Synthesis Of The Intermediate For Labetalol

Labetalol is a kind of medicine which is used to treat hypertension during gestational period,and is widely used in the treatment of pregnancy.5-[2-[bis(phenylmethyl)amino]acetyl]-2-hydroxy-benzamide is the important intermediate in preparing labetalol,however the traditional procedures have a lot of problems.Such as the ammonolysis reaction of methyl salicylate,traditional procedures used water as solvent which raised the yield of by-product and reaction time.And Friedel-Crafts acylation always used highly toxic organic solvents,which were hard to recycle and were harmful to the environment.Then ?-bromination reaction and finally amination with dibenzyl amine had the problems of low material availability ratio and yield.So the dissertation began with methyl salicylate to product 5-[2-[bis(phenylmethyl)amino]acetyl]-2-hydroxy-benzamide,through ammonolysis with water-free system,Friedel-Crafts acylation with molten salt,?-bromination with peroxide,amination with acid-binding agent.The improved technology has the characteristics of high production yield and environmental friendliness,and it provides practical experience and theory to product labetalol.The dissertation researched on ammonolysis reaction of methyl salicylate,with methanol as solvent,which avoiding the hydrolysis and increasing the yield.Finding the proper way to recycle ammonia and methanol,which decreasing emission of waste.The optimum condition was found:methyl salicylate:ammonia was 1:4(mol ratio);reaction temperature was 100?;reaction pressure was 0.8 MPa;reaction time was 2.0h.The yield of salicylamide was 92.7%.Then,the dissertation researched on Friedel-Crafts acylation of salicylamide with acetyl chloride,and the NaCl-AlCl3 molten salt system was used as both catalyst and solvent.It avoided the use of highly toxic solvents,which reduced the cost of recycling and contamination.The optimum condition was found:the NaCl-AlCl3 molten salt system was consisted of aluminium chloride and sodium chloride(the mol ratio was 1:1);reaction temperature was 140?;the equivalent of aluminium chloride was 1.8eq;the equivalent of acetyl chloride was 1.2eq;reaction time was 0.5h.The product was purified with acid-washing,percolation and recrystallization with the yield of 92.2%.The dissertation further researched on ?-bromination reaction of 5-acetyl-2-hydroxy-benzamide,and brominating agent was consisted of bromine and hydrogen peroxide,which increased the availability ratio of bromine atom.The optimum condition was found:the equivalent of bromine was 0.8eq;the equivalent of hydrogen peroxide was 0.4eq;the solvent was acetic acid;reaction temperature was 25?;and reaction time was 2.5h.Then the yield of 5-bromoacetyl-2-hydroxy-benzamide which purified by recrystallization was 78.1%.At last,the dissertation researched on amination between 5-bromoacetyl-2-hydroxy-benzamide and dibenzyl amine.Sodium carbonate worked as acid-binding agent which neutralized hydrogen bromide.It increased the availability ratio of dibenzyl amine and raised the yield.The optimum condition was found:the equivalent of sodium carbonate was 1.5eq;the equivalent of dibenzyl amine was 1.1eq;the solvent was methanol;reaction temperature was 40?,reaction time was 3.0h.The product was purified by recrystallization with the yield of 65.3%.According to the result of 1H-NMR and 13C-NMR,the conformation of the intermediate and product was correct.