ipso-Substitucije orto litiiranih derivatov benzena z različnimi elektrofili v cevnem mikroreaktorju

Otorepec, Domen (author), Plazl, Igor (mentor)

Farmacevtska industrija je panoga, kjer je znanost v povezavi z napredno tehnologijo ena izmed ključnih dejavnikov za uspešen razvoj in proizvodnjo API-jev. Proizvodni procesi potekajo večinoma v šaržnem in kontinuirnem načinu (reaktorji CSTR in PFR). Slednji je sicer nekoliko redkejši in se uporablja le za določene korake v sinteznih stopnjah, lahko pa vpeljuje celoten sintezni proces. V zadnjih dveh desetletjih je postal zelo aktualen kontinuirni proces v cevnih mikroreaktorjih. Ti ponujajo veliko prednosti, manjše investicijske stroške, manjše proizvodne prostore ..., mikroreaktorska tehnologija se začenja pojavljati ne samo v raziskovalnih laboratorijih, temveč tudi za proizvodnjo večjih količin produktov. V magistrski nalogi je predstavljena vpeljava organokovinske reakcije z izhodnima spojinama N,N-diizopropilbenzamid in 4-kloro-N,N-diizopropilbenzamid v cevni mikroreaktor. Reakcija metaliranja v prisotnosti o-usmerjajoče skupine in sledeča reakcija litiiranega intermediata z elektrofilom je sintezni postopek, ki se pogosto uporablja v sinteznih korakih proizvodnje farmacevtskih učinkovin. Uspeli smo dokazati, da lahko z uporabo cevnega mikroreaktorja izvajamo ta sintezna koraka pri sobnih pogojih z zadovoljivimi rezultati. Uporabljene elektrofile DMF, CH3I in N-metoksi-N-metilacetamid (Weinrebov amid) smo med seboj primerjali glede reaktivnosti in selektivnosti. Za najbolj selektiven elektrofil se je izkazal DMF, za najmanj selektivnega pa CH3I. Zaradi svoje reaktivnosti je reagiral neselektivno. Stranske produkte smo identificirali z LCMS. Med seboj smo primerjali tudi oba aromatska substrata z o-usmerjajočo skupino in njun vpliv na reaktivnost. Teoretično je bolj reaktiven 4-kloro-N,N-diizopropilbenzamid, ki na aromatskem jedru vsebuje elektron privlačno skupino, kar se je pokazalo tudi v eksperimentih. Opazne so dosti višje konverzije do želenih produktov v primerjavi z N,N-diizopropilbenzamidom. Vse reakcije potečejo v trenutku, saj je eksperimentalno pridobljen reakcijski čas vezave litija na substrat 0,5 s, teoretično še manj. Celokupni zadrževalni čas je znašal 19,7 s. Upoštevati je treba, da je cevni mikroreaktor sestavljen s hišnimi komponentami. V primeru uporabe sofisticiranih mikroreaktorskih sistemov bi lahko dosegli še krajši zadrževalni čas prvega dela reakcije in s tem višjo konverzijo.

• Language: Slovenian
• Keywords: orto litiiranje, ipso-substitucija, organokovinske reakcije, kontinuirni način, cevni mikroreaktor
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Year: 2019
• PID: 20.500.12556/RUL-110834
• COBISS.SI-ID: 1538448323
• Publication date in RUL: 20.09.2019

Secondary language

• Language: English
• Title: ipso-Substitutions of ortho lithiated derivatives of benzene with various electrophiles in tubular microreactor

Abstract

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.

• Keywords: ortho lithiation, ipso-substitution, organometallic reactions, continuous flow, tubular microreactor