Continuous flow technology helps synthesize anti-cancer drugs with low activity fluorideRead: 2972 Release time: 2019/6/10 17:10:44
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Continuous flow technology helps synthesize anti-cancer drugs with low activity fluoride
zui 便宜的试剂是CHF2Cl（氟利昂22）。 Recently, the application range of difluoromethyl-containing compounds in medicine and pesticides is increasing, and the cheaper reagent that directly introduces difluoromethyl zui is CHF2Cl (Freon 22). CHF2Cl has a huge output and is often used to produce fluoropolymers at relatively low cost. However, as CHF2Cl is a gas that strongly depletes the ozone layer and is controlled by the Montreal Protocol, the production and use of this substance has become increasingly restricted and expensive.
CHF3 (Freon 23) can also directly introduce difluoromethyl as a by-product generated during the production of CHF2Cl (Figure 1). CHF3 is a non-toxic and ozone-free gas, but the greenhouse effect of this gas is 15000 greater than CO2 Times, emissions to the environment are restricted by the "Kyoto Protocol" and currently can only be handled by incineration.
Figure 1. Synthesis of CHF2Cl produces large amounts of CHF3.
Due to the very low reactivity of CHF3, only recently has been reported in the literature to use CHF3 to synthesize difluoromethyl compounds in the laboratory. zui 近发表在了Green Chemistry上（Green Chem, 2018, 20, 108-112）。 In response to this problem, European continuous flow experts, Professor C. Oliver Kappe, University of Graz, Austria, and others conducted a series of studies on this topic. The research results have recently been published on Green Chemistry (Green Chem, 2018, 20, 108 -112).
zui 具代表性的是位于世界卫生组织基本药物标准清单中的依洛尼塞，一种抗癌药物，并在临床上用于非洲睡眠疾病以及卡氏肺囊虫肺炎的治疗， 一种与艾滋病相关的 zui 常见的机会xing感染疾病。 Professor Kappe et al. Tried to use CHF3 to synthesize and amplify difluoromethyl amino acids under continuous flow conditions. Difluoromethyl amino acids are effective irreversible inhibitors of selective amino acid decarboxylase. Currently, zui is typically located in the world. Ilonides in the WHO Essential Drug Standard List, an anticancer drug, and is used clinically in the treatment of African sleep disorders and pneumocystis carinii pneumonia, a common opportunistic infection associated with HIV disease.
There are two main methods for synthesizing difluoromethyl amino acids (Figure 2). The synthesis of difluoromethyl amino acids directly using CHF3 has not been reported in the literature.
Figure 2. Method for synthesizing difluoromethyl amino acids
The authors first performed the experiments under kettle conditions using diethyl phenylmalonate (Table 1).
Table 1. Difluoromethylation reaction of diethyl phenylmalonate with CHF3
By screening different organic bases and combining with the literature, we found that only LiHMDS can be used as the organic base to make the reaction produce corresponding products. The authors subsequently screened the reactions involving CHF3 using LiHMDS as the organic base under continuous flow conditions (Table 2).
Table 2. Difluoromethylation of methyl benzyl acetate under continuous flow conditions
By reducing the reaction temperature and increasing the pressure of the reaction system, the conversion and selectivity of the reaction are significantly improved. Subsequently, the authors tried different substrates using this reaction condition (Figure 3).
Figure 3. Difluoromethylation of CHF3 under continuous flow conditions.
The results show that except for the yield of 2c, which is lower than the kettle condition, the yields of other substrates are higher than the kettle condition or the preparation methods of some compounds have not been reported in the literature. In addition, the two The yield of the step reaction increased from 37% -40% of the original report using CHF2Cl to 76%.
to sum up:
The author uses the unusable by-product CHF3 produced during the production of polytetrafluoroethylene as a starting material, and can continuously synthesize difluoromethyl amino acids using continuous flow. These compounds are highly selective and strong for pyridoxal phosphate decarboxylase. Effective inhibitor.
The raw materials required for the reaction are cheap and readily available, and the product can be obtained in good yield and purity by simple hydrolysis and precipitation.
Since atomic economy, sustainability, reagent cost and reagent availability are important factors for industrialization reference, this process shows a good industrial application prospect.