A Telescopic, Sustainable Synthesis of the Key Starting Materials of Antipsychotic Drugs Quetiapine and Loxapine via Reductive Amidation

Abstract

Quetiapine, a dibenzothiazepine derivative, is an antagonist of serotonin and dopamine. It was approved by the Food Drug and Administration for the treatment of schizophrenia in 1997 and has been used as a commonly prescribed second-generation atypical antipsychotic drug. Loxapine is a dibenzoxazepine tricyclic compound used as an antipsychotic, antagonising dopamine and serotonin receptors for the treatment of acute and chronic schizophrenia. However, the preparation of their Key Starting Materials (KSMs) in the reported synthesis routes suffers from several significant restrictions, such as multistep synthesis, harsh reaction conditions, high cost factors, and the use of reagents that are environmentally unfriendly. In this work, we aimed to explore a telescopic green process for the synthesis of dibenzo[b,f][1,4]thiazepin-11(10H)-one and 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one, the two KSMs required for the commercial production of quetiapine and loxapine. The process involves an intermolecular base-mediated S_NAr reaction of 2-fluoro-1-nitrobenzene and methyl 2-mercaptobenzoate or methyl 2-hydroxybenzoate, followed by intramolecular reductive amidation employing sodium dithionite (Na₂S₂O₄) as the sole reagent. The S_NAr reaction was performed in the presence of K₂CO₃ in DMF at 90°C, followed by workup to give a crude product, which was treated with Na₂S₂O₄ in DMSO without any prepurification to obtain the desired cyclized KSMs. Unlike the commonly used metal/acid reagent for the reduction of nitro compounds, the developed process avoids the use of any metal reagent or acidic conditions. The key features include a reduced number of steps, a telescopic process avoiding purification of the first step product, and reductive amidation of unactivated esters without any externally added activating agent.

Keywords

quetiapine - loxapine - APIs synthesis - nitro reduction - reductive amidation - sodium dithionite (Na₂S₂O₄)

Supporting information

Green chemistry metrics of synthesized compounds 2a, 1, and 2 ([Supplementary Table S1]–[S3], available in the online version) and ¹H NMR and ¹³C NMR spectra of compounds 2a, 1, 2, and 2ab ([Supplementary Figs. S1]–[S6], available in the online version) can be found in the “[Supporting Information]” section of this article's webpage.

Publication History

Received: 14 January 2025

Accepted: 26 September 2025

Article published online:
13 November 2025

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