Optimizacija reakcije Suzuki-Miyaura v sintezi 4-aril-6-trifluorometilpirimidinskih antagonistov Tollu podobnega receptorja 8

Mrgole, Kristjan (author), Sova, Matej (mentor)

Reakcije Suzuki-Miyaura so ene izmed najpogosteje uporabljenih reakcij v organski kemiji, pri kateri pride do tvorbe ogljik-ogljik vezi s pomočjo kovinskega katalizatorja. Prednosti teh tipov reakcij so predvsem mili pogoji, neobčutljivost boronske kisline na vodo in zrak ter dober prenos laboratorijske metode na industrijski nivo. Optimizacija parametrov je tako ključni del načrtovanja reakcije, ki zagotavlja uspešnost in visok izkoristek posamezne sinteze. V sklopu magistrske naloge smo optimizirali reakcijo Suzuki-Miyaura na 2,4-dikloropirimidinu za nadaljnjo sintezo 4-aril-6-trifluorometilpirimidinskih potencialnih antagonistov Tollu podobnega receptorja 8 (TLR8). V začetku procesa optimizacije metode smo izbrali najbolj optimalno topilo, s katerim smo kasneje izvedli serijo reakcij z uporabo različnih katalizatorjev. Katalizatorju, ki je izkazoval najvišji izkoristek reakcije, smo določili najmanjšo količino, ki še zadošča za visok izkoristek, nato pa optimizirali še temperaturo same reakcije. Pri končni optimizirani metodi smo uporabili 1,4-dioksan kot topilo, 3 mol % katalizatorja tetrakis(trifenilfosfin) paladija(0) relativno na vstopni reaktant 2,4-dikloropirimidin pri temperaturi reakcije 90 ºC. Optimizirano metodo reakcije smo prenesli na 1. stopnjo sinteze potencialnih antagonistov TLR8, kjer se je izkazala kot učinkovita metoda za pripravo intermediata 2-kloro-4-fenil-6-(trifluorometil)pirimidina (1), medtem ko se pri sintezi 2-kloro-4-(furan-3-il)-6-(trifluorometil)pirimidina (2) ni izkazala kot najučinkovitejša metoda, saj je bil izkoristek nižji od pričakovanega. Intermediatoma 1 in 2 smo v nadaljevanju sinteze dodali 2-tiofenilmetilamin, da smo dobili končna produkta 4-fenil-N-(tiofen-2-ilmetil)-6-(trifluorometil)pirimidin-2-amin (3) in 4-(furan-3-il)-N-(tiofen-2-ilmetil)-6-(trifluorometil)pirimidin-2-amin (4), ki smo ju poslali na biokemijsko vrednotenje TLR8 antagonističnega delovanja. Preliminarni rezultati testiranj so pokazali, da spojina 3 izkazuje antagonistično delovanje na TLR8, medtem ko je spojina 4 še v fazi testiranj.

• Language: Slovenian
• Keywords: Reakcija Suzuki-Miyaura, optimizacija, katalizatorji, TLR8, antagonisti
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-122251
• Publication date in RUL: 02.12.2020

Secondary language

• Language: English
• Title: Optimization of Suzuki-Miyaura reaction in the synthesis of 4-aryl-6-trifluoromethylpyrimidine antagonists of Toll-like receptor 8

Abstract

Suzuki-Miyaura reactions are one of the most commonly used reactions in organic chemistry in which carbon-carbon bond is formed in the presence of a metal catalyst. The main advantages of this type of reactions are mild conditions, insensitivity of boronic acid to water and air as well as good transfer of the laboratory method to the industrial level. Optimization of parameters are a key part of reaction planning, which ensures the success and high yields of the selected synthesis. As a part of this master´s thesis, the Suzuki-Miyaura reaction on 2,4-dichloropyrimidine was optimized for further synthesis of 4-aryl-6-trifluoromethylpyrimidine class of potential Toll-like receptor 8 (TLR8) antagonists. At the beginning of the method optimization process, we selected the most optimal solvent, which was later used for a series of reactions using different catalysts. The catalyst that showed the highest reaction yield was further used for determination of the lowest amount which still led to high yields. Afterwards, the reaction temperature was optimized. For the final optimized method we used 1,4-dioxane as a solvent, 3 mol % of tetrakis(triphenylphosphine) palladium(0) catalyst relative to the input of 2,4-dichloropyrimidine and a reaction temperature of 90 ºC. The optimized reaction method was then transferred to the first step of the synthesis of potential TLR8 antagonists, where it was proved as an efficient method for the preparation of 2-chloro-4-phenly-6-(trifluoromethyl)pyrimidine intermediate (1), while in the synthesis of 2-chloro-4-(furan-3-yl)-6-(trifluoromethyl)pyrimidine (2) the method was showed to be less efficient since the yield was lower as expected. 2-thiophenylmethylamine was added to intermediates 1 and 2 to prepare the final products 4-phenyl-N-(thiophen-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine (3) and 4-(furan-3-yl)-N-(thiophen-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine (4), which were subjected to biochemical evaluation of TLR8 antagonist activity. The preliminary results showed that compound 3 possess some TLR8 antagonist activity, while compound 4 still needs to be evaluated.

• Keywords: Suzuki-Miyaura reaction, optimization, catalysts, TLR8, antagonists