3,256,288 United States Patent Office Patented June 14, 1966 W 2 -Cl, -Br or -SONH2, with an appropriate imino ether 3,256,288 hydrochloride having the formula -SUBSTITUTED AMNOALKYL-2-ARYLOXY METHYLEBENZRADAZOLE COMPOUNDS E Clarence L. Moyle, Care, and Diomed M. Cher, Mid land, Mich., assignors to The Dow Chemical Company, Midland, Mich., a corporation of Delaware W (III) No Drawing. Fied May 24, 1962, Ser. No. 197,285 wherein in this and succeeding formulas, E is -H, -R, 9 Claims. (C. 260-294.7) -CI, -Br, -OH, -OR or -CONH2 and R' is a lower alkyl group, to produce the desired benzimidazole product This invention is directed to benzimidazole compounds, O and R'OH, NH3 and HCl by-products. The gaseous NH particularly (a) N-substituted benzimidazole compounds and HCl generally evolve from the reaction mixture al having the formula though some of the HC1 may react with NH and remain in the reaction mixture as ammonium chloride salt or may react with the basic benzimidazole product and remain 5 as the hydrochloride salt thereof. / N Y In carrying out the preparation, substantially equimolar proportions of the reactants are employed although either reactant may be employed in excess. The reaction is O/C -o-o-( x, generally carried out at a temperature in the range of 20 and (b) mineral acid salts of these compounds. In this from 60 to 82° C. for a period of from about 20 to 72 and succeeding formulas-NR'R'' is di(lower-alkyl)ami hours. It is preferred that an alcoholic solvent be em no, piperidino, morpholino or pyrrolidino; X is -H, ployed in this process. Suitable solvents include metha - NO, -R, -Cl, -Br or -SONH2; Y is -H, -Br, nol, ethanol and isopropyl alcohol, and is conveniently -Cl, -OH, -OR, -R,-CONH2, -COOH, -COOR, 25 R'OH wherein R' corresponds to the alcoholic com -COOM, -COONH or -COOB; W is -H, -CH3 or ponent of the reactant imino ether. After completion of -Cl; n is an integer of from 2 to 3, inclusive; and where the reaction, the mixture is diluted with water with or in R is lower alkyl containing from 1 to 4 carbon atoms, without the addition of dilute alkali to precipitate the inclusive, M is alkali metal and -COOB represents an desired benzimidazole product as a white or light colored amine salt group where the salt forming base is selected 30 Solid. The latter may be recovered by filtration and puri from lower alkylamines and lower alkanolamines, fied, if desired, by conventional procedures. Alterna The expression “lower' as above employed indicates a tively, the product may be converted to the hydrochloride carbon content of from 1 to 4, inclusive. By "alkali salt and recovered as the salt or purified via the hydro metal' is meant sodium, potassium and lithium. By chloride Salt, “lower alkylamines' and “lower alkanolamines' are meant 35 In preparing the hydrochloride salt, the product ob amine bases which have one or more lower alkyl or lower tained as above described is dissolved in a suitable inert hydroxyalkyl radicals on the basic nitrogen and in which Solvent such as diethyl ether and dry hydrogen chloride lower designates from 1 to 4 carbon atoms. Typical gas bubbled into the solution to precipitate the desired amine bases, A, which form with -COOH, the amine benzimidazole hydrochloride compound. salt group, -COOB and which may also be designated 40 In an alternative method suitable for preparing most of -COOH-A, include methylamine, ethylamine, ethanol the compounds of the present invention, a substituted o amine, isopropanolamine, methylaminoethanol, ethylami phenylenediamine having the Formula II above is heated noethanol, diethanolamine, isopropylamine, n-propyla together with an appropriate phenoxyacetic acid having mine, n-butylamine, trimethylamine, diisopropylamine, the formula N-methyl-isopropylamine, N-methyl-sec.-butylamine, 2 45 aminopropyl alcohol, isopropylaminoethanol, n-butylami HO oc-CH-0-{ X noethanol, bis(2-hydroxypropyl)amine, triethylamine, tri W (IV) (n-butyl)amine, triisopropanolamine, triethanolamine, di wherein D is -H, -R, -C, -Br, -OH or -COOH, methylaminoethanol, diethylaminoethanol, dibutylamino in a mineral acid solution. ethanol, ethyldiethanolamine, dimethylamine, diethyla 50 In carrying out the reaction according to this method, mine and triisopropylamine. Substantially equimolar proportions of the reactants are The N-substituted benzimidazole compounds of the mixed together with dilute acid, preferably hydrochloric present invention have numerous pesticidal applications, acid, and the resulting mixture heated in the temperature both aquatic and terrestrial, and as such are adapted to range of from about 100 to 180° C., conveniently at be employed in agriculture, forestry and horticulture as 55 reflux temperature, for a period of from about 12 to 36 well as in removal of pests from recreational areas. The hours to obtain the desired benzimidazole produce as its compounds further have morphine-like action and are hydrochloride salt. The benzimidazole hydrochloride thus useful for exploring selected biological mechanisms Salt thus obtained may be mixed with dilute aqueous in laboratory animals such as making comparative studies alkali or ammonia to obtain the benzimidazole product as of drug response against writhing in mice for evaluating 60 an oil which solidifies on standing. Both the benzimi analgetic activity. dazole product and the hydrochloride salt may be purified The products of the present invention may be prepared according to methods of the art. by mixing together and causing to react an appropriately A third method of synthesis is especially adapted for substituted o-phenylenediamine having the formula the preparation of benzimidazoles having a 5-nitro sub 65 stituent CHNR'R''. -NE N A. -NE N E. (II) 70 C-C H-0-{ X wherein in this and succeeding formulas, A is -H, -R, ON- N/ = \w 3,256,288 3. 4. In this procedure which is a modification of the first In carrying out the optional step of preparing the iodo process hereinbefore described, the -NR'R' is introduced substituted compound, intermediate (VII) and a sub into the molecule after the formation of the benzimidazole stantially equimolar proportion or slight excess of potas nucleus. This modified procedure is preferred for the sium iodide are mixed together in an inert solvent and preparation of the particular benzimidazole compounds in the resulting mixture heated at reflux temperature for a which the particular o-phenylenediamine is difficulty avail period of from about 8 to 24 hours. Suitable solvents for able as 4-nitro-o-phenylenediamine. In this procedure, carrying out this step include methyl ethyl ketone and the following sequence of reactions is employed: acetone. During the heating period a reaction takes place with the formation of intermediate (IX) and potas (1) A 4-nitro-o-phenylenediamine having an N-hydroxy sium chloride by-product. At the end of the heating alkyl substituent (VI) is reacted with an appropriate O period the reaction mixture is allowed to cool whereupon imino ether (III) according to the procedure described the by-product potassium chloride precipitates as a solid. previously to obtain an intermediate benzimidazole The latter is removed by filtration, and the filtrate heated (VII). to vaporize a portion of the solvent and the remainder g Han OH diluted with water to obtain intermediate (IX) as a solid -NH precipitate. The latter is recovered by filtration. -- (III) - In carrying out the final step of the synthesis, inter ON -NH2 mediate (VIII) or (IX) is mixed with a substantially equimolar proportion of amine, RR''NH, in anhydrous (VI) 20 benzene and the resulting mixture heated at 100° C. at g nEI2n OH autonomous pressure to obtain the benzimidazole product N as the hydrochloride or hydroiodide salt which may be / E recovered as residue by vaporizing off the solvent. The residue is warmed with dilute hydrochloric acid and D-en-o-Kx filtered to remove unreacted starting amine as hydro ON- N/ W 25 chloride and the filtrate made alkaline with concentrated (VII) alkali to precipitate the desired benzimidazole product (2) Intermediate (VII) is reacted with thionyl chloride (V). The latter may be purified by conventional pro to produce an N-chloroalkyl-substituted benzimidazole cedures. 30 The mineral acid salts of the benzimidazole compounds (VIII). may be prepared by reacting an appropriate compound with Substantially equimolar proportions or small excess of an appropriate mineral acid. Water is a suitable reac tion medium. In the preparation of a hydrochloride salt, (VII) -- SOCl --> N/ -CH-O- ( mory x 35 the procedure of passing dry hydrogen chloride gas ON W through a dry ether solution of the benzimidazole as pre viously described is considered preferable. (VIII) The benzimidazole compounds which are esters, i.e., (3) Intermediate (VIII) may be reacted with potassium compounds wherein Y in Formula (I) is -COOR, may 40 be prepared by reacting the acid chloride derived from iodide to produce an iodoalkyl-substituted benzimida the appropriate carboxy substituted benzimidazole (i.e., zole (IX). compounds wherein Y in Formula is -COOH and pre G.H.I pared as above described) with the appropriate alcohol, N ROH, or its sodium salt, RONa. The exact amounts of / E. the reactants are not critical, some product being obtained (VIII) -- KI - c-CH-0-{ X in any case; usually, it is convenient to employ free al ON-- ? W cohol and in an excess, the excess alcohol functioning N as a solvent or reaction medium. The reaction may be (IX) carried out at from room temperature to the boiling (4) Intermediate (VIII) or (IX) is reacted with dialkyl 50 point of the alcohol or auxiliary inert solvent, if present, for a period of from several minutes to several hours. amine to produce the desired N-substituted benzimida Conveniently, the acid chloride is prepared as the first Zole (V).