Synthesis Of Cariprazine And Scopolamine Intermedaiates

Cariprazine is a D3/D2 receptor antagonist with the function of a D3 receptor partial agonist and belongs to the second class of antipsychotics.It has a remarkable curative effect on psychosis,especially schizophrenia,and it is better for the treatment of negative symptoms,and has fewer side effects,so it has broad market prospects.In the synthesis of cariprazine,we have done the following work:1.In the process of synthesizing trans 4-amino-cyclohexylacetate hydrochloride with p-nitrophenylacetic acid as a raw material,by adding a certain amount Concentrated hydrochloric acid,stepwise hydrogenation reduction,multiple recrystallization of the filtrate,etc.,the yield of the trans configuration product is greatly improved;2.The cis-4-amino-cyclohexyl ethyl acetate hydrochloride is oxidized by the amino group to absorb The steps of the electron nitro,strong base treatment and the like successfully convert the cis configuration into the trans configuration,followed by hydrogenation to obtain the reverse 4-amino-cyclohexyl ethyl acetate hydrochloride.The trans configuration of 4-amino-cyclohexylacetate hydrochloride in the filtrate before the reaction was cis configuration=2.98 and 4.78 after the trans configuration.After optimization,the yield of the first four steps is 20%higher than that of the literature;3.In the synthesis of 1-(2,3-dichlorophenyl)-piperazine hydrochloride,bis-(2-chloroethyl)is used.The method of combining the amine hydrochloride and the dichloroaniline avoids the use of expensive catalysts and reduces the cost of the route;4.In the trans 2-{1-[4-(N-tert-butoxycarbonyl)amino]In the synthesis of cyclohexyl}acetaldehyde,by first reducing the ester group to an alcohol,and then oxidizing to an aldehyde,the problem of excessive reduction directly when the ester group is reduced to an aldehyde is avoided,and sulfur trioxide pyridine is used in the subsequent oxidation reaction.The reaction conditions are mild and the economy is high.Scopolamine,as an M receptor antagonist,belongs to anticholinergic drugs,and it can play a role in antidepressant and rescue organophosphorus poisoning,and has broad market prospects while being able to better exert the regulatory functions of the peripheral system.In the synthesis of N-substituted-6,7-dehydrotropinone,a key intermediate of scopolamine,we completed the following work:Design a ring addition reaction using[4+3]:pyrrole,1,1-di The methoxyacetone is used as a raw material,and 1,1-dimethoxyacetone is protected and deprotected to form 2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}-2.-Acrolein;N-substituted pyrrole and 2-{[(1,1-dimethylethyl-dimethylsilyl]oxy}-2-prop-enal after[4+3]cycloaddition reaction An N-substituted-2-hydroxy-6,7-dehydrotropinone is formed which is then dehydroxylated to form the final product.This route avoids the synthetic route of industrially long intermediates,which is reduced from the 10-step reaction to 5 steps;in the synthesis of N-substituted-6,7-dehydrotropinone,[4+3]The use of the corresponding dienophiles and dienes,catalysts,solvents and their dehydroxylation reaction conditions in the cycloaddition reaction was explored.The route raw materials and the catalysts and reagents used in the reaction are all economical and easy to obtain,the reaction conditions are mild,the reaction cycle is greatly shortened,the post-treatment is simple,the yield of each step is high,and the total yield is 12.8%,which is 3.8%higher than the original route 9%.