Synthesis Process For The Preparation Of Loratadine

Loratadine is a non-sedating tricyclic antihistamine drug that can competitively inhibit the binding of histamine to H1 receptors.It is used for the treatment of allergic diseases without central nervous system sedation.It has good clinical effects and high safety.There are two main synthetic processes for loratadine,one is(1-methyl-4-piperidinyl)(3-(2-(3-chlorophenyl)ethyl)-2-pyridyl)-Methyl ketone is an intermediate synthesis route.The key steps of this route use Grignard reagents for condensation reaction.The reaction conditions are harsh,and it is easy to produce1,6-addition by-products,which are difficult to separate and purify,and the production cost is high;the other is tricyclic Ketone is an intermediate synthesis route,but the yield of the cyclization reaction in the carboxylic acid molecule is low and the6-position chlorinated tricyclic ketone isomer is difficult to separate.Based on the analysis of the existing synthetic route of loratadine,the synthetic route of2-cyano-3-methylpyridine via tricyclic ketone intermediate is determined by the synthesis route of the intramolecular cyclization reaction in the synthetic route.The key steps of the tricyclic ketone intermediate,the selective reduction of the olefin reaction when the olefin double bond and the aryl chloride are contained in the molecule,and the McMurry coupling reaction have been explored in detail,and other steps have been studied on this basis.Completed the optimization of the entire synthesis process.Through analysis and identification of the influence of different cyclization reagents and cyclization methods on the intramolecular ring-closure reaction of carboxylic acid and its by-products,it was found that polyphosphoric acid was used as the cyclization reagent,3-[2-(3-chlorophenyl))Ethyl]-2-pyridinecarboxylic acid can synthesize tricyclic ketone by intramolecular cyclization reaction under mild conditions,and the reaction system is relatively pure,and the tricyclic ketone intermediate can be directly recrystallized to separate the tricyclic ketone intermediate,which simplifies the separation operation.By further optimizing the process conditions,the yield of tricyclic ketones can reach 53%,which is 15% higher than the results reported in the literature.The selective reduction of intermediates containing olefins and aryl chlorides is very challenging.In the hydrogenation reduction reaction of3-chlorophenyl)vinyl]-2-picolinic acid,in order to avoid the removal of3-[2-(3-chlorophenyl)vinyl]-2-picolinic acid during catalytic reduction hydrogenation Halogens on the benzene ring.The effects of catalytic hydrogenation,catalytic transfer hydrogenation,and homogeneous catalyst hydrogenation on the selective reduction of olefins were discussed.It was found that the use of palladium/aluminum oxide catalysts can effectively avoid the removal of olefins while reducing olefins.The halogen on the benzene ring,the effect of the amount of catalyst and reaction solvent on the reaction was studied,the product yield was 90.3%,and the selectivity reached93:7,Through the analysis of the reaction mechanism,by-product structure identification,and formation mechanism of the McMurry coupling reaction of tricyclic ketone and 4-oxo-piperidine-1-carboxylic acid ethyl ester,the reaction of bases,reducing agents,and reaction solvents have been studied.It is found that the piperidine-titanium tetrachloride-zinc powder system can effectively inhibit the formation of by-products,the reaction conditions are mild,and the product can be obtained in high yield.Through further optimization of the process conditions,the yield of this step reached 92%.In addition,in the free radical bromination reaction,by studying the influence of reaction temperature,reaction solvent,reaction concentration,feeding method and other factors on the reaction yield,it is found that the reaction concentration is very important to the reaction.Lowering the concentration can effectively inhibit side effects.The production of the product increases the yield of the free radical bromination reaction to 67%;by studying the influence of different phosphate esters and reaction temperature on the Arbuzow reaction,and analyzing the reaction mechanism of the Wittig-Horner reaction,it is found that polar aprotic solvents and strong Alkali is conducive to the progress of the reaction.The Arbuzow reaction and Wittig-Horner reaction are proposed as a one-pot preparation process.By further optimizing the amount of alkali,reaction temperature,reaction time and other conditions,the yield of the two-step reaction one-pot method is improved.To 89.1%,the synthesis process has been further simplified.This article designed and optimized the synthesis process of loratadine,which has the characteristics of simple process,low production cost,easy purification of products,green process,safety and environmental protection,and has important application value and significance.