Practical synthesis of ( R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid: a key intermediate for a therapeutic drug for neurodegenerative diseases

Abstract

A practical method for the preparation of ( R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid ( R)- 2, a key intermediate for a therapeutic drug for neurodegenerative diseases, has been developed. rac-Methyl 6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-(propionyloxy)phenyl) hexanoate rac- 9b was synthesized from 2-methylnaphthoquinone in seven steps. An optically active ester ( R)- 9b was readily obtained from the corresponding racemic ester by lipase-catalyzed resolution, followed by sulfation or phosphorylation. Sulfation by a sulfur trioxide pyridine complex or phosphorylation by phosphoryl chloride enabled facile isolation of the optically active ester simply by extraction. Optically active acid ( R)- 2 was synthesized in excellent enantiomeric excess by hydrolysis of ( R)- 9b followed by recrystallization. The present synthesis of ( R)- 2 was accomplished in 10 steps without requiring chromatographic purification.