The Synthesis Of Ambroxol Hydrochloride And Bromhexine Hydrochloride

Ambroxol hydrochloride and bromhexine hydrochloride are the main effective ingredients of commonly used expectorants in clinic.They have the advantages of good curative effect,low toxicity and less adverse reactions.The market demand is increasing year by year.The reported synthetic processes are all based on the derivatives of 2-nitrotoluene such as 2-aminobenzaldehyde,methyl 2-aminobenzoate,2-nitrobenzaldehyde and o-toluidine,but the production of 2-nitrotoluene is full of danger and pollution due to the use of large amounts of concentrated nitric acid and sulfuric acid.Because of environmental pollution,some producers have been closed down,it led to the supply insufficient and price rising.As a result,the prices of ambroxol hydrochloride and bromhexine hydrochloride have risen sharply,so it is very important to find a new process for ambroxol hydrochloride and bromhexine hydrochloride.In this paper,2-amino-3,5-dibromobenzoic acid was prepared from phthalimide by Hoffmann degradation and bromination reaction.Than it was reacted with triphosgene to form 6,8-dibromoisatoic anhydride.The obtained 6,8-Dibromoisatoic anhydride was further reacted with trans-4-aminohexanol to give N-(trans-4-hydroxycyclohexyl)-3,5-dibromo-2-aminobenzylamide.Subsequently,ambroxol hydrochloride was synthesized from the obtained amide by zinc borohydride reduction and hydrochloric acid acidification.The total yield of the process was up to 58.6%.The new process combined the advantages of short synthetic route,mild reaction,good reaction selectivity,simple operation,stable process and easy enlargement.In conclusion,the process is suitable for industrialization.Bromohexine hydrochloride was synthesised via the reduction of 6,8-dibromoisatoic anhydride with sodium borohydride,chlorination of(2-amino-3,5-dibromophenyl)methanol with sulfoxide chloride and aminolysis of 2-amino-3,5-dibromobenzyl chloride with N-methylcyclohexamine.Therefore,the new process for preparing bromohexidine hydrochloride from phthalimide was obtained,and the total yield of the process was up to 58.4%.Compared with the traditional process,the new synthesis has the advantages of mild reaction conditions,safe and simple operation,easily purification of the products,high yield and low production cost.In short,it is a process that can be industrialized.