Intensified Continuous Flow Synthesis and Workup of 1,5-Disubstituted Tetrazoles Enhanced by Real-Time Process Analytics

Abstract

Continuous flow processing presents a solution for the safe and effective formation of 1,5-tetrazoles due to the small reactive inventory and absence of a reactor headspace. This has been exemplified using a model amide, 2-chloro-N-methylacetamide, activated using POCl3 to its corresponding imidoyl chloride, which reacts with trimethylsilyl azide. Initial scoping revealed that an excess of azide is vital to facilitate a clean reaction but also that a high concentration would dramatically accelerate the reaction without the need for greatly elevated temperature. In a short residence time of 10 min, complete conversion was achieved, resulting in 77–86% yield of the desired product in high purity (>99.7%) after recrystallization, omitting any chromatographic purification. The developed process reached an excellent space–time yield (1.16 kg L–1 h–1) due to its high concentration and short residence time. Successful technology transfer included development of a continuous workup, with pH-controlled quench in a CSTR, followed by extraction. During flow optimization, two orthogonal PAT methods were separately employed, NMR and FTIR, enabling real-time starting material and product quantification. Finally, the developed reaction protocol was demonstrated on a number of other substrates, achieving high yields in most cases, up to quantitative.

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…Sagmeister and co-workers 70 demonstrated real time process analytics and inline workup in the safe and effective continuous flow synthesis of 1,5 disubstituted-tetrazoles (Fig. 19).…”

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

“…5 The synthesis of tetrazole chloride intermediate 1 was recently reported in continuous flow, benefiting from high temperature processing with an improved safety profile. 6 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 1b, steps highlighted in blue). The onward chemical steps to the API in flow are described in an accompanying article ("Part 2").…”

Understanding the regioselectivity of 5-substituted 1H-tetrazoles alkylation

“…In contrast to 1,5-disubstituted tetrazoles (1,5-Tz), for which many methods are available to produce the desired compounds in high yields, 6 it remains a challenge to synthesize 2,5-Tz via a cycloaddition process. 7 Not only are these condensation reactions limited in the synthesis of N -aryl substituted 2,5-Tz, but functional groups such as amines or alcohols are also not compatible.…”