Mechanochemical synthesis of antihistamine active pharmaceutical ingredient cinnarizine

Abstract

Mechanochemical methods are recognized as an appealing, greener methods for producing various molecular compounds. It has gained significance across multiple disciplines, such as chemistry and material science, due to its eco-conscious nature, allowing it to be performed without solvents or with only minimal amounts of solvent. Mechanochemical approaches also stand out as a prominent synthetic approach, enabling efficient and rapid processes compared to conventional synthesis approaches. Their synthetic capabilities through a range of solid-state transformations, yielding diverse compounds including inorganic, organic, polymeric, metal-organic-framework, and organometallic materials, have been proved over the decades. Yet another captivating illustration of mechanochemical reactions is seen in the effective pharmaceutical drugs and medicine preparations. This upward trajectory is evident in the increasing adoption of solid-state methodologies within pharmaceutical material science. These mechanochemical attempts are branched under a recently emerging field, namely “medicinal mechanochemistry,” and have been quite efficient in the synthesis of active pharmaceutical ingredients (APIs) and drugs such as paracetamol. They are also employed for the alteration of APIs through processes like the formation of salts or cocrystals. However, a synthetic pathway of many APIs in which mechanochemistry is used as a bimolecular solid-state reaction initiator, is not available yet. Here, we show that utilizing ball milling of the reactants through a simple SN2 reaction a first generation H1 antihistaminic API, cinnarizine, can be synthesized in moderate yields (25-50%). The milling and reaction parameters are explored in terms of product yields and a comparison with a conventional synthetic route is also provided. Milling produces cinnarizine in 1-60 minutes, compared to conventional organic synthesis, 4-24 hours. This route brings an innovative perspective to synthesizing widely used APIs in medicinal mechanochemistry and its potential applications in industry.