Sustainable Synthesis of a Potent and Selective 5-HT₇ Receptor Antagonist Using a Mechanochemical Approach

Abstract

A mechanochemical procedure was developed to obtain PZ-1361 , a potent and selective 5-HT 7 receptor antagonist, with antidepressant properties in rodents. The elaborated protocol offered several advantages over classical batch synthesis, including improvement of the overall yield (from 34% to 64%), reduction of reaction time (from 60 to 5.5 h), limitation of the use of toxic solvents, and the formation of byproducts. This approach represents a rare example of the synthesis of biologically active compounds exclusively performed using mechanochemical reactions.

Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry

“…[21,[29][30][31][32][33][34][35] In this context, a recent study on the synthesis of the biologically active compound PZ-1361 clearly illustrates the benefits of applying ball milling techniques in organic synthesis (Scheme 1). [36] Compared with the classical protocol in solution to access PZ-1361, the mechanochemical route afforded the product faster, in higher yield, and with better green chemistry metrics (Scheme 1). [36] Similarly, quantitative solid-gas mechanochemical reactions can ease the isolation of the products while producing less waste.…”

“…[36] Compared with the classical protocol in solution to access PZ-1361, the mechanochemical route afforded the product faster, in higher yield, and with better green chemistry metrics (Scheme 1). [36] Similarly, quantitative solid-gas mechanochemical reactions can ease the isolation of the products while producing less waste. [37]…”

“…In this context, a recent study on the synthesis of the biologically active compound PZ‐1361 clearly illustrates the benefits of applying ball milling techniques in organic synthesis (Scheme 1). [36] …”

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties

“…Hence, the final compounds 6-19 were obtained by milling equimolar amounts of starting materials in the presence of K 2 CO 3 in moderate-to-high yields (65-94%). According to our previously reported findings on sulfonamide bond formation in the solid-state [29], sulfonylation of the primary amine function was significantly influenced by the nature of the substituent on the phenyl ring of the sulfonyl chloride. Regardless of the type of central amine core, the presence of 4-F and 3-Cl substituents enabled the formation of compounds 6, 7, 14 and 15 with high conversion rates in a relatively shorter time (1 min) than all other tested analogs (see Table S3).…”

“…Having identified the optimal reaction conditions, the same mechanochemical protocol was applied for the alkylation of Boc protected 4-aminomethylpiperidine to obtain intermediate 3 (96% purity) in a satisfactory yield (81%) (see Table S2). In the next step, primary amine derivatives 4 and 5, obtained upon treatment of Boc-derivative 2 and 3 with gaseous HCl [29,30], reacted in a ball mill with different substituted arylsulfonyl chlorides to generate the designed sulfonamide derivatives. Scheme 1.…”