Optimized synthesis of suvorexant and determination of eight residual solvents by headspace gas chromatography

This study presents an optimized synthetic pathway for suvorexant and establishes a robust method for the simultaneous determination of residual solvents. The synthesis commenced with chiral precursors, specifically (<i>R</i>)-3-(BOC-amino)butyric acid and <i>N</i>-benzyl glycine ethyl ester, employing a fragment splicing strategy. The target compound was synthesized through a sequence of nucleophilic reactions, BOC deprotection, cyclization, reduction, BOC protection, affinity substitution, and subsequent nucleophilic reactions, thereby circumventing the need for chiral separation. The post-treatment process was refined <i>via</i> recrystallization to yield the active pharmaceutical ingredient (API). For residual solvent analysis, a headspace gas chromatography (HS-GC) method was developed, utilizing a DB-624 capillary column (30 m × 0.53 mm, 3 μm) with programmed temperature control. The chromatographic conditions included an inlet temperature of 220 °C and a detector temperature of 280 °C, with detection <i>via</i> hydrogen flame ionization. The final product exhibited a purity of 99.92% and an overall yield of 65%. The HS-GC method demonstrated excellent resolution (<i>R</i> > 1.5) for eight residual solvents, including <i>n</i>-heptane, with linearity (<i>r</i> > 0.990) across the specified range, average spiked recoveries between 85-115%, and relative standard deviations (RSD) below 5.0%. The optimized synthesis is characterized by cost-effectiveness, operational simplicity, and high yield, rendering it suitable for industrial-scale production. The established HS-GC method exhibits high specificity and sensitivity, making it a reliable approach for residual solvent quantification.