This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively nonnucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.
An efficient, scalable, and cost-effective synthesis of a linker employed in a bioconjugation process with a peptide and a monoclonal antibody is presented. Several routes were investigated that resulted in the identification of a short synthesis to a key acid intermediate from inexpensive and readily available starting materials. The final coupling of this acid with an aniline to afford the desired linker has been optimized to produce multi-gram quantities of material for clinical studies. The very limited purifications needed for both intermediates and final product make this route amenable to scale.
An
optimized and scalable process to manufacture peptide–linker
conjugate 1 is reported that avoids the chromatographic
purification and lyophilization that are typically required for the
isolation of this type of compound. An operationally simple protocol
has been developed that couples the peptide to the linker in DMF followed
by precipitation with MeCN. A scalable synthesis of the linker is
also described which features the N-acylation of
2-azetidinone promoted by 1-propanephosphonic acid anhydride (T3P).
The number of operations during the second step of the synthesis (nitrobenzene
reduction to aniline) has been simplified by telescoping the aniline
into the next step (reaction with diglycolic anhydride to form an
acid), thus avoiding an additional isolation. Finally, two efficient
activation methods for the acid have been developed by means of the
corresponding pentafluorophenyl (PFP) and p-nitrophenyl
(PNP) esters.
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