Utilization of flow chemistry for the synthesis of bupropion, fluoxetine and amitraz

Abstract

In recent years, the utilization of flow technology in academic research groups has become increasingly popular especially with regards to the preparation of fine organic compounds such as natural products and Active Pharmaceutical Ingredients (API’s). Though many companies in the pharmaceutical sector still rely on traditional batch processing, evidence of the growing interest in continuous flow manufacturing has been noted. Continuous flow processing offers the possibility to develop fully automated synthetic routes towards specific targets with increased efficiency along with improved sustainability and in many cases safer manufacturing of organic substrates. Herein, discussion focus was placed on the most recent developments in flow chemistry and the incorporation thereof into batch synthetic steps in the continuous flow processing of API’s. Three main targets, namely bupropion, fluoxetine and amitraz were selected for investigation. The aim was to translate each of the individual stages towards the selected targets into viable flow processes that have the potential of overcoming the difficulties typically associated with traditional batch processes and additionally also linking the individual stages in order to obtain continual processes towards the syntheses of each of the mentioned targets. Focus was placed on enhancing the safety, overall greenness as well as cost effectiveness of the syntheses. Envisioned for the project, was the translation of viable flow processes towards the syntheses of the desired targets, employing both commonly used/known batch practices as well as flow chemistry techniques. The first target, bupropion, is an antidepressant belonging to the atypical class. The study performed demonstrated viable flow routes for each of the stand-alone stages involved in the synthesis. The first stage is a bromination reaction, which typically employs the use of toxic and hazardous liquid bromine was performed with the utilization of greener polymer-bound pyridinium tribromide packed in a column-bed reactor under flow conditions which ensured a far greener process with excellent yields associated. The second, nucleophilic substitution stage, is typically associated with high boiling solvents such as dimethylformamide and N-methyl-2-pyrrolidone as these solvents are known for their highly solubilising effects. Herein, we illustrated the use of arguably greener co-solvent system, 75% ACN:DCM for use in the desired chemical transformation. The flow process for the second stage employed a standard stainless-steel coil reactor along with a sonicated batch and a water quench-line to improve solubility of the reaction mixture. Furthermore, a telescoped process for the two-stage synthesis of bupropion based on the individual stand-alone flow processes in which a 69% conversion was obtained in a total reaction time of 3 hours has also been reported. The telescoped process also made use of an in-line biotage phase separator to simplify post-reaction work-up procedures associated with the synthesis of bupropion. The second target, fluoxetine, is an antidepressant of the selective serotonin reuptake inhibitors class. The synthetic route towards fluoxetine made use of a Mannich reaction, followed by a carbonyl reduction reaction, a subsequent debenzylation reaction and lastly a nucleophilic aromatic substitution reaction. The Mannich reaction requires aqueous acids, which can cause corrosion within some flow instrumentation. Several attempts to overcome this have been included and discussed. The second reduction reaction was translated into a viable flow route utilizing polymer-supported sodium borohydride packed in a column reactor under flow conditions which showed excellent conversions under flow conditions. The debenzylation reaction was also reported under flow conditions utilizing a standard ‘tube-in-tube’ gas module in order to saturate the solution with hydrogen gas prior to passing the solution through a palladium on carbon packed column reactor along with acetic acid as additive to increase the rate of the discussed chemical transformation. The last nucleophilic aromatic substitution reaction typically employs the use of non-green solvents such as dimethylformamide or dimethylacetamide which were replaced with greener tetrahydrofuran. The last stage was performed under flow conditions with the aid of a stainless-steel coil reactor along with a Swagelok filter designed to remove unwanted precipitates in-line. The telescoping of stages two and three was performed under flow conditions, replicating the individual flow processes, in which excellent conversions were noted in just 2 hours contrasted to the 12 hours required for the traditional batch process. The third target discussed is amitraz which is an insecticide and acaricide that forms part of broader pesticide active ingredients. The flow synthesis of amitraz was investigated specifically from semiamitraz starting material. The flow-based approached reported employs a Hastelloy coil reactor held at 250 oC in which conversions of 95% was noted in a total reaction time of 15 minutes without the addition of any acid catalyst. To summarize, both stages of bupropion were successfully translated to flow conditions with improved safety and greenness juxtaposed to the traditional batch process. The two stages were telescoped to produce 69% of bupropion. The second target, fluoxetine, requires some work with only two of the four stages, namely the reduction and debenzylation reactions, being successfully translated to flow conditions. Full conversion was obtained for the telescoped process of stages two and three after a reaction time of only 2 hours contrasted to the 12-hour batch procedure. Lastly, though additional optimization work is still required, a 95% conversion for amitraz has been reported in a total flow-based reaction time of 15 minutes with reduced costs due to the omittance of expensive acid catalysts. Overall, the utilization of flow chemistry in the syntheses of each of the named targets showed significant edge over traditional batch processing in terms of greenness, cost efficacy, reduction of total reaction time required as well as increased environmental pleasantness.