Patented Feb. 24, 1948 2,436,685

UNITED STATES PATENT OFFICE 2,436,685 SUBSTITUTED PPERAZINES Richard Baltzly, New York, and Emil Lorz, Yonkers, N. Y., assignors to Burroughs Well come & Co. (U. S. A.) Inc., New York, N. Y., a corporation of New York No Drawing. Application January 6, 1944, Serial No. 517,226 Claims. (C. 260-268) 2 This invention relates to N-monosubstituted tem. If two or more phases are present, major and N-N'-unsymmetrically disubstituted piper deviations from the theoretical proportions occur azines and has for an object to provide new com due to the different solubilities of the individual positions of the above type and a novel and im reaction products in the several phases. proved method of making the same. Thus, if piperazine is dissolved in water and Another object is to provide a method of mak benzoyl chloride added, the latter forms a Sep ing and isolating the above substances which is arate layer. When some mono benzoyl piper Suitable for commercial operation. azine has been formed, it is more soluble in the The main difficulty involved in preparing benzoyl chloride layer than the unsubstituted . monosubstituted piperazines, from which unsym O piperazine. Monobenzoyl piperazine therefore metrically disubstituted derivatives can also be passes into the non-aqueous layer, there to be obtained, resides in the production of a reaction benzoylated preferentially. As a consequence, mixture containing, in addition to substituted the dibenzoyl product predominates. piperazine and symmetrically disubstituted pi Similarly unsatisfactory results are obtained perazine, a considerable amount of monosub 15 if piperazine is reacted with an acyl halide or Stituted compound which can be readily isolated sulfonyl halide in absolute alcohol. The dihy from the other mixture components. On the dro-halides of piperazine are very slightly Sol oretical grounds it would be predicted that if uble in absolute alcohol. When the reaction has i mol of piperazine were reacted with 1 mol of proceeded so far that considerable amounts of an acyl or alkyl halide there should result A 20 acid have been produced, piperazine hydrohalide mol of monosubstituted piperazine and A mol precipitates, leaving in solution mono-substituted each of disubstituted and of unsubstituted piper piperazine to be substituted a second time with azine. out competition. The copending applications, Serial No. 476,914 According to the present invention piperazine of J. S. Buck and Richard Baltzly, filed Feb is reacted in a solution which is kept homoge ruary 24, 1943, now Patent No. 2,415,785, issued neous throughout the reaction with a reagent Se February 11, 1947, and Serial No. 517,225, of J. lected from the group consisting of the acyl an S. Buck and Richard Baltzly, filed January 6, hydrides, such as acetic anhydride, phthalic 1944, now Patent No. 2,415,787, issued February anhydride and succinic anhydride, the acyl hal 11, 1947, described methods for preparing mono 30 ides, such as benzoyl bromide, butyryl chloride aralkyl substituted piperazines and piperazines and ethylchlorocarbonate, the aryl sulfonyl hal monosubstituted with higher alkyls in which re ides, such as toluene sulfonyl chloride and the action mixtures of approximately this predictable substituted aryl sulfonyl halides, such as p composition are obtained. It was found, how acetamidobenzene sulfonyl chloride. ever, that similar treatments of piperazine with 35 In this manner mixtures are formed which agents containing acid radicals for the introduc contain, in addition to unsubstituted piper tion of an acyl or of a sulfonyl group frequently azine, and symmetrical disubstituted piperazine, yielded mixtures containing much Smaller pro considerable quantities of monosubstituted pi portions of mono-acyl-substituted or mono-sul perazine. The mixture components may be Sep 40 arated by utilizing the inability of the diacyl and fonyl-Substituted piperazines and, consequently, disulfonyl piperazines to form salts and the dif mono-acyl or mono-sulfonyl-substituted piper ferent solubilities of the salts of monoacyl and azines and their unsymmetrically disubstituted monosulfonyl piperazine and of unreacted pi derivatives could heretofore be prepared only by perazine. complicated methods requiring extraordinary pre 45 cautions. The following solvents have been found use We have found that this difficulty is readily ful in our acylating process: the aqueous COn Overcome if the reaction is carried out in the mercial alcohols, aqueous dioxane, aqueous ace presence of Such a solvent and under Such con tone and, where acetic anhydride is used as re ditions that the reactants remain in substan agent, glacial acetic acid. tially homogeneous solution throughout the 50 If the reaction is carried out with an acyl course of the reaction. halide, or with a sulfonyl halide, the hydro It was found that the above mentioned theo halide salts of the unreacted piperazine and of retical prediction as to the proportion of mono the monosubstituted piperazine are formed all Substituted compounds formed applies only if tomatically during the principal reaction. How the reaction is carried out in a homogeneous sys ever, the addition of an excess of a salt forming 2,436,685 3 4. agent may be desirable in certain cases. If an ethyl chlorocarbonate required about 30 min acylation is effected with an anhydride, it is utes. Shortly thereafter Solid was again ob necessary to add to the reaction mixture a strong served and two types of Crystal were apparent. acid such as hydrochloric acid, sulphuric acid or The solution was allowed to stand over-night. oxalic acid, in order to permit the formation of 5 In the morning the Solid was filtered off and the salts' and the successive yextraction "...of the Washed with:10 cc. of absolute ethanol. The un different mixture, components. . dissolved crystals. Were piperazine dihydrochlo After separation, if an unsymmetrically di ride. substituted piperazine is desired, the second sub The filtrate, which was acid to Congo red, was stituent is introduced on to the second.nitrogen evaporated in vacuo. The residue was dissolved atom by reacting the monosubstituted compound in Water and extracted twice with ether. The with a reagent such as for instance an alkyl ethereal extract, on evaporation, yielded 24 g. Of halide, a phenacyl halide, a substituted phenacyl piperazine, N,N', bis-ethyl-carboxylate, a gum halide, nitro urea, an isocyanate, a salt of thio that crystallized from hexane and then melted at cyanic acid, an isothiocyanic acid, a salt of S 15 '49 C. The aqueous layer was again taken down in alkyl iso-thiourea or an agent-containing an acyl . . vacuo and extracted with a minimum of absolute or a sulfonyl different from that present in the , , alcohol, a small residue of piperazine dihydro monosubstituted compound. chloride being again Separated. The yellow solu The following examples may serve to illustrate tion, on addition of ethylacetate and ether and Without limiting the invention. 20 Cooling deposited flesh-colored crystals of mono Eacample. 1 N-ethyl-carboxylate piperazine ... hydrochloride. Recrystallization from absolute alcohol with chair One-half mole (43 g) of anhydrous piperazine Coaling gave a colorless product. was dissolved in 300 cc. of glacial acetic acid. To this was added with stirring 51 g. (0.5 mol) of 25 Eacample. 5. . acetic anhydride. . The addition took 15 minutes One half mole (97 g.) of piperazine hexahy during which the temperature rose from 48 to 54 drate was dissolved in 200 cc. of dioxane, and 76 C. Stirring was continued for. A hour and the g. (0.4 mole) of p-toluene sulfonyl chloride dis - Solution was allowed to stand over-night. Fifty Solved in 100 cc. of dioxane were run in with cc. of concentrated. HCl was then added and the 30 stirring, the temperature being kept below 60° C. Solution was evaporated in vacuo. . The residue, After standing over-night the mixture was made a thick, red-brown syrup was extracted with 300 acid to Congo-red paper by addition of hydro cc. of hot benzene to remove the di-acetylpiper chloric acid and the mono-p-toluene sulfonyl azine. The benzene-insoluble ... material ... was piperazine hydrochloride isolated by the method treated with absolute; ethanol and the resulting 35 of Example 4. solution filtered off from piperazine dihydro chloride. On addition of ether and standing in ECample 6 the ... refrigerator : the mono-N-acetylpiperazine Following the method of Example 5, equi hydrochloride crystallized. , molecular proportions of p-acetamidobenzene Eacample 2 40 Sulfonyl chloride and piperazine were reacted to Tproduce mono-N-p-acetamidobenzene sulfonyl One half mole...of piperazine hexahydrate was piperazine hydrochloride which was hydrolyzed dissolved in 300 cc. of dioxane and 0.5. mole of With boiling dilute hydrochloric acid to yield benzoyl chloride was added with stirring, the mono-N-p-aminobenzene sulfonyl piperazine di temperature being-held at 40-50° C. The solu 45 hydrochloride. tion was stirred for an hour, made strongly acid We claim: with HCl and then : evaporated in vacuo. The 1. In a method of preparing N-substituted residue was extracted with hot benzene leaving piperazines, the steps of reacting piperazine with the hydrochlorides of piperazine, and mono a reagent selected from the group consisting of benzoyl piperazine. These were extracted with . 50 the acyl anhydrides, the acyl halides, the aryl absolute alcohol. leaving. behind piperazine hy Sulfonyl halides and the substituted aryl sulfonyl drochloride. Monobenzoyl piperazine hydro halides in the presence of a 'solvent selected from chloride was . then.: crystallized by addition of the group consisting of the aqueous commercial ether. alcohols, aqueous dioxane, aqueous acetone and Eacample 3 55 glacial acetic acid and maintaining the reaction One half. mole of piperazine hexahydrate was mixture in Such solvent in a single phase solution reacted in aqueous acetone with 0.5 mole of until the reaction is completed and the mixture butyryl chloride. After completion of the re contains, in addition to unreacted piperazine and action, excess. HCl was added and the solution N,N'-disubstituted piperazine, a substantial evaporated in vacuo. The dibutyryl piperazine 60 amount of mono-N-substituted piperazine, and Was removed by solution in hot benzene. Extrac Separating the mono-N-substituted piperazine tion with absolutelalcohol then served to dissolve from the unreacted piperazine and from the di monobutyryl piperazine hydrochloride and this Substituted piperazine, . Was crystallized by addition of absolute ether. 2. A method as claimed in claim 1, in which 5 the piperazine and the acid radical containing Eacample...4 agent are reacted in equimolecular quantities. One half mole (43 g.) of anhydrous piperazine 3. In a method of preparing N-substituted "was dissolved in 300 cc. of 95% ethanol. To this piperazines, the steps of reacting piperazine with was added, with mechanical stirring, 54 g. (0.5 a reagent selected from the group consisting of mole) of ethylchlorocarbonate. The solution 70 the acyl anhydrides, the acyl halides, the aryl warmed itself fairly rapidly (13 minutes) to 50° Sulfonyl halides and the substituted aryl sulfonyl C. whereupon water cooling was used to keep halides in the presence of a solvent selected from the temperature below 50° C. At this point solid the group consisting of the aqueous commercial began to separate and 50 cc. of water were added alcohols, aqueous dioxane, aqueous actone and to restore it to solution. The addition of the 75 glacial acetic acid and maintaining the reaction 2,436,685 S 6 mixture in Such solvent in a single phase solu - cooling the solution under addition of ethylace tion until the reaction is completed and the mix tate and ether to obtain crystalline piperazine ture contains, in addition to unreacted piperazine In On O-N-ethylcarboxylate. and N,N'-disubstituted piperazine, a substantial 7. A method of preparing mono-N-p-amino a lount of mono-N-substituted piperazine and benzene -sulfonyl piperazine dihydrochloride Separating the mixtures by utilizing the inability comprising the steps of dissolving equimolecular of the disubstituted piperazine to form salts and proportions of piperazine and p-acetamidoben the different Solubilities of the salts of monositio Zene-sulfonyl chloride in aqueous dioxane, stir stituted piperazine and of unreacted piperazine. ring the solution while the temperature is kept 4. A method as claimed in claim 3 in which 0 below 60° C., adding hydrochloride acid to pre after completion of the reaction a strong acid cipitate solid piperazine dihydrochloride, filter is added to the reaction mixture as a salt form iig, evaporating the filtrate in vacuo, dissolving ing agent. the residual in Water, extracting the N,N'-disub 5. A method of preparing mono-N-acetyl stituted piperazine with ether, evaporating in piperazine comprising the steps of dissolving an 5 vacuo, extracting with absolute alcohol, filtering hydrous piperazine in glacial acetic acid, adding off a further small quantity of piperazine dihy an equimolecular amount of acetic anhydride, drochloride, cooling the Solution under addition stirring until the reaction has been completed, of ethylacetate and ether to obtain crystalline adding hydrochloric acid, evaporating the solu mono-N-p-acetamidobenzene sulfonyl pipera tion in vacuo, extracting the di-acetyl pipelazine 20 zine hydrochloride and hydrolyzing this product with non-polar solvent, treating the residue with With boiling dilute hydrochloric acid to yield absolute ethanol to dissolve the mono-acetyl nono-N-p-aminobenzene sulfonyl piperazine di pipelazine hydrochloride, separating the solu hydrochloride. tion by filtering from the undissolved piperazine RICHARD BALTZLY. dihydrochloride and recrystallizing the mono 25 EMIL, ORZ. acetyl piperazine hydrochloride from the solution by the addition of ether. REFERENCES CEO 6. A method of preparing piperazine mono-N- The following references are of record in the ethylcarboxylate comprising the steps of dis file of this patent: solving piperazine in 95% ethanol, adding an 30 equimolecular amount of ethylchlorocarbonate, UNITED STATES PATENTS introducing, under constant stirring, sufficient Number Name Date water to keep the solution honogeneous through 2,113,357 Mietzsch ------Apr. 5, 1938 out the reaction, permitting after completion of 2,362,276 Joyne ------Nov. 19, 1944 the reaction the precipitation of solid piperazine 35 dihydrochloride, filtering, evaporating the fil OTHER REFERENCES trate in vacuo, dissolving the residue in Water, Journal of the Chemical Society (London) extracting the piperazine N,N' bis-ethyl carbox 1929, pages 39-49. ylate with ether, evaporating in vacuo, extract Journal of the Chemical Society (London) ing with absolute alcohol, filtering off a further 40 1914, Vol. 105, pages 221-2. small quantity of piperazine dihydrochloride, and Berichte, vol. 66, pages 113-115.