(46d) A Multistep Process for the Synthesis of Pharmaceutical Intermediates by An Ozonolysis–Reduction–Sequence Using Microchemical Engineering with An Integrated Miniaturized Fiber–Optical Diamond ATR Sensor in A Multipurpose Plant

Microstructured reactors have recently gained increasing importance as useful devices for chemical reactions and processes. Improved temperature management, shorter diffusion paths and higher specific interfacial areas increase mass and heat transfer rates. Furthermore, due to the low hold?up in microdevices the hazard of highly exothermic and explosive reactions is considerably reduced. Within a research project called ZOHIR these advantages were utilized in a multistep process using microchemical engineering for the preparation of intermediates of vitamin D analogs. Scheme 1 shows the reaction sequence, which was successfully performed in a microplant. A general flow chart for this two step process is depicted in Figure 1.

Scheme 1. Reaction scheme for the preparation of intermediates of vitamin D analogs in a two?step process using microstructured reactors.

Figure 1. Flow chart for the ozonolysis?reduction?process in microstructured devices.

By a pump educt A is fed to the microreactor, where it reacts with ozone in a gas/liquid?reaction. The ozonolysis of the double bond in A yields hydroperoxide B and aldehyde C. The reaction mixture is then pumped out of the reactor and analyzed online by a miniaturized Fibre?optical Diamond ATR sensor, which was developed in the course of this project. The subsequent reduction to alcohol D by sodium borhydride is performed in a mixer/residence time module combination without isolation.

Concerning the feasibility and optimization the two reaction steps in microreactors, ozonolysis and reduction have initially been investigated separately. For the ozonolysis, the miniaturized ATR sensor was used for the online?monitoring of the formation of hydroperoxide B and aldehyde C. It showed that already about 30% of aldehyde C is formed along with hydroperoxide species B during this step. These results were confirmed by quantitative offline HPLC?analysis of aldehyde C.

Additionally, for the ozonolysis step different microstructured reactors have been tested (Figure 2). Surprisingly, best results were obtained with a 5?channel?microreactor (Figure 3) giving quantitative conversion up to a flow rate of 0.26 mmol/min. In comparison for the same flow rate, lower conversions were detected for the 1?channel?micromixer and microreactors which are especially designed for liquid/gas?reactions, such as a falling film microreactor or a cyclone mixer.

Figure 2. Conversion of compound A in the ozonolysis?step of the multistep process for different flow rates and microreactors.

The reduction to alcohol D was also successfully performed in a 5?channel?microreactor (Figure 3). In combination with a residence time module, quantitative conversion was reached up to flow rates of 0.6 mmol/min with a threefold excess of NaBH₄.

Figure 3. 5?channel?microreactor utilized in the ozonolysis?step of the multistep process (source: mikroglas chemtech GmbH).

The overall process was then performed with two 5?channel?micromixers according to the flow chart given in Figure 1 and the desired product alcohol D was isolated in 72% yield.

In conclusion, we were able to run this two step reaction sequence in a continuous manner. The utilization of microstructured devices allows for the realization of a safe and highly controlled multistep process with online?analysis via FTIR. A 5?channel?microreactor turned out to be most suitable for the gas/liquid?reaction (ozonolysis). Additionally, the in situ reduction to alcohol D leads to a higher efficiency of the process.