Systhesis Of The Key Intermediate Of Preladenant

Preladenant is a new effective drug for anti-Parkinson’s disease developed by Merck, and it is still in the phase II clinical stage. However Preladenant is increasingly becoming hot issues at home and abroad because of its potentiality in Parkinson’s disease.1-(4-(2-methoxyethoxy)phenyl)piperazine is an important intermediate in the synthesis of Preladenant.This project put forward a new synthetic method of1-(4-(2-methoxyethoxy)phenyl)piperazine hydrochloride and made some optimizations on the basis of the proposed route reported. In this paper, N-(4-hydrophenyl)acetamide was taken as the raw material and after three reactions-etherification, hydrolysis and cyclization literally, the target compound1-(4-(2-methoxyethoxy)phenyl)piperazine hydrochloride would be obtained. Comparing with the reported literatures, the innovations of this paper were as follows:First of all, the reaction route was shortened, with a high yield.During the process of synthesizing N-(4-(2-methoxyethoxy)phenyl)acetamide, with the catalysis of NaBr, the traditional expensive etherification reagent2-bromoethyl methyl ether was replaced by much cheaper2-chloroethyl methyl ether, respectively. On the other hand, during the process of hydrolysis, basic hydrolysis was recoomended because of its high yield and drcrease in corrosion compared with acid hydrolysis.The effect of temperature and solvents, the ratio of substrate in each step and other factors on yield were investigated, and the optimal reaction conditions were obtained. The etherification reaction using2-chloroethyl methyl ether as etherification reagent, NaBr as catalyst and N,N-Dimethylformamide as sovlent was carried out at90℃for30h, and86.0%yield was obtained. The hydrolysis reaction using sodium hydroxide as catalyst was carried out at80℃for25h in a mixed sovlent of methanol and water(Vmethanol:Vwater=1:1), and the product was obtained in94.9%yield.In the final step, sodium carbonate was used as acid-capturer and n-butanol was used as sovlent. Cyclization was carried out at reflux for40h, and58.0%yield was obtained.The overall yield was no less than47.4%. The process is much of industrial value because of high yield, cheap and available materials and convenient operations. The purity and structure obtained were confirmed by GC, HPLC and1H-NMR.A new method was designed to improve the cyclization reaction for the low yield: the amine group of bis(2-chloroehtyl)amine hydrochloride was protected by4-toluene sulfonyl chloride, then cyclization and deprotection. Some preliminary exploration was also carried out.