Патент USA US2404299код для вставки
Patented July 16,1946 I 2,404,299 UNITED STATES PATENT OFFICE - 2,454,299 7 SUBSTITUTED IMIDAZOLJES Lucas P. Kyrides, Webster Groves, Mo., assignor ' to Monsanto Chemical Company, St. Louis, Mo., a‘ corporation of Delaware No Drawing. Application March 3, 1944, Serial No. 524,929 7 Claims. (Cl. 2.60—309) > The present invention relates to the produc tion of new therapeutic agents and insecticide , 2 during the synthesis of the imidazole derivative or immediately thereafter and before the product \According to the present invention, generally is isolated from the reaction mixture. The products of the present invention have "also. been found to possess utility as insecticides and toxicants for insecticide compositions; such ‘as sprays and powders in which the compounds are stated, new products which are of outstanding value as active agents against micro-organisms vents, adhesives, coating agents; repellents'and toxicants which are substituted lmidazole com pounds, and comprises the method of producing the compounds as well as the new products them- .; selves. . blended with suitable wetting agents; ?llers, ‘s01 are made by preparing substituted imidazoles of .10 other ingredients employed in ‘compounding in the type represented by the formula: The products of the present invention may be prepared by reacting ethylene diamine with a molecular'equivalent or less of an acylating agent 16 ‘comprising an aliphatic‘monocarboxylic acid have ing as-its alkyl or‘alkenyl residue one of the radi secticides. ‘ < ' ' ca'ls described hereinbefore" in the de?nition of in which R representsan acyclic‘ hydrocarbon R1 ‘withfrespect to the ‘formula. , The acid thus dodecyl, tridecyl, tetradecyl, pentadecyl and hex adecyl radicals, or a straight chain alkenyl radi acid, the alkyl e'stensuch as the butyl ester, or ‘employedwill be composed "of an alkyl oralker'iyl radical having'from- lOYto 16 carbon atoms in its structure and ‘R1 represents an acyclic hydrocar $20 residue “o‘ffthe proper chain length or withv the proper branchedchain components together with bon radical having from 1 to 5 carbon atoms in a carboxylic acid group, the carbon atom of which its structure. The acyclic hydrocarbon radical is not included in the contemplation of the‘cha'in represented by R may be composed of a straight length hereinbefore described. In place of the chain alkyl radical such as the decyl, undecyl, desirably thetm'ethyl' or ethyl ester, maybe‘cm cal, such as decenyl, undecenyl, dodecenyl, tri ployed, or the acyl halide such as the acyl chlo decenyl, tetradecenyl, pentadecenyl and hexade ride, or the acid anhydride. cenyl radicals in which one or more double bonds may be located in various positions in the chain. ' _ I The resulting mono-acyl amino derivative is then condensed with the aid of a suitable mild R1 may be a straight chain alkyl radical such as the methyl, ethyl, propyl, butyl and amyl radi cals, or a branched chain alkyl radical such as dehydrating agent, such .as powdered calcium oxide, to form the 2-alkyl (or 2-alkenyl) imidaz oline. The derivative thus prepared is then re the isopropyl, tertiary butyl and is‘oamyl radi acted with an alkylating agent having as its alkyl 35 cals._ Likewise, R1 may be an alkenyl radical hav residue one of the residuesdescribed hereinbe ing from 1 to 5 carbon atoms in its straight or fore in the de?nition of R with‘ respect to the branched chain structure, for example, the pro“ formula. The alkylating agent may be an alkyl penyl, butenyl and isobutenyl radicals. The wa-_ halide, such as lauryl ‘chloride or tride'c'yl bromide. ter-soluble salts of these compounds may be pre pared and are also valuable‘ as active agents :40 The derivative thus prepared is then dehydrogé'n; ated- with the aid of a suitable dehydrogenation against micro-‘organisms and‘as insecticide toxi cants. For example, the hydrochlorides, hydro bromides and acetates and other salts may be ‘employed: ‘ The new products and their water-‘soluble salts may be administered orally orparenterally and have been found to be unusually e?ective against catalyst, such as nickel, to form the l-alkyl (or alkenyl)-2-alkyl (or all?senyl). imidazole. In carrying out‘the preparation of the N-acyl ethylene diamine, it‘ is desirableito employ an hydrous ethylene diamine; However, ethylene micro-organisms such ‘as streptococcus in vitro diamine that is not substantially anhydrous may be employed. The anhydrous material facilitates and in vivo; The organiciand inorganic acid salts ' the attainment of somewhat higher yields. may be preparedv by dissolving the products in an aqueous solution containing the; stoichiometrical equivalent of a suitable acid, such as hydrochloric, hydrobromic, acetic acids and'the like, and the solution may be employed for parenteral adminis tration.= Also, the .acid salts maybe prepared ” ‘The following examplesjillustrate the process of the present ‘invention and the compounds re sulting therefrom. These examples arewbe construed‘ as merely illustrating and not as limit ing the scope of the present invention. 2,404,299 24 grams of 50% sodium hydroxide solution with agitation and ?ltered. The benzene layer of the ?ltrate was separated and distilled to remove the benzene. The residue was distilled at reduced pressure to recover the product. B. P. 151-155° C./6 mm. Yield of 1-n-decyl-2-methyl-4,5-di hydroimidazole, 41.3%. The material’ assayed A mixture, 'oi264 grams of anhydrous ethyl 99.8%. This material was dehydrogenated ac acetate (3 moles) and 540 grams of ethylene di cording to the method of Example 1. Yield of amine (9 moles) was heated in an autoclave at 100-110° C. for 36 hours. A pressure of about 10 1-n-decy1-2-methyl-imidazole, 90.5% of theory. B. P. 153-160° C‘./5.5 mm. 20 pounds was developed. The mixture was transferred to a still and the ethanoland excess Example 3 ethylene diamine were distilled o? at about-100' 1-n-Tetradecyl-2-methyl-imidazole mm. absolute pressure. The fractionation yield i ' CH—N—-CHg-(OH2)1a~CHa ed 203 grams (66.5%) . of partially _ crystallized 15v N -acetyl ethylene diamine at 133-139° C./27 mm. on C-OHs A mixture of 203 grams of N-acetyl ethylene N diamine and 560 grams of ?nely powdered cal A mixture of 60.7 grams of 2-methyl-4,5-di cium oxide was heated in'a ?ask immersed in an oil bath at 225—235° C. for 14 hours. After cool 20 hydroimidazole prepared according to the method ofExample 1, 83 grams of tetradecyl chloride‘ and 7 ing to 90—100° C., the mixture was extracted with Y110 cc. of xylene was re?uxed 18 hours at 145°C. three 500 cc. portions of alcohol. The alcohol The mixture was cooled to room temperature and _ was removed from‘ the extract by distillation and diluted with 125 cc_‘of water. To this mixture, the residue‘ was distilled at atmospheric ‘pressure. 13. P. 195—198° 0.- Yield of2-methyl-4,5-dihy 25 27.5 grams of 50% sodium hydroxide was added with agitation. The resulting mixture was-‘?l droimidazole, 88%. ' ' I tered and the xylene layerwas separated and dis A mixture of 100.8 grams of 2-Inethyl-4,5-di tilled to remove the xylene. The residue was hydroimidazole,v 123.0 grams of n-dodecyl chlo ride (0.6 mole) and’290 cc. of xylene was re?uxed at 148° C. for 16 hours and then cooled to 25° C. distilled at reduced pressure to recover the prod B..P.j190~193°' C./6 mm. .Yield of 1-n so tetradecyl-2-methy1-4,5-dihydroimidazole, j 34%. IA- solutionof 50 grams of 50% sodium ‘hydroxide solutionv in .33 cc. of water was added with agita The material assayed 97.4%. This material was dehydrogenated according to the method of Ex tion; The l’mixture'was ?ltered and the xylene layer was separated’ from the ?ltrate. vAfter 1'6‘. ample 1. The product was l-n-tetradecyl-2 moval‘of the xylene underreduced pressure‘, the "35 methyl-imidazole. B. P. 187-199° C./5.5 mm. residue was distilled, B." 'P. 177-184°_C./>6. min. The yie1d'Was’60.7f"g'raI_hs', 01‘ 40.2%, tialdulat'ed'on n-dodecyl chloride " charged. The. preeue': as» 'droimidazole. I ; 40 . ‘ 'In place of n-dodecyl chloride. n-dodecyl‘lbro 'mide'may'be employed. ' l ‘ ' ' mixture of 427.7 gramsof anhydrous methyl ' ' For the. dehydrogenation of 1-n-dedecy1-2 caproateand 592 grams of anhydrous ethylene diamine was reacted according to the method 45 was prepared by heating nickel formate in a of Example 1. The N-caproyl-ethylene diamine mineral oil until decomposition of the formate obtained was condensed with the aid of anhy occured. - The nickel catalyst may be prepared drous calcium oxide according to the method by other methods, for'example, the method dis of Example 1. The product was identi?ed as 2 closed in U. S. Patent 1,378,736, issued May 17, amyl-4,5_-dihydroimidazole. B. P. l50-l57° C./34 1921, to Ellis. Other suitable dehydrogenation methyl-4,5-dihydroimidazole, a nickel catalyst mm. The yield of this material was 56.8%, based catalysts, such as Raney nickel catalysts, may be employed. A mixture of.3.2 grams .ofjhe cata lyst thus preparedwand 60.7 grams of l-n-do on methyl ,caproate. The M. P. of the material was 53-54:.6" C. . decyl-2-methyl-4,5-dihydroimidazole was heated > V r’ Amixture of 168 grams with agitation to 225°-235°_C. until hydrogen was imidazole, 123 grams of n-dodecyl chloride, and no. longer evolved. The reaction mixture was cooled to 125° C. and 1/2 gram of the nickel cata Heating was resumed and con method ofExampleLand thejresulting' reaction mixture was treated with 50 grams of 50% sodium The'distilled product was 1-n-dodecyl-2-methyl 'layerand distillation of the residue, the material lyst was added. 200 ,cc. of xylene was reactedaccording to the solution in 300 cc. of Water. ' After ‘?l; tinued until ,the evolution of hydrogen‘ ceased. .60 hydroxide tration, removalofjxylene from the'non-aqueous The reaction mixture was then distilled in vacuo'. imidazole. V‘ e ' . , ' ' ' " recovered ‘was identi?ed as l-n-dodecyl-2-n , amyl-4,5-dihydroimidazole. ' This material was Example 2 'dehydrogenated ‘according to the method of Ex ample I 1. The‘ product was. l-n-dodecyle2éamyl ‘ . 0% 707cm .. .j. . N’. r - Armix'tu're of150.4 grams (0.6 mole) of 2i-meth'yli- ' ' 4,5-dihydroimidazole, prepared according to'i'the ’ method 'of’Example 1, 52.8 grams "(0.3 mole) of decyl chloride and ‘100 ‘cc. of benzene was re?uxed ' for 7 hours and :cooled to ‘room temperature. ' The mixture was vtreated with ‘150 cc. of water and ‘ eemptuna may bélpreparea by reeetilsee $735 mixture‘ or- 101 grams or 2-n'iethyli4',5-dihydro t imidazole. This latter'may then .be reacted ‘with n-dodecyl chloride according to the method of Example 2' with the resultant production of l-n grams of h'exadeoyl chloride and 110 'cci'of xylene and processing the reaction mixture according to the method of Example 2. The resulting mate dodecyl- 2-isopropyl-4,5-dihydroimidazole. This rial, 1 - n - hexadecyl-2-methyl-4,5-dihydroimid material may then be deh'ydrogenated according to the method of Example 1 to form l-n-dodecyl azole, may then be dehydrogenated according to the method of Example 1 to produce l-n-h'exa 2-isopropyl-imidazole. decyI-Z-methyI-imidazole. Example 6 1-n-Tridecyl-Z-methyl-imidazole Example 10 10 l-'Dodecyl-z-isobutenyl-imidazole (?H-—N-V-CH‘2- (CH2)11' CH3 V‘ CH ‘ -omv N I “ _ according to the method of Example 2, and'dehy ' . ‘ N _ \CHa r. ~ This compound may be prepareid‘by reactingya mixture of anhydrous methyl dimethacrylate and drogenating the resulting l-n-tridec‘yl-Z-methyl 4,5-dihydroimidazole according to the method of _ 20H: CH This product was prepared by reacting 2-meth an excess of anhydrous ethylene diamine accord ing to the method of Example 1. The product recovered from the reaction mixture, N-dimeth , Example 7 acroyl ethylene diamine, is then condensed with calcium oxide withwthe resultant production ‘of l-n-Dodecyl-Zcthyl-imidazole 2-isobutenyl-y4,5-dihydroimidazole. E1H—N—CH2- (CH2) 1o- CH3 CH ' OH———N;-CH:~-(CH2) 10- CH: v yl-4,'5- dihydroimidazole with ,tridecyl bromide Example 1. "6' "Example '1‘ to ‘produce 2-isopropyl-4i5-dihydro-‘ "imidazole ‘prepared according to Example v1,144 7 This latter product may then be reacted with n-dodecyl chlo ride according vto the method of Example 2 to o-om-cm form l-n-dodecyl-2-is0butenyl-4,5-dihydroimid N azole. This material may then be dehydrogen ated according to the method of Example 1 to form 1-dodecyl-2-isobutenyl-imidazole. This compound may be prepared by reacting a mixture of anhydrous methyl propionate and an excess of anhydrous ethylene diamine according to the method of Example 1 to form N-epro'pionyl ethylene diamine. This product may; be - con densed with calcium oxide according to the meth od of Example 1 to form 2-ethyl-4,5-dihydroimid- ‘ azole. This latter product'may be reacted with ' ' 011 n-dodecyl chloride according to the method of 0-035 % Example :‘2 to form 1-n-dodecyl-2-ethyl-4,5-di hydroimidazole. _ This material may thenlqe‘ de vThis compound may be prepared by reacting a hydrogenated according ‘to themethod of'Exam mixture of 101 grams of 2-methyl-4,5-dihydro-' ple 1 to form 1-n-dodecyl-2-ethylgimidaaole. ' ‘ Example 8 x l-n-Dodecy1-2-propenyl-imidazole ‘ ‘imidazole, prepared according to Example'l; 122 grams of ll-n-dodecenyl chloride and 200cc. of ' xylene according to the method of Example 1, and treating resulting reaction mixture as in Ex ample 1 to recover the product. This product may then be dehydrogenated according to the method of Example ,1 to form l-(n-dodecen-ll >C‘H—-N—-CH2-‘(QH2)m-CHa I‘ I OH G—CH=CH-CHB‘ \ V . . yl-l) -2-methyl-imidazole. Thisv compound may beprepared by reacting Example 12 a mixture of anhydrous methyl crotonate and an excess of anhydrous ethylene ‘diamine according "60 to'the method of Example 1' to produceNecro tonyl ethylene diamine, This product may be 1- (n-Tetradecen-12-y1-1) -2-propenyl-imidaz ole condensed with calcium oxide according to the method of Example 1 ‘to produce 2-propenyl-4,5'- _v ‘_ diliydroimidaz'ole'. This latter product may then be reacted with n-dodecylchloride according to the method of Example 1 with the resultant pro duction of l-n-,dodecyl42‘-'propenyl-4,5-dihydro imidazole. l N/ , ' . .c v This compound may be prepared by ‘reacting a mixture of 132 grams of 2-propenyl—4,5-dihydro; imidazole, prepared as in Example 8 according to the method of Example 1, 138 grams of 12-tetra This material may then be dehydro decenyl chloride and 200 cc. of xylene according , genated according to the method of Example 1 60 to the method of Example 1, and treating result to form 1-n-dodecyl-2-propenyl-imidazole. ing reaction mixture as in Example 1 to recover Example 9 l-n-Dodecyl-2-isopropyl-imidazo1e CH-N-CHz- (CH2)10- CH: l the product. 05 CH3 0% % -oH--o/‘ N ’ v Example 13 CH3 This compound may be prepared by reacting a 70 mixture of anhydrous methyl isobutyrate and an excess of anhydrous ethylene diamine according to the method of Example 1. The resulting prod uct, N-isobutyryl ethylene diamine, is condensed with calcium oxide according to the method'of 75 1-n-Decy1-2-amy1-imidazole CE C-CHa-(CHzh-CHa N A mixture of 2 mols of 2-amyl-4,5-dihydroimid azole, prepared according to the method of Ex ample 4, and one mol of n-decyl chloride was heated at 144-150° C. for 15 hours. The reaction product was diluted with Water, treated with a 5% excess of 50% sodium hydroxide, and extract 2,404,299 '7 ediwith'. n-butyl ' alcohol. The butyl . alcohol and ' 5._The some :‘unreacted 2 - amyl - 4,5_-'. dihydroimidazole 1-n+tetradecyl-2-methyl-imidazolev of the‘formula: ' , ‘ " ‘ ' Were removed from the vextract by distillation. i The residue was distilled, B. P. 143-174.5°/3.5 mm., and thereafter redistilled, B. P. 157-17073}; *' ‘ I ' ' ' - GH—yN—CHz-(CH2)12~CH: 0H" ' —CHzV I mm. This material was dehydrogenated accord ing to the method of Example 1. The product prepared for use as a therapeutic agent. was 1-n-decyl-2-amyl-imidazole. Yield 93.8%; 6. A process for preparing compoundsT'of‘the B. P. 149-176" O./3.5 mm.‘ formula type: v‘ c c ,1 The present invention is a continuation-in-part 10’ a N of my copending application S. N; 498,583, ?led August 13, 1943, which discloses the 4,5-dihydro - ,CH-if-R imidazole derivatives from which the novel thera peutic agents‘ of the present invention may be ' 7 _ _ N% , . v in which R represents an acyclic hydrocarbon 15 radical having from 10' to 16 carbon atoms in its derived as explained hereinbefore. I claim: } , structure and R1 represents an acyclic ‘hydrocar bon'radical having from 1 to 5 carbon atoms ‘in _ 1. _A compound of the group consisting of. sub stituted imvidazoles'of the formula type: its structure, said process comprising reacting v ethylene diamine with an alkyl ester of va mono 20 carboxylic acid in which a carboxylic group' is attached to a radical selected from the group of radicals de?ned hereinbefore as R1, heating the in which R represents an acyclic hydrocarbon ethylene diamine derivative thus formed in the radical having from 10 to 16 carbon atoms in its presence of a mild dehydrating agent, reacting structure‘ and Rrrepresents an acyclic hydrocar 25 the derivative thus formed with an alkyl halide bon radical having from 1 to 5 carbon atoms in having an alkyl radical selected from the group its structure andacid salts thereof,_preparedfor of radicals defined hereinbefore as R, heating useas therapeutic agents. ; V ' the derivative thus formed with a dehydrogena _- 2. Substituted imidazoles of the formula type: tionycatalyst and distilling oif the dehydrogena '30 . ' , 1(|_‘|;H___N_RI ' _ J 7.?A process for preparing compounds of the tion product; 1911:: Crew formula type: ‘ ' . ' ' " - ‘ ' J in which Rrepresents a straight chain alkyl rad ical‘uhaving from 10 to 16'carbon atoms in its structure and R1 represents an acyclic hydrocar bon radical having from 1 to 5 carbon atoms in its structure, prepared for use as therapeutic agents.v I ‘r 3. .The V1-n-decyl-2-methyl-imidazole of’ the formula: ‘ we‘ __ v j . inl'which‘R represents a straight chain ‘alkyl i radicalhaving from '10 to, '16 carbon atoms in 40 its structure and R1 represents anacyclic hydro- ' carbon radical having from 1 to 5 carbon atoms in its structure, said process comprising reacting V ethylene diamine with an alkyl ester of a mono- . ' uH_N—oH2-(c11i)tom CH . ‘ c-on, ' ‘ carboxylic acid in which a carboxylic group is " attached to a radical selected ‘from the group of .45 radicals de?ned hereinbefore as R1, heating the ethylene diamine derivative thus formed in the N. prepared for use as a therapeutic agent. 4. The 1-n-dodecyl-2-methyl-imidazole of the formula: V . ' _ - - -CH;—N—.—CH2-(OH2)in-,CH3> on ' ' - O-CHa N ‘e presence of a mild dehydrating agent, reacting the derivative thus formed with an’ alkyl halide ":50 having an alkyl‘ radical selected from the group a of ‘radicals de?ned hereinbefore as R, heating the derivative thus?formed with a dehydrogenation catalyst and distilling off the dehydrogenation product, ' " ' ' . 7 prepared for use as a therapeutic agent. 45,5 < ~ ‘ , LUcAs P; KYRIDES. '