Development of Scalable Synthesis of Chiral Sultam via a Chiral Phosphoric Acid-Promoted <i>tert</i>-Butyl Carbamate Deprotection–Resolution Sequence or Diastereoselective Hydrogenation

The discovery and process development for the synthesis of diastereopure sultam (1), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (1) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (2). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided >20 kg of (1). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (1), both reducing step count and improving overall yield relative to the resolution approach.

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Publication Details

Journal
Organic Process Research & Development
Published
2025-09-09
DOI
https://doi.org/10.1021/acs.oprd.5c00263
Primary Topic
Analytical Chemistry and Chromatography
Type
article
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article

Development of Scalable Synthesis of Chiral Sultam via a Chiral Phosphoric Acid-Promoted tert-Butyl Carbamate Deprotection–Resolution Sequence or Diastereoselective Hydrogenation

Jared Van Haitsma, Javier Magano, Liam S. Sharninghausen, Pengzhi Wang et al.
Organic Process Research & Development
Analytical Chemistry and Chromatography
article

Development of Scalable Synthesis of Chiral Sultam via a Chiral Phosphoric Acid-Promoted tert-Butyl Carbamate Deprotection–Resolution Sequence or Diastereoselective Hydrogenation

Jared Van Haitsma, Javier Magano, Liam S. Sharninghausen, Pengzhi Wang, Todd W. Butler, Christopher W. am Ende, Daniel W. Widlicka, Colin R. Rose, Giselle P. Reyes, Neal W. Sach, Zebediah C. Girvin, Caroline A. Blakemore, Subham Mahapatra, Bryan Li, Peter Morse, Nasir Khan, Adam R. Brown, Guochun Ma, Sarai Lara-Boykin
article en

Abstract

The discovery and process development for the synthesis of diastereopure sultam (1), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (1) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (2). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided >20 kg of (1). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (1), both reducing step count and improving overall yield relative to the resolution approach.

Organic Process Research & DevelopmentVol. 29(9)
Pfizer (United States) (US), Pharmaron (United Kingdom) (GB), Applied Physical Sciences (United States) (US)
Openalex Percentile: Top 78%
Analytical Chemistry and Chromatography
DOISourceOpenAlex
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