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United States Patent (19) 11) 4,450,277 Graf Et Al

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United States Patent (19) 11) 4,450,277 Graf Et Al United States Patent (19) 11) 4,450,277 Graf et al. 45 May 22, 1984 54 PREPARATION OF1-SUBSTITUTED 56 References Cited MIDAZOLES U.S. PATENT DOCUMENTS T5) Inventors: Fritz Graf, Speyer; Leopold Hupfer, 3,037,028 5/1962 Green .................................. 54.8/335 Friedelsheim, both of Fed. Rep. of Germany OTHER PUBLICATIONS Preliminary Brochure of BASF AG on 1- and 2-Me 73) Assignee: BASF Aktiengesellschaft, Fed. Rep. thylimidazole and 1,2-Dimethylimidazole Dated of Germany 9/1967. Lions, F., et al., J. Proc. Royal Soc. N.S.W., 74 (1941), 21 Appl. No.: 190,901 pp. 365-372. (22 Filed: Sep. 25, 1980 Primary Examiner-Richard A. Schwartz Attorney, Agent, or Firm-Keil & Witherspoon (30) Foreign Application Priority Data 57 ABSTRACT Oct. 8, 1979 IDE Fed. Rep. of Germany ....... 2940709 A process for the preparation of 1-substituted imidaz 51) Int. Cl. .................. C07D 233/58; C07D 233/60; oles by reacting an a-dicarbonyl compound with am CO7D 233/61 monia, an aldehyde and a primary amine in an aqueous 52 U.S. C. .................................... 548/346; 548/335; medium, in a single stage, at 20-150° C. 548/341; 548/342 58 Field of Search ................ 548/335, 346, 341, 342 3 Claims, No Drawings 4,450,277 ; 2 1 hyde, acetaldehyde, propionaldehyde, isobutyralde PREPARATION OF1-SUBSTITUTED hyde and benzaldehyde. MDAZOLES Examples of primary amines to be used as starting . components are monoamines of the formula X-NH2, The present invention relates to a novel process for 5 of the aliphatic, cycloaliphatic or aromatic series. Suit the preparation of 1-substituted imidazoles. able aliphatic radicals are straight-chain or branched 1-substituted imidazoles, such as N-alkylimidazoles, saturated or unsaturated hydrocarbon radicals of 1 to 20 can be prepared by catalytic alkylation of an imidazole carbon atoms, which may, for example, be substituted with an alkanol at an elevated temperature and under by HO-, (CH3)NH-, (CH3)2N-, H5C2NH-, superatmospheric pressure, or by reaction of an imidaz 10 H5C2O-, H3CO- or ether groups. Examples of cyclo ole with an alkyl chloride. These processes require the aliphatic radicals are cyclohexyl and norbornyl. Exam N-unsubstituted imidazole as an intermediate. ples of aromatic radicals are phenyl which may be sub stituted by H3CO-, (CH3)2N-, HsC2NH- or It is an object of the present invention to provide a H3COOC-. groups. Specific examples of suitable process which permits the direct preparation of N-sub 15 amines of the stated type are methylamine, ethylamine, stituted imidazoles in a single reaction stage. propylamine, octylamine, dodecylamine, aniline, me-. It is true that attempts have already been made to thoxyethylamine, ethoxyethylamine, dimethylamino prepare 1-substituted imidazoles from the starting mate propylamine, 3-amino-3-methyl-but-1-yne, 2-hydrox rials for the synthesis of imidazole, such as diacetyl, yethyl 2-aminoethyl ether, 3-aminopropanol, 3,3-dime ammonia, an aldehyde and an alkylamine, the Schiff thoxy-2-propylamine, 3-methylamino-1-propylamine, base first being formed from diacetyl and the amine and 20 methyl anthranilate and cyclohexylamine. Ammonia is then being reacted with the reaction product of the advantageously used in aqueous solution. aldehyde and ammonia. However, in this process, de The stated four starting materials are advantageously scribed in J. Proc. Royal Soc. N.S.W. 74 (1941), employed in the stoichiometric ratio, i.e. in a molar ratio 365-372, only low yields of the 1-substituted imidazoles 25. of 1:1:1:1. Deviations from these molar ratios are possi are obtained. ble but offer no advantage. We have found that the object stated above is The reaction is carried out in an aqueous medium at achieved and that 1-substituted imidazoles may be pre from 20' to 150° C., preferably from 70 to 120° C. In pared more advantageously, by a process wherein an some cases it is advantageous to add, as a solubilizing a-dicarbonyl compound, ammonia, an aldehyde and a 30: agent, a solvent which does not react with the starting primary amine are reacted in an aqueous medium, in a materials under the reaction conditions, such as a water single stage, at from 20' to 150 C. miscible alcohol. Specific examples of suitable solubiliz Using the novel process, it is possible to prepare 1 ing agents are ethanol, methanol and propanol. substituted imidazoles which may also be substituted in After the reaction, which as a rule is complete in positions 2, 4 and 5. Such compounds for example have 35 about 30 minutes, the reaction mixture is worked up, for the formula example by distillation or extraction, in order to isolate the imidazoles. Using the novel process, the 1-substituted imidazoles can be prepared smoothly and in good yield. Surpris ingly, only small amounts of the 1-unsubstituted imidaz oles are formed at the same time. The products are valuable intermediates, for example for the preparation of drugs or crop protection agents. - where R, R2 and R3 are hydrogens or aliphatic or 45° EXAMPLE 1. aromatic radicals and X is an aliphatic, cycloaliphatic or Preparation of 1-methylimidazole aromatic radical. - . Examples of suitable starting materials are a-dicarbo, A mixture of 145 parts of 40% strength aqueous gly nyl compounds of the formula Rl-CO-CO-R2, oxal solution and 75 parts of 40% strength aqueous where Rand R2 have the above meanings. Examples of so formaldehyde solution, and a mixture of 382.5 parts of aliphatic radicals are unsubstituted and substituted 4.4% strength aqueous ammonia and 77.5 parts of 40% straight-chain and branched alkyl, of 1 to 5 carbon strength aqueous methylamine solution are themselves atoms. Examples of aromatic radicals are unsubstituted mixed for 30 minutes in a stirred flask at 70 C. After and substituted phenyl or naphthyl. Examples of substit completion of the addition, stirring is continued for 30 uents of the aliphatic and aromatic radicals are HO-, 55 minutes at 70° C. The reaction mixture is then worked H3COOC- and H3CO-groups. Specific examples of up by distillation. 67.8 parts of 98.5% pure N suitable a-dicarbonyl compounds are glyoxal, diacetyl, methylimidazole (boiling point 63-65 C/3 mm Hg) benzil and methylglyoxal. are obtained, corresponding to a yield of 81.4%. Examples of suitable aldehydes are compounds of the EXAMPLE 2 formula R3-CHO, where R3has the above meanings. 60 Examples of aliphatic radicals in the aldehydes are Preparation of 1-phenylimidazole: straight-chain and branched alkyl, for example of 1 to 8 A mixture of 93.1 parts of aniline and 68 parts of 25% carbon atoms, which may be substituted by, for exam strength aqueous ammonia in 100 parts of propanol, and ple, phenyl or HO-, H3COOC- or H3CO-groups. a mixture of 145 parts of 40% strength aqueous glyoxal Examples of aromatic radicals which may be present in 65 solution and 75 parts of 40% strength aqueous formal the aldehydes are phenyl which is unsubstituted or dehyde solution are simultaneously stirred into 200 substituted by alkyl or by HO- or H3COOC-groups. parts of propanol in the course of 30 minutes, at 80 C. Specific examples of suitable aldehydes are formalde The mixture is then kept at 80 C. for a further 30 min 4,450,277 3 4. utes. Thereafter the solvent is stripped off under re 25% strength aqueous ammonia, are simultaneously duced pressure and the residue is subjected to fractional added dropwise, over 30 minutes, to 300 parts of propa distillation. 100.9 parts of N-phenylimidazole (boiling nol, at 50' C. After a further 30 minutes at 50 C., the point 128' C/2 mmHg) are obtained, corresponding to mixture is worked up by distillation. 52 g of 1,2,4,5-tet a yield of 70.0%. ramethylimidazole (boiling point 110/1.5 mm Hg), corresponding to 45.4% of theory, are obtained. EXAMPLE 3 Preparation of 1-octylimidazole EXAMPLE 8 64.6 parts of n-octylamine and 34 parts of 25% Preparation of strength aqueous ammonia are dissolved in 186 parts o f 10 1-(3,3-dimethyl-prop-1-yn-1-yl)-imidazole propanol and are introduced dropwise over 30 minutes, A mixture of 83 parts of 3-amino-3-methyl-but-1-yne simultaneously with a mixture of 72.5 parts of 40% and 170 parts of 10% strength aqueous ammonia, and a strength aqueous glyoxal solution and 37.5 parts of 40% mixture of 145 parts of 40% strength aqueous glyoxal strength aqueous formaldehyde solution, into a stirred solution and 75 parts of 40% strength aqueous formal flask. The temperature is kept at 65" C. After all has 1. 5 dehyde solution, are simultaneously added dropwise, been introduced, stirring is continued for 20 minutes at over 20 minutes, to 100 parts of water, whilst stirring, at 65 C., and the mixture is then worked up by distillation. 50 C. After all has been added, the mixture is stirred for 64.2 parts of 1-octylimidazole (boiling point 110' C/1 a further 30 minutes at 50 C. and is then worked up by mm Hg) are obtained, corresponding to a yield of distillation. 77.2 g of 1-(3,3-dimethyl-prop-1-yn-1-yl)- 71.3% of theory. 20 imidazole (boiling point 118/15 mm Hg), correspond EXAMPLE 4 ing to a yield of 66.0% of theory, are obtained. Preparation of 1-methylimidazole EXAMPLE 9 A mixture of 145 parts of 40% strength aqueous gly- 25 Preparation of 1-(2'-hydroxyethoxy-1'-ethyl)-imidazole oxal solution and 75 parts of 40% strength aqueous A mixture of 105 parts of 2-hydroxyethyl 2-amino formaldehyde solution, and a mixture of 77.5 parts of ethyl ether and 170 parts of 10% strength aqueous am 40% strength aqueous methylamine solution and 382.5 monia, and a mixture of 145 parts of 40% strength aque parts of 4.4% strength aqueous ammonia are introduced ous glyoxal solution and 75 parts of 40% strength aque simultaneously, over 30 minutes, into 100 parts of water 30 ous formaldehyde solution are stirred simultaneously in an autoclave at 110 C.
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