Патент USA US2403723код для вставки
Patented July 9, 1946 1 2,403,723 _ UNITED ‘ STATES ' 7' _ ‘ OFFICE , 2,403,723 f ‘_v p . ' “PREPARATION 0F1,2,4-0XADIAZOLES I Donald Kaisegrl'tiverside, 00ml, assignor to American Cyanamld Company, New York, N. Y.,acorporation ollltialn'e. ' ' V’ U " 7 No Drawing. Application June 23, 1944, - Serial N0. 541,845 , . . ‘ 57 Claims.’ (01. zoo-307i ' ' :_I~;l'. -. . _' '7 1 , . . . ,_ “as solution Willtake Place a "Short time after the pounds, nove11'reaction. products thereof, and to methods ofpreparingthesamle. ; y - . . '2 _; #I'his invention. relates tov new organic com a reaction has started- . v. . . 'The 3-a1ky1,’ cycloalkyl, and ,aryl-B-ureido 1. I I'h'ave discoveredlthatewhen3-alkyl, cycloalkyl, 1,2,fl-oxadiazoles which are used as intermedi . ates injthe present invention can be prepared-by ' heating together an acyl dicyandiamide and ‘hy and!aryl-s-ureido-1,2,4;oxadiazoles are hydro lyz'ed-byheating with anacid or. alkali in-a suit-. able‘v liquid reaction-medium containing at 1 least a:--small amount of water, a reaction takes place iii-accordance with the vfollowing.“ equation: i ., Y droxylamine, as shown, in Example 1,. The acyl v ' dicyandiamides are in turn prepared bysimply . '10. mixingdicyandiamide with a desired acyl halide oranhydride in a water-soluble alkali metal hy ‘ droxide in the presence of, a small amount of water and a nonehydroxylated solvent such as‘ acetone. ,, . p , .Agreatnumber of 3-alkyl, cycloalkyl, and aryl 5-.ureido-1,2,4-oxadiazoles can be employed in is the. reaction describedherein to ‘produce the new compounds 1 of the. , present, invention. Among these. may be speci?cally mentioned: 3-methyl 5-ureido-1,2,4-oxadiazole, In; the formulas R; is analkyl, .cycl'oalkyl, or. aryl 20' 1,2,4-oxadiazole, radical; The products of . the reaction, .3-alky1, cycloalkyl, ’ 3-n-butyl-5-ureido 3-isoamyli5-ureido-1,2,4soxa diazole, .3=dodecyle5-ureidoe1,2,4-oxadiazole, ,3 and‘ aryl-S-amino-1,2,4-oxadiazoles, ' are Knew; compounds and form .the .principalsube iect 'matterlof the I present invention. 1 The- 5 aminolgroup'i-si very. easily hydrolyzed to a, .—‘OH 25 group, and". the resulting compounds, ..3-'alkyl,‘ oxadiazole, oxadiazole, 3.-(p-hy_dr0xypheny1) -5-ureido-1,2,4 the purview of the present invention- .These' lat hydrolysis‘ofthe reaction mixture. . . , . TI’h‘eI hydrolysis of-3'-'alkyl, cycloalkyl, and aryl 5-'ureid'o-1~,2,4-oxadiazoles may. take place.‘ at 3=phenyl-5-ureido-1,2,4 .. 3-(p-nitropheny1)-5—ureido-1,2,4 oxadiazole, 3- (o-carboxyphen'yl) -5-.ureido-1,2,4 are also new compounds and are included ‘within ter' compounds are easily formed upon. continued 3- (wrhydroxydecyl) :5-ure ido,1,2,4-oxadiazole,. oxadiazole, . 3-cyclohexyl-5-ureidor1,2,4-oxadi 30 azole, and otheralkyl, cycloalkyl, and aryl-5 ureido-1,2,4-oxadiazo1es. ‘ L-Almost any commonly used acidic or alkaline , hydrolyzing agent may be used in the process des temperatures between about»'25°~~C'.: and 125? C. ., scribed herein; Among such conventional hy in_ an? alkaline ior acidic reaction‘. medium com 35 drolyzing agents are sodium. hydroxide, potas prising water. A convenient'meth'od ofconduct; sium. hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, barium hydrox ide; etc, and sulfuric acid, hydrochloric acid, acetic acid, nitric acid, phosphoric acid, etc. ing the reaction is to mix the reactantsfin‘a suit able solvent or diluent and heat thevreaction'mix ture under a re?ux condenser until the reaction is complete. This may-fbe determined by trap 40 Since the use “of acidic and alkaline hydrolyzing ping the ammonia evolved from the reaction mix ture and determining the amount so evolved until a theoretical quantity has been liberated. This procedure is illustrated in one :of the‘sp'eci?c ex ampleshereinafter described. " a ,. V‘ . - I. . ’ The time required-to complete’ the reaction may be vfrom about 1 hour to about 30 hours‘or more depending upon the utemperature‘ofthe reaction and the nature of the acid or alkaliemployed ‘as the hydrolyzing agent. -‘ T‘ e ' A suitable solvent for the “reactants may be water alone or ethanol, methanol, butanol, di agents is well understood. by thosein the ‘art, lure ther'de'soription thereof would. appear to be un ' necessary. ; a The. 3'-alkyl,i' cycloalkyl, ; and. >ary1-5-amino 45 1,2,4-oxadiazoles of the present inventionrare generally characterized as being basic, white crystalline, solids, easily to slightly soluble in ‘Water depending upon the nature of the 3-sub stituent. In general, they are not easily soluble in organic solvents but may be dissolved in small amounts in Cellosolve, aliphatic alcohols, pyr idine, dloxane, etc, ; They melt or decompose at oxane, Cellosolve, or’ otherwater-miscible sol highv temperatures, their melting points being vent, or a mixture ‘or-these solvents with each somewhat, dependent upon themanner in which other or with water.-» It will be understood, of, they are determined; The 3-alky1, cycloalkyl, and course-that, enoughwater is present to enable ' 4aryl:5-amino-l,2,¢l-oxadiazoles are useful for _,a the; hydrolysis to take place; as indicated. byithe variety of purposes including: as ,dyestuif inter mediates,» in the ‘preparation of'ch'emothera peuticuagents, in. the, preparation of 1 quaternary ammonium-compounds, and the like... equation: above. : Althoughll usually, dissolve the reactants before heating the reaction mixture,itf isinot necessary that they becompletely dissolved, 2,403,723 4 3 The 3-a1kyl, cycloalkyl, and aryl-5-hydroxy ’ 1,2,4-oxadiazoles are somewhat similar in physi cal properties to the 5-amino-oxadiazoles ‘but are‘ . . } ‘Example 3; .- Y‘ 7 > "A solution of 32.5 g. of 97 %v barium hydroxide octahydrate in 250 cc. of hot water was ?ltered characterized as being slightly more soluble in , ' ‘and added to 24.4 g. of 3-methyl-5-ureido-1,2,4 : oxadiazole in a 1-liter ?ask ?tted with a stirrer, water and having a higher melting or decompo sition point. ' nitrogen bubbling tube, and a condenser leading As previously stated, the 5-amino-oxadiazoles ‘to .a,-,safety bottle ‘and ?nally to an absorption are easily converted to the correspondingb-hye # ?ask containing 80cc. of 2.5 N hydrochloric acid. droxy-oxadiazoles upon continued 'hydrolysis; A stream of nitrogen was passed into the reaction and care must be exercised in the initial hydroly .10. mixture as the mixture was re?uxed gently. The sis if good yields of the 5-amino oxadiazoles; are 3 rate and extent of reaction was followed by titrat~ to be obtained. Also, as previously mentioned, ing the acid solution to determine the amount the stopped course at of thethe required reaction point mayby be observing followed‘ and the ‘ ' of ammonia evolved and by weighing the barium carbonate precipitated during the reaction. The amount of ammonia evolved from the reaction reaction was completed in 14 hours and.15_ ‘min mixture. Continued hydrolysis results in elimi utes. The reaction mixture'rwasf?ltered .and nation of an additional mole of ammonia through. cooled in an ice bath to precipitate awhite‘solid. replacement of the 5-amino'group-by-a hydroxy By continuous .‘ether, vextractionv of this'solid" ‘and group iii the presence or water; ' ‘ " I’ g . the'mother liquor "a total‘ of 11.2 g; ofgla‘ssy My invention will now be illustratedin greater} needles melting at 160-162“ C.‘ wasv obtained; ,By detail by means of the following specific examples recrystallizing a sample of 1. g.‘ of this'product which are given for purposes of illustration. and from 200 ‘cc. .of ether, a sample, meltingiat 163-164“ C." was obtained which analyzed ‘cor-,1 are not'to be ‘considered as limiting my inven tion to the particular details described therein.» ' Example} ' rectly for 3-methyl-5-amino-1,2,4-oxadiazole. ” To a suspension of. 131.6 g. of‘benzoyl dicyan A mixture of 20.4 g. (0.10 mol).-of,3-.phenyl-5 diamide in 1500 cc. of water was added a solution ureido-1,2,4-oxadiazole, 60 g. (0.60 mol) of con of 59 g. of hydroxylamine hydrochloride in .1500 ( centrated hydrochloric acid, 250 cc. of water, and 100 cc. of dioxane‘was heated to re?ux. The mixture foamed, and more dioxane and some bu cc. of water. i The mixture was stirred and heated and anadditional 500 cc. of water added. ' iAfteir‘ re?uxing 30 minutes, the mixture was cooled and the colorless solid filtered. washed with ‘water, tanol wereradded, After an hour’s heating, solu tion occurred. and dried. On analysis itproved to be 3—phenyl Re?uxing was continued 4 hours longer. The. brown solutioniwas clari?edxwith'. 351 Nuchar, and the ?ltrate evaporated on a ‘steam - .To'a solution-of 33 g. (0.50 mol) of 85%potase bath; “ Arresidue-of brown‘liquid and .solidre sium hydroxide in 250 cc. of water was added mained. Concentrated. hydrochloric acid .was 40.8 g. - (0.20 mol) of 3-phenyl-5-ureido-1,2,4 added andthe solid ?ltered, washed-with more. oxadiazole. On heating to re?ux, solution oc-. acid, and allowedto'dry. The material weighed curred, and ammonia began to be evolved. ‘After. 5-ureido-1,2,4-0xadiazole. ~ ‘ v y I L - . > ' 2 hours of heating, Nuchar was‘ added tothe light yellow solution, and it was then ?ltered. Cooling of the nearly colorless ?ltrate gave a small quan tity of long needles which melted at 160-162“ C. Crystallization from a'large volume of hot water gave slender, beautiful needles which .meltedat 164-165" C. and which analyzed correctly. £011.3 40 6.0. g. and decomposed at 188-'190° C. : Crystal-l lization from hot water raised the decomposition point to 197-198“ C., and fusion-with the prey viously isolated 3-pheny-5-hydroxy-1,2;4eoxadi phenyl - 5 1 amino-1,2,4-oxadiazole. .~ Thisjlzcom-é pound was soluble in acid,.rreprecipitated .by alkali, and insoluble in excess alkali. When; 1a portion was dissolved inwater which contained silver nitrate, addition‘ of a drop‘of ammonia pre cipitated a light, yellow, amorphous, silver salt, azole‘of the samemelting'point gave no depres_sion of the melting temperature. .In. this exame ple the hydrolysis was more drastic,'the starting material being converted ?rst into 3-phenyl-5 amino-l,2,4,-oxadiazole and then , to, 3-phenyl-5 hydroxy-1,2,4eoxadiazole without isolationv or the former -Iclaim:' 1. A~,method,of as in,, Examples preparing 1 Jand3. .' compounds , . l 1' having. ; thefollowing structural formula; . which decomposed at 192° C. . " . _ . ~ 0. Addition of acetic acid to the original alkaline 65 ?ltrate, obtained from the reaction immediately above, precipitated, 20 g. of colorless solid which decomposed at 188~190° C. Crystallization from in which ‘ R I’ is I amember .7' _'N= ¢or the‘ it—'X._‘ ‘group; consisting of a large volume of water which contained alittle alkyl, cycloalkyl, and arylradicals, and a methanol raised the decomposition . point to 60 member ofthe group "consisting of aminoand 19'l—198° C. The material was alkali soluble, 1 reprecipitated by acids, andinsolublezin excess acid. Analysis wasin good agreement vfor. 3 phenyl-5-hydroxy-1,2,4-oxadiazole. Example 2 ‘ In a further experiment using barium hydroxi ide in place of» potassium hydroxide the mixture was re?uxed for 17'hours. After separating the barium carbonate which had formed'in the vre 70 action mixture, 3-phenyl-5-amino-1,2,440Xadi-v azole ~ was recovered. No." 3-phenyl-5-hydrbxy 1,2,4-oxadiazo1e- was’ obtained when using'lthis mild hydrolyzing- agent under- the conditions of - ~ .15 this experiment.~~¥- ' 1 . 4-?“ ' , ' N-O ‘ ' hydroxy radicals which comprisesthe. step, of heating in the presence of a hydrolyzing agent a, compound having the formula I} ~ ' ; ‘I _ N-o % l _ \Ng simian. in whichR-is as de?ned above. . I i >~ ‘ ‘ 7i 2. A method }of» preparing 3-alkyl-5-amino 1,2},4-oxadiazoles which comprises heating‘. in the presence of a'hydrolyzing agent a 3'-alkyl~5-'ur'ei doe1,2,4-'Joxadiazole.- » -: ‘Y ‘ ' ' " I " a. 'Am'ethodb! preaaaféiiatslgmaatga 5 2,403,723 oxadiazoles which comprises heating in the pres ence of a hydrolyzing agent a 3-ary1-5-ureido 6 6. A method of preparing 3-ary1-5-amino-1,2,4 oxadiazoles which comprises heating at a tem ‘ ' perature within- the range of 25-125° C. in the 4. A method of preparing 3-e1ky1-5-amino presence of water and an alkali a 3-ary1-5-ureido 1,2,4-oxadiazo1es which comprises heating at a 5 1,2,4-oxadiazo1e. temperature within the range of 25-125° C. in 7 . A method of preparing 3-ary1-5-amino-L2A the presence of water and an alkali a 3-a1ky1-5 .oxadiazoles which comprises heating at’ a, tem ureido-1,2,4-oxadiazo1e. ‘ perature the range of 25-125° C. in the 5. A method for preparing 3-a1ky1-5-amino presence of water and barium hydroxide a 3-ary1 1,2,4-oxadiazole. 1,2,4-oxadiazo1es which comprises heating at a 10 S-ureido-1,2,4-oxadiazo1e. temperature within the range of 25-125° C. in the presence of water and an acid a. 3-a1ky1-5 ureido-1,2,4-oxa»diazo1e. ' DONALD W. KAISER.