沙库巴曲的工艺优化

Process optimization of sacubitril

以N-[(1R)-2-[1,1′-联苯]-4-基-1-(羟基甲基)乙基]氨基甲酸叔丁酯(化合物Ⅰ)为起始原料,经TEMPO(2,2,6,6-四甲基哌啶氧化物)氧化、Wittig反应和脱乙酯,重结晶后得到中间体Ⅴ;接着经10%Pd/C氢化还原后用m(正庚烷)∶m (乙酸乙酯)=1∶1重结晶得到关键中间体Ⅵ;最后经乙酯保护,酰胺化缩合得到目标产物沙库巴曲(化合物Ⅷ)。对关键氢化步骤的反应溶剂、添加剂、催化剂用量、反应温度、H_(2)压力、反应时间以及重结晶溶剂等反应参数进行了筛选,关键中间体Ⅵ的手性结构经手性HPLC方法分析,手性纯度99.98%;目标产物沙库巴曲的总收率约50%,产物经HPLC检测,纯度达100%。

N-[(1R)-2-[1,1’-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] carbamate tert-butyl ester(compound Ⅰ) was oxidized by TEMPO(2,2,6,6-tetramethylpiperidinooxy), followed by Wittig reaction, and ethyl ester removal, and then recrystallized to obtain intermediate Ⅴ. Key intermediate Ⅵ was obtained by recrystallization with mixed solvent [m(n-heptane)∶m(ethyl acetate) = 1∶1] after hydrogenation reduction of intermediate Ⅴ by 10%Pd/C. Finally, target product sacubitril(compound Ⅷ) was obtained by amidation after protection with ethyl ester. The reaction parameters such as solvent, additive, catalyst dosage, reaction temperature, H_(2) pressure, reaction time and recrystallization solvent affecting the key hydrogenation for the synthesis of intermediate Ⅵ were investigated. And a process route suitable for industrial production was determined and used to carry out three batches of kilogram scale. The chiral structure of key intermediate Ⅵ was analyzed by chiral HPLC, and the chiral purity was 99.98%. The target product had total yield of about 50% with a purity of 100% by HPLC.