Viloxazine Hydrochloride: Synthesis and Introduction

Synthesis of Viloxazine Hydrochloride

Viloxazine hydrochloride was synthesised using 2-ethoxyphenol as a raw material by a 4-step reaction. The specific synthesis steps are as follows:

In the first step, 2- ethoxyphenol 9.1 was treated with epichlorohydrin 9.2 in the presence of potassium carbonate and a phase-transfer catalyst (n-Bu₄NHSO₄) to produce epoxide 9.3 in a nearly quantitative yield. Next, epoxide 9.3 wassubjected to 2-aminoethyl hydrogen sulfate 9.4 in the presence of a strong base, triggering epoxide ring opening and subsequent cyclization to 2-morpholine 9.5 in 40% yield. Finally, the free-base amine 9.5 was treated with concentrated hydrochloric acid to prepare a salt that was recrystallized from aqueous isopropanol/EtOAc, delivering viloxazine hydrochloride in 99% purity.

Introduction of Viloxazine Hydrochloride

In April 2021, the USFDA approved viloxazine extended release (ER) capsules for the treatment of ADHD in pediatric patients aged 6−17 years. Viloxazine ER, discovered by Rune Healthcare and developed by Supernus Pharmaceuticals, is a novel formulation of an API marketed in the 1970s in Europe as an antidepressant for adults. The antidepressant (immediate release formulation) was discontinued in the early 2000s for business reasons unrelated to the safety or efficacy of the drug. Viloxazine is a selective norepinephrine reuptake inhibitor and also exhibits agonistic and antagonistic effects on serotonin receptors 5-HT_2Cand 5-HT_2B.

An in vivo study of viloxazine demonstrated an increase in extracellular 5-HT in the prefrontal cortex, a brain area associated with ADHD. Currently available ADHD treatments consist of stimulant and non-stimulant drugs. Viloxazine ER is the first non-stimulant drug approved to treat ADHD in nearly a decade and is an important addition to the available treatments of ADHD due to its tolerability and favorable pharmacokinetics.