Development of a scaleable process for the synthesis of a next-generation statin

Lindsay A. Hobson, Otute Akiti, Subodh S. Deshmukh, Shannon Harper, Kishta Katipally, Chiajen J. Lai, Robert C. Livingston, Ehrlic Lo, Michael M. Miller, Srividya Ramakrishnan, Lifen Shen, Jan Spink, Srinivas Tummala, Chenkou Wei, Kana Yamamoto, John Young, Rodney L. Parsons

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

This manuscript details the process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia-Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted as a method of controlling the final API quality.

Original languageEnglish
Pages (from-to)441-458
Number of pages18
JournalOrganic Process Research and Development
Volume14
Issue number2
DOIs
Publication statusPublished - 2010 Mar 19
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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    Hobson, L. A., Akiti, O., Deshmukh, S. S., Harper, S., Katipally, K., Lai, C. J., Livingston, R. C., Lo, E., Miller, M. M., Ramakrishnan, S., Shen, L., Spink, J., Tummala, S., Wei, C., Yamamoto, K., Young, J., & Parsons, R. L. (2010). Development of a scaleable process for the synthesis of a next-generation statin. Organic Process Research and Development, 14(2), 441-458. https://doi.org/10.1021/op100010n