Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 1: Azidation and [3 + 2] Cycloaddition,Organic Process Research & Development

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Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 1: Azidation and [3 + 2] Cycloaddition
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-03-30 , DOI: 10.1021/acs.oprd.3c00035
Peter Sagmeister _{1,

2} , Michael Prieschl _{1,

2} , Dainis Kaldre ₃ , Chethana Gadiyar ₄ , Christian Moessner ₃ , Joerg Sedelmeier ₃ , Jason D. Williams _{1,

2} , C. Oliver Kappe _{1,

2}

Affiliation

We report the use of continuous flow processing to enable the first two steps of a new route toward a cannabinoid receptor type 2 agonist, RG7774. First, an alkyl azide is formed using sodium azide at an elevated temperature. Flow processing allows this to be done in a safe and rapid manner, providing a quantitative yield in 1 min residence time. The subsequent [3 + 2] cycloaddition with 2-cyanoacetamide requires basicity within a fairly narrow range to facilitate the reaction while preventing the decomposition of starting materials. A kinetic model was proposed for the cycloaddition step, with validation in both batch and flow. Three different flow reactor setups were then examined to emulate combinations of plug flow reactors (PFRs) and continuous stirred tank reactors (CSTRs). The use of CSTRs enables operation above the solubility limit of the product, improving the mass intensity and productivity. The desired triazole product can consistently be isolated in ∼80% yield with >99% purity and ∼9.5 g/h productivity. This serves to lay the foundation for the remaining route development to RG7774. Furthermore, the developed kinetic models are used as a basis for the proposed scale-up setup of a combined PFR (1 L) + CSTR cascade (3 × 5 L) for a pilot scale, which would produce up to 8.9 kg/h of the triazole product.

中文翻译：

连续流动促进的 CB2 激动剂合成，第 1 部分：叠氮化和 [3 + 2] 环加成

我们报告了使用连续流处理来实现通往大麻素受体 2 型激动剂 RG7774 的新路线的前两个步骤。首先，在高温下使用叠氮化钠形成烷基叠氮化物。流动处理允许以安全和快速的方式完成此操作，在 1 分钟的停留时间内提供定量产量。随后与 2-氰基乙酰胺的 [3 + 2] 环加成需要相当窄范围内的碱度以促进反应，同时防止起始材料的分解。为环加成步骤提出了一个动力学模型，并在批次和流程中进行了验证。然后检查了三种不同的流动反应器设置，以模拟活塞流反应器 (PFR) 和连续搅拌釜反应器 (CSTR) 的组合。使用 CSTR 可以在产品的溶解度极限以上进行操作，从而提高质量强度和生产率。所需的三唑产物可以始终如一地以 ~80% 的产率、>99% 的纯度和~9.5 g/h 的生产率分离。这为RG7774的剩余航线开发奠定了基础。此外，开发的动力学模型被用作中试规模的 PFR（1 L）+ CSTR 级联（3×5 L）组合的放大设置的基础，这将产生高达 8.9 kg/h 的三唑类产品。

更新日期：2023-03-30

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