Research On Synthesis And Purification Process Of The Plerixafor

Plerixafox is developed by Genzyme Corporation and is a specific blocker of chemokine receptor 4(CXCR4).It can effectively promote the generation of blood stem cells in patients with non-Hodgkin’s lymphoma and multiple myeloma,and then meet the requirements of autologous stem cell transplantation to achieve the purpose of cancer treatment.Therefore,the application of Pleroxafor in the treatment of cancers with stem cell transplantation is of great significance.Plerixafox appeared on the market for the first time in the United states in December 2008.At present,the generic drugs have not been approved for producing in China.Thus,the study of its synthetic technology is very valuable.A number of literatures have been reported on synthesis routes of Plerixafox.According to the starting materials,they were divided into two categories: the first type started from 1,4,8,11-tetraazaheterocycles.In the second type,Plerixafox was obtained with methyl acrylate as the raw material.The first method had many disadvantages,suah as: the raw material was expensive and hard to get,there were many byproducts in the selective protecting process.The second method can overcome these shortcomings,but the information provided by the literatures was relatively simple and required further research.Based on the second method,the design of the experimental program was carried out,and a systematic study was conducted on the synthesis and refining process of Plerixafox.The main work was as follows:(1)The research on synthetic processThe obtained synthesis route was: the route started from methyl acrylate,then Plerixafox was obtained after a series of chemical reactions including amino compound,ring formation,N-alkylation reaction and deprotection reaction.The optimum reaction conditions of the first step can be got: the molar ratio of methyl acrylate and ethylenediamine was 1:14,the reaction temperature was 68° C,and the reaction time was 3.5 h.The optimized yield was closed to the quantitative reaction.The optimum reaction conditions of the second step were obtained as follows: the molar ratio of compound II and dimethyl malonate was 1:1.1,the reaction time was 20 h,methanol was used as the reaction solvent,the recrystallization solvent was a mixed solvent of methanol and n-hexane with a volume ratio of 3:2.The yield was 2.1% higher than the literature value after optimization.The optimum reaction conditions of the third step can be got: acetonitrile was used as the solvent,the molar ratio of the compound III and the dibromobenzyl was 2.2:1,and N,N-diisopropylethylamine was used as the acid-binding agent with the molar ratio of 6:1 to compound III.Potassium iodide was used as the catalyst,the molar ratio of potassium iodide and p-dibromobenzyl was 1:10 and the reaction time was 35 h.The yield was 6.7% higher than the value in the literature after optimization.The optimum reaction conditions of the fourth step were as follows: sodium borohydride-glacial acetic acid was used as a reducing agent,the molar ratio of compound IV and reducing agent was 1:28,the recrystallization solvent was a mixed solvent of acetone and water with a volume ratio of 11:1.The yield and purity were improved after optimization.The total yield of the optimized process was 23.4%,which was 8.4% higher than that of the original process.(2)Research on refining methodsThe crude product was refined by anti-solvent recrystallization method.The best process conditions were as follows: tetrahydrofuran was used as the easily soluble solvent and acetone as the anti-dissolving solvent with the volume ratio of 1:6,reverse feeding was used and the stirring rate was 3000 r/min.Refined product was analysed by HPLC and the purity reached 99.3%.The solubility of Plerixafox in pure water,ethanol,acetone,ethyl acetate,toluene,n-hexane,and toluene-acetone was measured by the equilibrium method and the solubility data were well correlated by the modified Apelblat equation and(CNIBS)/Redlich-Kister equation.The determination of solubility provided the accurate experimental basis for anti-solvent recrystallization.In addition,the thermal analysis of the manufactured products by TG-DSC showed that the melting temperature,melting enthalpy and decomposition temperature were in agreement with the literature values.In this paper,the synthesis and refining process of Plerixafox were studied.The obtained process has the advantages of available raw materials,mild conditions,convenient operation and 99.3% purity of the final product,which provide the basis for industrial large-scale preparation.