Synthesis of 5-Substituted 1H-Tetrazoles from Nitriles by Continuous Flow: Application to the Synthesis of Valsartan

Abstract

An efficient continuous flow process for the synthesis of 5-substituted 1H-tetrazoles is described. The process involves the reaction between a polymer-supported triorganotin azide and organic nitriles. The polymer-supported organotin azide which is in situ generated with a polystyrene-supported triorganotin alkoxide and trimethylsilylazide, is immobilized in a packed bed reactor. This approach is simple, fast (it takes from 7.5 to 15 min) and guarantees a low concentration of tin residues in the products (< 5 ppm). The process was developed to aryl-, heteroaryl-and also alkylnitriles and was applied for the synthesis of valsartan, an angiotensin II receptor antagonist.

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

“…Continuous flow chemistry has been previously used successfully for esterification reactions by diazotization of amines. 14,19 In the case of 1 H -5-monosubstituted tetrazole alkylation, the use of the continuous flow technology was complicated by solubility problems with the substrates. Nevertheless, using THF as solvent, the continuous flow reaction could be performed at 140 °C with a residence time of 15 min, to produce 57% of 1a and 14% of 1b (Scheme 4).…”

Advances in Tetrazole Synthesis – An Overview

“…Substituted alkyl and aryl derivatives can be successfully prepared in less reaction time and can be easily isolated in high purity with a small concentration of tin residues. [126] Copper complexes were applied for [3 + 2] cycloaddition and A 3 -coupling reactions by Singh et al. [127] The salen-type ligands and metals act through active participation to provide catalytic reactions efficiently.…”

“…The reaction of trimethylamine, benzonitrile, and tributyltin azide afforded the tetrazole a 93 % yield. Substituted alkyl and aryl derivatives can be successfully prepared in less reaction time and can be easily isolated in high purity with a small concentration of tin residues [126] …”

Transition Metal Exchanged Hydroxyapatite/Fluorapatite Catalysts for C−C and C−N Bond Forming Reactions

“…We considered using the present catalytic system for the synthesis of 5‐susbtituted 1H‐tetrazoles in comparison to its conventional synthesis by (2+3)‐cycloaddition between an azide and a nitrile, [53] where strong Lewis acids and toxic metals are involved. Tetrazoles are an important pharmaceutical moieties due to their significant role in supramolecular and coordination chemistry, and in medicinal chemistry as carboxylic acid isosteres as they enhance the activity and availability of the active pharmaceutical ingredient [54] . Demko and co‐workers, [55–57] reported an innovative catalytic system for the synthesis of tetrazoles by using Zn salts as catalyst by addition of sodium azide to nitriles.…”