Patented May 4, 1954 2,677,686

UNITED STATES PATENT OFFICE 2,677,686 PYRAZINEDERVATIVES AND METHO) OF PREPARING THE SAME Victor K. Smith, Jr., Feari River, and Samuel Kushner, Nanuet, N. Y., assignors to American Cyanamid Company, New York, N. Y., a corpo ration of Maine No Drawing. Application 5uly 22, 1952, Serial No. 300,336 8 Claims. (C. 260-250) 2 This invention relates to mono-substituted ous layer is extracted with a solvent, such as di pyrazine. More particularly, it relates to substi ethyl ether. The ether can be concentrated and tuted-2-carbonyl pyrazine. the desired compound crystallized out Or the The role of vitamins in nutrition is well known ether can be removed and the product distilled. i and assumes greater importance as new informa 5, The reaction of the present invention may be tion is made available concerning the particular carried out at a temperature of -10° to 15° C. function of each. Recently it has been found The reaction is complete in from about a few that folic acid was effective in curing macrocytic ininutes up to about tWO hours. anemias and other blood conditions. Also, Com The process of the present invention is de pounds which are folic acid antagonistS, Such as scribed in greater particularity by the following aninopterin, have been found useful in treating specific examples which are given by way of ill abnormal blood conditions such as leukemia. lustration and not limitation. it is well established that nicotinamide is an im Eacample 1 portant, vitamin of the B complex group and its deficiency is the specific cause of pelagira. Exactly 5.5 gms. (2 moles) of magnesium turn We have now found that certain Substituted ings is placed in a dry, three-necked, round pyrazines hereinafter defined have the property bottomed flask fitted with a mercury-Sealed Stir of inhibiting the nicotinamide response of L. rer, a reflux condenser and drying tube, a drop arabinosus and exhibit an antagonistic effect on ping funnel, and a removable ice bath. Then nicotinamide growth response in chicks. The 33 gns. (2 moles) of methyl iodide is dissolved compounds therefore assume importance in ex in 50 ml. of anhydrous ether in a dry Erlenmeyer perimental medicine and nutrition since vitamin flask. A Small portion of this latter solution is deficiency symptoms may result from the pres introduced into the round-bottomed fiask along ence of antagonists as well as from the absence With a minute iodine crystal. As soon as the of the Vitamin. 25 reaction commences, 200 ml of anhydrous ether The compounds of the present invention may is added. With slow stirring, the remainder of be illustrated by the following general formula: the methyl iodide solution is now added drop Wise just rapidly enough to maintain vigorous refluxing. After complete formation of the ^ - a Grignard reagent, the mixture is cooled by means of the ice bath and then 12 gms. (1 mole) of cy anopyrazine dissolved in 50 ml. of anhydrous O ether is added dropWise. During this addition in which R is an alkyl or aryl radical. the temperature of the mixture is kept at 0°-5 These compounds are crystalline solids or rel 3. by use of the ice bath and vigorous stirring is atively high boiling liquids. They are Soluble in maintained. A Solid precipitates from solution ether, chloroform, carbon tetrachloride, etc. and during this addition. Cold water is then added somewhat Soluble in Water. siowly with vigorous stirring until the precipitate The compounds of the present invention are has dissolved. The ice bath is used to keep the prepared by reacting cyanopyrazine with an mixtul'e cool. The entire liquid mixture is then lkyl or aryl magnesium iodide Or bromide in transferred to a Separatory funnel and the two the presence of an anhydrous solvent. liquid layers are separated. The aqueous residue, The intermediates used in the process of the after saturation with potassium chloride, is present invention may be, for example, methyl washed twice With ether and the ether Washes iodide, ethyl iodide, propyl iodide, butyl iodide, are added to the original ethereal extract. The Inethyl bromide, ethyl bromide, propyl bromide, 45 cornbined ether Solutions are dried with an buty bromide, bromobenzene, iodobenzene, bro nonaphthalene, iodonaphthalene, and the like. hydrous magnesium Sulfate and filtered. The in carrying out the process of the present in filtrate is concentrated to Small volume and wention the cyanopyrazine is mixed With the cooled, thereby causing the 2-acetylpyrazine to desired intermediate under anhydrous conditions 50 Crystallize from Solution. in an anhydrous solvent at a temperature below Eacample 2 5° C. The product separates as a Solid complex which is decomposed by Water or ice. Follow To 20 g. of bromobenzene in 50 cc. of diethyl ing solution of the product in the reaction mix ether was added 2.5 g. of magnesiuin turnings. ture, the two layers are separated and the aque 55 The phenylmagnesium bromide obtained is re 2,677,686 3 4. acted with 10.5 g. of cyanopyrazine. After add in which R is a member of the group consisting ing ice, the complex was decomposed with an of alkyl, naphthyl and phenyl radicals which com monium chloride and the product was extracted priseS reacting a member of the group consisting With ether. The ether was distilled off and the of an alkyl magnesium halide, naphthyl magne benzoylpyrazine Was distilled from the residue 5 Siurn halide and phenyl magnesium halide With and had a boiling range of 190°-200° C./20 mm. Cyanopyrazine and recovering said compound The product was further characterized by the therefrom. preparation of the 2,4-dinitrophenylhydrazine of 6. A method of preparing a lower alkyl carbonyl the benzoylpyrazine. pyrazine which comprises reacting a lower alkyl We claim: O magnesium bromide With cyanopyrazine and re 1. Compounds having the general formula: covering Said compound therefron. 7. A method of preparing acetylpyrazine which comprises reacting methyl magnesium bromide With cyanopyrazine and recovering said com pound therefron. 8. A method of preparing benzoylpyrazine in which R is a member of the group consisting which comprises reacting phenyl magnesium of alkyl, naphthyl and phenyl radicals. bromide with cyanopyrazine and recovering Said 2. A lower alkyl carbonyl pyrazine. compound therefrom. 3. Acetylpyrazine. 20 4. Benzoylpyrazine. No references cited. 5. A method of preparing compounds having the formula: O /Y, -R 25 NN