A novel and scalable process is developed for the industrial synthesis of vadadustat. The four-step process is one step shorter compared to the reported routes with an increase in total yield to 49.1%. Detailed optimizations furnish vadadustat with a purity of >99.5% through cross-coupling, aromatic substitution and nitrile hydrolysis, amidation, and ester-ether deprotection. The process is also robust and was demonstrated in a kilogram laboratory. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.
A design of experiments (DoE) approach was applied to the development and optimization of the manufacturing process to prepare linagliptin. DoE techniques such as a central composite face-centered design and a fractional factorial design were applied to obtain the critical process parameters and establish the optimal reaction conditions. With process-related impurities determined and successfully removed, a robust high-yielding and high-purity procedure was identified, which has been successfully demonstrated at a 100 g scale level to prepare the desired product in a 68% overall isolated yield and high-performance liquid chromatography (HPLC) purity of around 99.9%.
This paper presents the development of two generations
of routes
for the synthesis of the key intermediate 8-Cl of siponimod.
The first generation focuses on a cyanation reaction followed by alkaline
hydrolysis to introduce the benzoic acid group, replacing the hazardous
nucleophilic carboxylation mediated by n-BuLi in
the reported manufacturing route. Furthermore, the use of LiAlH4 for the carboxylic acid reduction is substituted with a milder
acid anhydride reduction enabled by NaBH4. Overall, the
first-generation route demonstrates an 11.6% increase in yield over
8 steps, effectively addressing concerns related to scale-up effects
and safety-critical operations. In the second generation, a two-step
synthesis involving nickel-catalyzed Kumada–Corriu coupling
and Blanc chloromethylation is devised to produce benzyl chloride 8-Cl, starting from the readily available and cost-effective
material 1-halo-2-(trifluoromethyl)benzene 9. The second-generation
route is successfully demonstrated at large scales ranging from hundreds
to kilo grams, resulting in a remarkable 32.5% yield increase and
approximately 65% reduction in process mass intensity for the synthesis
of intermediate 8-Cl.
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