Recently, difluoromethyl-containing compounds have become more and more widely used in medicines and pesticides, and the reagent which is directly introduced into difluoromethylzui is CHF2Cl (Freon 22). CHF2Cl has a large production volume and is commonly used in the production of fluoropolymers at relatively low cost. However, since CHF2Cl is a strongly ozone depleting gas and is controlled by the Montreal Protocol, the production and use of this substance has become increasingly limited and expensive.
CHF3 (Freon 23) can also directly introduce difluoromethyl as a by-product produced during the production of CHF2Cl (Figure 1). CHF3 is a non-toxic and ozone-depleting gas, but the greenhouse effect of this gas is 15,000 larger than that of CO2. Times, emissions to the environment are restricted by the Kyoto Protocol and can only be disposed of by incineration.
Figure 1. Synthesis of CHF2Cl produces a large amount of CHF3
Due to the very low reactivity of CHF3, only recently, there have been reports in the literature on the synthesis of difluoromethyl compounds in the laboratory using CHF3. In response to this problem, a famous European continuous flow expert, Professor C. Oliver Kappe of the University of Graz in Austria, and others conducted a series of research on this subject. The research result is published recently in Green Chemistry (Green Chem, 2018, 20, 108-112).
Prof. Kappe et al. attempted to synthesize and amplify difluoromethyl amino acids using CHF3 under continuous flow conditions. Difluoromethyl amino acids are effective irreversible inhibitors of selective amino acid decarboxylase. Currently, Zui is representative of the world. Ilonine in the WHO List of Essential Medicines, an anticancer drug, and clinically used for the treatment of African sleep disorders and Pneumocystis carinii pneumonia, a common opportunistic infection associated with AIDS disease.
There are two main methods for synthesizing difluoromethyl amino acids (Fig. 2). The direct synthesis of difluoromethyl amino acids using CHF3 has not been reported in the literature.
Figure 2. Method for synthesizing difluoromethyl amino acids
The authors first tested the diethyl phenylmalonate under kettle conditions (Table 1).
Table 1. Difluoromethylation of diethyl phenylmalonate with CHF3
By screening different organic bases, it was found in the literature that only the use of LiHMDS as an organic base enables the reaction to produce the corresponding product. The authors then conditionally screened the CHF3-involved reaction using LiHMDS as an organic base under continuous flow conditions (Table 2).
Table 2. Difluoromethylation of diben methyl acetate under continuous flow conditions
By lowering the reaction temperature and increasing the pressure of the reaction system, the conversion and selectivity of the reaction are significantly improved. Subsequently, the authors attempted different substrates using this reaction condition (Figure 3).
Figure 3. CHF3 difluoromethylation under continuous flow conditions
The results showed that except for the 2c yield, the yield of other substrates was higher than the kettle condition or the preparation method of some compounds has not been reported in the literature. In addition, two of Ilonise (2k) The step reaction yield was increased from 37% to 40% of the original reported use of CHF2Cl to 76%.
to sum up:
The authors used the unusable by-product CHF3 produced in the manufacturing process of PTFE as a starting material, and the continuous flow can directly synthesize difluoromethyl amino acids, which are highly selective and strong in pyridoxal phosphate decarboxylase. Inhibitor.
The raw materials required for the reaction are inexpensive and readily available, and the product can be obtained in good yield and purity by simple hydrolysis and precipitation.
Since atomic economy, sustainability, reagent costs, and reagent availability are important factors in industrialization, the process has shown good industrial application prospects.
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