Convergent, kilogram scale synthesis of an Akt kinase inhibitor

Pintipa Grongsaard; Paul G. Bulger; Debra J. Wallace; Lushi Tan; Qinghao Chen; Sarah J. Dolman; Jason Nyrop; R. Scott Hoerrner; Mark Weisel; Juan Arredondo; Takahiro Itoh; Chengfu Xie; Xianghui Wen; Dalian Zhao; Daniel J. Muzzio; Ephraim M. Bassan; C. Scott Shultz

doi:10.1021/op300031r

Convergent, kilogram scale synthesis of an Akt kinase inhibitor

Pintipa Grongsaard, Paul G. Bulger, Debra J. Wallace, Lushi Tan, Qinghao Chen, Sarah J. Dolman, Jason Nyrop, R. Scott Hoerrner, Mark Weisel, Juan Arredondo, Takahiro Itoh, Chengfu Xie, Xianghui Wen, Dalian Zhao, Daniel J. Muzzio, Ephraim M. Bassan, C. Scott Shultz

Research output: Contribution to journal › Article › peer-review

Abstract

The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions.

Original language	American English
Pages (from-to)	1069-1081
Number of pages	13
Journal	Organic Process Research and Development
Volume	16
Issue number	5
DOIs	https://doi.org/10.1021/op300031r
State	Published - May 18 2012
Externally published	Yes

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Organic Chemistry

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Grongsaard, P., Bulger, P. G., Wallace, D. J., Tan, L., Chen, Q., Dolman, S. J., Nyrop, J., Hoerrner, R. S., Weisel, M., Arredondo, J., Itoh, T., Xie, C., Wen, X., Zhao, D., Muzzio, D. J., Bassan, E. M., & Shultz, C. S. (2012). Convergent, kilogram scale synthesis of an Akt kinase inhibitor. Organic Process Research and Development, 16(5), 1069-1081. https://doi.org/10.1021/op300031r

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abstract = "The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions.",

author = "Pintipa Grongsaard and Bulger, {Paul G.} and Wallace, {Debra J.} and Lushi Tan and Qinghao Chen and Dolman, {Sarah J.} and Jason Nyrop and Hoerrner, {R. Scott} and Mark Weisel and Juan Arredondo and Takahiro Itoh and Chengfu Xie and Xianghui Wen and Dalian Zhao and Muzzio, {Daniel J.} and Bassan, {Ephraim M.} and Shultz, {C. Scott}",

year = "2012",

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doi = "10.1021/op300031r",

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T1 - Convergent, kilogram scale synthesis of an Akt kinase inhibitor

AU - Grongsaard, Pintipa

AU - Bulger, Paul G.

AU - Wallace, Debra J.

AU - Tan, Lushi

AU - Chen, Qinghao

AU - Dolman, Sarah J.

AU - Nyrop, Jason

AU - Hoerrner, R. Scott

AU - Weisel, Mark

AU - Arredondo, Juan

AU - Itoh, Takahiro

AU - Xie, Chengfu

AU - Wen, Xianghui

AU - Zhao, Dalian

AU - Muzzio, Daniel J.

AU - Bassan, Ephraim M.

AU - Shultz, C. Scott

PY - 2012/5/18

Y1 - 2012/5/18

N2 - The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions.

AB - The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions.

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DO - 10.1021/op300031r

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JO - Organic Process Research and Development

JF - Organic Process Research and Development

IS - 5

ER -

Convergent, kilogram scale synthesis of an Akt kinase inhibitor

Abstract

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