Synthesis Of CDK4/6 Inhibitor Abemaciclib And Pulmonary Hypertension Orphan Drug Selexipag

Abemaciclib(Verzenio),a drug that selectively inhibits inhibitors of cyclin-dependent kinases 4 and 6(CDK4/6),is used to treat negative-HER2 advanced or recurrent breast cancer.Selexipag(Uptravi)is an orally administered prostacyclin receptor(PGI2 receptor)agonist for the treatment of adult pulmonary hypertension.The main work in this thesis can be summarized as follows:(1)Synthesis of Abemaciclib:Using isopropylamine as a starting material,abemaciclib was prepared through a series of reactions including acetylation,addition elimination,nucleophilic substitution of benzene rings,boronic acid esterification and deboronation in a Suzuki coupling reaction to give the intermediate6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazo-le;The intermediate 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine was obtained from 6-bromo-3-pyridinecarbaldehyde by reductive amination and substitution reaction.The last two intermediates undergo Buchwald-Hartwig coupling reaction to synthesize abemaciclib.The reaction mechanism and reaction conditions involved in the synthesis unit were analyzed and discussed,and the route process was optimized.The product was confirmed by ~1HNMR and the purity was 99.15%by HPLC.Compared with the literature,the total yield increased from 25.0%to 44.6%.(2)Synthesis of Selexipag:1,2-Diphenyl-1,2-ethanedione and 2-aminoacetamide hydrochloride were used as starting materials to synthesize the title compound by six steps:cyclization reaction,halogenation reaction,substitution reaction,basic hydrolysis and amide condensation reaction.The reaction mechanism and reaction conditions involved in the synthesis unit were analyzed and discussed,and the route process was optimized.The product was confirmed by ~1HNMR and the purity was 98.62%by HPLC.Compared with the literature,the total yield increased from 29.59%to 60.20%.