The Synthesis Of N-arylquinazolin-2-amine

Hepatocellular carcinoma(HCC)is an complex and diverse malignancies,accompanied by a variety of genetic and epigenetic changes[1].Fifty six million Chinese died of HCC each year,accounting for 45%of the number that died of HCC every year in the world,which result in that China is the highest HCC incidence country[2].Fibroblast growth factor receptor 4 can start the HCC tumor growth,especially when it is highly expressed or lead to structural activation by gene mutation,ultimately,lead to tumor cell's proliferation and growth.[3-4]Therefore,FGFR4 inhibitors will play a important role in HCC treatment.Cancer discovery reported that BLU9931 is the first FGFR4 inhibitors developed by blueprint.As the first high selective FGFR4 inhibitors,BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19[5].N-arylquinazolin-2-amine is the key intermediate of compound BLU9931.It is necessary and important to develop a new synthesis route that simple,economical and green for BLU9931 and its intermediate.Until now,there is only one reported synthesis method for BLU9931 and N-arylquinazolin-2-amine which developed by Blueprint in 2015.In this method,2-amnio-5-bromobenzoic acid can get N-arylquinazolin-2-amine by oxidation,addition,substitution,Suzuki coupling,chlorination,Buchwald-Hartwig coupling.Afterwards BLU9931 can be obtained from N-arylquinazolin-2-amine by reductive amination,acylation,and the total yield is 5%.There are many negative factors in this route.Firstly,it is dangerous to use Borane and phosphorus oxychloride.Secondly,there is a harsh operating conditions when use Buchwald-Hartwig Coupling which Limit the amount of production.Thirdly,it's low total yield limit us obtaining large number of product to resach.Finally,Expensive catalyst and feedstock made this route too expensive to accord atomic economic criteria and violated green chemistry.In summary,it is necessary to develop an efficient and affordable Synthesis route of BLU9931 and N--arylquinazolin-2-amine.In our study,we got N-arylquinazolin-2-amine from cheap 3-bromobenzaldehyde though nitration,reductive amination,addition,suzuki coupling,substitution,chlorination,and the total yield is 26.6%.Our success in efficient synthesising of N-arylquinazolin-2-amine means the synthesis of BLU9931 can be achieve in a efficient,affordable and security ways.Finally,we obtained N-arylquinazolin-2-amine from 3-bromobenzaldehyde in yield 27%and got BLU9931 in a total yield 17%.All of compound affirmed by 1H NMR,MS,HPLC.