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

✍ Scribed by Tatsuya Ito; Tomomi Ikemoto; Toru Yamano; Yukio Mizuno; Kiminori Tomimatsu

• Publisher: Elsevier Science
• Year: 2003
• Tongue: English
• Weight: 203 KB
• Volume: 14
• Category: Article
• ISSN: 0957-4166
• DOI: 10.1016/s0957-4166(03)00580-9

✦ Synopsis

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-(1,4dimethoxy-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.