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

## TL;DR

This paper describes a more efficient way to make the drug suvorexant and a reliable method to test for leftover solvents in the final product.

## Contribution

An optimized synthesis of suvorexant and a validated HS-GC method for residual solvent analysis are introduced.

## Key findings

- The optimized synthesis achieved 65% yield and 99.92% purity without chiral separation.
- The HS-GC method detected eight residual solvents with high resolution and accuracy.
- The method showed linearity (r > 0.990) and recoveries between 85–115% with RSD < 5.0%.

## Abstract

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 (R)-3-(BOC-amino)butyric acid and N-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 via 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 via 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 (R > 1.5) for eight residual solvents, including n-heptane, with linearity (r > 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.

This study presents an optimized synthetic pathway for suvorexant and establishes a robust method for the simultaneous determination of residual solvents.