沙库必曲中间体(R)-2-(叔丁氧羰基氨基)-3-(联苯-4-基)丙醇的合成

Synthesis of The Intermediate of Sacubitril,(R)-2-(t-Butoxycarbonylamino)-3-(biphenyl-4-yl)-propan-1-ol

采用D-酪氨酸衍生物为原料,与苯磺酰氯反应制得叔丁氧羰基保护的D-苯丙氨醇苯磺酸酯,经还原,再在5 mol%N-杂环卡宾(NHC)钯催化剂(IMes)Pd(Py)Cl作用下与苯硼酸经过Suzuki-Miyaura偶联反应得到沙库必曲重要中间体(R)-2-(叔丁氧羰基氨基)-3-(联苯-4-基)丙醇,总产率大于57%,ee值大于99%。

Using D-tyrosine derivatives as raw materials,and tert-butoxycarbonyl protected D-phenylalaninol benzene sulfonate was generated in the reaction with benzyl sulfonyl chloride.After reduction,the target product was generated in the presence of 5mol%palladium catalyst(IMes)Pd(Py)Cl under the reaction of phenyl boronic acid by Suzuki-Miyaura coupling reaction.The key intermediate of Sacubitril,(R)-2-(t-Butoxycarbonylamino)-3-(biphenyl-4-yl)-propan-1-ol,was prepared with the overall yield of more than 57%.Both the chemical purity and optical purity are more than 99%.