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

doi:10.1021/op100010n

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 journal › Article › peer-review

23 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 language	English
Pages (from-to)	441-458
Number of pages	18
Journal	Organic Process Research and Development
Volume	14
Issue number	2
DOIs	https://doi.org/10.1021/op100010n
Publication status	Published - 2010 Mar 19
Externally published	Yes

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

Hobson, LA, Akiti, O, Deshmukh, SS, Harper, S, Katipally, K, Lai, CJ, Livingston, RC, Lo, E, Miller, MM, Ramakrishnan, S, Shen, L, Spink, J, Tummala, S, Wei, C, Yamamoto, K, Young, J & Parsons, RL 2010, 'Development of a scaleable process for the synthesis of a next-generation statin', Organic Process Research and Development, vol. 14, no. 2, pp. 441-458. https://doi.org/10.1021/op100010n

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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.",

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AU - Hobson, Lindsay A.

AU - Akiti, Otute

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AU - Katipally, Kishta

AU - Lai, Chiajen J.

AU - Livingston, Robert C.

AU - Lo, Ehrlic

AU - Miller, Michael M.

AU - Ramakrishnan, Srividya

AU - Shen, Lifen

AU - Spink, Jan

AU - Tummala, Srinivas

AU - Wei, Chenkou

AU - Yamamoto, Kana

AU - Young, John

AU - Parsons, Rodney L.

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AB - 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.

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

Abstract

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