Synthesis 2024; 56(04): 686-692
DOI: 10.1055/s-0040-1720087
special topic
Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients (APIs)

Exploratory Process Development of a Pulmonary Arterial Hypertension Clinical Compound via a Late-Stage Pd-Catalyzed Buchwald–Hartwig C–N Coupling

Russell F. Algera
,
Andrew Davidson
,
David K. Herbert
,
Yajing Lian
,
Fangfang Liu
,
Yiyang Liu
,
Asaad Nematalla
,
Jared L. Piper
,
Javier Magano
,
,
Bao Nguyen
,
Jeffrey W. Raggon
,
Joseph P. Rainville
,
Anil Rane
,
Yong Tao
,
Ke Wang
,
Hatice G. Yayla

Pfizer Inc.


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Abstract

The development of a robust process for a Pd-catalyzed Buchwald–Hartwig C–N coupling reaction to manufacture PF-06842874, a clinical candidate for the treatment of pulmonary arterial hypertension, on kilogram scale is reported. The variability in reaction kinetics initially encountered was resolved via the use of sodium tert-butoxide as a homogeneous base and a careful selection of precatalyst by examination of the catalyst activation mechanism. Extraction with aqueous acid followed by careful pH adjustment allowed us to isolate the product with excellent purge of impurities. The process was successfully implemented in up to 18 kg demonstration.

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Eingereicht: 08. Juni 2023

Angenommen nach Revision: 31. Juli 2023

Artikel online veröffentlicht:
04. September 2023

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