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

A practical method for the preparation of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-hydoxyphenyl)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. (C) 2003 Elsevier Ltd. All rights reserved.