Synthetic method of difluoro methylpyridine derivative

Abstract

The invention provides a synthetic method of a difluoro methylpyridine derivative. The method comprises the following steps: (1) mixing cuprous halide, PPh3, an organic solvent and first strong alkali, and (2) enabling an oxime ester compound as shown by formula I and a ketene compound as shown by formula II to react with second strong alkali to obtain a formula III compound; the synthetic methodutilizes Cu (I) to catalyze an active beta-CF3-substituted ketene fluoro-building block and enables oxime ester to be subjected to [3 plus 3] cycloaddition reaction to prepare a fluorine-containing group-substituted nitrogen heterocyclic ring compound. Fluoroalkyl can be introduced at 4-position fixedly, the operation is safer, simpler and more convenient compared with a direct fluorination method, a fluoroalkyl group is introduced when a pyridine ring is synthesized, meanwhile, the reaction condition is relatively mild, the compatibility of functional groups is relatively good, and the application range of a substrate is wide. The formula is shown in the description.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a method for synthesizing fluorine-containing alkyl pyridine derivatives. Background technique [0002] Pyridine compounds are important structural units ubiquitous in natural products, bioactive molecules, and pesticide chemicals. They are synthetic raw materials and intermediates for many chemicals such as drugs and materials, and are also important constituent units of catalyst ligands in organic synthesis. [0003] A large number of studies and facts have shown that when a fluorine atom is introduced into a molecule, it will have an important impact on a series of biological activities and physical and chemical properties of the compound, such as: metabolic stability, solubility, lipophilicity, etc. At present, many marketed drugs, pesticides, Special materials are all fluorine-containing compounds, among which there are many compounds with a large number of fluori...

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Problems solved by technology

[0006] Among the above methods of introducing difluoromethyl at the 4-position, whether it is direct fluorination or difluoromethylation, they often have special requirements on the substrate structure, poor universality, and do not have good functional group selection nature, often generate complex and relatively high proportion of by-products, separation and purification are difficult, and the atom economy is low, and its wide application in organic synthesis is greatly limited; difluoromethyl block method can fix the site while constructing pyridine ring The introduction of difluoromethyl is efficient and convenient, but because difluoromethyl synthetic building blocks are not easy to prepare, the synthesis is cumbersome, and the cost of reagents is high, which greatly limits its application in synthesis. Although there are very few using trifluoromethyl The examples of 4-difluoromethylpyridine compound based on synthetic building blocks are often built on the basis of special substrate structures, and it needs to be realized by introducing auxiliary functional groups through design. The route is circuitous and the steps are cumbersome, so it is only used for In a small amount of total synthetic applications

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