Unit:
Department of PharmacyLibrary of the School of Science
Author:
KLIMOPOULOU DESPOINA-THOMAI
Supervisors info:
Μαράκος Παναγιώτης, Καθηγητής Τμήμα Φαρμακευτικής, ΕΚΠΑ, (Επιβλέπων),
Νικολαΐς Πουλή, Καθηγήτρια Τμήμα Φαρμακευτικής, ΕΚΠΑ,
Νικόλαος Λουγιάκης, Αναπληρωτής Kαθηγητής Τμήμα Φαρμακευτικής, ΕΚΠΑ
Original Title:
ΣΥΝΘΕΣΗ ΥΠΟΚΑΤΕΣΤΗΜΕΝΗΣ ΠΥΡΡΟΛΟ[2,3-c]ΠΥΡΙΔΙΝΗΣ ΩΣ ΕΝΔΙΑΜΕΣΟΥ ΓΙΑ ΤΗΝ ΠΑΡΑΣΚΕΥΗ ΠΑΡΑΓΩΓΩΝ ΤΟΥ OSIMERTINIB
Translated title:
SYNTHESIS OF A SUBSTITUTED PYRROLE[2,3-c]PYRIDINE AS INTERMEDIATE FOR THE PREPARATION OF OSIMERTINIB ANALOGS
Summary:
The present thesis is focused on the synthesis of a suitably substituted pyrrolo[2,3-c]pyridine derivative which will be used as an intermediate for the preparation of Osimertinib analogs. In the introductory part, the concept and pathogenesis of cancer at a molecular level are analyzed, with focus on non-small cell lung
cancer (NSCLC). A detailed discussion is provided concerning the causes of NSCLC, the underlying molecular mechanism, the relationship between NSCLC and mutations of the epidermal growth factor receptor (EGFR), as well as the therapeutic methods that are being used for its treatment. The most common mutations of EGFR observed in patients with NSCLC are deletion on exon 19, point mutation on codon
858 of exon 21, and the point mutation T790M on exon 20, which causes the development of resistance in patients that are being treated with tyrosine kinase inhibitors (TKIs). Emphasis is provided on the existing methods of chemotherapy, immunotherapy, and personalized treatments, focusing on the use of tyrosine
kinase inhibitors. The concept of tyrosine kinase and tyrosine kinase inhibitors is further analyzed, while the mechanism of action of the inhibitors is discussed in detail. The existing three generations of tyrosine kinase inhibitors are compared, ending up to the lead compound of this thesis, Osimertinib, a thirdgeneration TKI that was introduced to overcome the resistance that patients develop due to the T790M mutation. In the chemistry section that follows, the synthetic pathway for the preparation of a crucial
intermediate is described that will be used for the preparation of the drug’s analogs. The main reaction mechanisms of the individual steps are commended, together with a brief description of the 1H-NMR spectra of the new derivatives. As starting material, 2-amino-3-nitro-4-picoline was used, which was successively introduced to diazotization and hydrolysis, chlorination, ring-closure following the Leimgruber-Batcho methodology, Friedel-Crafts acylation, methylation, and acyl group elongation, in order to result in the target compound.
Main subject category:
Science
Keywords:
EGFR,TKIs,NSCLC,cancer,T790M,pyrrole[2,3-c]pyridine
Number of references:
100
File:
File access is restricted until 2026-12-13.
KLIMOPOULOU TELIKO.pdf
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File access is restricted until 2026-12-13.
