Recent developments in heterocycle labeling with carbon isotopes

Abstract

Heterocycles play an essential role in modern pharmaceutical and agrochemical developments, representing a very common structural unit in marketed drugs. Over the 46 new drugs approved in 2017 by the FDA, 25 contain in their structure a heterocyclic core. The development of novel and straightforward labeling strategies for the effective insertion of carbon isotopes into heterocylic scaffolds is an inspiring and vibrant field of research. The use of carbon-11, carbon-13, and carbon-14 isotopes is well established in life science and particularly in pharmaceutical and agrochemical industry. Their introduction into small organic molecules represents a crucial step for the radiochemists. Because the labeling should occur in metabolically stable positions and in the shortest synthetic route, their incorporation into the heterocycles represents a viable solution. This review summarizes recent contributions to this area of research through the analysis of different industrial and academic cases.

Selective Conversion of Carbon Dioxide to Formaldehyde via a Bis(silyl)acetal: Incorporation of Isotopically Labeled C1 Moieties Derived from Carbon Dioxide into Organic Molecules

“…In view of the fact that heterocycles play an important role in pharmaceuticals, much effort has been directed towards the formation of isotopically labeled derivatives, and developing routes that utilize CO 2 has been emphasized . Therefore, we have also demonstrated that the reaction of D 2 C­(OSiPh 3 ) 2 with N -methyl-1,2-phenylenediamine in DMSO affords N -methylbenzimidazole- d 1 . , In addition, 2 H NMR spectroscopy demonstrates that the formal oxidation of the [CH 2 ] moiety is achieved by the formation of water, in accord with the aforementioned ability of DMSO to act as an oxidizing agent …”

Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

“…Urea derivatives are common functional groups in medicinal chemistry and are often found in pharmaceuticals. , In 2018, Hesk and co-workers at Merck applied a strategy, published a few years earlier, for the labeling of 7 , a potent inhibitor of the NPY 5 receptor . A trapping of radioactive carbon dioxide by the aniline 5 under basic conditions, followed by an addition of POCl 3 as a dehydrating agent, led to the generation of an isocyanate intermediate.…”

Nano-Domains of Nuclear Magnetic Moments for Gravitational Stimulation of Biological Processes

“…14 N can compensate for 15 N. There is no stable isotope of negative NMM for C to compensate for 13 C incorporation. Although recently scientists observed the ability of unstable 11 C (with negative NMM) in 11 CO2 to directly insert into carbonates unlike 12 C (with null NMM) and 13 C (with positive NMM) [25]. There is no stable isotope of positive NMM of O to counter by LeChatelier Principle the negative NMMs as 17 O is deposited within systems.…”

“…Such gravitational fields in hidden ways stimulate novel chemistry, optics, thermodynamics, transport, and transmutations within the nanobaths and of the nanobaths. In these effects of gravity on life, the author discloses that gravity is a force that caused the organization of life on earth by self-activation of clustering of organic molecules forming biomolecules having elements with stable isotopes of nonzero NMMs like: 1 H, 2 D, 13 C, 14 N, 15 N, 17 O, 25 Mg, 31 P and 33 S and other elements in essential minerals having nonzero NMMs. This notion is not proven but follows from the author's theory.…”