2,403,633 Patented Oct. 1, 1946 S PATENT. QFFICEJ * UNITED ‘STATE 2,408,633 1 ' PRODUCTION ‘OF SUBSTITUTED QUINAZO LONES FROM ORGANIC PHOSPHAZO COM‘ POUNDS Alfred Guenther, Riegelsville, Pa., and Jack F. Morgan, Phillipsburg, N. .L, ,assignors to Gen :eral Aniline & Film Corporation, New York, _ N. Y., a corporation of Delaware , . NoDrawing. Application April '1, 1945, Serial No. 587,213 ' 10 Claims. (01. zoo-+251) l 2 The present invention relates to the prepara-' ethyl,’ propyl, butyl, amyl, lauryl and the like, tion of substituted quinazolones and to such alkoxy such as methoxy, ethoxy, propoxy and the like, X is alkyl as above and Y is an aliphatic It has been suggested that quinazolones be pre pared by the interaction of acylanthranils with amines. While this method can be operated to give good yields, it nevertheless requires the em ployment of intermediates which are highly un stable with respect to moisture. Consequently, ' considerable care must be exercised in the han 10 radicalsuch as alkyl as above and alkylamino such as methylamino, ethylamino and the like, quinazolones. dling of the intermediates if satisfactory yields are to be obtained. - ' Most of the other methods‘which have been employed for the production of quinazolones re an aromatic radical such as phenol, tolyl, anisyl, phenetyl, m-nitrophenyl, p-chlorophenyl, naph thyl, phenylamino and the like, cycloaliphatic such as cyclopentyl, cyclohexyl and the like, or a heterocyclic nitrogenous nucleus such as Pyri-, dyl, quinolyl, and the like. Where Y is alkyl amino or phenylamino, the alkyl or phenyl rad-, ical will be separated from the quinazolone nitro gen by an —NH—, group. The aromatic or het 15 erocyclic nucleus represented by the character R quire the use of such high temperatures as nec essarily cause some decomposition of the react may be benzene, naphthalene, anthracene, an ants. For example, 2-methyl-3-phenyl-4-quinaz olone has been prepared by heating o-acet thraquinone, dibenzofurane, carbazole, diphenyl amide benzanilide to temperatures of 175 to 210° Thereaction is effected by heating N-acyl-o amino-cyclic carboxylic acid with the organic phosphazo compound in a suitable solvent there for. The degree of heating required depends on the’ nature of the reactants and may vary consid ene sul?de and the like. C. These procedures suffer fromthe disadvan tages that the decomposition involved not only lowers the yield but through .by-product forma tion decreases the purity of the desired end prod- V . erably. While it is preferred to eifect the reac uct. It has now been discovered that substituted 25 tion by re?uxing the reaction mixture, it should be borne in mind that it is possible to carry out quinazolones can be prepared while avoiding the the reaction by heating to a temperature below disadvantages of the prior art by heating an or the boiling point of the reactants. ganic phosphazo compound with an N-acyl-o The N-acyl aminocyclic carboxylic acids em amino carboxylic acid in an organic solvent. These products react together smoothly at mod 30 ployed may be represented by the following for eratelyelevated temperatures to produce the de mula: ‘ sired quinazolones in a pure condition and in H NCOZ good yields. The organic phosphazo compounds are prepared by the reaction of phosphorus tri R \COOH chloride and primary amines, which are common stable materials. The preparation of substituted in which Z is alkyl such as methyl, ethyl, proe quinazolones by the reaction of organic phos phazo compounds and N-acyl-o-amino carbox pyl, .butyl, amyl, octyl, decyl and the like, and R has the values given above, the amide group stitute the purposes and objects of the present 40 and the carboxylic acid group being in o-posi tion of the nucleus represented by R. Exam ylic acids and the quinazolones so obtained con invention. 1 ' ples of such compounds are: The quinazolones, the production of which is contemplated herein, have the following structural formula: . V _ , r i I , ' / \c-x ‘ R N-acetyl-o-amino naphthoic acid l ‘/N---Y C II o ' N-acetyl anthranilic acid N-acetyl-5-chloro anthranilic acid 45 N-propionyl anthranilic acid N-butyryl anthranilic acid , .. ' to in which R is an aromatic or heterocyclic ‘nu cleus which may be substituted by monovalent groups, “for example, nitro, halogen,_such as ch10. ' rine, bromine and the like, alkyl such as’methyl, 55 N -acetyl-5-nitro anthranilic acid N-acetyl-?-methyl anthranilic acid N-acetyl-5-ethoxy anthranilic acid and the like. The organic phosphazo compounds, the reac tion of which is contemplated herein, have the following general formula: (a-n-gr-nrnm > ' 2,408,633 4 a lone. While the quantities of the reactants may be varied from that indicated in the equation, it is found that for best results the molar propor in which n is 1 or 2 and R represents an aliphatic chain such as methyl, ethyl, propyl, butyl, amyl, octyl, dodecyl, stearyl, and the tions designated’ should beresorted'to; The substituted quinazolones of the present like, an alicyclic nucleus such as cyclopentyl, cyclohexyl or the like, an aromatic nucleus such as phenyl naphthyl, anthracyl and the invention may be utilized as intermediates in the like, or a heterocyclic nucleus such as pyridyl, formation of dyestuffs. quinolyl, carbazolyl, diphenylene oxide, diphen The following examples serve to further illus trate the invention‘. but it is to be understood that these examples are illustrative and not lim itative in nature‘. The parts are by weight. ylene sul?de and the like. The radical rep" resented by R may also be sub‘stitut'e'd‘by such" substituent groups as halogen such as chlo rine, bromine and the 1ike,.alk'yl such asethyl, Example: I. '—‘ 2=m'ethyZ-3-phenyZ-4-quinazolone methyl, as methoxy, propyl, ethoxy, butylpropoxy and the’ and like,’ thealkoxy; like; amino‘;~ such substituted amino such as alkylated amino,- iiv e.,v 150 :parts' of a toluene solution containing 10.7 - parts'of‘ crude“phenylphosphazoanilide dimethylamino, diethylamino and the~like,'and sulfo. , l is’ treated with 17.9 parts of N-acetylanthranilic The organic phosphazo compounds are read ily produced by the reaction of an organic'prih mary amine with phosphorous trichloride, pref acid.. The‘ mixture is agitated, heated to the reflux temperature, and agitation thereof main tained at this temperature-for 1 to 2-hours. The erably'in the ratio'of 5:1, and in the presence-of anlorg'a'nic solvent. The organic primary amine suspension is treated WlthBOO parts‘of- 5% sodium carbonate solution and the toluene ‘removed’ by which? is" employedv may be aliphatic such as steam distillation. methylamine', ethylamine, propylamine, _butyl— amine, octylamine, dodecylamine and the like, water and dried. an‘ alicyclic amine such as. cycl'opentylamine, cyclohexylamine, and the like, an aromatic There is thus obtained 19.3 parts of a crude product melting at 138 to 140° C. This» quan tity represents 82% of- the theoretical yield. By amine such as aniline, o-toluidine, m-toluidine, p-toluid'ine, m-chloraniline, o-anisidine, m. nitro aniline, p-amino diphenylamine, ni phenylen'e diamine, p-phenylene diamine, ben zidine, 4.4’-diaminodlphenyl methane,v alpha naphth-ylamine, sulfanilicv acid or a heterocyclic amine such as 2-amino pyridine, 2-amino‘ quino line, 2'-amin0 diphenylene oxide,‘ and the like. The amine should in no case contain in the 0 or p-position' to the amino nitrogen,‘ a nitro or carbonyl group. When amines of the ‘latter constitution are employed, either no'reaction ensues The white solid- which re mains is separated’ by ?ltration, washed with re'crystallizing from alcohol, pure 2-methyl-3 phenyl-4-quinazolone meltingat 147 to 148° C. is obtained. _ . bons such as benzene, toluene and the like, the chlor derivatives thereof, such‘ as monochlor benzene; monochlortoluen'e and the like, normally liquid aliphatc hydrocarbons such as octane, solvent naphtha, kerosene and their chlor deriva tives such as- ethylene chloride,,butyl chloride, N, on a. / \C/ or the reaction takes place with vigorous decom 40 position resulting in a tarry, unidenti?able mass. The solvents used should be‘ inert to the re act‘ants and should be normally liquid. Suitable solvents are normally liquid aromatic hydrocar , A benzo-substitutedv quinazolone of the follow ing formula is obtainedv by replacing the N acetylanthranilic acid-by. 25.5 parts of Z-N-acetyl 35 amino-3-naphthoic acid. (l The phenylpho'sphaz‘oanili'de' employed in this re action is obtained by heating 260 parts of toluene 4' and'186 parts‘ of aniline't'o‘ 50° C‘. and adding in the course of one-half hour 55' parts of phosphorus trichlo'ri‘de and 43 parts of toluene". The mix ture is agitated during the‘ addition of the‘ phos phorus‘ tri'chloride'and for one hour thereafter. 50 Thev aniline‘ hydrochloride which is' formed is octyl chloride and ohlor kerosene and normally ?ltered o? andthe'?ltrate'used'directly or‘ evapo liquid nitrogenous heterocyclic bases such as _ r‘a‘te‘d‘a'nd' dried“ to is'ola‘te'th‘e crude phenylphos pyridine, quinoline and the like. phazoanilide. ' ‘ The reaction by which the substituted quin azolones are produced, assuming that the N acyl-o-amino carboxylic acid is N-acetyl anthra nilic acid and the organic. phosphazo compound is phenyl phosphazo anilide, may be graphically represented as follows: ' Example II. — 2-methyle3'ep-chlorophenyk4 quz'nazolone . . The procedure is thefsame as in' Example" I ex‘ cept‘ that there are used as the organic phospha'zb compound‘ 14.6 parts of‘ 4'.4"-dichlorphenylphos O phazoanilide. The 4.4’ - dichlo'rpheiiylphos phazoanilide is obtained in a manner similar“ to that utilized to producethe'uns'ubstitut‘ed .ph‘e'riyl phosphaz'oanilide. Example N CH" / \ l/ C 2 - l. N \/ C Y n 0 It Will be observed that according to this formula 1 mol of the phosphazocompound is reacted for each 2 mols of the N-acyl-o- amino carboxylic acid to yield 2 mols ofthe‘sub'stituted quinazo ' . ' III. -— 2-methyZ-3-phenyl-6-chloro-4 quinazolone The procedure is the same as in Example I ex cept that there is used in lieu of N-acetyl-anthra nilic acid 21.35 parts of N-acetyl-5-ch1oro anthranilic acid. | Example v IV. - 2-methyZ-3-p-methyZphenyZ-4- qui'hazolone The ‘procedure isf the same as in Example-1; ex- ‘ cept thatthere is3 used lieu~ofetheipheny-lphbse-l 2,408,633 phazoanllide 12.11 parts of p-toluylphosphazo p’-toluidide. Analysis This phosphazo compound is prepared in a manner similar to that utilized in preparing the phenylphosphazoanilide. Example V.—2-methyl-3-butyl-4-quinlczolone N Calculated Found Percent Percent 9. C ________________________________________ __ 12. 36 9. 60 12. 15 A solution of 73 parts of N-butylamine and 130 parts of toluene is agitated and treated drop Various modi?cations of the invention will oc wise with a solution of 27.5 parts of phosphorus 10 cur to persons skilled in the art and we there? fore do not intend to be limited in the patent trichloride and 22 parts of toluene. The sus granted except as required by the prior art and pension thus obtained is agitated and heated at the re?ux temperature for one hour. The hot the appended claims. I reaction mixture is ?ltered and the solid amine We claim: 1. The process of producing substituted quin hydrochloride washed with 150 parts of hot tolu 15 azolones which comprises heating an organic ene. About 48 parts (73% of the theoretical) of phosphazo compound having the general formula N-butylamine hydrochloride are thus recovered. 50 parts of the toluene ?ltrate, which contains roughly about 9.2 parts of the butylphosphazo butylamide are diluted with 100 parts of tolu 20 wherein n is selected from the class consisting of 1 and 2, and R is selected from the class con ene and to the resulting solution there are added sisting of an aliphatic chain, an alicyclic nucleus, 17.9 parts of N-acetylanthranilic acid. The mix an aromatic nucleus and a heterocyclic nucleus ture is heated to the re?ux temperature and agi and is free from nitro and carbonyl groups in tated for a period of about 2 hours. To the re o- and p-position to its linkage to the, remainder action mixture there is then added a sui?cient of the molecule with an N-acyl-o-aminocyclic amount of 5% sodium carbonate solution to ren carboxylic acid selected from the class consist der the reaction mixture alkaline and the tolu ing of aromatic and heterocyclic carboxylic acids ene is removed by steam distillation. The solid in the presence of an inert, normally liquid or remaining is separated by ?ltration, washed with ganic solvent. Water and recrystallized from alcohol. 30 2. The process as de?ned in claim 1 wherein The product is pure Z-methyl-B-butyl-Il-quin 1 mol of the organic phosphazo compound is em azolone. ployed for each 2 mols of the N-acyl-o-amino Example VI.—2-methyZ-3-lauryZ-4-quinazolone carboxylic acid. 3. The process as de?ned in claim 1 wherein The procedure is the same as in Example V 35 R is an aliphatic chain. ' except that there are used 185 parts of lauryl 4. The process as de?ned in claim 1 wherein amine in lieu of 73 parts of N-butylamine. R is an aromatic nucleus. Example VII.—~2-methyZ-3-cycZOhexyZ-4-quinazo 5. The process as de?ned in claim 1 wherein Zone R is a heterocyclic nucleus. 6. The process as de?ned in claim 1 wherein 99 parts of cyclohexylamine are dissolved in 40 the reactants are heated to the re?ux tempera 130 parts of toluene and while agitated treated with a solution of 27.5 parts of phosphorus tri chloride diluted with 22 parts of toluene. The resulting suspension is re?uxed with agitation for a period of 1 hour and ?ltered to remove ture of the solvent. 7. The process as de?ned in claim 1 wherein 45 the N-acyl-o-amino cyclic carboxylic acid is of the benzene series. cyclohexylamine hydrochloride. 79.1 parts of the 8. The process of producing 2-methyl-3-phen cyclohexylamine hydrochloride are recovered, representing 97% of theory. The solid is washed with 150 parts of hot tolu yl-4-quinazolone which comprises re?uxing 1 mol ene. 123 parts of the toluene ?ltrate, which con tain roughly about 11.3 parts of the cyclohexyl phosphazo cyclohexylamide, are diluted with 50 parts of toluene and there is then added 17.9 parts of N-acetylanthranilic acid. The mixture is heated to re?ux until hydrogenchloride is no of phenylphosphazoanilide with 2 mols of N-ace tyl anthranilic acid in the presence of toluene. 9. The process of producing 2-methyl-3-lauryl 4-quinazolone which comprises re?uxing 1 mol of lauryl phosphazo lauryl amide with 2 mols of N-acetyl anthranilic acid in toluene. 10. The process of producing 2-methyl-3-a pyridyl-4-quinazolone which comprises re?uxing longer given off, whereupon the suspension is 1 mol of a-pyridylphosphazo pyridyl amide with treated with su?icient 5% sodium carbonate so 2 mols of N-acetyl anthranilic acid in toluene. lution to render the reaction mixture alkaline. The toluene is removed by steam distillation leav 60 ing a light tan solid which upon treatment; with hydrochloric acid yields pure white 2-methyl-3 cyclohexyl-4-quinazolone hydrochloride. ALFRED GUENTHER. JACK F. MORGAN.