Synthesis of [(14) C]omarigliptin.

Area of Science:

• Medicinal Chemistry
• Radiochemistry
• Organic Synthesis

Background:

• Omarigliptin (MK-3102) is a dipeptidyl peptidase-4 inhibitor investigated for type 2 diabetes.
• Development of radiolabeled compounds is crucial for pharmacokinetic and metabolic studies.
• Previous synthetic routes for [(14)C]Omarigliptin encountered challenges with reagent stability.

Purpose of the Study:

• To develop an efficient and reliable synthesis for [(14)C]Omarigliptin.
• To overcome limitations of previous synthetic strategies, particularly the instability of the (14)C-DMF-DMA reagent.
• To establish a robust method for preparing the key radiolabeled pyrazole intermediate.

Main Methods:

• Synthesis of a novel radiolabeled synthon, (14)C-biphenylmethylformate, from (14)C-sodium formate.
• Construction of the key (14)C-pyrazole moiety using the new synthon.
• Regioselective N-sulfonation of the pyrazole intermediate via a dehydration-sulfonation-isomerization sequence.
• Overall five-step synthesis of [(14)C]Omarigliptin.

Main Results:

• The new (14)C-biphenylmethylformate synthon was prepared in one step with 92% yield.
• The stable synthon enabled successful construction of the key (14)C-pyrazole moiety.
• The regioselective N-sulfonation was achieved effectively.
• [(14)C]Omarigliptin was synthesized in five steps with a 25% overall yield.

Conclusions:

• An efficient and improved synthetic route for [(14)C]Omarigliptin has been established.
• The use of (14)C-biphenylmethylformate circumvents the instability issues associated with previous reagents.
• This optimized synthesis provides a reliable method for producing radiolabeled Omarigliptin for research purposes.