Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

Abstract

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 SNAr 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%.

Trendbericht Organische Chemie 2024

“…52) Dass Flowsynthese in mehrstufigen Synthesen nützlich ist, zeigen die effizienten Synthesen von Dithiothreitol (DTT), 53) des HIV-Integrase-Inhibitors Dolutegravir (11) 54) und des CB2-Agonisten RG7774 (12). [55][56] Mehrstufige automatisierte Synthesen komplexer Zielmoleküle, die durch Bayes'sche Optimierung gesteuert werden, stellten Baldwin 57) und Bourne 58) vor.…”

The role of PAT in the development of telescoped continuous flow processes

“…Recently, an example of the use of in-line UV-vis spectrometry as PAT from Kappe and co-workers was published, in collaboration with Roche (Scheme 25). 67,68 A new route towards the cannabinoid receptor type 2 agonist, RG7774 68, was developed using a combination of batch and continuous flow processing, containing a total of seven reaction steps. Of relevance to this review was the use of inline UV-vis spectrometry as a PAT tool for the monitoring of the outflow, containing 69, from an intermediate amine scavenging treatment, which was telescoped with the final nucleophilic aromatic substitution step in flow.…”

“…Scheme 25 Telescoped amine scavenging with nucleophilic aromatic substitution in flow using in-line UV-vis spectrometry developed by Kappe and co-workers 67,68. …”

Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 1: Azidation and [3 + 2] Cycloaddition

“…The onward chemical steps to the API in flow are described in an accompanying article ("Part 2"). 7 With the in situ formation and consumption of benzylic azide cycloaddition partner 2 in mind, the use of continuous flow has clear advantages in both safety and reaction throughput. 8 By minimizing the reactive inventory, combined with the absence of headspace and mechanical stirring, the risk of explosive decomposition of azide species (metal/organic azides or hydrazoic acid) is avoidable.…”

“…The present article discusses the development of a 2-step continuous sequence in which benzylic azide 2 is formed and cyclized with cyanoacetamide 3 to furnish triazole intermediate 4 (Figure b, steps highlighted in blue). The onward chemical steps to the API in flow are described in an accompanying article (“Part 2”) …”