Practical synthesis of a HIV integrase inhibitor

Yong Li Zhong, Brenda Pipik, Jaemoon Lee, Yoshinori Kohmura, Shigemitsu Okada, Kazunobu Igawa, Chie Kadowaki, Akihiro Takezawa, Shinji Kato, David A. Conton, Hua Zhou, Anthony O. Ring, Robert A. Reamer, Donald R. Gauthier, David Askin

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1245-1252
Number of pages8
JournalOrganic Process Research and Development
Volume12
Issue number6
DOIs
Publication statusPublished - Nov 21 2008

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HIV Integrase Inhibitors
human immunodeficiency virus
inhibitors
synthesis
Integrase Inhibitors
routes
chromatography
Chromatography
purification
Amides
amides
Amines
Purification
isolation
amines
chemistry
Crystalline materials
costs
Costs

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Zhong, Y. L., Pipik, B., Lee, J., Kohmura, Y., Okada, S., Igawa, K., ... Askin, D. (2008). Practical synthesis of a HIV integrase inhibitor. Organic Process Research and Development, 12(6), 1245-1252. https://doi.org/10.1021/op800153y

Practical synthesis of a HIV integrase inhibitor. / Zhong, Yong Li; Pipik, Brenda; Lee, Jaemoon; Kohmura, Yoshinori; Okada, Shigemitsu; Igawa, Kazunobu; Kadowaki, Chie; Takezawa, Akihiro; Kato, Shinji; Conton, David A.; Zhou, Hua; Ring, Anthony O.; Reamer, Robert A.; Gauthier, Donald R.; Askin, David.

In: Organic Process Research and Development, Vol. 12, No. 6, 21.11.2008, p. 1245-1252.

Research output: Contribution to journalArticle

Zhong, YL, Pipik, B, Lee, J, Kohmura, Y, Okada, S, Igawa, K, Kadowaki, C, Takezawa, A, Kato, S, Conton, DA, Zhou, H, Ring, AO, Reamer, RA, Gauthier, DR & Askin, D 2008, 'Practical synthesis of a HIV integrase inhibitor', Organic Process Research and Development, vol. 12, no. 6, pp. 1245-1252. https://doi.org/10.1021/op800153y
Zhong, Yong Li ; Pipik, Brenda ; Lee, Jaemoon ; Kohmura, Yoshinori ; Okada, Shigemitsu ; Igawa, Kazunobu ; Kadowaki, Chie ; Takezawa, Akihiro ; Kato, Shinji ; Conton, David A. ; Zhou, Hua ; Ring, Anthony O. ; Reamer, Robert A. ; Gauthier, Donald R. ; Askin, David. / Practical synthesis of a HIV integrase inhibitor. In: Organic Process Research and Development. 2008 ; Vol. 12, No. 6. pp. 1245-1252.
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