Patented Feb. 11, 1947 2,415,786 UNITED STATES PATENT OFFICE

UNSYMMETRICALLY SUBSTITUTED PPERAZINES Johannes S. Buck, East Greenbush, and Richard Baltzly, New York, N. Y., assignors to Bur roughs Welcome & Co. (U. S. A.) Inc., New York, N.Y., a corporation of New York No Drawing. Application January 6, 1944, serial No. 517,224 9 Claims. (C. 260-268) 2 This invention relates to N-monosubstituted According to the present invention, these diffi and N-N'-unsymmetrically disubstituted piper culties are overcome by treating piperazine with azines and has for an object to provide new com a halide of benzyl or of a substituted benzyl to positions of the above type and a novel and im form a reaction mixture containing, in addition proved method of making the same. to unreacted piperazine and di-N-N'- Substituted Another object is to provide a method of mak piperazine, a substantial amount of N-mono sub ing and isolating the above substances which is stituted piperazine separating the mono-N-sub Suitable for commercial Operation. stituted piperazine from the unreacted piperazine In our copending application Serial No. 476,914, and the disubstituted piperazine, introducing the filed February 24, 1943, of which the present ap O desired substituent on to the second N' nitrogen plication is a continuation in part and in our atom of the mono-N-substituted piperazine, then Copending application Serial No. 517,225, filed removing the benzyl or substituted benzyl group January 6, 1944, which is also a continuation in by catalytic hydrogenation. part, We have described certain methods for mak As catalysts for this hydrogenation, platinum, ing and isolating substituted piperazines of the palladium and nickel are all suitable, but We pre type fer in general to use palladium since, while CEI-CI equally or perhaps more effective in removing a benzyl group, it is practically devoid of any N /N-R tendency to reduce aromatic rings. CH-CH 20 The term benzyl derivatives as used in the where R is an aralkyl, or a higher alkyl, and R' present specification and claims, includes the is either hydrogen or a second radical different halogen derivatives such as p-chlorobenzyl and from R. organic derivatives such as anisyl The present invention refers to a new and dif ferent process for making any of the above com 25 pounds, which new process can also be used for 4-phenyl-benzyl or alpha-menaphthyl (alpha the production of numerous mono-N-substituted naphthyl-methyl). and unsymmetrically N,N'-disubstituted piper The method according to the present invention azines, many of which are not obtainable at all permits the preparation of numerous mono by any of the processes described in our above 30 alkyl, mono-acyl and other monosubstituted mentioned copending applications, nor by any piperazines with a very high yield. of the methods known in the art. A particular advantages of the process accord The main difficulty involved in preparing mono ing to the invention is that it is possible to obtain Substituted piperazines, from which unsym monosubstituted piperazines of the type metrically disubstituted derivatives can also be 35 CH-CH2 obtained, resides in the isolation of the substance H-N NR from the unreacted piperazine and the disubsti / tuted piperazine which are present and which CH-CH in many cases have similar boiling points. in which R" is a radical, such as a lower alkyl Amines are extremely hard to separate by frac 40 having less than 8 carbon atoms, which when in tional distillation unless their boiling points are troduced into unreacted piperazine will not pro Widely separated. Furthermore, the classical duce a separable mixture of mono- and di methods of separating secondary from tertiary substituted compounds, or a radical Such as an amines are of no avail in this case, since a mono acyl, an aryl sulfonyl or a substituted aryl Sul substituted piperazine reacts as both a secondary 45 fonyl, which will produce such separable mixtures and a tertiary amine. Even where a mixture con only under certain conditions, or a radical of taining mono- and symmetrically disubstituted relatively small inherent stability such as piperazines of widely different boiling points or acyloxyalkyl, hydroxyphenaikyl, carbamido, Sub Solubilities is formed, the separation of the mono stituted carbamido and carbamidino. Substituted compounds from the disubstituted 50 From the mono-N substituted piperazines ob reaction products and the unreacted piperazine tained in this manner, unsymmetrically disub is frequently difficult or even impossible if the stituted piperazines of any desired type may be stability of the introduced substituent is insuff obtained by introducing on to the first N nitrogen cient to Withstand the conventional separation atom made available by the preceding catalytic methods such as fractional distillation. SS hydrogenation, the desired substituent which is 2,415,786 3 4 different from the substituent present in the (equals alpha naphthyl-methyl) piperazine was monosubstituted compound but may be selected Separated as in Example i. from the Same group. Subsequently the monosubstituted compound Thus, it is possible to produce unsymmetrically was reacted with butyl chloride to yield N-alpha N-R, N'-R'-disubstituted piperazines where R. naphthyl-methylene-N'-butyl piperazine hydro represents a radical selected from the group con chloride. On addition of 1 equivalent of hydro sisting of the lower alkyls having less than 8 chloric acid and removal of the alpha-menaph carbon atoms, acyl, aryl sulfonyl, substituted thyl group by catalytic hydrogenation, mono-N'- aryl sulfonyl, acyloxyalkyl and hydroxyphenialkyl butyl piperazine dihydrochloride was crystallized and R' represents a radical Selected from the 10 from alcohol ether. group consisting of the lower alkyls having less than 8 carbon atoms, acyl, aryl Sulfonyl, Substi Eacample 5 tuted aryl sulfonyl, acyloxyalkyl, phenacyl, sub Anisyl chloride (CH3O C6H4CH2C1) (1 mol) stituted phenacyl, hydroxyphen alkyl, carbamido, (from anisyl alcohol (CH3OC6H4CH2OH) and hy substituted carbamido, thiocarbamido, substi 15 drogen chloride) was reacted with piperazine (1. tuted thiocarbamido and carbamidino. . mol) in absolute alcohol solution. The bulk of The following examples may serve to illustrate, the dianisyl piperazine formed as a by-product without limiting the invention. Separated towards the end of the reaction as its Eacample 1 dihydrochloride and was filtered off. The solvent was evaporated from the filtrate, the residue Piperazine hexahydrate was dissolved in ab 20 diluted with water, basified and the anisyl piper Solute ethanol and benzyl chloride added with azine extracted with ether. The Small amount stirring. After standing overnight the alcohol of impurities remaining was separated by vac was distilled off and the residue partitioned be uum distillation. . tween ether and sodium hydroxide solution, The 25 The mono-N-anisyl piperazine so produced was greater part of the unreacted piperazine re reacted in benzene with p-nitrobenzoyl chloride. mained in the aqueous layer. The ethereal layer The resulting compound, N-anisyl-N'-p-nitro was dried over K2CO3 and distilled in vacuo to benzoyl piperazine hydrochloride separated and separate pure monobenzyl piperazine from the was recrystallized from alcohol. On drastic cat dibenzylpiperazine. 30 alytic hydrogenation in alcoholic solution at room The monobenzyl piperazine was methylated by temperature With a platinum catalyst, first the the procedure of Clarke, Gillespie and Weiss nitro group was reduced to an amino group and hauss (J. Amber. Chem. Soc., 55, 4571 (1933)), thereafter the anisyl group was split off to yield and the product, after liberation of the base was the mono-N'-p-amino-benzoyl piperazine dihy treated with benzoyl chloride to remove any 35 drochloride. monobenzyl piperazine that had remained un Eacample 6 reacted. Basic material Was again liberated with Fourteen parts by weight of mono-N-benzy pi alkali and distilled in vacuo. The product, N perazine (Example 1) were reacted in alcoholic benzyl-N'-methyl piperazine, was crystallized as Solution With five parts by weight of ethylene the dihydrochloride from absolute alcohol-ether 40 oxide yielding 17 parts of crude N-benzyl-N'- mixture and this dihydrochloride was hydrogen hydroxyethyl piperazine. This was then ben ated catalytically in glacial acetic acid with the ZOylated by the Schotten Baumann method and aid of palladized-charcoal. After filtration from the product purified by crystallization as the di the catalyst and evaporation of the solution in hydrochloride. This material, N-benzyl-N'-ben vacuo, the product, mono-N-methyl piperazine 45 zoyloxyethyl piperazine dihydrochloride was hy dihydrochloride was crystallized from methanol drogenated with hydrogen and palladized char ether. coal in 80% acetic acid solution yielding toluene Eacample 2 and mono-N'-benzoyloxyethyl piperazine dihy Piperazine hexahydrate was treated in abso drochloride. lute alcohol with p-chlorobenzyl chloride and the Eacample 7 mono-N-p-chlorobenzylpiperazine was separated Mono-N-p-chlorobenzyl piperazine as ob from the unreacted piperazine and from disub tained according to Example 2, was treated with stituted piperazine by fractional distillation. a slight excess of phenacyl bromide to yield N-p- The mono-p-chloro-benzyl piperazine was re chloro-benzyl-N'-phenacyl piperazine. This was acted with ethyl bromide to yield N-p-chloro catalytically hydrogenated to mono-N'-(beta benzyl-N'-ethyl piperazine hydrobromide. An phenyl-beta-hydroxyethyl) piperazine. other equivalent of hydrobromic acid was added to give the dihydrobromide and this product was Eacample 8 catalytically hydrogenated. After filtration from Anisyl chloride (CH3O C6H4 CH2Cl (1 mol) the catalyst and evaporation of the solution in 60 (from anisy alcohol (CH3OC6H4CH2OH) and hy vacuo, mono-N'-ethyl piperazine dihydrobromide drogen chloride) was reacted with piperazine (1 was crystallized from alcohol ether. mol) in absolute alcohol solution. The bulk of the dianisyl piperazine formed as a by-product Eacample 3 separated towards the end of the reaction as its 85 dihydrochloride and was filtered off. The sol Mono-N'-propyl piperazine. dihydrochloride vent was evaporated from the filtrate, the residue was obtained in the process according to Example diluted with water, basified and the anisyl piper 2, by using propyl chloride instead of ethyl bro azine extracted with ether. The Small amount mide. . of impurities remaining was separated by Vac Eacample 4 '70 uum distillation. Piperazine hexahydrate was dissolved in abso The mono-anisyl piperazine so produced was lute alcohol and an equimolecular amount of treated with chloro-acetocatechol forming N alpha-naphthyl-methyl chloride was stirred into anisyl-N'-(3,4 - dihydroxyphenacy) piperazine the solution. The mono-N-alphamenaphthyl 5 which was isolated as its dihydrochloride. DraS

E. 3,323.738 tic catalytic hydrogenation of this concoli at room temperature with a plain. Catalyst, Eace i2ple i5 yielded mono-N'-(beta, a 3.4 is dihydroxyphenya A32-S'agnetiay pigera2ire as obtained from beta-hydroxyethyl) piperazine, Example was treated with p-acetamidobenzene Eacample 9 s sfonyl chloride to produce N-p-acetannidobe zerie-Sulfonyl-N'-methyl piperazine which was N-benzyl piperazine as obtained according to hydrolyzed by warm hydrochloric acid to form Example 1, was dissolved in 95% alcohol and a mono-N-p-aminobenze sulfonyl-N'-methyl pip slight excess of nitrourea was added. The solu e'szine dihydrochloride. tion was warmed cautiously until evolution of gas O had ceased. The solution was then acidified Eacample 6 with HCl, evaporated and the product, N-benzyl Mono-N'-ethyl piperazine as obtained from N'-carbamido piperazine hydrochloride puri Example 2 was reacted with ethylene oxide to fied by recrystallization from alcohol-ether mix produce N-hydroxyethyl-N'-ethyl piperazine. ture. 5 This was then benzoylated by the Schotten Bau This product was catalytically hydrogenated in mann (nethod and the product derived by crystal lization as the hydrochloride of N-benzoyloxy piperazine.glacial acetic acid to yield mono-N'-carbando ethyl-N'-ethyl piperazine. Eacample i0 Eacample 17 2b The process according to Example 9 was re Mono-feethyl piperazil:e as obtained from peated using phenyl isocyanate as a reagent in Example 2 was treated With chloro-acetocatechol stead of nitro urea. After catalytic hydrogena to form N- (3,4-dihydrogyphenacyl)-N'-ethyl tion mono-N'-phenylcarbamido piperazine was piperazine which was isolated as its dihydrc obtained. 25 chloride, Eacample li Eacampie i8 The process according to Example 9 was re Mono-N'-ethyl piperazine as obtained from peated using p-toluene-Sulfonyl chloride as a re Example 2 was reacted with p-toluene-sulfonyl agent. The product obtained from Subsequent chloride to yield N-p-toluene-sulfonyl-N'-ethy catalytic hydrogenation was mono-N'-p-toluene 30 piperazine. sulfonyl piperazine monohydrochloride. Eacample 19 Eacample 2 Mono-N'-propyl piperazine as obtained from Example 3 was reacted with an equinolecular The process according to Example 9 was re amount of benzoyl chloride to produce N-ben peated using p-acetamidobenzene-sulfonyl chio zoyl-N'-propyl piperazine. ride as a reagent. Catalytic hydrogenation yielder ed mono-p-acetamidobenzene-Sulfonyl pipera Ecc.nple 20 zine monohydrochloride which was hydrolyzed Mono-N'-propyl piperazine as obtained from by hydrochloric acid to give mono-p-aminoben 40 Example 3 was reacted with p-acetamido-bein zene sulfonyl piperazine dihydrochloride. Zee-sulfonyl chloride to obtain N-p-acetamido enzieae-sulfonyl-N'-propyl piperazine. Eacample 13 Eacom.ple 21. N-benzyl piperazine (Example 1) was Warned in dilute alcoholic solution with S-methyl isothi iono-N'-butyl piperazine as obtained from ourea, sulfate. Methyl mercaptan was evolved Example 4 was treated with a slight excess of and from the solution, on evaporation and addin phensacy fromide to yield N-phenacyl-N'-butyl tion of acetone, N-benzyl-N'-carbanidino pio piperazine. perazine sulfate crystallized. It was purified 37 Eacample 22 crystallization from aqueous acetone. Upon catalytic reduction, the benzyl group was elimi ... parts ?ay weight of in cro-N'-bef,2O3/oxy nated and mono-N'-carbanidino piperazine sul ethyl piperazine dihydrochloride, 3 obtained fate was obtained. from Example 6, were dissolved in 50 parts of Any of the mono-substituted compounds ac water and 2.8 parts of Eritro urea and 4.2 parts cording to Examples l to 15 may be treated with 55 of sodium bicarbonate were added with stirring a suitable agent for introducing on to the free N aiad gettle waiting. After standing at about 80° a desired second substitutent. In this mannei C. fo: A cit the Solution was evaporated in a great variety of unsymmetrically disubstituted ge residue extracted with 90% ace piperazines can be produced. The following ex sciation was filtered from undissolved BC soid (asisiy Sodium chloride) and acidified with amples may serve as illustrations of said disub hydro::clic acid. The product, N-carbamido stituted compounds and of the methods of pre N-teazoyloxyethyl piperazine hydrochloride, paring the same. They are not intended to limit soo; crystasilized and was purified by recrystalli the scope of the invention. zation from aqueous acetone. Eacample 14 35 Eacample 23 Mono-N'-methyl piperazine as obtained ac cording to Example 1 was treated with chloro fio?o-N-carbamido piperazine as obtained acetocatechol to form N-(3,4-dihydroxypher from Example 9 was treated with phenacyl bro acyl)-N'-methyl piperazine which was isolated as mide to yield N-phenacyl-N'-carbamido pipera its dihydrochloride. This in turn was hydroge 0 zine. nated catalytically at room temperature with a Eacample 24 platinum catalyst giving N-(beta-3,4-dihydroxy Mono-N'-(beta-phenyl-beta-hydroxyethyl) pi phenyl-beta-hydroxyethyl)-N'-methyl pipera perazine dihydrochloride, as obtained from Ex zine. g ample, Was treated with one equivalent of po 2,415,786 7 8 tassium bicarbonate and one equivalent of potas araky substituted piperazine a substituent Se sium thiocyanate to produce N-thiocarbamido lected from the group consisting of the lower N'-(beta-phenyl-beta-hydroxyethyl) piperazine. alkyls having less than 8 carbon atoms, acyl, aryl Sulfonyl, substituted aryl Sulfonyl, acyloxyalkyl, Eacample 25 hydroxyphen alkyl, carbamido, substituted car Mono-N'-benzoyloxyethyl piperazine dihydro bamido and carbamidino, and then removing the chloride, as obtained from Example 6, was dis aralkyl group by Catalytic hydrogenation. solved in ice water and the base liberated by care 4. A method of preparing unsymmetrically ful addition of sodium hydroxide Solution. The N-disubstituted piperazines comprising the steps oily base was extracted with benzene and the of treating piperazine with an aralkyl halide hav extract was dried briefly Over potassium car ing the general formula bonate. The solution was then treated with phenyl isothiocyanate to form N-phenylthio carbamido-N'-benzoyloxyethyl piperazine. YKXCH-x Other applications of our new method will 5 readily occur to those, skilled in the art, in which X is a halogen and Y is a radical of the We claim: group consisting of H and Substituents unreactive 1. In a method of preparing N-Substituted pi in the reaction to form a reaction mixture, con perazines the steps of treating piperazine with an taining in addition to the unreacted piperazine aralkyl halide having the general formula, 20 and the Symmetrically di-N-substituted pipera zine, a Substantial amount of mono-N-aralkyl 4 DCH-x substituted piperazine, separating the mono-N- Y aralkyl-Substituted piperazine from the unre in which X is a halogen and Y is a radical of acted piperazine and from the disubstituted pi the group consisting of H and substituents un 25 perazine, introducing one of the desired substi reactive in the reaction to form a reaction mix tuents on to the second (N') nitrogen atom of ture, containing in addition to the unreacted pi the mono-N-aralkyl substituted piperazine, re perazine and the symmetrically di-N-substituted moving the aralkyl group by catalytic hydrogena piperazine, a substantial amount of miono-N- tion and introducing a second desired substituent 30 different from said first substituent on to the aralkyl substituted piperazine, separating the first (N) nitrogen atom in place of the removed mono-N-aralkyl-substituted piperazine from the aralkyl. unreacted piperazine and from the di-substituted piperazine, introducing the desired substituent 5. A method of preparing unsymmetrically N on to the second (N), nitrogen aton of the nono disubstituted piperazines comprising the steps of aralkyl substituted piperazine, and then remov treating piperazine with an aralkyl halide having ing the aralkyl group by catalytic hydrogenation. the general formula 2. In a method of preparing N-substituted piperazines the steps of treating piperazine with an aralkyl halide having the general formula Y 40 in which X is a halogen and Y is a radical of the group consisting of H and substituents unreactive Y in the reaction to form a reaction mixture, con in which X is a halogen and Y is a radical of the taining in addition to the unreacted piperazine group consisting of H and Substituents unreactive 45 and the symmetrically di-N-substituted pipera in the reaction to form a reaction mixture, con zine, a substantial amount of mono-N-aralkyl taining in addition to the unreacted piperazine Substituted piperazine, separating the mono-N- and the Symmetrically di-N-Substituted pipera aralkyl-substituted piperazine from the unreact zine, a substantial amount of mono-N-aralkyl ed piperazine and from the disubstituted pipera substituted piperazine, separating the mono-N- 50 zine, introducing on to the second (N) nitro aralkyl-substituted piperazine from the unre gen atoms of the mono-N-aralkyl substituted pi acted piperazine and from the di-substituted pi perazine a Substituent selected from the group perazine by fractional distillation, introducing consisting of the lower alkyls having less than 8 the desired. Substituent on to the second (N) carbon atoms, acyl, aryl Sulfonyl, substituted nitrogen atom of the mono-aralkyl substituted 55 aryl Sulfonyl, acyloxyalkyl and hydroxyphenalkyl, piperazine, and then removing the aralkyl group removing the aralkyl group by catalytic hydro by catalytic hydrogenation. genation and introducing on to the first (N) 3. In a method of preparing N-monosubstituted nitrogen atom in place of the removed araky a piperazines the steps of treating piperazine with Second desired Substituent different from said an aralkyl halide having the general formula 80 first Substituent, Said second substituent being selected from the group consisting of the lower alkyls having less than 6 carbon atoms, acyl, aryl & Doh-x Sulfonyl, substituted aryl Sulfonyl, acyoxyalkyl, Y phenacyl, Substituted phenacyl, hydroxyphenacy, in which X is a halogen and Y is a radical of the 65 carbamido, substituted carbamido, thiocarban group consisting of H and substituents unreactive ido, Substituted thiocarbamido, and carbamidino. in the reaction to form a reaction mixture, Con 6. A method of preparing N-carbamido-N'- taining in addition to the unreacted piperazine benzoyl-oxyethyl piperazine comprising the steps and the Symmetrically di-N-substituted pipera of dissolving piperazine hexahydrate in absolute Zine, a substantial amount of mono-N-aralkyl 70 ethanol, adding benzyl cholride, distilling off the substituted piperazine, separating the mono-N- alcohol, extracting the reacted piperazine with aralkyl-substituted piperazine from the unreact ether, distilling in vacuo to separate mono-N- ed piperazine and from the di-substituted piper benzyl piperazine from dibenzyl piperazine, re azine by fractional distillation, introducing on acting the mono-N-benzyl piperazine with ethyl ... to the second (N) nitrogen atom of the mono 75 ene oxide to form N-benzyl-N'-hydroxyethyl pi

< 2,415,786 10 perazine, benzoylatingtoN-benzyl-N'-benzoyloxy zine, where R is an acyloxyalkyl and R' represents ethyl piperazine dihydrochloride, hydrogenating a radical Selected from the group consisting of With palladized charcoal in acetic acid to elimi-, , hydrogen, carbamido. Substituted carbamido, nate the benzyl group, treating the mono-N'- thiocarbamido, substituted thiocarbamido and benzoyloxyethyl piperazine hydrochloride ob tained in aqueous solution. With nitro urea, and NH sodium bicarbonate, evaporating in vacuo and --NH. acidifying with hydrochloric acid to form crystal JOHANNES S. BUCK. line N-carbamido-N-benzoyloxyethyl piperazine RICHARD BALTZLY. hydrochloride. O 7. A method of preparing N-thiocarbamido-N'- REFERENCES (CITED (beta-phenyl-beta-hydroxy ethyl) piperazine The following references are of record in the . comprising the steps of dissolving piperazine in file of this patent: absolute ethanol, adding benzyl chloride, distilling FOREIGN PATENTS off the alcohol, extracting the reacted piperazine 5. With ether, distilling in vacuo to separate mono Number Country Date N-benzyl piperazine from dibenzy piperazine, 698,687 French ------Feb. 3, 1931 reacting the mono-N-benzylpiperazine in alco hol Solution with phenacy bromide to form N OTHER REFERENCES benzyl-N'-phenacyl piperazine, acidifying this Journal Chem. Soc. (London), vol. 105, pages With hydrochloric acid and hydrogenating it 20 221-2, 1914. catalytically to remove the benzyl group and re Journal Chem. Soc. (London), pages 39-49, duce the keto group so as to yield mono-N'-(beta 1929. phenyl-beta-hydroxyethyl) piperazine, treating Beilstein, vol. XXIII, pages 5, 9, 11. this product in alcohol solution with potassium 25 Berichte, vol. 66, pages 113-115. thiocyanate and potassium bicarbonate in equiv Chem. Abstracts, 1930, pages 2749-2751 citing: alent quantities and crystallizing the product, N Bull. Soc. Chim. (4), vol. 45, pages 1172-1189, thiocarbamido-N'-(beta-phenyl - beta - hydroxy 1929, ethyl) piperazine as its dihydrochloride. Chen. Abstracts, 1938, page 942, citing: Journal 8. N-carbamido-N'-benzoyloxyethyl piperazine. 30 Amer. Chem. Soc., vol. 59, pages 2570-2, 1937. 9. An unsymmetrical N-R-N-R' pipera