| At present,environmental problems are increasingly serious.The ideas of reducing emissions of ‘three wastes’,saving energy and sustainable development are the direction when scientists design new chemical reaction systems.There are many safety and environmental accidents every year,which cause incalculable losses to enterprises.The deep-seated reason is that there are defects in the process.Therefore,we need to evaluate safety and environmental protection in process design.Ambroxol hydrochloride is a new expectorant with good clinical effect and good market prospects.There are many synthetic routes of ambroxol hydrochloride.Most of them have high energy consumption,large pollution and complicated operation which are easily to cause safety and environmental incidents during production.In this paper,o-aminodibromobenzaldehyde was used as raw material to react with(E)-p-aminocyclohexanol following with reduction and HCl salt formation three steps to obtain product.The total yield of the reaction was 92%.It not only solved the problem of safety and environmental protection,but also had low energy consumption and high economic efficiency.The first part: The lab-scale preparation.Ambroxol base was synthesized from o-aminodibromobenzaldehyde and(E)-p-aminohexanol with toluene as solvent and DMAP as catalyst reacting at 110 ℃.The yield of the reaction was 96%,which was higher than that reported in the literatures.Among the screened catalysts such as formic acid,triethylamine and DMAP,DMAP was found to be the best.Among the screened solvents such as methanol,ethanol,ethyl acetate,toluene,xylene,toluene was with the highest condensation reaction yield.We optimized the temperature from 68 to 140 ℃ and found that the highest yield was obtained at 110 ℃.Ambroxol was obtained by reduction of ambroxol base with 0.3% platinum-carbon as catalyst and under pressure of 1.1 MPa hydrogenation at 60 ℃.The yield of ambroxol was high up to 98%.Raney nickel,palladium carbon,platinum carbon and sodium borohydride were screened for reduction,and platinum carbon was found to have the highest catalytic activity.We optimiazed the platinum-carbon content from 0.2% to 1.0%,and found that the platinum-carbon dosage of 0.3% was the best.We optimized the hydrogenation pressure from 0.1 to 1.2 MPa and found that 1.1 MPa was the best.Ambroxol hydrochloride was obtained by the reaction of ambroxol with 20% hydrochloric acid in ethanol at 10 ℃.The yield of ambroxol hydrochloride was 98%.We screened methanol,ethanol,acetone,and water several kinds of reaction solvents,and found that ethanol was the best solvent for the salt formation reaction.We screened the temperature from 0 to 50 ℃ and found that the best temperature for salt formation was 10 ℃.We screened the amount of hydrochloric acid from 1.0 to 1.8 equiv.and found that the amount of hydrochloric acid had the best effect at 1.5 equiv.In addition,the structures of ambroxol base,ambroxol and ambroxol hydrochloride were confirmed by NMR and MS.The second part: Pilot test.The lab-scale preparation process was enlarged and three batches of pilot tests were carried out.From the aspects of safety,environmental protection,energy consumption,economic efficiency and quality,it has been verified that it meets the requirements of lab experiment and route design.The main dangerous devices are centrifuge and hydrogenation vessel.According to the “Key Monitoring Parameters,Basic Requirements for Safety Control and Recommended Control Scheme for Key Supervision of Hazardous Chemical Technologies”,safety devices are set up for these two processes to automatically interlock,and thus the safety level can be reduced to four acceptable levels.During the pilot test period,the emission value of exhaust gas is lower than the stipulated value of the emission standard GB16297-1996.The production rate of waste water is 1,the production rate of high concentration wastewater is 0.1,and the production rate of dangerous solid wastes is 0.06.The “three wastes” produced in the whole process are very small and can be treated to below the standard value.In terms of energy consumption,the equivalent energy consumption of added value of process industry is 0.0297 tce,which is much lower than the target value of energy consumption per unit of added value of industry in the 13 th Five-Year Plan(0.406 tce).In terms of economic efficiency,the gross interest rate is about 60%.The net interest rate is expected to be about 30% except for additional costs such as management,and the economic efficiency is relatively high.In terms of quality,the quality of three batches of ambroxol hydrochloride in lab-and pilot-scale prepartion meet the requirements of the 2005 edition of the Chinese Pharmacopoeia.In summary,ambroxol hydrochloride was synthesized by three-step reaction sequences.Firstly,ambroxol base was synthesized from o-aminodibromobenzaldehyde and p-aminocyclohexanol under the catalysis of DMAP,and then reduced by hydrogen under the catalysis of platinum carbon to afford ambroxol.Finally,ambroxol reacted with hydrochloric acid to form its HCl salt.The total yield was 74% higher than these reported in literature.The developed process meets the requirements of safety,environmental protection,energy consumption,quality and economic efficiency.Moreover,it is simple and lays a foundation for further industrialization. |
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