沙库巴曲的工艺优化

Process optimization of Sacubitril

摘要:

对沙库巴曲的制备工艺进行了工业化改进，以商业化产品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，CAS:1426129-50-1)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, CAS: 149709-62-6)。对关键的氢化步骤做了反应溶剂、添加剂、催化剂、温度、压力、时间，以及重结晶溶剂等反应参数进行了详细的筛选，确定了一条适合工业化生产的工艺路线，并用该路线进行了连续三批公斤级的放大。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%；目标产物沙库巴曲总收率约50%，产物经HPLC检测，纯度100%。

Abstract:

The preparation process of Sacubitril was industrially improved. The commercial product N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid 1,1-dimethylethyl ester (compound Ⅰ, CAS:1426129-50-1) was used as starting material. The intermediate V was obtained by TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) oxidation, Wittig reaction, deethyl ester and recrystallization. The key intermediate Ⅵ was obtained by recrystallization with m(n-heptane)∶m (ethyl acetate) = 1∶1 after hydrogenation reduction of Pd/C. Finally, the target product Sacubitril (compound Ⅷ, CAS: 149709-62-6) was obtained by amidation after protection with ethyl ester. The key hydrogenation step was selected in detail in terms of reaction parameters such as solvents, additives, catalysts, temperature, pressure, time, and recrystallization solvents. A process route suitable for industrial production was determined, and three batches of kilogram scale in succession were carried out. The chiral structure of the key intermediate Ⅵ was analyzed by chiral HPLC, and the chiral purity was 99.98%. The total yield of the target product was about 50%, and the purity of the product was 100% by HPLC detection.