Study On The Synthesis Of Ambrisentan

Ambrisentan developed by Denver Myogen biological pharmaceutical companies of United States,is a kind of selective endothelin receptor antagonist,which is used to treat Pulmonary arterial hypertension. According to competitine binding experiments of ETA receptors, Ambrisentan has a strong ETA receptor antagonist activity.But, the synthetic route of Ambrisentan is very complex, the synthesis conditions are harsh, and the cost of raw materials is higher,it can not meet market demand.For example, boron trifluoride diethyl ether need carefully carry out the reaction under anhydrous and oxygen-free conditions. Chiral separation of chlorine phenylethylamine is byproduct of BASF process. It failed to find suppliers in the domestic market, which greatly limits the use of such drugs.Compared to previous reaction process, we have made bold improvement, by changing the reagents and solvents. In this paper, benzophenone and methyl chloroacetate as raw materia,l went through Darzens reaction, epoxidation ring opening reaction, ester hydrolysis reaction, chiral resolution reaction, nucleophilic substitution reaction, having successfully synthesized S active configuration Ambrisentan. In this paper, we use p-toluenesulfonic acid monohydrate as catalyst of epoxidation ring opening reaction, to replace boron trifluoride diethyl ether; We use L- proline methyl ester hydrochloride as a chiral resolving agent to react with 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid. L- proline methyl ester hydrochloride is very cheap and has rich source.We use recrystallization method to purify the target product ambrisentan. By purification,the purity and chromaticity of target product has been greatly improved. Liquid purity. can reach more than 95% through determining the chiral purity of the compound by chiral column.In this paper, we have optimized the synthetic process and have discussed the factors influenced the reaction yield in every step.By changing a single variable method, we draw the conclusion. In Darzens reaction,the optimum temperature,time,and solvent is 0℃, 6h and Methyl tert butyl ether,respectively. In epoxidation ring opening reaction,the optimum catalyst is p-toluenesulfonic acid monohydrate, its dosage is 3mmol and the optimum,reactiong time is 5h. In ester hydrolysis reaction, the optimum temperature,time,and alkaline reagent, is 94℃, 3h and KOH, respectively. In chiral resolution reaction, the dosage of Methyl tert butyl ether is 30 ml, optimum, time 3h, and the molar ratio of 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid wih L- proline methyl ester hydrochloride is 1:1.2. In nucleophilic substitution reaction, the optimum alkaline reagent, solvent, time is sodium hydride, N,N-dimethylformamide and 6h, respectively.In this paper, we redesigned the scheme by changing the synthetic route. Compared with precious synthetic method, we get the reason why it is not suitable for process synthesis.Under laboratory conditions, we completed experimental study of amplifying, which has improved product yield and purity. We accounted for the raw material costs on basis of market price, and concluded the importance of solvent recovery.The chemical structure of Ambrisentan is correct, detected by M.p, UV, FTIR, NMR.