CẢI TIẾN TỔNG HỢP ACID (E)-4-(PIPERIDIN-1-YL) BUT-2-ENOIC HYDROCLORID LÀM CHẤT TRUNG GIAN QUAN TRỌNG TRONG ĐIỀU CHẾ THUỐC ĐIỀU TRỊ UNG THƯ PHỔI DACOMITINIB

Abstract

Background: Dacomitinib, an EGFR tyrosine kinase inhibitor (TKI), was approved by the FDA and EMA in September 2018 and March 2019, respectively, as a first-line treatment for adult patients with non-small cell lung cancer (NSCLC). In the synthesis of dacomitinib, (E)-4-(piperidin1-yl)but-2-enoic acid hydrochloride (LT-03) is an essential intermediate. There are now many methods for synthesizing LT-03 that have been published by authors worldwide, most of which use starting materials derived from crotonic acid (alkyl crotonates). This study presents a novel approach for the direct synthesis of LT-03 from crotonic acid, a readily available and inexpensive raw material. Objectives: using a new synthetic approach from readily available crotonic acid under suitable conditions in Vietnam to obtain LT-03. Materials and Methods: The synthesis of LT-03 from crotonic acid involves three stages: first, crotonic acid is brominated to form the intermediate (E)-4-bromobut-2-enoic acid (LT-01); next, LT-01 is N-alkylated with piperidine to provide (E)-4(piperidin-1-yl)but-2-enoic acid (LT-02); and lastly, the hydrochloride salt (LT-03) is formed. Spectroscopic techniques such as infrared spectroscopy (IR), mass spectrometry (MS), and nuclear magnetic resonance spectroscopy (¹H-NMR, ¹³C-NMR, DEPT, as well as two-dimensional HSQC and HMBC) were used to confirm the compounds' structures. Results: Numerous optimal conditions for the synthesis and purification of the compounds were investigated and selected. The yields for the stages producing LT-01, LT-02, and LT-03 were 74.5%, 78.9%, and 97.9%, respectively. The accurate structures of the intermediates and final product were validated by data on melting temperatures, IR spectra, MS, and NMR. Conclusions: Under the appropriate conditions, LT-03 was successfully synthesized in Vietnam utilizing a novel technique from easily accessible crotonic acid, with a three-stage total yield of 57.5%.