izpis_h1_title_alt

Sinteza kalijevih aciltrifluoroboratov kot sinteznih prekurzorjev v farmacevtski kemiji
ID Bohinec, Špela (Author), ID Časar, Zdenko (Mentor) More about this mentor... This link opens in a new window, ID Šterman, Andrej (Co-mentor)

.pdfPDF - Presentation file, Download (2,68 MB)
MD5: 8343EA64D1091F0BCBE54A78FBCC4971

Abstract
Kalijevi aciltrifluoroborati (KAT-i) so bor vsebujoče organske soli, ki so zaradi svoje velike uporabnosti v sintezni kemiji pričele dobivati na pomenu v zadnjih desetih letih; predvsem kot reagenti za hitre sklopitvene reakcije, kot je tvorba amidne vezi in kot prekurzorji za sintezo aminoborovih kislin. Te so uporabne kot biokemijski označevalci in zdravilne učinkovine, katerih primer je zaviralec proteasoma bortezomib, ki je indiciran za zdravljenje diseminiranega plazmocitoma. Potencial delovanja aminoborovih kislin kot skupine spojin je mnogo širši od delovanja na samo eni tarči, znane in tržene so namreč že učinkovine na drugih tarčah. Ob širokih možnostih uporabe aminoborovih kislin in praktičnosti hitre tvorbe amidnih vezi iz KAT-ov se pojavlja nuja po iskanju novih in izboljšanih sinteznih poti za KAT-e. Zato smo po literaturnih postopkih sintetizirali strukturno različne KAT-e in optimizirali sintezne postopke. Z raznoliko strukturo sintetiziranih KAT-ov smo želeli smo želeli predstaviti, da je naš sintezni postopek primeren za sintezo raznolikih KAT-ov in zato splošno uporaben. Sintetizirali smo usmerjeno knjižnico KAT-ov, katerih stranske verige vključujejo raznolike, tudi konkurenčno reaktivne funkcionalne skupine, substituente z različnimi elektronskimi vplivi in sterično različne substituente. Načrtovali smo sintezo 22 KAT-ov; 10 aromatskih in 12 alifatskih. Pri tem je bilo 14 KAT-ov že znanih, od tega samo štirje komercialno dostopni, in 8 popolnoma novih. Izmed 8 novih KAT-ov je bila sinteza uspešna pri 4 KAT-ih. V sintezne poti smo uvedli izboljšave predvsem na področju natančnejšega spremljanja poteka reakcij, ekonomičnosti in širokega strukturnega razpona substratov. Uvedli smo primerno zaporedje dodajanja reagentov in s tem zmanjšali nastajanje stranskih produktov. Ugotovili smo, da so vse reakcije močno občutljive na temperaturo, mešanje in kvaliteto (starost) reagentov ter da je že zaradi majhnih odmikov od predpisanega postopka reakcija bila neuspešna. Prepričani smo, da bi se v nadaljnjem delu tega raziskovalnega projekta morali osredotočiti na natančnejše spremljanje reakcij in s tem na bolj natančno zaznavanje kritičnih korakov ter parametrov. Še vedno namreč ostaja odprto vprašanje izboljšanega sinteznega postopka za pripravo primarnih alifatskih KAT-ov, učinkovitejše preprečitve nastajanja stranskih produktov tekom reakcije, izpopolnitev izolacije in nenazadnje večjega izkoristka. Zaključimo lahko, da rezultati in ugotovitve iz tega magistrskega dela vsekakor predstavljajo napredek v sintezi KAT-ov, ki jih lahko uporabimo za sintezo aminoborovih kislin – ključnih gradnikov zaviralcev proteasoma.

Language:Slovenian
Keywords:kalijevi aciltrifluoroborati, acilborani, organoborove spojine, aminoborove kisline, bortezomib.
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2020
Publication date in RUL:02.06.2020
Views:548
Downloads:239
Metadata:XML RDF-CHPDL DC-XML DC-RDF
:
Share:AddThis
AddThis uses cookies that require your consent. Edit consent...

Secondary language

Language:English
Title:Synthesis of potassium acyltrifluoroborates as synthesis precursors in pharmaceutical chemistry
Abstract:
Potassium acyltrifluoroborates (KATs) are boron-containing organic salts, which became important over the past ten years due to their high utility in organic synthesis; particularly as remarkable reagents for rapid coupling reactions, such as the amide-forming ligation, and as prominent precursors for the synthesis of aminoboronic acids. Those are used as biochemical markers and as active substances in therapy, of which the most known is bortezomib. This proteasome inhibitor is indicated for the treatment of multiple myeloma. The potential of aminoboronic acids is much broader than their effect on a single target. Thus, some of the already marketed active substances from this class act on different targets. Given the wide potential of aminoboronic acids and great utility of the amide-forming ligation from KATs, there is a need to find new and advanced synthetic pathways for KATs. Therefore, structurally different KATs were synthesized according to the literature procedures, which we optimized. With the wide structural diversity of KATs we wanted to present the generality of the synthesis process for structurally different KATs. We have synthesized a library of KATs with diverse functional groups on the side chain, substituents with various electronic effects and sterically different substituents. In total, we planned the synthesis of 22 KATs; 10 aromatic and 12 aliphatic. Out of those 22, 14 KATs were already known and only 4 out of these 14 were commercially available. In the category of 8 completely new KATs, synthesis of 4 new KATs was successful. Synthetic improvements were mainly implemented in the area of a more accurate monitoring of the reaction, economic aspect and a wide structural range of substrates. We have also ensured the appropriate sequence of reagent addition and consequently lowered the formation of side products. We have discovered that all reactions are highly sensitive to the temperature, mixing and reagent quality (freshness). Even small deviations from prescribed procedure lead to the failure of the reaction. To conclude, we believe that further work should focus on closer monitoring of reactions and thus detecting critical steps and parameters. Namely, the questions of improving the synthetic procedures of aliphatic KATs, more effective prevention of the production of side products during the reaction, better isolation process and, ultimately, greater yield, remain open. Results and findings of this master's thesis represent a valuable advance in the synthesis of KATs, which can be used as precursors of aminoboronic acids – key building blocks of proteasome inhibitors.

Keywords:potassium acyltrifluoroborates, acylboranes, organoboronic acids, aminoboronic acid, bortezomib.

Similar documents

Similar works from RUL:
Similar works from other Slovenian collections:

Back