The Synthesis And Preliminary Form Research Of The New Anti-breast Cancer Lapatinib Ditosylate Monohydrate

Breast cancer as the most common malignancy in women worldwide,has become a disease with second mortality only to lung cancer in the world.Due to the high recurrence rate,poor specificity,serious adverse reactions,the physical and psychological pains and other shortcomings,traditional treatments such as surgery,radiotherapy,chemotherapy,endocrine therapy,are limited in clinical applications.Targeted therapy becomes a hot topic in breast cancer treatments recently.This paper introduces the pathogenesis and treatments of breast cancer,emphasizing some therapeutic agents.A representative drug of targeted therapy against breast cancer,lapatinib ditosylate monohydrate,N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinam-ine bis(4-methylbenzenesulfonate)monohydrate,was developed by GlaxoSmithKline as a dual human epidermal growth factor receptor EGFR and HER-2 reversible small molecule tyrosine kinase inhibitor.Approved by the US FDA in 2007,the lapatinib ditosylate monohydrate was indicated in combination with capecitabine,for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER-2.It is an oral sustained-release tablet and its trade name is Tykerb.Moreover,Lapatinib has the advantages of a high cure rate,well tolerance and low side effects,as well as it is an oral tablet instead of an intravenous drug,so that it is more convenient in applications.As a new targeted anti-breast cancer drug,lapatinib has an enormous prospect in the field of anti-breast cancer.Therefore,the study of its synthetic process will have a great significance.On the basis of accessing numerous relevant literatures,nine reported synthetic routes are summarized.The commercialized and inexpensive intermediate 1,(N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-quinazolin-4-amine)is selected as the starting material,considering the advantages and disadvantages of reaction conditions,yields and work-up of reported synthetic routes.Firstly intermediate 1 occurs Suzuki coupling reaction with 5-formyl-furan-2-yl boronic acid,and then reacts with 2-methanesulfonyl-ethylamine hydrochloride by Borch reduction reaction to get Lapatinib.After that,Lapatinib develops into salt with toluenesulfonic acid monohydrate.Finally,lapatinib ditosylate monohydrate is obtained in isopropanol and water.Firstly,a small scale process route optimization is carried out.In the Suzuki coupling reaction,the reaction factors including reaction solvent,the amount of catalyst,the reaction molar ratio and reaction time as well as work-up,are optimized to solve the problems of incomplete reaction and improve the yield of the product.In the Borch reduction reaction,the reaction factors including the reaction molar ratio,the reaction temperature,the reduction time of NaBH4 and work-up,are optimized to reduce the main impurity of the product.Moreover,combining the two-step reaction into one-step process simplifies the operation.In the reaction of generating lapatinib ditosylate,the reaction factors that reaction solvent,the reaction molar ratio,reaction time and reaction temperature,are optimized to cut down the reaction time and improve the yield and purity of the product.In the research on the form of lapatinib ditosylate monohydrate,we compare the advantages and disadvantages of three kinds of methods for preparing the form,and select the method for in-depth study,which has easy operations,a relative good yield,and the form has not been confirmed yet.Through a microscope,TGA-DSC and XRPD to explore the crystallization process,we obtain a new method for preparing the pharmaceutical form of lapatinib ditosylate monohydrate.In this paper,the synthetic process of lapatinib ditosylate monohydrate is optimized to increase the total yield from 43.20%to 85.83%.Surprisingly,the purity of the final product has reached over 99.89%.Finally,in the study of process amplification,the stability of the yield and purity of the product at the level of 50-100g is explored and optimized to achieve a stable amplification process route at the level of 100g,which provides reliable datas for the pilot.All the products were characterized by 1H-NMR,MS and their structures were confirmed.The form of lapatinib ditosylate monohydrate was characterized by XRPD and TGA-DSC.