Study On Synthesis Of(1R,4R)-4-((2-Amino-3,5-Dibromobenzyl)Amino)Cyclohexan-1-Ol Hydrochloride

In this paper,three different reaction routes have been developed to synthesis(1R,4R)-4-((2-amino-3,5-dibromobenzyl)amino)cyclohexan-1-ol hydrochloride(ambroxol hydrochloride)from methyl anthranilate.And the most reasonable reaction conditions for each unit reaction have been determined.In the first reaction route,in order to solve the problem about the metal hydroxide residue in the reduction of methyl 2-amino-3,5-dibromobenzoate,a series of reducing ionic liquids have been designed.The recyclable ionic liquid reducing agent performs a reduction reaction in the absence of a solvent to avoid the generation of metal hydroxide residue.Meanwhile,the reduction yield was increased to 85%,and the ionic liquid could be recycled after recycling.In the second reaction route,modified red aluminum was used as a reducing agent to directly reduce methyl 2-amino-3,5-dibromobenzoate to 2-amino-3,5-dibromobenzaldehyde,avoiding the previous route One of the tedious steps of using sodium borohydride for reduction followed by oxidation with manganese dioxide.At the same time,two steps of the final generation of Schiff base and imine in Route 1 also be merged into a single step called reductive amination.And the method for indirect reductive amination of sodium borohydride has been chosen because of the reducing agent cost.Besides,this method achieved a high reaction yield of ambroxol.In the third reaction route,methyl anthranilate and trans 4-aminocyclohexanol can directly form 2-amino-N-(trans-4-hydroxycyclohexyl)benzamide.And then we reduced and brominated the amide to get the ambroxol.During transesterification,the amount of(1R,4R)-4-aminocyclohexan-1-ol was excessive.But due to the absence of other side reactions in the system,unreacted raw materials could be recovered and reused,and the reaction cost could be further reduced.In the process of amide reduction,borane-THF complex was used as a reducing agent.The post-reaction treatment is simpler;the production cost is lower;and the reaction yield is relatively high.