Primjena flow-kemije u makrociklizacijskim reakcijama: rekonstrukcija makrolidnog prstena

master's thesis

• Title (english): Continuous flow macrocyclization reactions: macrolide ring reconstruction
• Author: Patricia Debogović
• Mentor: Irena Škorić (mentor)
• Mentor: Goran Kragol (komentor)
• Committee member: Irena Škorić (predsjednik povjerenstva)
• Committee member: Dragana Vuk (član povjerenstva)
• Committee member: Goran Kragol (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2021-02-25, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Azitromicin je poznati makrolidni antibiotik koji se koristi u liječenju brojnih bakterijskih infekcija. Strukturnim modifikacijama na makrolidnom prstenu proširuje se spektar biološkog djelovanja makrolida što je izuzetno bitno za područje medicinske kemije. U cilju rekonstrukcije postojećeg makrocikličkog skeleta putem ovog je rada provedena sinteza, optimizacija reakcijskih uvjeta te spektroskopska karakterizacija novih makrocikličkih azitromicinskih dijastereoizomera. Ukupna sinteza ciljanih spojeva izvedena je u tri reakcijska koraka. Azitromicin seko-amidni derivati 3a i 3b dobiveni su 9a-amidacijama iz azitromicin seko-estera 1a i N-Fmoc-(R)-3-amino-3-(3-klorofenil)-propanske kiseline 2a ili N-Fmoc-(S)-3-amino-3-(3-klorofenil)-propanske kiseline 2b. Sinteza derivata 3a i 3b isprobavana je u različitim uvjetima među kojima su se optimalnim pokazali oni koji uključuju bazu DIPEA-u i reagens HATU u DMF-u. Hidrolizom derivata 3a i 3b pripravljeni su azitromicin seko-kiselinski derivati 4a i 4b primjenom LiOH×H2O u vodi i THF-u. Makrociklički azitromicin amidni derivati 5a i 5b dobiveni su intramolekulskim 13-amidacijama u flow-reaktorskom sustavu uz opsežnu optimizaciju reakcijskih uvjeta. Flow-amidacije isprobavane su uz uporabu različitih reagensa pri čemu je HATU dao brzu i potpunu konverziju pa je taj reagens korišten u daljnjim reakcijama. Amidacije u flow-reaktoru provođene su pri različitim reakcijskim koncentracijama, vremenskom zadržavanju i pri različitim temperaturama. Optimizacijama je ustanovljeno da optimalni uvjeti obuhvaćaju koncentraciju flow-smjese od 12,5 mM, vremensko zadržavanje od 5 min i temperaturu od 75 ºC čime je postignuta potpuna konverzija uz minimalni udio neželjenog dimerskog nusprodukta. U tim su uvjetima sintetizirani konačni, makrociklički azitromicin amidni derivati 5a i 5b uz DIPEA-u i HATU u DMF-u na većoj sintetskoj skali u flow-reaktoru. Strukture dobivenih dijastereoizomera 5a i 5b potvrđene su 1D i 2D NMR spektroskopijom putem čega je dokazan i konformacijski izomerizam derivata 5a i 5b.

Abstract (english)

Azithromycin is a macrolide antibiotic used for the treatment of numerous bacterial infections. Structural modifications of macrolide ring expand the biological activity of macrolides, which is very important for the field of medicinal chemistry. In order to reconstruct the existing macrocyclic skeleton, the synthesis, optimization of reaction conditions and spectroscopic characterization of new macrocyclic azithromycin diastereoisomers were performed. The final targets were synthesized in three reaction steps. Azithromycin seco-amide derivatives 3a and 3b were obtained by 9a-amidations from azithromycin seco-ester 1a and N-Fmoc-(R)-3-amino-3-(3-chlorophenyl)-propionic acid 2a or N-Fmoc-(S)-3-amino-3-(3-chlorophenyl) propionic acid 2b. The synthesis of derivatives 3a and 3b was tested under various reactions conditions. The chosen conditions included base DIPEA and reagent HATU in DMF. By hydrolysis of derivatives 3a and 3b, azithromycin seco-acid derivatives 4a and 4b were prepared using LiOH×H2O in water and THF. Macrocyclic azithromycin amide derivatives 5a and 5b were obtained by intramolecular 13-amidations in flow reactor with extensive optimization of the reaction conditions. Flow amidations were tested by using different reagents. Reagent HATU enabled fast and complete conversion, so this reagent was used in further reactions. Amidations in the flow reactor were performed at different concentrations of reactions, at different retention times, and at different temperatures. It was established that optimal conditions of intramolecular amidation included concentration of reaction of 12.5 mM, retention time of 5 min, and temperature of 75 ºC. Under these conditions, complete conversion was achieved with a minimal percentage of undesired dimeric by-product. Therefore, the final targets, macrocyclic azithromycin amide derivatives 5a and 5b, were synthesized under optimized conditions using DIPEA and HATU in DMF on a larger scale in the flow reactor. The structures of obtained diastereoisomers 5a and 5b were confirmed by 1D and 2D NMR spectroscopy, which also proved the conformational isomerism of derivatives 5a and 5b.

• Keywords: azitromicinski derivati; amidacija; hidroliza; flow-reaktor; makrociklizacija
• Keywords (english): azithromycin derivatives; amidation; hydrolysis; flow reactor; macrocyclization
• Language: croatian
• URN:NBN: urn:nbn:hr:149:995738
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Applied organic chemistry; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Access restricted to students and staff of home institution
• Created on: 2023-04-05 12:26:51