Patent GB-752331-A (GB)
Title: Improvements in or relating to n, n-disubstituted piperazines and process of preparing the same
IPC: C07D295/04
Filed: 1949-07-23
Abstract: Compounds of the formula <FORM:0752331/IV(a)/1> where R1 is C1-C4 alkyl, C1-C4 alkanol, guanyl or dialkylaminoalkyl (up to 6 carbon atoms in all), R2 is hydrogen or C1-C4 alkyl, R3 is aryl and R4 is aryl, heterocyclic or alicyclic (if R1 and R2 are both alkyl they contain not more than 4 carbon atoms between them), are obtained by (1) treating R1-piperazine with R2R3R4CX; (2) treating R2R3R4C-piperazine with R1X; (3) reacting R2R3R4C-NH2 with N-R1-b b 1-dihalodiethylamine; (4) treating an N-monoacylpiperazine with R2R3R4C-halide and reducing the acyl group to alkyl (e.g. with formic acid or lithium aluminium hydride); (5) treating R2R3R4C-N (CH2CH2Hal)2 with R1-NH2; (6) (R1= methyl or ethyl)treating R2R3R4C-piperazine with formaldehyde or acetaldehyde in the presence of formic acid; or (7) (R1=methylol) reacting R2R3R4C-piperazine with formaldehyde; in these reactions X is chlorine, bromine or iodine, or is methylthio if R1 is guanyl.  The products give quaternary salts with methyl chloride, bromide or iodide. Preferred products are N-benzhydryl-N1-methyl- or ethyl-piperazines, where the benzhydryl group may be substituted with halogen, alkyl or alkoxy.  In methods (1) and (2) there is preferably added an alkaline material, e.g. an alkali carbonate. Method (1) is also facilitated by the presence of an alkali halide such as sodium iodide, and butanol as solvent.  The products form salts with acids such as sulphuric, phosphoric, hydrochloric, hydrobromic, laevulinic, acetic, tartaric, oxalic and tannic. Examples show the preparation of the following bases and their salts : N - (p - chlorobenzhydryl) - N1 - methylpiperazine, N - (p - bromobenzhydryl) - N1-methylpiperazine, N - benzhydryl - N1 - methylpiperazine, N - (p - methoxybenzhydryl) - N1-methylpiperazine, N - (p : p1 - dichlorobenzhydryl) - N1 - methyl - piperazine, N - benzhydryl - N1 - ethylpiperazine, N - benzhydryl-N1 - (b  - hydroxyethyl) - piperazine, N - benzhydryl - N1 - (b  - dimethylaminoethyl) - piperazine, N - (p - iodobenzhydryl) - N1 - methylpiperazine, N - [a  - (2 - pyridyl) - benzyl] - N1-methylpiperazine, N - (p - fluorobenzhydryl)-N1 - methylpiperazine, N - (p - methylbenzhydryl) - N1 - methylpiperazine, N - (a  - cyclohexyl - p - chlorobenzyl) - N1 - methylpiperazine, N - (p - chlorobenzhydryl) - N1 - ethylpiperazine, N - (o - chlorobenzhydryl) - N1-methylpiperazine, N - [a  - (2 - thienyl) - benzyl]-N1 - methylpiperazine, N - benzhydryl - N1 - n-butylpiperazine, N - (p - chlorobenzhydryl)-N1 - n - butylpiperazine, N - (m - chlorobenzhydryl) - N1 - methylpiperazine, N - benzhydryl - N1 - methylolpiperazine, N - [a  - (2-thienyl) - p - chlorobenzyl] - N1 - methylpiperazine, N - (p - chlorobenzhydryl) - N1-(4 - hydroxy - n - butyl) - piperazine, N - (a -methylbenzhydryl) - N1 - methylpiperazine and N - benzhydryl - N1 - guanylpiperazine. The preparation of the methiodide of N-(p-chlorobenzhydryl) - N1 - methylpiperazine is also described.  Other products are listed with various substituents, including two different halogens in the benzhydryl group, and also R4=furyl, pyrimidyl and cyclopentyl. Mono-substituted piperazines which are intermediates for the above are made as in Specification 752,332, i.e. by reacting N-carbalkoxypiperazine with the appropriate halide and hydrolysing and decarboxylating the product.  Details are given of the production of N-(p-chlorobenzhydryl - N1 - carbethoxypiperazine, N - benzhydryl - N1 - carbethoxy - piperazine, N - carbethoxy - N1 - n - butylpiperazine, N-carbethoxy - N1 - (4 - hydroxy - n - butyl)-piperazine and their decarboxylation products, together with salts of the latter, in particular N-benzhydryl-piperazine d-tartrate.  Intermediates of the formula R3R4CHCl are made as follows: p-fluorobenzhydryl chloride, p - iodobenzhydryl chloride, a - cyclohexyl-p-chlorobenzyl chloride, and a -(2-thienyl)-p-chlorobenzyl chloride from the corresponding carbinols and hydrogen chloride; a -(2-pyridyl)-benzyl chloride from the carbinol and thionyl chloride. a -Cyclohexyl-p-chlorobenzyl alcohol is obtained from p-chlorobenzaldehyde and cyclohexylmagnesium bromide. a -(2-Thienyl)-p-chlorobenzyl alcohol is prepared from p-chlorobromobenzene, magnesium and a -thiophenaldehyde.  The starting materials for method (5) are made by reacting diethanolamine with R2R3R4C-halide to give R2R3R4C-N(CH2CH2OH)2 and treating the latter with hydrogen halide or thionyl halide. Details are given where R2=H, R3=phenyl and R4=p-chlorophenyl.  a -Methylbenzhydrylamine is obtained by treating a ,a -diphenylpropionamide with potassium hypobromite.  According to the Specification as open to inspection under Sec. 91 (4) the invention includes the intermediates (R1=H) which can be made by methods (1), (3) and (5) above.  Intermediates of the type N-alkyl-N1-carbalkoxypiperazine may additionally be made by reacting N-carbalkoxypiperazine with an aldehyde in the presence of formic acid, and treating the product with a mineral acid. N-(p-chlorobenzhydryl)-morpholine is also mentioned as an intermediate.  This subject-matter does not appear in the Specification as accepted.  Specification 752,332 is referred to.ALSO:Compounds of the formula <FORM:0752331/VI/1> where R1 is C1-C4 alkyl, C1-C4 alkanol, guanyl or dialkylaminoalkyl (up to 6 carbon atoms in all), R2 is hydrogen or C1-C4 alkyl, R3 is aryl and R4 is aryl, heterocyclic or alicyclic (if R1 and R2 are both alkyl they contain not more than 4 carbon atoms between them) show antihistamine and antispasmodic activity; acid addition and quaternary salts are included.  The water-soluble salts (e.g. sulphates, phosphates, hydrochlorides, hydrobromides, laevulinates, acetates, tartrates) may be administered as aqueous solutions.  These and other salts (e.g. tannates), as well as the bases themselves, can be made up as tablets or capsules with the usual bases.  Preferred compounds are those in which R1 is methyl or ethyl, R2 is hydrogen and R3 and R4 are phenyl which may be substituted by halogen, alkyl or alkoxy; N-(p-chlorobenzhydryl)-N1-methyl-piperazine is an example. According to the Specification as open to inspection under Sect. 91(4), R1 in the above formula may be hydrogen.  In the Specification as accepted such compounds are described only as intermediates for making the desired products.  Specification 752,332, [Group IV (b)], is referred to.