Pharmaceutical industry is one of the leading industries, where science and high technology are necessary for successful development and production of APIs. Processes are mostly carried out in batch or continuous (CSTR or PFR) way. PFR reactors are used less ferquentlly than CSTR and can be used to perform single reaction steps or whole reaction sequences, together with purification steps. In last two decades implementation of organic reactions in tubular microreactors became very popular. Microreactors offer many advantages, smaller investment costs, production space, etc..., therefore microreactor technology does not appear only in research laboratories, but also in the production of APIs.
In this master’s degree, implementation of microreactor technology for directed ortho lithiation with subsequent ipso-substitution with two various substrates N,N-diisopropylbenzamide and 4-chloro-N,N-diisopropylbenzamide is described. Ortho metalation is a common synthetic step in API production. We have shown on successfull implementation of DOM and subsequent ipso-substitution in a tubular microreactor by room conditions with satisfying results. Three electrophiles, DMF, CH3I and N-metoxy-N-methylacetamide were compared by reactivity and selectivity. It turns out, that the most selective is DMF, showing the highest and cleanest conversion of all anticipated products. The less selective was CH3I. Through reaction using this electrophile, some byproducts were formed, which were identified using LC-MS. We have also compared substrats bearing DMG with respect to their reactivity. Theoretically more reactive is 4-kloro-N,N-diisopropylbenzamide because of electron accepting group. In this thesis, thsi hypothesis was confirmed. All reactions were very fast. (flash reactions). Experimental determination of reaction time of lithiathed intermediate is about 0,5 s or theoretically even less. Overall residence time of reaction mixture is 19,7 s.
It should be noted, that microreactor system was composed of common laboratory equipment. In case of using more sophisticated microreactor devices, we could most probabbly reach even shorter residence time for the first part of reaction and higher conversion.