Optimized Synthesis of Suvorexant and Determination of Eight Residual Solvents by Headspace Gas Chromatography

Abstract

An efficient and industrially viable synthetic pathway for suvorexant was established through a fragment coupling approach utilizing chiral precursors, specifically (R)-3-(BOC-amino)butanoic acid and N-benzyl glycine ethyl ester. The synthesis encompassed a series of sequential steps, including nucleophilic substitution, BOC deprotection, cyclization, reduction, BOC protection, affinity substitution, and a final nucleophilic reaction, culminating in the target compound without necessitating chiral separation. The purification process was refined through recrystallization to effectively eliminate impurities. Concurrently, a Headspace Gas Chromatography (HS-GC) method was developed for the simultaneous quantification of eight residual solvents, including n-heptane, employing a DB-624 capillary column (30 m×0.53 mm, 3 μm) coupled with flame ionization detection. The method exhibited superior resolution (all >1.5), robust linearity (r > 0.990), satisfactory recovery rates (85–115%), and high precision (RSD < 5.0%). The final product attained a purity of 99.92% with an overall yield of 65%. These results substantiate the proposed synthetic route as a practical and scalable methodology, and the validated HS-GC method as a sensitive and specific tool for routine residual solvent analysis in suvorexant

Keywords: Synthetic Process Optimization, Suvorexant, gas chromatography, Headspace Sampling, Residual Solvents