The Condensation of Aminoantipyrine. III (1). The Synthesis of Methylrubazoic Acid

[CONTRIBUTION FROM THE CHEMICAL LABORATORY TRINITY OF COLLEGE] THE CONDENSATION OF AMINOANTIPYRINE. 111. (1). THE SYNTHESIS OF METHYLRUBAZOIC ACID' EDGAR EMERSON AND LINDLEY CLAIR BEEGLEe Received June 89, 1943 It has been shown that aminoantipyrine in some of its reactions acts like the reducing amines, such as p-aminophenol, p-phenylenediamine, and p-dimethylaminoaniline (la). Since p-dimethylaminoaniline reacts with l-phenyl-3methylpyrazolon-5 (2) to give compound (I)it was believed that aminoantipyrine should react with the pyrazolon to give a compound of analogous structure (11). c H5 6 C6H6 I N N II / \ I N c=o 1 H3C C - - C = N o N N (CH& II / \ HaCC-C=N-C= (1) CsH5 I N c=o o=c / \NCH3 1 I I C CHI (11) Methylrubazoic Acid Both compounds (I) and (11) have been prepared by condensing the pyrazolon with the corresponding nitroso compounds. Compound (I) was prepared by Sachs and Barschall (3) from nitrosodimethylaniline and 1-phenyl-3-methylpyrazolond and (11)was reported by Proscher (4)who made it from the pyrazolon and nitrosoantipyrine (IV). These reactions would seem to emphasize the apparent similarity of the condensation reactions of nitrosodimethylaniline and nitrosoantipyrine. Many phenol-like compounds have been found to give the aminoantipyrine color test (1). The structures of the colored compounds formed in the test may be inferred from the data accumulated relating t o the structures of the coupling components. However, it was felt necessary to prove the structure of a colored compound of this type by standard chemical means. For this purpose the reaction product formed by the oxidation of an equimolar mixture of aminowas selected because it formed antipyrine and 1-phenyl-3-methylpyrazolond in good yield and presumably it had been prepared by another route (4). An inspection of the formula for methylrubazoic acid (11)reveals the absence 1 From the thesis presented to the Committee on Graduate Students at Trinity College by Lindley Clair Beegle in partial fulfillment of the requirements for the Degree of Master of Science. 2 Present address American Cyanamid Co., Stamford, Conn. 429 430 EMERSON AND BEEGLE of any acid hydrogen in the molecule and, therefore, one would not expect the compound to be soluble in alkali; nor would one expect a deepening of color when the substance is treated with alkali since there is no salt-forming group present. However, Proscher reported that methylrubazoic acid dissolves in ammonia and dilute alkalies with a change in color from red to purple. Proscher also reported the compound to be insoluble in benzene. These properties are those of rubazoic acid (111)' not of methylrubazoic acid. Moreover the empirical formula was incorrectly reported and the calculated composition agreed neither with the formula reported nor with the correct one. c Ha s CeHs Ce H s N N N I N I / \ H3 C - - - CCNC C=O 1 I I HOC / \ II (111) Rubazoic Acid / \ N Ha CN c=o CCH, Ha C C= CNO I i I (IV) Nitrosoantipyrine The work of Proscher was repeated and the reaction took place in the manner he described. His statement that the reaction product could not be obtained in crystalline form was also verified. It was found that the reason for this was gross contamination of the desired product by other products of high molecular weight. The molecular weight of Proscher's product varied and in some determinations attained a value of over 500 whereas the calculated value is 373. The Signer method (5)for molecular weights was used and found to be highly satisfactory. It is suggested that a reason for the somewhat anomalous condensation product(s) may be found in the structure of nitrosoantipyrine (IV). The fixation of the 3 4 double bond and the influence of a nitroso group ortho to the 3-methyl group might activate this group in the same manner that the methyl groups in quinaldine and in 2,4-dinitrotoluene are activated. Polymerization by condensation of the nitroso group with the 3-methyl group of another molecule might take place to an undetermined extent and thus account for the high molecular weight observed in Proscher's impure methylrubazoic acid. Methylrubazoic acid prepared by oxidizing an equimolar mixture of aminoantiproved to be a product which was pyrine and 1-phenyl-3-methylpyrazolond easily purified and obtained as crystals from methanol (mol. wt. 364; m.p. 175-176'). A quantitative hydrolysis of the crystalline material yielded equimolar quantities of aminoantipyrine (V) and 1-phenyl-3-methyl-4-ketopyrazolon-5 (VI). Methylrubazoic acid was also prepared by the condensation of aminoantiThe purified condensation pyrine with 1-phenyl-3-methyl-4-ketopyrazolon-5. product melted a t 174-176' and the melting point with the previously crystallized product was 174-176". 43 1 SYNTHESIS OF METHYLRUBAZOIC ACID CS& CsHs 1 N N / \ II + o=c /N\ c=o 1 I H,NC= CsHs I N NCH3 2?.&!~, I CH? Ha C C - CsHs I N / \ H,CC--C=N-C= (V) (XI o=c c=o / \ NCHa I I I II CCHj I N CCHi (11) i C6Hs C8H.S Irj N I N / \ CSHS o=c I c=o CSHS I N I / \ / \ I I N c=o I + o=c / NCHJ I I H~NC=I=CCHJ C=O C CHz \ These reactions serve to establish the structure of methylrubazoic acid and, by analogy, the structures of many of the other colored products formed in a positive aminoantipyrine test. The structure of the colored compound from 1,3-diphenylbarbituric acid, barbituric acid, and diketohydrindene are represented by (VII), (VIII), and (IX) where Ap- represents the antipyryl radical. C6 Hs N- CEO O=C1 I C=N-Ap 1 I CsHsN-C=N (VI11 HN-C=O O=CI I C=N-Ap I I HN-C=O (VIII) O\ /c=o )C=N--hp c=o (IX) EXPERIMENTAL Molecular weights. The molecular weights were determined in an apparatus modified from Signer ( 5 ) . Ground glass caps were used on the filling tubes and to one of the caps a ground glass stopcock was sealed to permit evacuation after charging the apparatus. Chloroform was used as a solvent and the ground glass joints were lubricated with a manitolglycerine mixture in which the solvent is insoluble. Carefully purified azobenzene was used as the reference compound. After charging the apparatus it was inclosed on the shelf of an ordinary steel locker until equilibrium was attained. Preparation of methylrubazoic acid from nitrosoantipyrine (IZ). The procedure of Proscher (4) was followed and i t yielded a red amorphous powder soluble in dioxane, acetone, benzene, chloroform, ethanol, and methanol, insoluble in water, ligroin, and alkalies. It is hydrolyzed by mineral acids. Repeated extraction with methanol resulted in an unidentified white material. The “methylrubazoic acid” had a molecular weight of over 500. Preparation of methylrubazoic acid from aminoantipyrine. Aminoantipyrine (10 9.) was dissolved in 350 cc. of distilled water and mixed with a solution o 1-phenyl-3-methylpyrasof 432 EMERSON AND BEEGLE 1011-5 (8.8 9.) and sodium hydroxide (2.0 g.) in 50 cc. of distilled water. Potassium ferricyanide (66 g.) and sodium carbonate (7.8 9.) were dissolved in 200 cc. of distilled water and this solution was added to the first with good stirring over a period of 1-2 minutes. Stirring was continued for five minutes after which the copious red precipitate was separated a t the pump. The product was suspended in 500 cc. of water and stirred for 30 minutes, after which i t was separated by filtration. This process was repeated as long as the filtrate gave a test for ferrocyanide with ferric chloride. The yield of the crude product was 15 g. After crystallization from methanol, transparent garnet-red prisms having a slight green reflex were obtained. These melted at 1 5 1 6 ; mol. wt. 364,calc'd 373. Solu7-7' ble in dioxane, acetone, benzene, chloroform, ethanol, and methanol. Slightly soluble in ether and insoluble in water, ligroin, and alkalies. Soluble in mineral acids with decomposition. This compound was prepared by Preparation of 1-phenyl-3-methyl-4-ketopyrazolon-6. the method of Sachs (3). Recrystallized from ligroin the bronze needles melted at 118-120O (lit. 119"). Hydrolysis of methylrubazoic acid. Crystalline methylrubazoic acid (0.152 g.) was stirred for 1 hour with 2.5 cc. of 6 N sulfuric acid and 10 cc. of ether. This mixture was extracted continuously with ether until the extract was water-white. The extract was washed with water and dried over calcium chloride. When the ether was evaporated the (0.076g.). It was identified residue was found to be 1-phenyl-3-methyl-4-ketopyrazolon-5 by the melting point and the melting point of a mixture of i t with authentic material. The aqueous layer of the extract was made basic with sodium hydroxide and continuously extracted with benzene for 6 hours. Evaporation of the benzene extract left a residue of aminoantipyrine (0.071 g.) identified by the melting point, mixed melting point, and a derivative ,-benz ylidineaminoantipyrine. Preparation of methylrubazoic acid f r o m its hydrolytic products. Aminoantipyrine (1.0 g.) and 1-phenyl-3-methyl-4-ketopyraeolon-5 9 . ) were each dissolved in 95% ethanol. The (0.9 two solutions were mixed and warmed on a steam-bath for 10 minutes and after the mixture cooled to room temperature i t was poured into 100 cc. of cold water. Yield of crude product 1.5 g. Recrystallized from methanol i t melted a t 1 4 1 6 . The mixed melting point with 7-7' 7-7' the previously described crystalline product was 1 4 1 6 . SIJMMARY Methylrubazoic was found to be erroneously reported. It was prepared by two new methods and some of the properties are described. The structures of some of the colored products formed from aminoantipyrine and phenol-like compounds have been verified. HARTFORD, CONN. REFERENCES (1) (a) Part I, J. Org. Chem., 3, 153 (1938); (b) Part 11, J. Org. Chem., 8,417 (1943). (2) British Patent, 478990. AND Ber., (3) SAWS BARSCHALL, 36, 1437 (1902). Ber., (4) PR~SCHER, 36, 1436 (1902). (5) SIGNER, Ann,, 478, 246 (1930);CLARK,n d . Eng. Chem., Anal. Ed., 13, 820 (1941). I