Design And Syntheses Of Some Fluorinated Selective RAR Agonists And Synthetic Methodology Study

Selective RAR agonists are effective drugs for the treatment of acne and some cancers. Due to the side effects of the marketed drugs, it is definitely necessary to search for new compounds in order to improve their receptor affinity and selectivity, the therapeutic index and so on. For the sake of screening novel potential RAR agonists, the hetero atoms were introduced into the scaffold derived from Adapalene and other active compounds of the type, and fluoro-atom was also introduced to the substituents in the molecule to increase the diversity of the newly designed compounds. Hence, four types of novel compounds were designed in this thesis. Six novel compounds and twelve new intermediates were synthesized via four synthetic routes.The synthetic methodology was extensively studied. In order to synthesize target compounds ZB-1-ZB-2 and ZB-4-ZB-5, a series of phenylboronic acids were synthesized form 4-bromophenol in a 4-step sequence including Fridel-Crafts reaction, Bn-or MOM-protection of the phenol and so on. And then these compounds were brought to Suzuki reaction with methyl 6-bromo-2-naphthoate or 6-bromoquinoline-2-carboxylat. After the deprotection of the phenol, the OH group was etherized with CHF2 to give the difluormethylated esters which could be easily hydrolyzed to give the targets.Similarly, Methyl 6-bromo-2-naphthoate or 6-bromoquinoline-2-carboxylate were coupled with 5-fluoro-phenylboronic acid obtained from 2-fluorophenol in a 5-step sequence including bromination, Fridel-Crafts reaction, Bn-or MOM-protection of the phenol and so on. CHF2 was introduced into coupling compounds after the deprotection of the phenols, and the target compounds ZB-3 and ZB-6 were obtained after the final hydrolysis.