Method for the preparation of (.+-.)-calanolide A and intermediates thereof

US6043271A · kind A · utility

Assignee

• Sarawak MediChem Pharmaceuticals, Inc. · US

Inventors

• Michael T. Flavin · Darien, US
• Ze-Qi Xu · Naperville, US
• John D. Rizzo · Downers Grove, US
• Alla Kucherenko · Naperville, US
• Albert Khilevich · Glenview, US
• Abram Kivovich Sheinkman · Naperville, US
• Vilayphone Vilaychack · Elgin, US
• Lin Lin · Chicago, US
• Wei-Yu Chen · Taichung, TW
• William Allen Boulanger · Mahomet, US

Key dates

• Filing date: Aug 2, 1995
• Grant date: Mar 28, 2000
• Expiry date: Aug 2, 2015

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D493/14
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing a viral infections using (.+-.)-calanolide or (-)-calanolide is provided.