Method for the preparation of (+)-calanolide a and analogues thereof

US5892060A · kind A · utility

Assignee

• Sarawak MediChem Pharmaceuticals, Inc. · US

Inventors

• Michael T. Flavin · Darien, US
• Ze-Qi Xu · Naperville, US
• Albert Khilevich · Glenview, US
• David E. Zembower · La Grange, US
• John D. Rizzo · Downers Grove, US
• Shuyuan Liao · Northbrook, US
• Aye Mar · Chicago, US
• Lin Lin · Chicago, US
• Vilayphone Vilaychak · Elgin, US
• Darko Brankovic · Bolingbrook, US
• Sergey Dzekhster · Chicago, US
• Jinjun Liu · Tuji, CN

Key dates

• Filing date: Mar 1, 1996
• Grant date: Apr 6, 1999
• Expiry date: Mar 1, 2016

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. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.