A new route to the cannabinoid receptor type 2 agonist, RG7774, has been developed circumventing an alkylation with poor regioselectivity as the final step. In the new synthetic route, this side chain is incorporated from the beginning. In this article, the development of the final four transformations is detailed, using a combination of batch and flow processing. Due to poor solubility, an N-pivaloylation was performed in batch, followed by cyclization at up to 200 °C, enabled by flow processing. The following chlorination and S_NAr steps were examined in both batch and flow for improved handling of hazardous reagents and intermediates, as well as enhanced heat transfer. A workup between these two steps was found to be vital in preventing side product formation from residual dimethylamine. To achieve this on a laboratory scale, a continuous solid phase treatment was developed, whereby two cation exchange columns (containing SCX-2 silica) were cycled, with monitoring by UV/vis analysis. These four steps were demonstrated with a combined yield of 72%, which serves as a significant positive contribution to the new route’s high overall yield of 53%.

中文翻译：

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连续流动促进的 CB2 激动剂合成，第 2 部分：环化、氯化和胺化

已经开发出一种通往大麻素受体 2 型激动剂 RG7774 的新途径，该途径绕过了区域选择性差的烷基化作为最后一步。在新的合成路线中，这条侧链从一开始就被纳入。在本文中，结合使用批处理和流处理，详细介绍了最后四种转换的开发。由于溶解度差，N-新戊酰化分批进行，然后在高达 200 °C 的温度下进行环化，通过流动处理实现。下面氯化和S _N对批次和流程中的 Ar 步骤进行了检查，以改进对危险试剂和中间体的处理，以及增强热传递。发现这两个步骤之间的后处理对于防止残留二甲胺形成副产物至关重要。为了在实验室规模上实现这一目标，开发了连续固相处理，其中循环使用两个阳离子交换柱（含有 SCX-2 二氧化硅），并通过 UV/vis 分析进行监测。这四个步骤的综合收率为 72%，这对新路线 53% 的高总收率起到了显着的积极贡献。