| Palbociclib was developed by Pfizer Inc.of the United States and was approved by the FDA on February 3,2015.It was approved by the European Medicines Agency on November 9,2016 and sold by Pfizer in the United States and Europe under the trade name Ibrance.Palbociclib is a small molecule inhibitor of the cyclin-dependent kinase(CDK4/CDK6),which was approved for use with letrozole for the treatment of postmenopausal estrogen receptor positive(ER +)And human epidermal growth factor receptor negative(HER2-)late breast cancer.In this paper,based on the analysis of the existing synthetic route,a 2-aminopyridine was designed as a raw material to synthesize papoxidone side chain intermediate 4-(6)by bromination,oxidation,coupling and hydrogenation.-aminopyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester,and the synthesis process was optimized.In this paper,the structures of the intermediates were synthesized by NMR and their purity was tested by liquid chromatography.First,the synthesis of 2-amino-5-bromopyridine in this paper,the use of liquid bromine direct bromination,the purpose is to reduce the cost of raw materials,while optimizing the reaction conditions,high yield,high purity 2-amino-5-bromopyridine;The crude product was recrystallized from methanol and the yield was 67%and the purity of the product was 99%.Secondly,4-(6-nitro-2-bromo-pyridine)was oxidized to nitro,Pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was synthesized by coupling with 2-nitro-5-bromopyridine and Boc-piperazine as a starting material.Finally,4-(6-amino Pyridin-3-yl)-piperazine-l-carboxylic acid tert-butyl ester The nitro group is efficiently converted to an amino group using a clean,non-polluting palladium-carbon catalytic hydrogenation.In this paper,the synthesis process of 4-(6-aminopyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was established and the desired results were obtained.Industrial production provides a basis. |
PDF Full Text Request