CH605873A5 - Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn. - Google Patents

Abstract

Prodn. of 1-benzhydryl-4-cinnamyl-piperazine (I) comprises reacting benzhydrylpiperazine (II) with cinnamaldehyde (III) in the presence of formic acid. Reaction is pref. in an inert solvent, e.g. xylene Reaction without solvent is pref. at 120-150 degrees C.(I) has antihistamine and blood circulatory stimulating activities.

Description

  

  
 



   The benzhydryl4cinnamyl-piperazine is used in chemotherapy as an antihistamine and blood circulation enhancer. Its manufacture is described in Belgian patent specification No. 556 791 (1957). According to this patent, either benzhydrylpiperazine is condensed with cinnamic acid and the resulting l-zenznyaryle-cmna-moyl-piperazine is reduced with lithium aluminum hydride to 1-benzhydryl4-cinnamyl-piperazine, or the condensation takes place between cinnamylpiperazine and benzhydryl chloride.



  Both processes are rather complicated, and in the first case there is also the danger of lithium aluminum hydride.



   We have now found that 1-benzhydryl-4-cinnamyl-piperazine can be prepared in a simple manner from cheaper raw materials in good yield. For this purpose, benzhydrylpiperazine and cinnamaldehyde are condensed in the presence of formic acid, with or without a solvent. The ratio of the components is generally equimolecular, but can easily be varied (e.g. 10% excess of formic acid). The smooth reaction enables a relatively pure product to be separated off immediately, either in the form of its base or a salt with organic or inorganic acids.



   example 1
26.5 g (0.2 mol) of cinnamaldehyde are added to a solution of 50.5 g (0.2 mol) of benzhydrylpiperazine (F. 91-92) in 400 ml of xylene, a white precipitate being formed with an exotherm. 10 g (0.22 mol) of 98-100% formic acid are added to this mixture and the mixture is slowly heated to the boil.



  The reaction proceeds with evolution of CO2 and the precipitate gradually dissolves. After the mixture has been refluxed for 8-12 hours, the reaction solution is cooled and, to remove the excess formic acid, washed neutral with highly dilute NaOH or NH3 solution and then with water. The separated xylene solution is dried over K2CO3, filtered and the 1-benzhydryl-cinnamyl-piperazine is obtained in pure form by evaporating the solvent in vacuo and recrystallizing the residue from ethanol.



   Melting point: 118-120 ". Yield: 75-85% of theory.



   The dichlorohydrate of 1-benzhydryl-4-cinnamylpiperazine can be precipitated from the dried and filtered xylene solution by adding the necessary amount of an alcoholic hydrochloric acid solution, which is then recrystallized from ethanol or isopropanol.



   Melting point: 190-192 ". Yield: 85-90% of theory.



  Example 2
A mixture of 50.5 g (0.2 mol) of benzhydrylpiperazine, 26.5 g (0.2 mol) of cinnamaldehyde and 10 g (0.22 mol) of 98,000,000 formic acid is slowly heated, with the evolution of CO2 arises, which is then heated to 120-130 for 8-12 hours. The cooled melt is then digested with a little dilute NaOH solution, whereby a crystalline precipitate is formed, which then recrystallized from ethanol yields the pure 1-benzhydryl-4-cinnamyl-piperazine. This base can be converted into dichlorohydrate with an ethanolic hydrochloric acid solution;

 

   PATENT CLAIM
Process for the preparation of 1-benzhydryl4-cinnamylpiperazine, characterized in that benzhydrylpiperazine is reacted with cinnamaldehyde in the presence of formic acid.



   SUBCLAIMS
1. The method according to claim, characterized in that the above reaction in an inert solvent such. B. xylene is carried out.



   2. The method according to claim, characterized in that the reaction is carried out at a temperature between 120 and 1500 without a solvent.

** WARNING ** End of DESC field could overlap beginning of CLMS **.



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. The benzhydryl4cinnamyl-piperazine is used in chemotherapy as an antihistamine and blood circulation enhancer. Its manufacture is described in Belgian patent specification No. 556 791 (1957). According to this patent, either benzhydrylpiperazine is condensed with cinnamic acid and the resulting l-zenznyaryle-cmna-moyl-piperazine is reduced with lithium aluminum hydride to 1-benzhydryl4-cinnamyl-piperazine, or the condensation takes place between cinnamylpiperazine and benzhydryl chloride. Both processes are rather complicated, and in the first case there is also the danger of lithium aluminum hydride. We have now found that 1-benzhydryl-4-cinnamyl-piperazine can be prepared in a simple manner from cheaper raw materials in good yield. For this purpose, benzhydrylpiperazine and cinnamaldehyde are condensed in the presence of formic acid, with or without a solvent. The ratio of the components is generally equimolecular, but can easily be varied (e.g. 10% excess of formic acid). The smooth reaction enables a relatively pure product to be separated off immediately, either in the form of its base or a salt with organic or inorganic acids. example 1 26.5 g (0.2 mol) of cinnamaldehyde are added to a solution of 50.5 g (0.2 mol) of benzhydrylpiperazine (F. 91-92) in 400 ml of xylene, a white precipitate being formed with an exotherm. 10 g (0.22 mol) of 98-100% formic acid are added to this mixture and the mixture is slowly heated to the boil. The reaction proceeds with evolution of CO2 and the precipitate gradually dissolves. After the mixture has been refluxed for 8-12 hours, the reaction solution is cooled and, to remove the excess formic acid, washed neutral with highly dilute NaOH or NH3 solution and then with water. The separated xylene solution is dried over K2CO3, filtered and the 1-benzhydryl-cinnamyl-piperazine is obtained in pure form by evaporating the solvent in vacuo and recrystallizing the residue from ethanol. Melting point: 118-120 ". Yield: 75-85% of theory. The dichlorohydrate of 1-benzhydryl-4-cinnamylpiperazine can be precipitated from the dried and filtered xylene solution by adding the necessary amount of an alcoholic hydrochloric acid solution, which is then recrystallized from ethanol or isopropanol. Melting point: 190-192 ". Yield: 85-90% of theory. Example 2 A mixture of 50.5 g (0.2 mol) of benzhydrylpiperazine, 26.5 g (0.2 mol) of cinnamaldehyde and 10 g (0.22 mol) of 98,000,000 formic acid is slowly heated, with the evolution of CO2 arises, which is then heated to 120-130 for 8-12 hours. The cooled melt is then digested with a little dilute NaOH solution, whereby a crystalline precipitate is formed, which then recrystallized from ethanol yields the pure 1-benzhydryl-4-cinnamyl-piperazine. This base can be converted into dichlorohydrate with an ethanolic hydrochloric acid solution; PATENT CLAIM Process for the preparation of 1-benzhydryl4-cinnamylpiperazine, characterized in that benzhydrylpiperazine is reacted with cinnamaldehyde in the presence of formic acid. SUBCLAIMS 1. The method according to claim, characterized in that the above reaction in an inert solvent such. B. xylene is carried out. 2. The method according to claim, characterized in that the reaction is carried out at a temperature between 120 and 1500 without a solvent.