Desvenlafaxine succinate

Description

Desvenlafaxine Succinate is a dual serotonin and norepinephrine reuptake inhibitor (SNRI) that was approved for the treatment of major depressive disorder (MDD) in the United States in 2008. In order to improve the efficacy and safety profile of venlafaxine, Wyeth discovered and developed one of the major metabolites of venlafaxine, namely the O-desmethyl metabolite (desvenlafaxine). Desvenlafaxine is also being developed for the treatment of moderate to severe vasomotor symptoms associated with menopause (i.e., hot flashes and night sweats) and is also in phase III clinical trials to study it’s effectiveness in treating fibromyalgia and neuropathic pain.

Uses

Antianxiety therapeutic

Synthesis

Desvenlafaxine has been prepared via two different routes, and both are described in the scheme. The first route involved simple demethylation of venlafaxine (67) using L-selectride in dimethoxyethane giving desvenlafaxine 68 as its free base in 91% yield. Compound 68 was then recrystallized with succinic acid in acetone/ water to give desvenlafaxine succinate (VIII) in 86% yield. An alternative method to prepare desvenlafaxine is described in the bottom portion of the scheme. 4-Benzyloxyphenylacetic acid 69 was converted to its corresponding acid chloride upon treatment with thionyl chloride and catalytic DMF in refluxing methylene chloride. The crude reaction mixture was added to a solution of dimethylamine hydrochloride and triethyl amine in methylene chloride at 5 ??C to give dimethylacetamide 70 in 90% yield. Deprotonation of 70 with LHMDS in THF at -70 ??C followed by addition of cyclohexanone gave alcohol 71 in 82% yield. Reduction of the acetamide with borane THF complex in refluxing THF produced dimethyl amine 72 in 66% yield. Catalytic hydrogenation in the presence of 20% Pd/C effected debenzylation of 72 to give desvenlafaxine free base 68 in 87% yield.