Study On Synthesis Technology Of Papoxilin Key Intermediates

Breast cancer is a hormone-dependent malignancie that cancer cell growth receptors are regulated by multiple hormones.In the endocrine treatment of advanced breast cancer clinical research,the drug application effect of papoxilin combinated with letrozole is gradually progressing.Papoxilin as a new anti-cancer drug was the first CDK 4/6 inhibitor to be approved by FDA.This product is able to inhibit the growth of G1 phase ER+ breast cancer cells compared with the current clinical drug.In II clinical study,it has a significant therapeutic effect and more newly increased indications approved,making the research and market value of 4-(6-aminopyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester for the synthetic of papoxilin side chain constantly rising.In this paper,the process of using 2-aminopyridine as the starting material is designed to obtain 4-(6-aminopyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester through brominetion,oxidation,coupling and reduction on the basis of the literature,and the influencing factors of the reaction were systematically explored,The current process is optimizated through detailed analysis of the reaction procedure.The synthesis of 5-bromo-2-aminopyridine was carried out by selecting acetone as the reaction solvent and N-bromosuccinimide as the brominating agent,the optimum feed molar ratio of Bromide reagent and 2-aminopyridine was 1.00~1.05:1,the reaction temperature is 0~5 oC,the reaction product was post-treated with methylene chloride,more green and environmentally friendly,the by-product succinimide was effectively recovered,the recovery rate was 94.0%.The product yield of the brominated reaction was 95.5% and the purity was 98.9%.The synthesis of 5-bromo-2-nitropyridine(II)was carried out by selecting a solution used 98% sulfuric acid and 30% hydrogen peroxide in a volume ratio of 3:1 as the oxidizing agent,the amount of hydrogen peroxide is 4.5 equivalents,the reaction temperature was 50 oC and the reaction time was 3 h.The crude product was purified using methanol as recrystallizetion reagent.The product yield of the oxidation reaction increased from 72% to 73.4%,purity greater than 99%.The synthesis of tert-butyl ester(III)of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was carried out by selecting acetonitrile as reaction solvent,avoiding a larger generation of impurity III-1.Through orthogonal test the optimum feed molar ratio of 1-(tert-butoxycarbonyl)-piperazine and 5-bromo-2-nitropyridine was 2.00:1,the reaction temperature is preferably 70~75 oC,the amount of the solvent is 6 mL/g(II),and the crude reaction is carried out using ethyl acetate as the recrystallization solvent The The product yield of the coupling reaction increased from 80% to 85% and the purity was 99.1%.The synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-piperazine-1-carboxylate was carried out by using methanol as the reaction solvent,the hydrogenation reaction pressure was 300 KPa,the optimum amount of catalyst Pd/C was 5%,the reaction temperature was 35 oC and the hydrogenation reaction time was 8 h,the reaction conditions are more moderate than the literature.The yield of the product was 95% and the purity was 99.3%.The structure and purity of these substances were confirmed by 1HNMR and HPLC and so on.Compared with the traditional process,this paper uses cheap 2-aminopyridine as the starting material,the reaction solvent or the recrystallization solvent of each step was recycled,The key products were purified to meet the standards.In this thesis,the process operation,product yield and purity as well as environmental protection have been improved to a certain extent.