Synthesis of [¹⁴C]omarigliptin

Abstract

An efficient synthesis for [(14) C]Omarigliptin (MK-3102) is described. The initial synthesis of a key (14) C-pyrazole moiety did not work due to the lack of stability of (14) C-DMF-DMA reagent. Thus, a new radiolabeled synthon, (14) C-biphenylmethylformate, was synthesized from (14) C-sodium formate in one step in 92% yield and successfully used in construction of the key (14) C-pyrazole moiety. Regioselective N-sulfonation of the pyrazole moiety was achieved through a dehydration-sulfonation-isomerization sequence. [(14) C]MK 3102 was synthesized in five steps from (14) C-biphenylmethylformate with 25% overall yield.

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

“…13 The incorporation of 14 C, 13 C or 11 C (*C) units into drug molecules or precursors by the formation of a *C-C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, 14-18 *CH3I, [19][20] or other small molecules derived by reduction of *CO2. [21][22][23][24][25] The direct exchange of carboxylate groups with CO2 offers the potential for simple and cost-effective syntheses of C-labelled small molecules, particularly as CO2 (or BaCO3) is the feedstock for all radiolabelled carbon-based precursors. 26 The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.The use of redox active hydroxyphthalimide ester substrates in combination with Ni-based mediators and stoichiometric metal reductants enables carboxylate groups to undergo net exchange with CO2 (Fig 1A ).…”

“…Metal-catalyzed 1 H/ 3 H exchange is widely used in drug development to introduce long-lived radiolabels into target molecules. − The loss of 3 H labels through (bio)­chemical reactions and metabolic shifting due to primary kinetic isotope effects are liabilities of 3 H-labeling approaches. , ADME tracer compounds with greater stability can be obtained by using 14 C radiolabels . Similarly, 11 C isotopologues of native bioactive molecules enable PET probe generation without changes to their biological or pharmacological properties. , The incorporation of 14 C, 13 C, or 11 C (*C) units into drug molecules or precursors by the formation of a *C–C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, − *CH 3 I, , or other small molecules derived by reduction of *CO 2 . − The direct exchange of carboxylate groups with CO 2 offers the potential for simple and cost-effective syntheses of C-labeled small molecules, particularly as CO 2 (or BaCO 3 ) is the feedstock for all radiolabeled carbon-based precursors . The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.…”

Recent developments in heterocycle labeling with carbon isotopes

“…Once more, the use of hydrazine proved fundamental for the synthesis of condensed heterocycles. 59 In this case, the synthesis previously developed by the medicinal chemistry group was not viable and the radiochemists at Merk had to develop a whole new approach. The source of radioactivity chosen in this strategy was [ 14 C]-sodium formate, which was reacted in the presence of biphenyl precursor 62 to give the corresponding formate [ 14 C]-63.…”

“…Omarigliptin, a compound currently in use for the treatment of diabetes mellitus type 2, was radiolabeled in 2016 by the Hesk group on the pyrazole ring. Once more, the use of hydrazine proved fundamental for the synthesis of condensed heterocycles . In this case, the synthesis previously developed by the medicinal chemistry group was not viable and the radiochemists at Merk had to develop a whole new approach.…”