Improved, Solvent Free, Atom Efficient Commercial Process for the Synthesis of Diphenhydramine Hydrochloride

Abstract

Background: Literature reports various methods for the synthesis of diphenhydramine hydrochloride each of these has one or the other drawback such as low as ~39% atom efficiency or high reaction temperature, usage of corrosive bromine and formation of hazardous by product or else it requires strong scrubbing system which generates huge amounts of inorganic waste, in some cases molar equivalents of P-toluenesulfonic acid was used which was further eliminated as waste with low product output and thus not economically viable, literature also reports continuous flow process which requires PFA tube reactor with very high temperature ~175°C addition to this it also uses IPA-HCl for salt preparation which is prone for the formation of genotoxic impurity 2-chloropropane. Methods: Objective of present work is to overcome the limitations studied in literature to improve the process in terms of atom efficiency, cost effectiveness, robust, commercially viable, industrially scalable, minimum environmental hazards considering principles of green chemistry. We have developed the process in such as way that atom efficiency at halogenation stage is enhanced by ~93% compared to ~39% when diphenylmethane reacts with bromine. HCl gas generated in-situ or if needed supplied to prepare diphenhydramine hydrochloride salt instead of using IPA-HCl to eliminate chances of formation of genotoxic impurity if any. Conclusion: In order to achieve the continuous improvement process, we have developed modified process for the synthesis of diphenhydramine hydrochloride which elimination of use of corrosive bromine, overall time cycle reduced by ~40%, overall process atom efficiency enhanced by ~45%, eliminated chance of formation of genotoxic impurity by avoiding use of IPA-HCl solvent for final stage, by carrying out reaction in either water as a universal green solvent or solvent free conditions with high yield to obtain pharmacopeial quality of the final active pharmaceutical ingredient. We assert to have a better process in terms of atom efficiency, minimal wastage, operability and quality. Keywords: Diphenhydramine, solvent free reaction, atom efficiency, bromine, Active Pharmaceutical Ingredient (API).