High-selectivity deuteration method of 2-methyl azacyclo compound

Abstract

The invention discloses a high-selectivity deuteration method of a 2-methyl azacyclo compound. The method is carried out according to the following steps: adding a 2-methyl azacyclo compound shown asa formula I, a formula II or a formula III, an oxidant and an additive into a dry Schlenk reaction tube; and in the presence of a protective gas, adding deuterium water and an organic solvent into thereaction tube, performing a stirring reaction at 50-100 DEG C for 2-12 hours to obtain a reaction solution, and performing post-treatment on the reaction solution to respectively obtain a deuteratednitrogen-containing heterocycle shown in a formula IV, a formula V or a formula VI. The method provided by the invention is based on a free radical process, is efficient, can synthesize methyl-d3 substituted nitrogen-containing heterocyclic compounds which are difficult to prepare by conventional methods, and is high in deuteration rate of reaction; the method is carried out under a neutral condition and has low requirements on equipment; a catalytic amount of an oxidant is used, and additives are cheap and easily available; reaction conditions are mild, and energy consumption is reduced; theyield is high, the substrate universality is strong, the operation is simple and convenient, and the like.

Description

[0001] (1) Technical field [0002] The invention relates to a method for synthesizing organic compounds, in particular to a method for highly selective deuteration of 2-methyl nitrogen heterocyclic compounds. [0003] (2) Background technology [0004] Deuterated compounds are an important class of high value-added chemicals. It can be widely used as a solvent in the field of nuclear magnetic resonance spectroscopy, and can also be used to reveal the mechanism of organic reactions. More importantly, in the field of medicinal chemistry, replacing hydrogen atoms with deuterium atoms has become an ideal drug modification method. On the one hand, the introduction of deuterium into the non-metabolized and non-action sites of drug molecules can track the dynamics of drug molecules in the body, and study the absorption, distribution, metabolism, and excretion of drug molecules without affecting the drug’s action. . On the other hand, since the carbon-deuterium bond is about 6-9 ti...

AI Technical Summary

Problems solved by technology

In 2017, Yin's group reported the deuteration method of 2-methyl nitrogen-containing heterocyclic rings under relatively mild conditions (80-120°C). However, this method not only requires an acid as a catalyst, but also has a general chemoselectivity (For example, there is no selectivity between the methyl group at position 2 of quinoline and the methyl group at position 4, see Org. Biomol. Chem., 2017, 15, 2507.)

To further reduce the reaction temperature of the deuteration reaction of 2-methyl nitrogen-containing heterocyclic ring, it is necessary to add a metal catalyst or use DMSO-d6 as a deuteration reagent, but the use of expensive metal catalysts and deuteration reagents will limit its Application in drug development (see Angew.Chem.Int.Ed.2017,56,1634. and J.Org.Chem.2017,82,4289.)

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