Efforts toward optimization and improvement for the synthesis of LCZ696 employing design of experiment (DoE) principles are described. By increasing the purity of intermediates and mitigating impurity risk during each step, a telescoped process was developed via removal of isolation of intermediates with the overall yield increased by 28.5% from 45.3% to 73.8%. And the whole production cycle was also shortened from 12 days to 7 days with simplified operations and restored process greenness. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.

中文翻译：

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通过采用按质量设计（QbD）原则对LCZ696进行优化和工艺改进

描述了采用实验设计（DoE）原理优化和改进LCZ696合成的努力。通过提高中间体的纯度并降低每个步骤中的杂质风险，通过去除中间体的分离作用开发了一种伸缩方法，其总收率从45.3％增至73.8％，增幅为28.5％。整个生产周期也从12天缩短为7天，简化了操作并恢复了过程的绿色。同时，对相应的杂质分布进行了详细研究并充分记录。