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Continuous Flow Oxygen Oxidation
Release time：2019-10-09 17:23:26
The multiphase gas-liquid reaction process is an important type of reaction in the pharmaceutical industry. Using conventional methods, special equipment is usually required to effectively amplify the results obtained in the batch reactor test to the production scale. The continuous flow micro-reaction system can achieve high-efficiency mass transfer and heat transfer in the gas-liquid reaction process, and smoothly realize technology conversion and scale-up production. The use of microreaction technology platforms to study gas-liquid reactions is an important area of pharmaceutical and chemical industry.
In the pharmaceutical industry, the oxidation process plays an important role. To date, the pharmaceutical industry has continuously reported the application of many continuous flow oxidation processes in microchannel reactors. Oxygen has good reactivity and abundant resources, is non-toxic and harmless, and is an excellent oxidant, and can also reduce the separation cost after the reaction.
However, in scale production, oxygen is too active, difficult to control and prone to safety accidents, which greatly limits its application in traditional industrial production. The microreaction system has a small liquid holding capacity, a large heat exchange area, and the process is easy to control, so the oxygen oxidation reaction has broad application prospects in the microreaction technology.
Substituted pyridine derivatives are important precursors for many drug molecules. Of particular importance is 3-picolinic acid, known as vitamin B3, which is an essential nutrient for humans. The previously reported synthetic methods require longer reaction times or the use of harsh operating conditions and reagents, such as the use of metal catalysts, and the yields are not high. The oxidation reaction and results of 3-picolinic acid and its derivatives are shown in Table 1.
Table 1. Results of methylpyridine oxidation reaction and reaction equation under traditional conditions
As an alternative, the authors developed a continuous flow oxidation process that achieved almost 100% conversion of all three derivatives in 5 minutes.
Studies have shown that aprotic solvents can avoid deprotonation, and the solvent is more polar and has good solubility to the carboxylate, which can effectively prevent the precipitation of carboxylate and block the reactor. Basic conditions favor the reaction, with potassium hydroxide, potassium t-butoxide, potassium t-amok and lithium diisopropylamide (LDA) being candidates. Among them, potassium t-pentoxide is one of the most suitable solvents because of its high solubility in an organic solvent.
In the pilot study, DME, t-amok and hexamethylphosphoramide (HMPA) were used as a mixed solvent, and compound 3 (p-methylpyridine) had a very high conversion rate, compound 1 (o-methylpyridine) and compound. 2 (m-methylpyridine) has a moderate conversion rate (as shown in Table 2).
Table 2. Experimental results under the conditions of methylpyridine
Figure 1. Schematic diagram of the structure of the reactor. The volume of the liquid held in the microreactor is 240 μl.
Using a continuous flow microreactor, Compound 3 was oxidized using pure oxygen and a yield of greater than 95% was obtained at room temperature over a residence time of 2.5 bar and 5 minutes. The reduction in reaction residence time is due to the good mass transfer performance of the microreactor and the enhanced gas-liquid mass transfer of the excess oxygen to achieve complete conversion.
Table 3. Experimental results of pure oxygen oxidation of methylpyridine in a microreactor
As can be seen from Table 3, the solvent has a great influence on the reaction. As in column 1a, the mixed solvent THF/DME was used instead of the mixed solvent DME/Toluene, and the yield of the compound 1 (o-methylpyridine) was 89%. The experimental conditions of 1a have very low oxidative conversion rates for compound 2 (m-methylpyridine). Compound 2 was able to give 100% conversion in a mixed solvent of DMPU and THF. In the oxidation reaction of the continuous flow microreactor, the concentration of the reactants, the reaction temperature and the residence time are also important to ensure the solubility and fluidity of the carboxylate formed by the reaction.
Table 4. Experimental results of microreactor air oxidation of methylpyridine
For safety and economic reasons, the process of using air instead of oxygen is very attractive, and the authors have also conducted experiments on this. Compound 3 was oxidized in 2.5 bar of air for 1 minute to reach 100% yield. Compound 1 achieved only 70% yield even after 5 minutes of reaction at 10 bar. Compound 2 was reacted at 10 bar for 5 minutes with a yield of only 78%. The results are shown in Table 4.
Interestingly, solvent selection for each substrate is key to achieving high conversion. Compound 1, DME is superior to DMPU; for compound 2, DME severely inhibits the conversion of the reactants, while the yield in DMPU is greatly improved; Compound 3 can obtain higher yields in the presence of DME and DMPU. The exact cause of these differences is unclear. The results are shown in Table 5.
Table 5. Effect of Solvent on the Oxidation Reaction
This study successfully verified the feasibility of the application of methylpyridine oxygen oxidation in a microreactor. Although there are still some unfavorable factors such as low concentration and expensive solvent in the future production. However, the use of continuous flow reactors, the use of pure oxygen, air and hydrogen peroxide for oxidation is a safe, clean, environmentally friendly method, it is worth learning and can develop more and better processes.
References: Chem. Commun., 2012, 48, 2086–2088