Патент USA US2404300код для вставки
Patented July 16, 1946 2,404,300 v @PATENT OFFICE.‘ , ‘ UNITED JISTATESF 7 Lucas Kyrides', Webster Groves, and Ferdinand - ‘ B. Zienty, St. Louis,_Mo., assignors to Monsanto, ' Chemical Company, St. Louis, Mo., a corpora ‘a tion of Delaware No'Drawingl' Application March 22, 1944, - Serial No. 527,074 ' 7 Claims. 1 The present invention relates to the productionv thesis of the imidazole derivative or immediately thereafter and before the productis isolated from, cants which are substituted imidazole compounds, and comprises the method of producing these compounds as well as'the new products them ' . According to the present invention, generally stated, new products which are of outstanding value as active agents against micro-organisms the The reaction products mixture. of the present‘invention . a , have _ also 5 been found to possess utility as insecticides and toxicants for insecticide compositions,_ such asv sprays and powders in which the compounds are blended with suitable wetting agents, ?llers, sol vents,‘ adhesives, coating agents, _ repellents, and are made by preparing substituted imidazoles of 10 the type represented by the formula: i (Cl. 260-—309) of new bactericidal agents and insecticide toxi selves. ‘ ‘ ‘ other ingredients employed in compouhdingin- V t secticides. . - - I The products of the present invention maybe prepared by reacting ethylene \diamine, with a molecular equivalent or less of an ‘acylating agent. 15 comprising an altiphatic monocarboxylic acid.‘ having as its alkyl residue one ofv the radicals described hereinbefore in the de?nition, of R1 in which R represents an acyclic hydrocarbon‘ radical having froml to 5 carbon atoms in its with respect to the formula. The acid thus em‘ ployedwill be composed of'a straight'chain alkyl residue of the proper chain length together with structure and R1 represents an acyclic hydrocar a carboxylic acid group, thecarbon atom of ‘which, vbon radicalhaving fromlO to 16 carbon ‘atoms is not included in the contemplation of the chain in its structure. The acyclic hydrocarbon radi length hereinbefore described. Inthe place of the cal represented by R may be a straight chain alkyl acid5thealkyl ester, such as the butyl ester; or: radical such as the methyl, ethyl, propyl, butyl and amyl radicals, or a branched chain alkyl radi .26 desirably the methyl or ethyl ester, may be CHI-f cal such as the isopropyl, tertiary butyl and iso ' ” ployed, or the acyl halide such as the acyluchlo ride, or the acid anhydride. The resulting mono amyl radicals. Likewise R may be an alkenyl acyl amino derivatives is then'condensed. with radical having from 1 to 5 carbon atoms in its the aid of va suitable mild dehydrating agent, straight or branched chain structure, for ex ample, the propenyl, butenyl and isobutenyl radi , such as; powdered calcium oxide, to form the 2 cals. The acyclic hydrocarbon radical repre sented by R1 may be composed of a straight chain ’ n-alky1_-4,5-dihydroimidazole.' ' The derivative thus prepared is then reacted with an alkylating agent having as its alkyl or alkenyl residue one alkyl radical such as the decyl, undecyl, dodecyl, of the residues described hereinbefore in the def tridecyl, tetradecyl, pentadecyl and hexadecyl radicals, or a straight chain alkenyl radical, such ’35- inition of R with respect to the formula. The alkylating agent may be a mineral acid ester such as the decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and hexadecenyl rad as an alkyl sulfate or alkenyl sulfate. Also, the alkylating agent may be an alkyl halide or an icals in which one or more double bonds may be located in various positions in the chain. The alkenyl halide. The “derivative thus prepared is r water-soluble salts of these compounds may be : prepared and are also valuable therapeutic agents and insecticide toxicants. For example, thehy drochlorides, hydrobromides and acetates and’ other salts may be employed. , 45 . The new products andrtheir water-lsoluble salts have been found to be unusually effective against micro-organisms such as streptococcus in vitro and in vivo. The organic and inorganic acid salts may be prepared ‘by dissolving the products to in an aqueous solution containing the‘stoichio metrical equivalent’ of. a suitable acid," such as then dehydrogenated with the aid of a suitable dehydrogenation catalyst, such asnickel, to form' the l-alkyl '(or 'alkenyl)'-2—alkyl (or alkenyl‘) .imidazole. , ~ ' ' ’ In carrying out the preparation of .the N-acyl ethylene diamine, it is‘desirableto employ an hydrous ethylene diamine. However, ethylenedi amine that is not substantially anhydrous may g be employed. The anhydrous material facilitates the attainment of somewhat higher yields. The following examples illustrate ‘the process of the present invention and the compounds result hydrochloric, hydrobromic, acetic acids, and the ing, therefrom. These examples are tofbe' con‘ like, and the solution may be employed. Also, strued as merely illustrativeand not as limiting the acid salts may be prepared during the syn; 5.5 the scope of the‘ present invention. " ‘ . 2,404,300 '3 EXAMPLE I. 150 cc. of water and approximately 150 cc. of bu tyl alcohol was added to the reaction mixture 1 -methyl-Z-n-undecyZ-imidazole slowly with agitation. The mixture was then 'cfH—N+oHa CH C-CH2(CH2)~0~ CH3, \ ¢ 4 grams of 50% sodium hydroxide in approximately . 5 agitated for 1 hour at roomtemperature. The ' butyl alcohol layer was separatedand thereafter ‘ distilled to remove butyl alcohol and Water. The residue was then distilled at reducedpressure to A mixture of 1'11 grams (0.75 moles) of ethyl . I laurate and 135 grams (2.25 moles) of anhydrous I recover the product. The B. P. of the product 12 hours. The reaction mixture was transferredv ‘was 145 180 mm’Was The meld of ploduct was v‘770.3% ‘andC'/5/2 the assay substantially-100%. to a stilland the alcohol and'excess ethylene di The product was identi?ed as ,2-n-amyl-2-n-‘un ethylene-diamine was re?uxed at 110-112“, C. for 3. ; o 1 - . amine were removed by distillation. The’ yield V decyl-dihydroimidazole. ‘ A mixture of 4.2» grams of crude N-acylated ethylene diamine was/1'72‘ ‘ vof nickel catalyst, prepared according ‘to the method of Example I, and 37.1 grams of l-amyl grams. A mixture of 162 grams of the crude N-'acyl= is 2en-undecyl-4,5-dihydroimidazole was heated with ethylene diamine and‘ 187 grams of powdered1 . agitation to 212-246" C. vuntil hydrogen was no calcium oxide was heated with stirring at 225° longer evolved. The reaction mixture was then C(for 36 hours. The reaction mixture was cooled distilled. The fraction distilling at 18§~210°/5 and extracted 3 times with about 350 cc. of_ al- 20 mm. was recovered. The product was l-amyl cohol at room temperature. The alcohol was re Z-n-undecyl-imidazole. Yield 76.6%. . 1 . moved by distillation and ‘the product "was dis tilled‘by reduced pressure. 'The'boilirig point‘of ‘ ' EXAMPLE III ‘ 1 -methyl-2-n-decyZ-imidazole the ‘product was ISO-189° C./10 mm. ‘The M. P.’ of. the product was >87 uct was 98.5 grams. ' 2's CH—N-—CHs 7 Thelproduct was" identi?ed as 2-undecyl-4,5-di hydroimidazole. To 56.5‘ grams of 2-undecyl 4,5-dihydroimidazole was added 31.7 grams of - . A mixture of 160.5 grams of the ethyl ester dimethyl sulfate‘ over a period of 32 minutes. 30 of n-undecanoic acid and'135grams of anhydrous ethylene diamine was reacted according to the The temperatureof the reaction mixture'was method of Example I. The resulting N-un maintained atmabout 85° 'C. To the reaction mix decanoyl ethylene diamine was condensed with ture was added’approximately 150 cc. of water,‘ anhydrous calcium oxide according to the meth and the mixture was stirred until the solid ma terial had dissolved. A solution of 20 grams of‘ 35 od of Example I. The resulting 2-n-decyl-4,5 50% sodium hydroxide and approximately 15000.3 dihydroimidazole was then reacted with dimeth yl sulfate according to the method of Example I of butylalcohol was added to the mixture with‘ agitation. aThamixture was then filtered, and‘ to form 1,-methyl-2-n-decyl-4,5-dihydroimida the butyl alcohol layer'of' the ?ltrate was dis zole. This material may then be dehydrogenated The tilled to‘ remove butyl alcohol _. and water. _The 40 ' according to the method of Example I. residue was'then distilled at reduced pressure~ to: recover the product. The B. P. of the product product is 1-methy1-2-n-decyl-imidazole. was 16'7—1'72° -C./6 mm. The yield of product was 38%‘ and the assay was 96.2%. The product was 1 -methyl-Z-n-dodecyZ-imidazole‘ EXAMPLE IV V identi?ed ‘as g1-methyl;2¢n-undecyle4,5-dihydro cH-m-om imidazolea ‘ ‘ i I _ CH I ‘ For the ‘dehydrogenation of 1-n-dodecyl-2 methyl-4,5-dihydroimidazole, . a dam-(croutons ‘ ' ‘ N nickel ‘ catalyst was ‘prepared by heating nickel formate in a A mixture of 162 grams of the methyl ester of mineral oil until decomposition of the formate 50 tridecanoic acid was reacted with 135 grams of occurred. The nickel catalyst may be prepared anhydrous ethylene diamine according to the method of Example I. The resulting N-tridec ' by other; methods, for example. the method dis closed in‘U. S. Patent 1,378,736,-issued May v1'7, anoyl ethylene diamine was condensed with an be employed. A mixture of 3.1 grams of the cat imidazole. This product was then reacted with dimethyl sulfate according to the method of Ex 1921, ‘to Ellis. Other suitable dehydrogenation hydrous calcium oxide according. to the method catalysts, such as Raney' nickel catalysts, may 55 of Example ‘I to form 2-n-dodecyl-4,5-dihydro alyst thus prepared and 30.9 grams .of l-methyl '2-n-undecyl-4,5 -.dihydroimidazole was heated with agitation to 226° C.-246° C. until hydrogen ample I to form 1-methyl-2-n-dodecyl-4,5~dihy .droimidazole. This material may then be dehy drogenated according to the‘method of Example I. The product'is l-methyl-2-n-dodecyl-imida was no longer‘ evolved. The reaction mixture was then distilled; B. P. 166-203°/5 mm. The product’ was 1-methy1-2-n-undecyl - imidazole. Yield 85.3%. . v zole. ' EXAMPLE V v EXAMPLEII . ‘ 1 -n-amyl-j2 -n-undecyZ-imidazole ' 05 oH--_N—o11l-‘(oHl)‘a-c11'3 on '\ o-onMoHm-om ¢ ‘ ~ _ " N This compound may be'prepared by reacting To 84.9 grams ‘of, 2-n-undecyl-4,5-dihydroim 70 2-n-dodecyl-4,5-dihydroimidazole, prepared ac idazole heated to 140-150° was added dropwise cording to the methodof Example IV, with di 21.7.. grams of. n-amyl chloride. The tempera ethyl sulfate according, tov themethod of Ex ture of; the reaction mixture was held at 147-154“ ample, I using the stoichiometrical proportions C. for a total of 16 hours.v Thereaction mixture desired therein. This material may then be de- ' was then cooled to 60° C. A solution of 17.1 2,404,300 5 . hydrogenated according to‘the method of Ex ample I. The product is 1-ethyl-2-n-dodecyl imidazole. A mixture of 270 grams ('1 mole) of crude N-n-' tetradecanoyl ethylene diamine and 280 grams (5' moles) of powdered calcium oxide was heated With agitation at 225-230“ C. for.v 36 hours. The - EXAMPLE VI 1 -isop1opyZ-2 -n-dodeeyl-imidazole /CHs " 5 mixture was then cooled and extracted with al-, cohol. The alcohol layer was separated and the solvent was removed therefrom by evaporation, ' leaving 130 grams of crude amine base. The base foH5~N~on '“ Y .CH: ' . CH , ' was distilled, yielding 70‘ grams of a paleyellow, crystalline, waxy solid material identified as 2-n , 10 'C—-CH;.(CH2)10.CH3 tridecyl imidazoline -(2-n-tridecyl-4,5-dihydro \N% . imidazole) ; M. P., 87-88° C. with slight previous This compound may be ‘prepared by reacting softening. rI'his productmay then be reacted with 2-n—dodecyl-4,5-dihydroimidazole, prepared ac- it dimethyl sulfate according to the method of Ex ample I, using the stoichiometrical proportions cording to‘ the method of Example IV, with iso propyl chloride according to the method of .Ex described therein. ample II using the stoichiometrical proportions ‘ methyl-2~n-tridecyl-4,5-dihydroimidazole. This The resulting product is 1 material may then be dehydrogenated according described therein. This material may "then be to the method of Example I. The product is 1 dehydrogenated accordingto the'method of Ex . ample I. The product is_l-isopropyl-2-n-dodecyl- 20 methyl-Z-n-tridecyl-imidazole. In place of calicum oxide, other suitable de imidazole. / - EXAMPLE VII hydrating agents, such as other alkaline-earth ‘ oxides, for example, barium oxide, and other mild dehydrating agents, may be employed. However, 1 -allyl-Z-n-dodecyl-imidazole CH—N—~CH1.CH=CH1' (")H \ calcium oxide is the desired agent because of its —CH:.(CH2)lu-CHI ¢ ‘ cheapness and e?iciency. ' i EXAMPLE X ‘ This compound may be prepared by reacting 1 -methy_l-2-n-tetradecyZ-imidazole 2-n-dodecyl-4,5-dihydroimidamle ‘prepared ac-. cording to the method of Example IV, with allyl bromide according to the method of Example II, using the stoichiometrical proportions described therein. This material may'then be'dehydro This compound may be prepared by reacting a mixture of 183 grams of the methyl ester of pen tadecanoic acid and 135 grams of ethylene d1-' amine according to the method of Example I. genated according to the method of Example I. 35, The product is substantially 1-ally1-2-n-dodecy1 imidazole, ' EXAMPLE VIII The resulting N-pentadecanoyl ethylene diamine 1 -methaZZyl-2-n-dodecyZ-imidazole was condensed with anhydrous calcium oxide ac cording to the method of Example I to form 2-n tetrad'ecyl-4,5-dihydroimidazole._ The product was reacted with dimethyl sulfate according to the method ofv Example I, using the stoichiometrical proportions described therein. The resulting product was 1.-methyl-2-n-tetradecyl-4,5-dihy This compound may be prepared by reacting 2-n-dodecyl-4,5-dihydroirnidazole, prepared ac cording to the methpd of Example IV, with meth allyl chloride according to the method'of Ex ample II, using the stoichiometrical proportions described therein. This material may then be dehydrogenated according to the method of Exa ample I. The product is substantially I-meth allyl—2-n-dodecyl imidazole. EXAMPLE . IX droimidazole. This material may then be dehy drogenated according to the method of Example I. The product is 1-methyl-2-n-tetradecyl _ imidazole. It is desirable to use anhydrous ethylene di amine in the process described in this and other examples to facilitate the attainment of higher yields. VHowever, ethylene diamine that is not substantially anhydrous may be employed. ' ' ExAMPLa E ' 1-methyl-zan-pentadecyl-imidazole . 1-meth.yl-Z-n-tridecyl-imidazole CH——N—-CHa CH \N ’ —CHi-(CH2)11.CH3 I to " A mixture of 426 grams. (1.5 moles) of n-butyl myristate and 270 grams (4.5 moles) of anhy drous ethylene diamine was re?uxed at 115° C. for 10 hours. The excess ethylene diamine and the butanol resulting ‘from the acylation were then distilled off, the distillation‘being'completed at a reduced pressure of 10 mm. . The crude prod uct remaining in the still weighed 377 grams and melted at about ‘122°’ C. with extensive previous softening. 'After recrystallization from alcohol, ?lH—-N-0Hi on éo-ormomm-ong N v I _ . A mixture of 193.5 grams of methyl palmitate was reacted with 135 grams of anhydrous ethylene diamine according to the method‘of Example I. The resulting N -palmitoyl ;ethylene_diamine was condensed with anhydrous calcium oxide accord ing to the method of Example I to form 2-n pentadecyl-4,5-dihydroimidazole. This product 0 was reacted with dimethyl sulfate according to the method of Example I to form l-m'e'thyl-z-n pentadecyl-4,5-dihydroimidazole.‘ v This material may then be dehydrogenated' according to'the the M. P. was 150-1520 C. The product was found method of Example I. The product is' l-methy'li‘ to be appreciably soluble in benzene. ~ 75 Z-n-pentadecyl-imidazole.‘ ‘ ' ‘ \ " 2,404,399 ~ 8 1 LethgZ-Z -undecyI-imidazole ("3H-—.N—C1H5 o'—oHz.(oH5)».0H@' CH N Fifty grams of 2-undecyl44,5-dihydroimidazole ' ' This compound may be prepared by reacting a was melted and held at 70-80° C. ‘The melt was mixture- of 204 grams of methyl margarate and 10 agitated while 19 cc. (34.4 grams) of ‘diethyl 135 grams of anhydrous ethylene diamine ac sulfate was added slowly and simultaneously with cording to the method of Example'I. The re 8.9 grams of sodium hydroxide in sufficient water sulting N-heptadecanoyl ethylene diamine is con to make 20cc. After all the diethyl sulfate had densed‘ with anhydrous calcium oxide according been added, the reaction mixture Was heated for to the method of Example I to form 2-n-hexa 2 hours at 80° C. and thereaftercooled approxi- ' 15 decyl-4,5-dihydroimidazole. This product is re 'mately to room temperature. To this reaction acted with dimethyl sulfate according to the . mixture was added 100 cc. of butanol and 40 method of Example I to form 1-methyl-2-n-hexa grams of 50% caustic soda solution. The mix decyl-4,5-dihydroimidazole. This material may ture was stirred for 11/2 hours. The butanol lay then’be dehydrogenated according to the method er was separated fromrthe mixture and’ washed 20 of Example I. The product isl-methyl-Z-n-hex twice with 50 cc. of water. The washed material adecyl-imidazole. was dried over anhydrous sodium sulfate and the butanol was remoyed'by distillation. The re maining material was distilled at reduced pres 25 sure, B. P. 200/226“ C./12 mm.,=and redistilled,‘ B. P. FIG-178° C./21/g mm.._ Yield of l-ethyl-Z-n undecyl-4,5-dihydroimidazole, 23.5 grams. This 5 material was dehydrogenated according to the method of Example I. The product was l-ethyl 2-n-undecylimidazole. ' This compound may be prepared by reacting a 80 The present invention is a continuation-in mixture of 318 grams of the methyl ester of 2-n part of copending application S. N. 498,584, dodecenoic acid and 270 grams of anhydrous ?led August 13, 1943, which discloses the 4,5-di ethylene diamine according to the method of hydroimidazole derivatives from which the thera Example I. They resulting N-(n-dodecen-Z-oyl-l) peutic agents of the present invention may be ethylene diamine may then be treated with an 35 derived. ' hydrous calcium oxide according to the method We claim: of Example I to form ‘Z-(n-undecen-l-yl-l) -4,5 1. A compound of the group consisting of sub dihydroimidazole. This product may then be re stituted imidazoles of the formula type: acted with dimethyl sulfate according to the 40 method of, Example I to form 1-methy1-2(n undecene l-yl- 1) -4,5-dihydroimidazole. This ma terial may then be dehydrogenated according to the method of Example I. The product is sub stantially 1 - methyl- 2 -(n-undecen-1-yl-1) -imi dazole. - EXAMPLE IHV -' 1 -alZyl-2-(n-tridecen-1 -'JZ-1) -imidazole CH—N——R (‘5H 6-K. N in which R represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure and R1 represents an acyclic hydro carbon radical having from 10 to 16 carbon atoms in its structure and acid salts thereof, prepared for use astherapeutic agents.“ 60 > . 2. Substituted imidazoles of the formula type: (|JH—N—R dH o-m This compound may be prepared by reacting N 1.5 moles of the methyl ester of Z-n-tetradecenbic acid with 4.5 molesiofzanhydrous ethylene di amine according to the method of Example I. in which R represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure and R1 represents a straight chain alkyl radical having from 10 to 16 carbon atoms in its- structure, prepared for use as therapeutic The resulting N-(n-tetradecen-2-oyl-1) ethylene diamine may then be treated with anhydrous calcium oxide according to the method of Ex ample I to form 2-(n-tridecen-1-yl-1)-4,5-di hydroimidazole. This compound may then be re acted with allyl chloride asin Example VII ac cording to the method of Example II to form 1 agents. _ ' 3. The 1-methyl-2-n-undecyl-imidazole of the formula: ' CH—-N——CH3 allyl-2- (n-tridecen- l-yl- 1) -4,5-dihydroimidazole; 65 and if dimethyl sulfate is-used as the alkylating agent the corresponding l-methyl compound is formed. The material 1-allyl-2-(n-tridecen-l yl-l) -4,5-dihydroimidazole may then be dehydro genated according to the method of Example’ I. The product is substantially l-allyl-z-(n-tride cen-1-yl-1)-imidazole. , The dehydrogenation product of 1-methyl-2-(n-tridecen-l-yl-l)-4,5 dihydroimidazole is . substantially »1-methyl-2-,(n-' tridecen-l-yl-l) -imidazole.v 1 prepared for use as a therapeutic agent. 4. The 1-methyl-2- (n-tridecene-l-yl-l) limi dazole of the formula: ?H-NAJH; c-oH=oH-(oHz)w-om _oH 75 prepared for use as av therapeutic agent. > - ' 2,404,300 10 5. The 1-methyl-2-n-tridecyl-imidazole oi the formula: ‘ dehydrogenation catalyst and distilling o? the dehydrogenation product. _ 7. A process for preparing compounds of the <“3H--N-oH1 C--CH2-(CHz)u-CH: formula type: CH \ CH—N—R N II CH prepared for use as a therapeutic agent. 6. A process for preparing compounds of the formula type: OH-——N—-’-R (I511 é-QR: N a 10 | % C-Rr in which R represents an acyclic ‘hydrocarbon radical having from 1 to 5 carbon atoms-in its structure and R1 represents a straight chain radi cal having from 10 to 16 carbon atoms in its structure, said process comprising reacting eth-" in which R represents an acyclic hydrocarbon ylene diamine with an‘ .alkyl ester of a mono radical having from 1 to 5 carbon atoms in its 15 carboxylic group attached to a radical selected 7 structure and R1 represents an acyclic hydrocar from the group of radicals de?ned hereinbefore‘ ' bon radical having from 10 to 16 carbon atoms as R1, heating the acyl ethylene diamine deriva in its structure, said process comprising reacting ethylene diamine with an alkyl ester of a mono carboxylic group attached to a radical selected from the group of radicals de?ned hereinbefore as R1, heating the acyl ethylene diamine deriva-; tive thus formed in the presence of a mild dehy drating agent, reacting, the derivative thus formed tive thus formed in the presence of a mild de hydrating agent, reacting the derivative thus formed with an alkylating agent having at least one hydrocarbon radical, each. of which is se lected from the group of radicals de?ned herein before as R, heating the derivative thus formed‘ with a dehydrogenation catalyst and distilling off with an alkylating agent having at least one 25 the dehydrogenation product. hydrocarbon radical, each of which is selected from the group of radicals de?ned hereinbefore LUcAs P. KYRlDES. as R, heating ‘the derivative thus formed with a FERDINAND B. ZIENTY.