A robust, green, and sustainable
manufacturing process has been
developed for the synthesis of gefapixant citrate, a P2X3 receptor
antagonist that is under investigation for the treatment of refractory
and unexplained chronic cough. The newly developed commercial process
features low process mass intensity (PMI), short synthetic sequence,
high overall yield, minimal environmental impact, and significantly
reduced API costs. The key innovations are the implementation of a
highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine
synthesis in flow, a simplified sulfonamide synthesis, and a novel
salt metathesis approach to consistently deliver the correct active
pharmaceutical ingredient (API) salt form in high purity.
Gefapixant citrate (MK-7264) is a
P2X3 antagonist for the treatment
of chronic cough. The second generation manufacturing route developed
for the Step 3A/3B formylation–cyclization reaction to generate
the key intermediate diaminopyrimidine (1) (AF-072) required
a significant excess of ethyl formate (EF), potassium tert-butoxide (KOt-Bu), and guanidine•HCl (G•HCl)
when both steps were run as batch processes. It was imperative to
develop an alternative process that required less of each reagent
and generated less carbon monoxide byproducts, as the annual production
of the final active pharmaceutical ingredient (API) is expected to
be over 50 MT. In addition, the second generation process was misaligned
with our company’s strategy of having the best science in place
at the first regulatory filing. The final flow–batch process
described herein, which features a flow-based formylation combined
with a batch cyclization, has been performed on a 500 kg scale and
now requires 35% less EF (leading to a 70% reduction in waste carbon
monoxide), 38% less KOt-Bu, and 50% less G•HCl.
These improvements, along with a twofold increase in concentration,
have resulted in a 54% reduction in the step process mass intensity
(step-PMI) from the second generation two-step batch–batch
process (PMI of 17.16) to the flow–batch process (PMI of 7.86),
without sacrificing reaction performance.
The
manufacturing route toward gefapixant citrate generates a trace
amount of cyanide as a byproduct of a reaction employing the reagent
chloroacetonitrile. In the development of a cyanide control strategy,
conventional process and analytical approaches fell short because
of challenges and incompatibilities with the matrices of the process
and waste streams. To overcome these, we identified and adapted specific
procedures for cyanide control. Our strategy ensured safety for patients,
operators, and waste management.
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