliphatic radical, or a C2-C20 aromatic radical;
• and Q1 is hydrogen or an isotope thereof.