We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet–Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH₂O in the Pictet–Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.

中文翻译：

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迈向EMA401的可扩展综合和过程，第I部分：后期过程开发，路线侦察和ICH M7评估

我们提出钠（3 S）-5-（苄氧基）-2-（二苯基乙酰基）-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸盐（EMA401，olodanrigan），一种血管紧张素II 2型拮抗剂。该手稿的特点是对用于后期临床用品的最终游戏进行了工艺优化，概述了在侦查关键中间体苯丙氨酸衍生物的路线中确定的合成策略，以及潜在形成的剧毒双（双氯甲基）的分析控制策略。 ）醚（BCME）。从苯丙氨酸衍生物开始，我们描述了从早期阶段到后期阶段的最终过程的优化，并因此改善了PMI因子。该序列包括Pictet-Spengler环化和酰胺偶联，这是最后一个形成键的步骤，并且在试点工厂中成功完成了175千克规模的制造过程。修改后的工艺条件消除了第一步羧酸的原位活化，避免了REACH列出的溶剂DMF，并导致PMI改善了3倍。在最终结晶中，在复杂的固体中发现了新的，热力学上更稳定的原料药广泛的多晶型物筛选过程中EMA401的状态图。开发了一种适合大规模生产的方法来制备新的多晶型物，从而避免了任何特殊设备的需求，例如早期工艺所需的流化床干燥。在第二部分中，介绍了一些用于苯丙氨酸衍生物关键中间体的路线筛选的合成方法。总而言之，我们讨论了BCME的分析控制策略，由于同时存在HCl和CH，形成了BCME。₂ Ø在百达-斯宾格勒环化，不能被排除。将使用ICH M7控制选件4的工具计算的BCME净化因子与加标实验的实际结果进行了比较。