[CONTRIBUTION FROM THE DEPARTMENT OF PHARMACOLOGY, VANDESIBILT UNIVERSITY SCHOOL OF MEDICINE]
DIACYLUREAS. I. PREPARATION AND PROPERTIES OF DIACYLUREAS DERIVED FROM NORMAL ALIPHATIC ACIDS* ROGER W. STOUGHTON Received December 16, 1957; revised February 18, 1958
A survey of the literature on the simple open-chain diacylureas revealed only a few scattered references, many of which were in the patent literature and gave only meager details as to the chemistry and hypnotic action of these compounds. In view of their structural position, intermediate between the monoacylureas and the barbiturates, it was believed that the preparation and study of these diacylureas would be of interest. The present communication deals with compounds derived from normal aliphatic acids and the correlation of their properties with the existing data. The preparation of compounds derived from other acids is already under way and will form the basis of later communications.
+ COClz -+ RCONHCONHCOR + 2 HC1 RCONCO + R’CONH2 -+ RCONHCONHCOR’ RCONHCONHz + R’COC1 BoRCONHCONHCOR’ % + HCl 2 RCOOCzHs + NHzCONH:! RCONHCONHCOR + 2 C2H60H 2 R&(OH)CONHCN + 3 H2O &C(OH)CONHCONHCOC(OH)Ra + 2 NHa + COz 2 RCONHz
(1) (2)
(3)
(NaOCzHs)>
(4)
--+
(5)
The synthetic methods that have been reported parallel those employed in the preparation of the barbiturates. Schmidt’ first prepared diacetylurea in 1872 by the condensation of two molecules of acetamide with one molecule of phosgene (equation 1). Later Bornwater2 substituted oxalyl chloride for phosgene, but this modification probably is applicable to only
* Presented before the Division of Medicinal Chemistry at the Ninety-fourth Meeting of the American Chemical Society, Rochester, N. Y., September 10, 1937. 1 SCHMIDT, J . prakt. Chem., 6 , 63 (1872). * BORNWATER, Rec. trav. chim., 31, 118 (1912). 514
DIACYLUREAS
515
a few amides? A second method, consisting of the reaction of an acylisocyanate with an amide (equation 2), was suggested by Scholl,' and has received some recognition in the patent literatureV6 Another method6v7consists in the reaction of an acid halide or anhydride with a monoureide in the presence of a catalyst (equation 3). This procedure was found to be the most convenient laboratory method for the preparation of the normal aliphatic diureides and was the one employed in this investigation. It also makes possible the preparation of compounds with two different acyl groups attached to the urea nucleus. The only successful attempt to prepare a diacylurea by the condensation of an ester with urea in the presence of sodium ethylate (equation 4) was reported by Clemmensen and Heitman.8 They prepared a series of diureides derived from a-hydroxy acids. Several monoureidesghave been synthesized by this method, but no unsubstituted diacylureas; yet it is the most common procedure for the preparation of barbiturates. When the ethyl esters of the normal aliphatic acids were condensed with urea by means of sodium ethylate, the only products ever isolated were the corresponding monoureide, amide, and sodium cyanate. Furthermore, it was found that the diacylureas derived from the normal aliphatic acids reacted in the cold with sodium ethylate to form an ethyl ester and the monoacylurea, which was further decomposed on heating to sodium cyanate and the amide. Thus it appears that the normal aliphatic esters, unlike hydroxy acid esters, condense with urea to form only a monoureide under the conditions ordinarily employed. Clemmensen and Heitman8 also reported the preparation of the hydroxy acylureas by the hydrolysis of the corresponding acylcyanamides (equation 5 ) . In the present investigation eighteen new diureides, with both similar and dissimilar acyl groups attached to the urea part of the molecule, have been prepared in good yields by the reaction of an acid chloride with a monoacylurea in benzene solution with a little sulfuric acid as catalyst. It has been assumed that each of the two acyl groups is always attached to a different nitrogen atom in the urea to form a symmetrical compound, and no evidence indicating that this is not true has been obtained. Diacetylurea obtained from acetamide and phosgene or oxalyl chloride was found to be identical with that obtained from the acetylation of monoFIOEE,ibid., 34, 289 (1915). QCHOLL, Ber., 23, 3516 (1890). 6 BAYER & Co.,German Patent 286,760,Dec. 6 , 1913. WERNER, J. Chem. Soc., 109, 1120 (1916). 7 BAYER & Co.,British Patent 132,795, Sept. 16, 1919. 8 CLEMMENSEN AND HEITMAN, Am. Chem. J . , 40,280 (1908);42,319 (1909). ( a ) STENDAL, Compt. rend., 196, 1810 (1933); ( b ) JERZMANOWSKA-SIENKIEWICZOWA, Roczniki Chem., 16, 510 (1935). 3
4
516
ROGER W. STOUGHTON
acetylurea. Werner6 has suggested that the second acyl group is attached to the oxygen atom to form a pseudo-ureido ester. Several of the compounds with different acyl groups in the same molecule have been prepared by treating the two different monoureides with the proper acyl chloride, and identical compounds were always obtained; for instance, the compound obtained by treating acetylurea with butyryl chloride was the same as the one obtained from butyrylurea and acetyl chloride. Consequently, such a pseudo-structure is very unlikely. These compounds are soluble in alkali, as would be expected inviewof the presence of enolizable hydrogen, but are almost immediately hydrolyzed to a monoureide and a fatty acid salt. Clemmensen and Heitmanns claimed that the di(a-hydroxyacy1)ureas were stable t o cold alkali and acted only as dibasic acids. The N,N’-diacylureas appeared to go into solution on the addition of one equivalent of alkali, but it was difficult to obtain quantitative data on this point because of the rapidity of hydrolysis. Acids promoted hydrolysis at a slower rate than alkalies, but even boiling water hydrolyzed these compounds slowly. Unlike the barbituric acids, these simple diacylureas decompose readily on heating and could not be satisfactorily distilled. Werner6 decomposed diacetylurea and, from the products isolated, he postulated decomposition as occurring simultaneously in two different ways (equations 6 and 7).
+ RCN + COz RCONHCOR + (HCNO),
RCONHCONHCOR+RCONHz
3 RCONHCONHCOR+3
(6)
(7)
This result has been confirmed by a quantitative study of the decomposition of sym-dienanthylurea. Carbon dioxide was evolved, enanthonitrile distilled off, and from the residue enanthamide, dienanthamide, and cyanuric acid were obtained. The amounts of these various products were in excellent stoichiometrical agreement with the above equations and indicated that in this case approximately two-thirds of the original material had decomposed according to equation 6 and the remaining third according to equation 7. These nineteen diacylureas form a series of compounds which it is interesting to compare with the barbituric acids. The most striking difference is the instability of the former towards alkali and heat. However, this is a difference in degree only, as the barbituric acids are themselves hydrolyzed more or less rapidly to form monoureides. This instability towards alkali made it impossible to prepare the simple diacylureas by using a basic condensing agent, as is the common procedure with the malonylureas. It should be pointed out that the diureides of other types of acids would be expected to have properties somewhat different from
DIACYLUREAS
517
those of the ones described here. This has already been demonstrated in the case of compounds derived from the a-hydroxy acids. It is also interesting to note that these N,N'-diacylureas were found to give no color test with the cobaltous acesate reagent of Koppanyilo as do the barbituric acids. Because of the similarity of these compounds to the barbiturates, their pharmacological properties are of interest. No study of the hypnotic properties of the previously known diacylureas was found in the literature, but the patent^^,^ on the bromine-substituted derivatives contain the statement that such compounds possess hypnotic and sedative properties. Consequently, preliminary studies of these new substances as hypnotics have been made and are reported briefly here. When administered intravenously to white mice, the most active compounds (those containing eight to ten carbon atoms) had a minimum effective dose of from eighty to cine hundred and fifty milligrams per kilogram of body weight. As a group they had an activity comparable with that of the common bar. biturates, but the anesthesia produced was very short, averaging only one or two minutes. They were, however, inactive when administered intraperitoneally or orally except after large doses. Even though these compounds appear in vitro to be stable a t the pH of blood, they must be destro,yed very rapidly in the body to be such very short-acting hypnotics. On oral administration, large doses must be given in order that the drug may be absorbed more rapidly than it is destroyed. The anesthesia produced, in contradistinction to that of many of the barbituric acids, is characterized by marked analgesia and absence of excitement. More completle pharmacological studies will be reported elsewhere a t a later date. EXPERIMENTAL
P:ropionyZurea.-In a large test-tube, stoppered with a cork loosely fitted with a thermometer, were placed 6 g. of urea, 15 cc. of propionic anhydride, 5 cc. of propionic acid and 0.4 cc. of concentrated sulfuric acid. This was placed in a beaker of boiling water and stirred occasionally with the thermometer. Soon after the urea dissolved, the temperature rose to 105-llOo,and in five minutes crystals began to appear in the solution. Fifteen minutes after the appearance of the first crystal, the temperature had dropped to 98'; the test-tube was cooled, and 20 cc. of water was added. After standing one hour in the ice-box, the crystals were collected, washed with saturated sodium bicarbonate solution and finally with water. This gave 8.5 g. (78g)) of a pure product. n-ButyryZurea.-In a 200-cc. 3-necked flask, fitted with mechanical stirrer, reflux condenser, and dropping funnel, were placed 10 g. (0.17 mole) of urea, 25 cc. of benzene and two drops of concentrated sulfuric acid. This was warmed on a steam bath and to the boiling solution 15 g. (0.15mole) of n-butyryl chloride was added ~
~~
lo
KOPPANYI, DILLE, MURPHY, AND KROP,J . Am. PhaTm. ASSOC., 23, 1074 (1934).
518
ROGER W. BTOUGHTON
drop-wise over a period of fifteen minutes. After four hours of refluxing the mixture was cooled, and the solid t h a t had formed was collected and washed with a little petroleum ether. The product was transferred to a beaker, and washed, first with sodium bicarbonate solution, and then with water. The other monoacylureas were prepared exactly as described above by substituting a proportionate amount of the proper acyl chloride. I n all cases the product obtained after washing with sodium bicarbonate was pure enough t o be used in the synthesis of diacylureas. The analytical samples were recrystallized from n-butyl alcohol. The yields varied from 75 to 85 per cent., based on the amount of acyl chloride used. The physical properties of these compounds are recorded in Table I. Preparation of sym-diacyZureas.-This procedure is illustrated by the preparation of N-acetyl-N'-propionylurea. In a 200-cc. flask fitted with a reflux condenser were placed 12 g. (0.1 mole) of propionylurea, 30 cc. of dry benzene, 10 g. (0.13 mole) of acetyl chloride, and three drops of concentrated sulfuric acid, and the mixture was refluxed on a steam bath. Hydrogen chloride was evolved and the ureide slowly dissolved. After four to six TABLE I PROPERTIES OF TEE MONOACYLUREAB URBA
Acetyl-' Propionyln-Butyryl-" n-Valeryln-Caproyln-Enanthyln-Capr ylyl-Qa
I. P.,
"c.,CORRECTBD 216-217 2 10-21 1 173-174 182-183 192-193 191-192 191-192
PER CENT. NITROQEN
FORMULA
caHsN
202
C~HSN~OZ CsHioNzOi C6HlZNZOl CJIirNzOz C sHisNzOz c oHi 8NzOz
Calc'd
Found
27,44 24.13 21.53 19.43 17.71 16.27 15.04
27.33 24.21 21.32 19.45 17.76 16.12 14.97
~~MOLDENEAUER, Ann., 94, 101 (1855). hours' heating, the evolution of hydrogen chloride ceased and a clear, straw-colored solution was obtained. This was cooled, diluted with 100 to 200 cc. of petroleum ether, and allowed to stand in the ice-box over night. The white solid t h a t separated was collected, washed with a 10 per cent. sodium bicarbonate solution, and recrystallized. All the diacylureas with the exception of the diacetylurea were prepared as above by substituting proportionate amounts of the proper acylurea and acyl chloride. Slightly better over-all yields were obtained in the case of those diureides with different acyl groups when the monoureide of the acid with the higher molecular weight was prepared first and then treated with the acyl halide of the lower molecular weight. Even with compounds in which both acyl groups were the same, satisfactory yields could be obtained only by isolating the intermediate monoacylurea rather than by trying to force the reaction through in one step. Yields of between 75 and 85 per cent. were obtained. When available, the acid anhydride could be substituted for the acid chloride, but the latter seemed preferable in most cases. The physical properties of these compounds are recorded in Table 11. They were all white crystalline substances, soluble in the common organic solvents
519
DIACYLUREAS
but only slightly soluble in petroleum ether. Diacetylurea was soluble in water t o the extent of 7 per cent. at 25", and the aqueous solubility of the others decreased regularly as the molecular weight increased. The diacylureas were much more soluble, both in water and organic solvents, than the corresponding monoacylureas; for instance, monoacetylurea dissolved in water t o the extent of only 2 per cent., and was only slightly soluble in hot alcohol. This difference was less noticeable in the compounds of higher molecular weight. These substances were soluble in dilute alkali but were almost immediately hydrolyzed by i t t o monoureides and salts of fatty acids. The acyl group with the smaller molecular weight was always hydrolyzed off more rapidly, and, therefore, compounds with larger acyl groups were TABLE I1 PROPERTIES OF THE DIACYLUREAS M. P.,
UREA
e., COR RECTED
SOLVENT FOR RECRYBTALLLIZATION
FORMULA
PER CENT. NITROQEN
Mc'd Found
-sym-Diacetyl-6 N-Acetyl-N '-propionylsym-DipropionylN-Acetyl-N '-butyrylN-llutyryl-N '-propionylN-Acetyl-N '-valerylsym-DibutyrylN-I'ropionyl-N '-valerylN-Acetyl-"-caproylN-Butyryl-N '-valerylN-Caproyl-N'-propionylN-Acetyl-N'-enanthylsym-DivalerylN-Butyryl-N '-capr ylylN-Enanthyl-N '-propionylN-Acetyl-N '-caproyllV-Caproyl-N '-valerylsym-Dicaproylsym-Dienanthyl-
54-15: 12-11; 05-1Of 80-81 96-97 66-67 86-87 82-83 85-86 75-76 92-93 80-81 83-84 66-67 82-83 92-93 80-81 87-88 80-90
50% Acetic acid Benzene cCl4 Bz.-pet. ether Dil. methanol Bz.-pet. ether Bz.-pet. ether Dil. methanol Bz.-pet. ether Dil. methanol n i l . methanol Bz.-pet. ether Bz.-pet. ether Pet. ether Bz.-pet. ether 50% Acetic acid Bz.-pet. ether Bz.-pet. ether Be.-pet. ether
19.44 17.72 16.27 16.27 15.05 15.05 13.99 13.99 13.99 13.08 13.08 13.08 12.27 12.27 12.27 12.27 11.56 10.93 9.85
19.29 17.65 16.18 16.43 14.90 15.10 14.01 14.03 13.93 13.08 13.09 13.20 12.21 12.30 12.37 12.26 11.65 10.98 9.94
slightly more stable than those with smaller. I n cold.water or dilute acids they appeared t o be perfectly stable for several days, but were hydrolyzed slowly on boiling. They were also slightly soluble in strong acids. Decomposition of dibutyrylurea with sodium ethylate.-To a solution of 0.4 g. of sodium in 25 cc. of absolute alcohol was added 3.5 g. of dibutyrylurea, and the mixture was allowed to stand over night a t room temperature. An equal volume of anhydrous ether was added and the solution poured into an ice-hydrochloric acid mixture. The ether layer was separated, dried with calcium chloride, and distilled. After the ether had been removed, 1.5 g. of a liquid boiling a t 118-121" was collected and identified as ethyl butyrate. The aqueous layer was concentrated under a vacuum and 0.4 g. of dibutyrylurea was isolated from it. In a second experiment the solution was heated for two hours, and a white precipi-
520
ROGER W. STOUGHTON
tate of sodium cyanate was obtained. On evaporation of the alcoholic mother liquors, a small amount of butyramide separated. The same products were also obtained when monobutyryl urea was refluxed with sodium ethylate. These experiments were repeated with dicaproylurea with similar results. Pyrolysis of sym-dienanthy1urea.-Five grams of sym-dienanthylurea was placed in a small distilling flask fitted with a thermometer, so placed that the bulb was below the surface of the liquid, and a side-arm test-tube that served as a receiver. This was connected with two U-tubes filled with soda lime. The flask was heated in a mineral-oil bath a t such a rate that the inside temperature reached 230" in two hours. A t 80" the compound melted to a clear colorless liquid; a t 160-170" small TABLE I11 HYPNOTICACTIVITY MINIMUM EFFECTIYE DOBE UREA
10. OF CARBON ATOM
sym-DiacetylN-Acetyl-N '-propionylsym-DipropionylN-Acetyl-N '-butyrylN-Butyryl-N'-propionylN-Acetyl-N '-valerylsym-DibutyrylN-Propionyl-N '-valerylN-Acetyl-N '-caproylN-Butyryl-N '-valerylN-Caproyl-N'-propionyl N-Acetyl-N '-enanthylsym-DivalerylN-Butyryl-N '-caproylN-Enanthyl-N'-propionylN-Acetyl-N '-caprylylN-Caproyl-N '-valerylsym-Dicaproylsym-Dienanthyl-
5 6 7 7 8 8 9 9 9 10 10 10 11 11 11 11 12 13 15
:ntravenously htraperitone- Orally g./kg. ally g./kg. g./ke.
2.3 1.5 0.35 0.23 0.17 0.15 0.11 0.14 0.09 0.10
-
0.08
-
-
>3.0 2.3 1.5 1.2 1.1 1 .o 0.8 0.9 0.7 0.9 1.2 0.6 1.1 1.2 2.5 >3.0 >3.0 >3.0 >3.0
bubbles of carbon dioxide were evolved, the liquid became cloudy, and a grayish precipitate deposited; and a t 200" a colorless liquid began to collect in the receiver. A t the end of two hours the mixture was cooled slightly and the last traces of volatile material were swept over by the application of a vacuum to the system. The soda lime tubes were weighed, and i t was found that 0.5 g. of carbon dioxide had been absorbed. The volatile liquid was redistilled, and 1.3 g. of material boiling a t 181-184" was obtained. This proved t o be enanthonitrile, and was characterized by the formation of a-iminoheptylmercaptoaceticacid hydrochloride.'* The nonvolatile residue within the flask, which had solidified on cooling, was treated with 19
CONDO, HINKEL,FASSERO, AND SHRINER, J . Am. Chem. Soc., 69,231 (1937).
DIACYLUREAS
521
20 cc. of warm benzene. The grayish solid did not dissolve. It was recrystallized from water and 0.25 g. of a white solid, which was identified as cyanuric acid, was obtained. The benzene solution was diluted with petroleum ether and allowed to stand in the ice-box. A yield of 1.4 g. of a white solid, which proved t o be crude enanthamide, was obtained. After recrystallization from benzene-petroleum ether mixture, i t was obtained pure and melted a t 95-96'. The original benzene-petroleum ether mother liquors were evaporated to dryness under a vacuum, and 1.5 g. of a cream-colored solid remained. After recrystallization from dilute methanol, fine colorless needles, which had a melting point of 92-93', were obtained. This compound proved identical with the product obtained by refluxing enanthamide with enanthyl chloride, and was dienanthamide. Anal. Calc'd for C1,Ht,NOp: N, 5.80. Found: K, 5.85. These results indicate that approximately two-thirds of the original material decomposed as indicated by equation 6 and one-third as indicated by equation 7. Pharmacological experiments.-Preliminary studies of these compounds as hypnotics have been made on male albino mice. Those members of this series which were soluble enough in water to allow a saline solution to be injected into the tail vein without using excessive quantities of fluid were administered intravenously. Secondly, all substances were tested intraperitoneally by injection of a 4 per cent. acacia emulsion. Finally, a 5 per cent. acacia emulsion of a few of the most active compounds was given orally by means of a stomach tube. Five or more mice were used at each dose level, and three or four levels close to the minimum effective dose were studied. The minimum effective dose was taken as that dose which would cause 50 per cent. of the animals to lose the ability to right themselves. Because of the small number of animals used, the results, as recorded in Table 111, are approximate only, but accurate enough t o give a general idea of the relative activity of these compounds. The length of anesthesia varied greatly with the route of administration: On intravenous injection of a minimum effective dose of the more active compounds, anesthesia was induced at once but lasted only about one minute; on intraperitoneal injection, anesthesia was produced in three to five minutes and maintained for ten t o fifteen minutes; while on oral administration the animals remained anesthetized for approximately one hour after an induction period of from five to fifteen minutes. While no thorough study of the toxicity of these substances has been made, preliminary experiments with a few of the most active compounds indicated that the minimum lethal dose on intraperitoneal injection was two or three times greater than the minimum effective dose. SUMMARY
( I ) The available data on aliphatic diacylureas has been summarized. (2) A series of nineteen diacylureas derived from normal aliphatic acids has been prepared by the reaction of acid chlorides with monoacylureas, and their physical and chemical properties have been studied. These compounds resemble the barbituric acids with the exception that they are hydrolyzed very rapidly by alkali and are unstable to heat. (3) Compounds with eight to ten carbon atoms in the molecule are active hypnotics when administered intravenously, but are relatively inactive on oral administration.
