L. GOLDMAN AND J. H. LVILLIAhIS
6078 [CONTRIBUTION FROM
THE
Vol. 76
CHEMICAL AND BIOLOGICAL RESEARCH SECTION,LEDERLE LARORATORTES DIVISION, AMERICAN CYANAMID COMPANY]
Derivatives of 1-Piperazinecarboxylic Acid as Sedatives1 BY L. GOLDMAN AND J. H. WILLIAMS RECEIVED JUNE 25, 1954
A series of esters of 4-acyl- and 4-aroyl-1-piperazinecarboxylic acid represented by formula I1 has been synthesized and characterized. Several have been found to possess sedative properties.
In studying the pharmacological properties of various derivatives of piperazine i t has been noted2 that some possess sedative properties when tested in animals; Nonas3 has reported that N,N-diethyl1-piperazine~arboxamide~ (I) has possible clinical usefulness as a daytime sedative. Since various amides and urethans exhibit sedative and hypnotic properties,6 i t was decided to synthesize derivatives of piperazine represented by formula I1 in which N4 is substituted with an acyl or aroyl group and N' is substituted with a carbalkoxy or carbaralkoxy group. R'
piperazinecarboxylic acid reveals that the peak sedative activity is reached in the ethyl ester 111. The compounds listed in Table I were synthesized by reaction of an alkyl or aralkyl ester of 1piperazinecarboxylic acid with an anhydride (procedures A, B and C) or with an acyl or aroyl halide under Schotten-Baumann conditions in the presence of sodium hydroxide (procedure D) or sodium bicarbonate (procedure E) ; or with a molar excess of the ester of 1-piperazinecarboxylic acid in an anhydrous solvent (procedures F, G, H and I). Experimental8
The intermediate methyl, ethyl, n-butyl and benzyl esters of 1-piperazinecarboxylic acid were prepared by the , ~ Goldman, methods of Moore, et ul.,' Stewart, et ~ l . and et ~ 1 . ~ Ethyl 0 t~uns-2,5-dimethyl-l-piperazinecarboxylate was prepared as described previously." 2-Methylbutyryl chloride was obtained in 92% yield as previously described.'Z 2-Ethyl-n-caproyl Chloride.-it-Butylethylmalonic acid 11, R = alkyl or aryl I was decarboxylated t o 2-ethyl-n-caproic acid in 96% yield R' = alkyl or aralkyl according to the method of Raper.'S Reaction with thionyl R' = H or methyl chloride according to Levene and KunaI4 for the (-)gave 2-ethyl-n-caproyl chloride, b.p. 73" (17 mm.), Among the 4-acyl and aroyl derivatives of ethyl isomer in 87% yield. TiffeneauI5 reports b.p. 85-90' (20 mm.); 1-piperazinecarboxylate listed in Table I, a number Leve?e and Kuna14 report b.p. 62-64' (10 mm.) for the were found to be active as sedatives when tested (-)-isomer. 3-Methylvaleryl Chloride.-sec-Butylmalonic acid,lE obwith the asymptomatic dose in rats in activity tained in 76% yield by saponification of the ethyl ester,l6 cages. In the normal acyl series there is a narrow was decarboxylated'7 t o give a 93% yield of 3-methylvaleric range of activity with the peak ( 4 f ) reached a t acid,'s which reacted with thionyl chloride according t o Colongelg to give a 65% yield of 3-methylvaleryl chloride, C4--C6in ethyl 4-n-butyryl-1-piperazinecarboxylate (111) and in ethyl 4-n-valeryl-1-piperazinecarboxyl- b.p. 73-75' (80 mm.); Hommelen'g gives b.p. 142.5-143.0' mm.) ate (XIII). In the branched-chain acyl series (749 It-Caprylyl Chloride.-Obtained in 96% yield by reaction there is a wider range of activity with the peak of n-caprylic acid with phosphorus pentachloride. Averill, et a1.,20 had synthesized this compound by the reaction of /-7 n-caprylic acid with oxalyl chloride (method of Adams and n-CaH7CON SCOzCzHj UlichZ*). \A Procedure A. Ethyl 4-Acetyl-1-piperazinecarboxylate I11 (IV).-A solution of 31.6 g. (0.2 mole) of ethyl l-piperazinecarboxylate? in 100 ml. of glacial acetic acid was treated, (4+) a t isovaleryla (XIV), and 3+ activity for the with cooling, with 20.4 g. (0.2 mole) of 97% acetic an2-methylbutyryl (XV), 3-methylvaleryl (XVIII) hydride. The resulting solution was heated for 1 hour on a and 2-ethylcaproyl (XXII) derivatives. The iso- steam-bath and then evaporated in vucuo to remove the acid. Distillation in vacuo of the residual sirup gave caproyl derivative (XVII) is much more toxic than acetic 33.7 g. (84%) of colorless liquid, b.p. 143-145' (0.3 mm.), the previously mentioned compounds and a t the nZ5n1.4865. .\
.
asymptomatic dose level (30 mg./kg. orally) the compound is inactive. The aroyl derivatives (XXV, XXVI, XXVII, XXVIII) are inactive. -4 compdrison of the methyl, ethyl, n-butyl and benzyl esters (IX, 111, X , X I ) of 4-n-butyryl-l(1) Presented before t h e Division of Medicinal Chemistry, 126th National Meeting of t h e American Chemical Society, ?iew York, K. Y., September 12-17, 1954. ( 2 ) R. W. Cunningham, et al., private communication. (3) G. Nonas, N . Y. S t a l e J. M e d . , SO, 1257 (1950). (4) S. Kushner, L. M. Brancone, R . I. Hewitt, W. L. McEwen and Y.SubbaRom: H . W. Stewart, R. J. Turner a n d J. J. Denton, J. Org. Chcm., 13, 144 (1948). (5) S. Frankel, "Die Arzneimittel-Synthese," Julius Springer, Rerlin. 1927, p. 522. (6) During the course of this investigation R. B. Keller a n d R . A . LaForge, J . A m . Pharm. Assoc., Sci. Ed., 41, 301 (1952), reported t h e synthesis of X I V a n d found t h a t it does not show promise as a sedative.
(8) All boiling points and melting points are uncorrected. (9) H . W, Stewart, R. J. Turner a n d J . J. Denton: S. Kushner, L. hI. Brancone, IV. L. hlcEwen, R. 1. I-iewitt and Y.SubbaRow, J . O r f . C h e m . , 13, 134 (1948). (10) L. Goldman and J. H. XTilliams, ibid., 18, 815 (1953). (11) (a)H. W, Stemart, IY.Q. Quinones, E. G. Lee a n d J. J. Dentnn, ibid., 18, 1478 (1953): (1,) K. If. Beck, K. E. Hamlin and A . W. X'eston, THISJ O U R X A L . 7 4 , 005 (1952),not identified as trans isomer. (12) R. Leimu, Sei.., 70B, 1040 (1937). (13) H. S. Raper, .I. Cherii. Soc., 91, 1831 (1907). (11) I'. A. Levene and hI. Kuna, J . Bioi. Chem., 140, 259 (1941). (15) 15. hl. Tiffeneau, BZLLL, sac. chinz., [ A J , 33, 183 (1923). (16) F. Ehrlirh, Eirv., 41, 1453 (1908). (17) P. van Rumburgh, Rcc. Lvnr. chim., 6 , 150 (1887). (18) h1, Ilommelen, Brtil. POC. c h i i n . B r i g . , 42, 213 (1933). (IO) J . Colonge, B u l l . sac. ( h i m , , 141, 49, 4 1 1 (1931). (20) 13. I'. Averill, J. N. Roctie a n d C. G. King, T H I S J O C R N - ~ I . , 51, 866 (1929). (21) R. Adams and L. H. T'lich, i b i d . , 4 2 , 603 (1920)
DERIVATIVES OF 1-PIPERAZINECARBOXYLIC ACID
Dec. 5, 1954
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6079
LLOYDH. SBIITH,
6080
JR., AND PETER YATES
iTol,SG
Procedure B. Ethyl truns-4-Acetyl-2,5-dimethyl-l-piper- crystals of ethyl I-piperazinecarboxylate hydrochloride.22 azinecarboxylate (V).-A mixture of 18.6 g. (0.1 mole) of The filtrate was distilled to remove the ethyl acetate and the and 25 residual red-brown liquid was distilled in 'UUCUO. The prodethyl tr~ns-2,5-dimethyl-l-piperazinecarboxylate~~ ml. of acetic anhydride was refluxed for 8 hours. The re- uct, 89 g. (97oj,), was obtained as a colorless liquid, b.p. sulting solution was distilled in vucuo. After removal of ~ 130-131" (0.5mm.), n * 5 1.4840. acetic acid and acetic anhydride two fractions were obProcedure G. Ethyl 4-(3-Methylvaleryl)-l-piperazinetained: (a) 7.2 g. of colorless liquid, b.p. 128-143" (15 carboxylate (XVIII) .-3-Methylvaleryl chloride (13.5 g., mm.) (mainly ethyl truns-2,5-dimethyl-l-piperazinecar- 0.1 mole) was added dropwise t o 34.8 g. (0.22 mole) of boxylate); (b) 10.2 g. of nearly colorless viscous liquid, b.p. ethyl 1-piperazinecarboxylate in 2\50 ml. of ether with 120-163' (5 mm.) (mainly b.p. 163"). Fraction b was re- cooling. After standing overnight a t room temperature the distilled and after removal of 3.0 g. of forerun, b.p. 113-163' reaction mixture was filtered to remove 19.6 g. (100%) ( 5 mm.), 5.1 g. (22%) of T' was obtained as a viscous yellow of ethyl I-piperazinecarboxylate hydrochloride. The filliquid, b.p. 163' ( 5 mm.). After standing for a long- time trate was washed with l N hydrochloric acid, water and the material solidified. 5% sodium bicarbonate, and dried over magnesium sulfate. Procedure C . %-Butyl4-n-Butyryl-1-piperazinecarboxylate The ether was removed on a steam-bath and the residual ix) .-To 37.2 E. (0.2 mole) of n-butvl 1-DiDerazinecarboxvl- liquid was distilled in oucuo to yield 22.3 g. (87%) of XVIII ate,g 31.6 g. N.2 mole) of n-butyrk anhydride was added as a colorless liquid, b.p. 137-140' (0.04 mm.), n Z 51.4840. ~ with mixing and cooling. The resulting solution was heated Procedure H. Ethyl 4-Myristoyl- 1-piperazinecarboxylon a steam-bath for 1 hour and then distilled through a ate (XXIV).-To a solution of 63.3 g. (0.4 mole) of ethyl Yigreux column. After removal of the n-butyric acid, 40.8 1-piperazinecarboxylate in 350 ml. of ether, 49.4 g. (0.2 g. (80%) of X was obtained as a colorless liquid, b.p. 155mole) of myristoyl chloride was added in portions with 156' (0.4 rnm.), 12251) 1.4820. shaking and cooling. After standing overnight a t room Procedure D. Benzyl 4-n-Butyryl-1-piperazinecarboxyl- temperature the mixture was filtered to remove 38.4 g. ate (XI) .-To a stirred mixture of 44 g. (0.2 mole) of benzyl (99%) of ethyl 1-piperazinecarboxylate hydrochloride. l-piperazinecarboxylate10and ice were added simultaneously The filtrate was washed with 5% sodium bicarbonate and and dropwise 32 g. (0.3 mole) of n-butyryl chloride and 100 dried over Drierite. The dried solution was heated on a ml. of 4 N sodium hydroxide; ice was added as required to steam-bath to remove the ether, leaving 71.1 g. (96%) of maintain an excess. A colorless oil separated. The mix- XXIV, m.p. 35-36.5". Recrystallization from hexane gave ture was kept cold by means of an ice-bath and stirring was colorless crystals, m.p. 36.538'. continued for 3 hours. The oil was extracted into chloroProcedure I. Ethyl 4-n-Caproyl-1-piperazinecarboxylate form and the chloroform extract was washed with 0.5 N (XVI).-To a cold solution of 63.3 g . (0.4 mole) of ethyl 1hydrochloric acid and then with water and dried over piperazinecarboxylate in 350 ml. of ether, 26.9 g. (0.2 mole) magnesium sulfate. The dried extract was evaporated of n-caproyl chloride was added carefully, immediately in YUCUO to remove the chloroform and the residual liquid producing a precipitate of ethyl 1-piperazinecarboxylate was distilled in vacuo to yield 43.2 g. (75%) of nearly color- hydrochloride. After standing a t room temperature for 2 hours 100 ml. of water was added to dissolve the precipitate. less liquid, b.p. 197-203' (0.3 mm.), n z 61.5353. ~ Procedure E. Ethyl 4-p-Nitrobenozyl-1-piperazinecar- The layers were separated and the ether layer was washed boxylate (XXVI).-A mixture of 31.6 g. (0.2 mole) of ethyl successively with 5% hydrochloric acid, water and 5% 1-piperazinecarboxylate, 37.1 g. (0.2 mole) of p-nitrobenzoyl sodium bicarbonate, and dried over magnesium sulfate. chloride and 33.6 g. (0.4 mole) of sodium bicarbonate in The ether xvas removed on a steam-bath and the residual yellow liquid, 46.1 g. (9OQ/o), was distilled zn eucuo. 300 ml. of water was stirred a t room temperature for 7.5 pale The product was obtained as a nearly colorless liquid, b.p. hours and then heated on a steam-bath for 30 minutes. 130-136' (0.05-0.08 mm.), n 2 3 . 8 ~1.4835. The resulting precipitate was removed by filtration and Acknowledgment.-The authors are indebted to crystallized twice from absolute ethanol (using Norit) , yielding 27.5 g. (45%) of very pale yellow crystals, m.p. Mr. W, L. hIcEwen and associates for synthesis of 91-92'. When recrystallized from absolute ethanol the some intermediates, to Mr. L. M. Brancone and product had m.p. 91.5-92.5'. associates for the microanalyses and to Dr. R. \T. Procedure F. Ethyl 4-Isobutyryl-1-piperazinecarboxylate Cunningham and associates for the pharmacological (XII).-To a cold stirred solution of 150 g. (0.95 mole) of ethyl 1-piperazinecarboxylate in 1 1. of ethyl acetate, 50 g. testing. (0.47 mole) of isobutyryl chloride was added dropwise. PEARLRIVER,N. Y. After standing for 1.5 hours a t room temperature the (22) K - R Jacobi, B e y , 66B, 113 (1933). mixture was filtered to remove 91.9 g. (100%) of colorless
[CONTRIBUTION FROM
THE DEPARTMENT OF CHEMISTRY OF HARVARD UNIVERSITY AND THE DIVISIONOF PHYSIOLOGY O F THE PCBLIC HEALTH RESEARCH INSTITUTE O F NEW YORK CITY]
KUTRITIOS AND
The Synthesis of 4-Amino-2 (3H)-oxo-5-imidazolecarboxamide BY LLOYD H. SMITH, JR.,' AND PETER TATES? RECEIVED JUSE 22, 1931
4-Amino-2(3H)-oxo-5-imidazolecarboxarnidehas been synthesized by the action of base on carboxamidoaminocyanoacetamide. Its structure has been proved by hydrolytic degradation to 2,4-dioxo-5-imidazolecarboxamideand to hydantoin. Biological testing of C'3-labeled material gave no evidence of its being a precursor of uric acid.
Introduction I n 1945, Stetten and Fox3 discovered a new diazotizable amine in cultures of E . coli whose growth was inhibited by sulfadiazine or sulfapyridine. The amine was subsequently identified by Shive, et u Z . , ~ (1) Junior Fellow, Society of Fellows of Harvard University. (2) Inquiries regarding this article should be addressed t o this author a t Harvard University. (3) M. R. Stetten a n d C. L. Fox, J. B i d . Chcm., 161, 333 (1915). (4) W.Shive, W.W. Ackermann, M. Gordon, M. E. Getzendaner a n d R. E. Eakin, THIS JOURNAL, 69, 725 (1947).
as 4-amino-5imidazolecarboxamide(I). Isotopic studies have demonstrated this compound to be a purine precursor in a number of biological systems including y e a ~ t the , ~ pigeon16the rat' and man.s In man, with a ureotelic nitrogen metabolism, uric ( 5 ) W. J . Williams, Fcdevatiorz Proc., 10,270 (1981). (6) W. P. Schulman, J . hI. Buchanan and C. S . Miller, ibid., 9, 225 (1950). (7) C. S. Miller, S. Gurin and D. W. Wilson, Sciewcc, 112, 654
(1950). (8) J. E. Seepmiller, personal communication.
