Practical Synthesis of a HIV Integrase Inhibitor

• Published in: Organic process research & development Vol. 12; no. 6; pp. 1245 - 1252
• Main Authors: Zhong, Yong-Li, Pipik, Brenda, Lee, Jaemoon, Kohmura, Yoshinori, Okada, Shigemitsu, Igawa, Kazunobu, Kadowaki, Chie, Takezawa, Akihiro, Kato, Shinji, Conlon, David A, Zhou, Hua, King, Anthony O, Reamer, Robert A, Gauthier, Jr, Donald R, Askin, David
• Format: Journal Article
• Language: English
• Published: American Chemical Society 21-11-2008
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op800153y

A practical and efficient synthesis of the potent HIV integrase inhibitor 1 is described. Starting from readily available 3,4-dihydro-2H-pyran, the six-step synthesis features a through process without purification of any of the intermediates until the isolation of crystalline intermediate 7. After deprotection and classical resolution, amine 8 was isolated with excellent enantiopurity. A final amide coupling completed the synthesis of 1 in 7.6% overall yield from DHP. This chromatography-free route is more cost effective and increases the overall yield by nearly 3 times when compared with the original Med Chem synthethic route. This improved chemistry was used successfully to prepare multikilogram quantities of integrase inhibitor 1.