Meta- and Para-deuterated Arenes Based on DCL™

Background & Overview

The synthesis of deuterium-labeled organic compounds has received increasing attention, especially after the FDA approval of deuterated benzazines in 2014. The selective incorporation of deuterium instead of hydrogen represents the uniqueness of a new class of chemistry.

The preparation of complex deuterated drugs, either by de novo synthesis or the introduction of D at pre-functionalized positions, has proven to be time-consuming and costly. Therefore, we constructed a unique DCL™ platform for the efficient incorporation of deuterium into biologically active molecules, based on a direct hydrogen isotope exchange method of aromatic C-H bonds. While ortho-C-H deuteration has been well explored over the years, meta- and para-C-H deuteration are underexplored. Our platform thus focuses on extending the synthetic strategies of meta- and para-deuterated arenes.

Existing Strategy for the Synthesis of Meta- and Para-deuterated Arenes

When multiple unequal C-H bonds exist in the target molecule, the strategy to rapidly generate complex molecules from simple molecules using functionalization of unactivated carbon-hydrogen (C-H) single bonds is difficult. The ortho-selectivity can be generated by the formation of six- or seven-membered cyclic pre-transition states with the assistance of directing groups. But proximity-driven reactivity prevents activation of remote C-H bonds. The use of a nitrile-containing template can directly activate the distal meta-C-H bond of the bound arene. Since then, the path to template-assisted meta- and para-C-H functionalization has been performed, such as olefination, arylation, acetoxylation, amination, alkynylation, ketonation, silylation, Germanium, cyanide and iodide. Nitrile, pyrimidinyl, and pyridyl directing groups have been used for these transformations.

Pyrimidine directing group

Meta-C-H deuteration of phenylacetic acid and sulfonyl ester derivatives was achieved using d₄-acetic acid as the D source with the help of a pyrimidine-based directing group. Drugs such as ibuprofen, flurbiprofen (an antipyretic analgesic), naproxen, homoveratrol, and indomethacin, as well as the herbicide dichloropropionic acid, can all be meta-deuterated using this strategy.

Fig.1 meta-C–H deuteration of phenyl acetic acids derivatives using a pyrimidine directing group.^[2]

Pyridine Directing Group

The meta-C-H deuteration of phenylacetic acid, benzylphosphonates, benzylsulfonates and alcohols can be achieved using pyridine-containing directing groups with d4-acetic acid as the deuterium source.

Fig.2 meta-C–H deuteration using a pyridine containing directing group.^[2]

DCL™ in Meta- and Para-deuterated Arenes

Our DCL™ technology platform can effectively solve the difficult problem of meta-deuterated aromatics synthesis, and provide technical means for the study of drug properties of such compounds. We optimized the reaction conditions over the existing deuterium strategy to achieve a broad substrate range, high deuterium incorporation, and high reaction yields.

The chemical team of BOC Sciences has rich experience in the synthesis of deuterated compounds, and can complete the selective deuteration of small molecular structures and the 100-gram scale amplification of deuterated compounds, helping customers and partners to achieve their goals in R&D projects.

Intellectual Property Protection

BOC Sciences has always regarded intellectual property as the most valuable asset of the company and its customers. We have signed non-disclosure agreements with customers and employees before the project starts, and provide synthetic route design and synthesis services in strict accordance with the terms of the non-disclosure agreement, striving to provide customers with target compounds in the shortest time possible.

References

1. Manna P, et al. Palladium-catalyzed directed synthesis of ortho-deuterated phenylacetic acid and analogues. Organic & Biomolecular Chemistry. 2021, 19(28): 6244-6249.
2. Prakash G, et al. C–H deuteration of organic compounds and potential drug candidates. Chemical Society Reviews. 2022.