QIH-N-Ommhom
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Patented Apr. 5, ‘1949 2,466,177 UNITED STATES PATENT OFFICE 2,466,177 \ HYDAN TOIN S AND METHODFOR OBTAININ G ‘ THE SAME Loren M. Long, Detroit, Mich, 'assignor to Parke, Davis & Company, Detroit, Mich., a corpora tion of Michigan No Drawing. Application lMarch '11, 1946, Serial No. 653,711 5 Claims. (Cl. 26.0-—.3.09.5 ) 1 2 This invention relates to 1-allyl-5-phenylhy route to human patients suffering from-epilepsy. dantoin and its alkali metal salts and also to a In the case of children over the age of six the method for obtaining these products 1-allyl-5 average daily dose is between about 0.2 and 0.4 phenylhydantoin has the formula, gram per day while the dosage for adults is usu ally about -.0.6 gram per day. For best results and prolonged therapeutic effect about 0.2 gram of the drug should be taken before each meal. QIH-n-ommhom I have found that ,1-allyl-5-phenylhydantoin maybe prepared by a unit process starting with The new compounds of'the present invention 10 are powerful anticonvulsants and are particularly benzaldehyde cyanohydrin and allyl amine. The valuable in the treatment of the grand mal form ?rst step in this unit process is to react the benz of epilepsy. aldehyde cyanohydrin and the allyl ‘amine to The use of hydantoins in the treatment of epi obtain the corresponding aminonitrile, This phase or .step of the process is usually carried out lepsy is well-known to the art. The most effec .15 tive compounds of this type are probably those by simply bringing the two reactants together in which contain two hydrocarbon substituents in an inert organic solvent such as ether'or benzene. the ?ve position. Some other 5,'5-disubst'ituted After the formation of the aminonitrile is com hydantoins which have proved of value are those plete, the water layer which separates from the mixture is withdrawn and the solvent distilled. which have an additional substituent(s) in the 20 one and/ or three positions of the ring. However, The next step in the process is the treatment of in general, the ‘hydantoins which ‘have only one the ‘crude aminonitrile with potassium cyanate hydrocarbon substituent in the ?ve position show in the presence of ‘acid at about 5° C. .to obtain very little or no anticonvulsive activity. I have the corresponding ureido nitrile which is then hy found this to be particularly true of the l-alkyl drolyzed by boiling with acid to obtain the desired S-phenyl hydantoins. These particular hydan . hydantoin. In the prior ,art the reaction between toin derivatives possess no activity as antican similar aminonitriles and potassium cyanate has always been carried out in the presence of weak vulsants and are, in addition, very toxic com pounds. It was surprising to ?nd that 1-allyl-5 acids such as acetic acid while the subsequent hydrolytic reaction has been effected by boiling phenyl hydantoin is an extremely potent and 30 nontoxic anticonvulsant since the only structural the ureido nitrile with mineral acid. However, in di?erence between this compound and the in this particular case I have found that the reac active and toxic 1-alkyl-5-phenyl hydantoins is tion between the aminonitrile and the cyanate salt may also be carried out below about 10° C. that the compounds of the present invention have in the presence of a strong mineral acid such as an unsaturated alkyl rather than a saturated hydrochloric or hydrobromic acid and the result alkyl radical in the one position of the ring. Per ant ureido nitrile subsequently hydrolyzed by haps even more surprising was the discovery that merely boiling the solution. In general, it is not replacing the hydrogen atom in the ?ve position necessary to add any more mineral acid before of the hydantoin ring in 1-allyl-5-phenyl hydan hydrolyzing the ureido nitrile although if rather toin by an alkyl radical results in the formation 40 dilute mineral acid is used in the cyanate-amino of a class of hydantoin compounds which are nitrile reaction, it is sometimes advisable to add a almost completely devoid of anticonvulsant activ small amount of mineral acid to insure complete ity and which ‘are extremely toxic. ness of the hydrolysis reaction. The chief ad Some of the 5,5-disubstituted hydantoins of the vantages of my modi?ed process over the analo prior art, for example 5,5-diphenyl hydantoin, 45 gous processes of the prior art lie principally in suffer the disadvantage that they must be admin its simplicity and lower cost. istered in the form of their alkali metal salts in The alkali metal salts of 1-allyl-5-phenylhy order to obtain the maximal therapeutic eifect. dantoin may be conveniently prepared by dis However, in accordance with my invention I have solving the hydantoin in excess sodium or potas found that it is not necessary to administer 50 sium hydroxide and precipitating the salt from 1-allyl-5-phenyl hydantoin as its alkali metal the solution by addition of a Water-miscible or salts since the free hydantoin produces just as ganic solvent such as methanol, ethanol, n-pro bene?cial a therapeutic effect as its alkali metal panol, acetone, dioxane and the like, Alterna salts. The compounds of the present invention tively, equivalent amounts of sodium or potas may be conveniently administered by the oral 55 sium hydroxide and the hydantoin may be react 2,466,177 cipitated from the reaction mixture by the addi ed in aqueous solution and the resulting aqueous tion of n-propanol. solution of the salt evaporated to dryness under Another method of preparing the salts of the reduced pressure. The alkali metal salts of present invention consists in adding an alcoholic 1-ally1-5-phenyl hydantoin obtained by either of solution of the hydantoin to an alcoholic solution these two procedures are white, water-soluble, of sodium or potassium hydroxides or ethylates. amphorous ‘powders which are, because of their For example, 10 g. of thehydantoin dissolved in water-solubility, particularly useful for oral ad absolute ethanol is added to an absolute ethanol ministration of this valuable therapeutic agent. solution containing 4 g. of potassium ethylate. The ‘invention is illustrated by the following speci?c example without limitingit thereto. 10 The white potassium salt which separates is re 39.9 g. of benzaldehyde cyanohydrin dissolved moved by ?ltration, washed with alcohol and in 50- cc. of ether is mixed with 17.1 g. of allyl dried. What I claim as my invention is: amine. The solution turns yellow and becomes 1. A compound of the class consisting of l-allyl quite warm and as the reaction proceeds the 5-phenyl hydantoin and its corresponding alkali water which is formed separates. After the re 15 metal salts. ‘ action is complete, the water is drawn off and the 2. 1-Allyl-5-phenyl hydantoin. ether evaporated. The thick liquid residue which 3. The sodium salt of l-allyl-5-phenyl hy consists of the intermediate aminonitrile is added dantoin. to a solution of 42 cc. of concentrated hydro 4. The potassium salt of 1-ally1-5-phenyl hy chloric acid and 300 cc. of water. The resulting 20 dantoin. 1 solution is cooled to 5° C. and a total of 30 got 5. A unit process for the preparation of l-allyl potassium cyanate added in small portions with 5-phenyl hydantoin which comprises reacting frequent shaking. After all the cyanate is added, benzaldehyde cyanohydrin with allyl amine in an the mixture is allowed to stand in an ice bath inert organic solvent, removing said solvent from for one-half hour and then heated on a steam 25 the reaction mixture, reacting the crude amino bath for one-half hour. 300 cc. of concentrated nitrile so formed with an alkali metal cyanate at hydrochloric acid is added and the mixture evap a temperature below about 10° C. and in the pres orated to dryness. The residue which consists ence of aqueous mineral acid, hydrolyzing the of the crude 1-allyl-5-phenylhydantoin is washed intermediate ureido nitrile by heating the acidic with 300 cc. of cold water and then dissolved in 30 dilute sodium hydroxide solution. The alkaline reaction mixture and isolating the product so formed. solution is decolorized by treatment with activated LOREN M. LONG. charcoal, ?ltered and the product reprecipitated by acidifying the ?ltrate with hydrochloric acid. REFERENCES CITED The crude hydantoin is ?nally puri?ed by re 35 crystallization from alcohol-water mixture to . The following references are of record in the yield 32 g. of the pure white crystalline product; ?le of this patent: M. P. 955° C. FOREIGN PATENTS 10‘ g. of 1-allyl-5-phenyl hydantoin is dissolved in a small amount of water containing 1.85 g. of 40 Number Country Date sodium hydroxide and the resulting solution evap 769,667 France ___________ .. June 11, 19734 orated to dryness under reduced pressure. The OTHER REFERENCES light colored, amphorous residue consists of the desired sodium salt of 1-allyl-5-phenyl hydantoin. Jour. fur Praktische Chemie (2) , vol. 66 (1902), page 236. ' ' By substituting an equivalent amount of potas 45 Karrer, “Organic Chemistry,” 2nd edition sium hydroxide for sodium hydroxide in this pro-' cedure, one obtains the potassium salt. Instead (1946), page 283. of evaporating the solution, the salt can be pre .