November 26, 2021

Fluorinated Pharmaceutical Intermediates

Fluorine has a unique atomic structure: it is a halogen element in the second period of the periodic table, with seven electrons in its 2p orbital, and consequently, it has more physical and chemical properties. Firstly, the C and F elements are located in the same period of the periodic table, i.e., the nuclear charge increases while the outer electrons are increasingly attracted to the nucleus, and thus the polarity becomes smaller. Secondly, the fluorine atom is the smallest in terms of substituent groups, except for the hydrogen atom. Again, Pauling's "electronegativity theory" shows that fluorine is the most electronegative element, with a value of 3.98. Therefore, the bond energy of the C-F bond is the highest among the C-X single bonds. The introduction of fluorine atoms or fluorine-containing groups into the molecules of compounds results in a corresponding change in the distribution of intermolecular electron clouds and intermolecular dipole torches, which brings about the most direct change in the physical and chemical properties of the compound molecules themselves, making the properties of fluorine-containing compounds more prominent. In the 16th century, fluorine began to attract the interest of scientists, and in 1530, Agricola proposed that the main component of fluorite was CaF2. In 1764, Marggraf used fluorite as the main raw material to obtain a "gaseous substance" by the action of sulfuric acid. In 1886, Moissan obtained fluorine gas for the first time by electrolysis of anhydrous HF based on the previous research, and in 1892, Swarts made a major discovery in a catalytic experiment using antimony trifluoride as a catalyst: fluorine could replace some chlorine elements in hydrogen fluoride, which announced the beginning of fluorine chemistry. After years of research and development, fluorine chemistry is now being used in a wide range of applications, deepening the position of fluorinated substances in people's minds. At present, the existence of fluorine resources in nature is mainly inorganic fluoride, while natural organic fluoride is very scarce.

China's fluorine chemical industry has been developing slowly compared with western countries, but China is based on the international market, focusing on the focus of fluorine chemicals, and according to China's specific national conditions - abundant fluorite resources, abundant labor resources, and large market potential, China has great confidence in developing the fluorine industry, and after years of development, the current fluorine chemical system is perfect and there are many fluorine chemical professionals. chemical professionals. The great influence of China's fluorine chemical industry has attracted the attention of large fluorine chemical enterprises from all over the world, and the development level of China's fluorine chemical industry has been further improved through cooperation and exchange. At present, the fluorine chemical industry, as one of the industries strongly supported by China, is developing vigorously, and it is even listed as a high-tech industry in China. China's support and abundant resources have established a good trend for the industrialization and industrialization of fluorine chemistry in China in the future. For fluorochemical products, China has mastered certain manufacturing capabilities, and the technology for fluorine plastics and fluorine drugs is relatively mature and close to the world's advanced level.

The fluorine atoms themselves and their attachment to certain compound molecules give new properties to the new compounds, giving them more specific physical and chemical properties and physiological activity. The introduction of fluorine atoms into compounds is now used in various materials such as polymers, physiologically active materials, etc. Because of the presence of fluorine atoms in the material structure, they play an important role in the corresponding fields of electronics, chemical industry, atomic energy industry, pharmaceuticals, and pesticides.

Before fluorine can be used in the study of pharmaceutical compounds, a systematic analysis of the lead compound is required, and then fluorine atoms are introduced into the compound at specific positions according to the compound structure. Of course, the molecules of the compounds are also altered with their internal chemical environment, for example, their lipid solubility is improved, i.e., they can be rapidly decomposed in the organism, thus changing their biological effects. Over the years, organofluorine drugs have gained a lot of attention and recognition in the pharmaceutical industry. The synthesis of organic fluorinated compounds has never ceased to be explored. With the advancement of research, fluorinated compounds are now used in different drugs, such as antiviral drugs, antitumor drugs, antihyperlipidemic drugs, etc.

Fluorinated compounds and fluorinated materials are currently used in many fields, and fluorinated pharmaceuticals are of great importance. In this thesis, 4-fluorocyclohexanone, 2,2-difluoropropanol, and 2-amino-3-Bromo-5-fluoropyridine are important intermediates or raw materials for the synthesis of anti-cancer drugs, anti-leukemia drugs, and antibiotic drugs, respectively. The original synthetic routes of these three compounds were found to have low product yields, high raw material costs, and cumbersome process routes, which were not conducive to production scale-up. In this thesis, the synthetic route was re-optimized based on the original synthetic route, and the factors such as reaction dosage ratio, reagent dosage, fluorinating agent dosage, reaction time, reaction temperature, etc. were systematically investigated, and after the experimental demonstration, a process route with low raw material cost, high target product yield and suitable for pilot scale up production was derived.

(1) The synthesis of 4-fluorocyclohexanone was based on 1,4-cyclohexanedione mono ethylene glycol ketal, and the target compound 4-fluorocyclohexanone was obtained by the three-step reaction of DAST fluorination, Pd/C hydrogenation, and acidic hydrolysis, and the palladium-carbon hydrogenation reaction was one of the common hydrogenation methods in the industrial scale-up experiments. The purity of the target compound was 98.5% and the yield was 78.5%.

(2) 2,2-difluoropropanol was synthesized from ethyl pyruvate, and the target compound 2,2-difluoropropanol was obtained by the two-step reaction of DAST fluorination and sodium borohydride reduction. In this synthetic route, the DAST fluorinating agent was effective in the up-fluorination of the carbonyl group, and the intermediate product was of high purity and free of excess impurities. In the second step of the reduction reaction, the addition of zinc chloride makes the sodium borohydride more active. The synthetic route is simple, with high purity of intermediates and low cost of raw materials. The purity of the target compound was 98.9% and the yield was 82.4%.

(3) 2-Amino-3-Bromo-5-fluoropyridine was synthesized from 2-amino-5-nitropyridine, and the target compound, 2-amino-3-Bromo-5-fluoropyridine, was obtained by the five-step reaction of acetylation (ammonia protection), nitration reduction, diazotization, hydrolysis, and bromination reaction. In this synthetic route, there are many reaction steps and many influencing factors, and the best reaction conditions were obtained by small trial optimization of many factors. The purity of the target compound was 98.5% and the yield was 72.1%.

(4) 4-fluorocyclohexanone and 2-amino-3-Bromo-5-fluoropyridine have been customized on a 100 g scale, and 2,2-difluoropropanol was produced in a 100 L feeding reactor and a kilogram scale pilot plant. The whole synthesis process is based on industrial production, and the key reaction mechanism of the route is discussed to provide data for subsequent production.

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