MXPA00012504A - Procedure for producing formyl imidazoles - Google Patents

Abstract

A new procedure for the catalytic conversion of hydroxy methyl imidazoles to formyl imidazoles is described. The catalysis takes place in the presence of a peroxide. Formyl imidazoles are important intermediate products for pharmaceutical substances.

Description

PROCEDURE FOR THE DEVELOPMENT OF FORMI IMIDAZOLES DESCRIPTIVE MEMORY This invention relates to a new process for the preparation of formylimidazoles of the general formula wherein R1 represents an alkyl group, by catalytic oxidation of hydroxymethylimidazoles of the general formula in an alkaline medium, in which R1 has the aforementioned meaning. Formylimidazoles are important intermediates, for example, for the production of pharmaceutical substances such as diuretics or antihypertensives (WO-A 92/20651). Previous processes have been known for the preparation of formylimidazoles. In CH-A 685496, a process is described in which the catalytic oxidation of hydroxymethylimidazoles or formylimidazoles is carried out in the presence of noble metal catalysts such as platinum / bismuth, platinum black, platinum or palladium on activated carbon, with insufflation of oxygen. Therefore, the task of the invention was to achieve the availability of an economical and improved process for the preparation of formylimidazoles. In this invention, this task was solved by means of the method defined in claim 1. In claim 1, the hydroxymethylimidazoles of the general formula wherein R 1 signifies the aforementioned, are catalytically oxidized in an alkaline medium in the presence of a noble metal catalyst and a peroxide for formylimidazoles of the general formula where R1 has the meaning mentioned above. R1 represents a hydrogen or an alkyl group, or more particularly a straight or branched chain alkyl group with 1 to 6 atoms C. Specifically, this may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and its isomers as well as hexyl and its isomers. The preferred meaning of R1 is butyl. The hydroxymethylimidazoles can be easily processed as starting compounds as specified, for example, in WO-A 92/20651 or as in E.F. Godefroi e tal., Trav. Chim Recueil Pays Bas, 91 .. 1383 (1972). Platinum, palladium, rhodium, or gold can be used as a noble metal catalyst. The noble metal is best used in combination with metals such as, for example, bismuth, lead, cerium or indium as the second component. The preferred catalysts are platinum / bismuth or platinum / lead. The noble metal catalyst is used by itself or is attached to a vehicle such as, for example, activated carbon, silicon dioxide, jai.M.MÍMli, i, l, i, l, M - ^ - Í-MÍIÍ-ÍÉ ------------ Ml ^^ rt T n aluminum, silicon-aluminum oxide, oxide of zirconium or titanium oxide. It binds preferably to activated carbon. The noble metal catalysts bound to activated carbon can be obtained commercially, for example, from Degussa. The appropriate percentage of the noble metal bound to a vehicle is between 0.1 to 15% by weight, and preferably between 0.5 and 7% by weight, in relation to the carrier material. Preferably, the noble metal catalyst is used in an amount of 0.05 to 1.0 mole% of noble metal base relative to 10-hydroxymethylimidazole, and an amount of 0.1 to 0.4 mole of noble metal base in particular is especially preferred. with hydroxymethylimidazole. Organic or inorganic peroxides are used as peroxides. For example, hydrogen peroxide, perborates, a percarboxylic acid, tert-butyl hydroperoperoxide, cumol hydroxyperoxide, perbenzoic acid, m-chloroperbenzoic acid, monoperphthalic acid or peracetic acid are suitable. Particularly suitable is hydrogen peroxide used in an aqueous solution in 10% to 30%. In addition to the catalytic oxidation, the hydrolysis of the methyl ester of hydroxymethylimidazoles of the general formula II takes place in an alkaline medium. The alkaline medium is best obtained by the addition of an alkali metal hydroxide, an alkali metal carbonate or an alkali metal acetate to the reaction mixture. The alkali metal hydroxide is ~~ - ^ ^ "....,. ... ^^ ufa. ^, ^. .. -rfÍ-fc-JtotAa "- '"' ** "» '• "• - - • •" &"; - &" - "M used preferably in a ratio of 1: 0.05 to 5 and still better in a ratio of 1: 3, relative to the molar amount used of the hydroxymethylimidazole of the general formula II. The catalytic oxidation takes place in better form in an alkaline medium in the presence of water, a solvent miscible in water or mixtures thereof. Particularly suitable miscible solvents in water are, for example, alcohols or carboxylic acids with 1 to 6 C atoms or ketones such as, for example, acetone or methyl ethyl ketone. Preferably mixtures of water and water miscible solvents are used. Catalytic oxidation is best carried out at a temperature of 20 ° to 120 ° C, preferably 50 ° to 100 ° C. After the standard peroxide dosing time of 0.5 to 3 hours, the compound of the general formula I can be isolated in the standard form after a sufficient secondary duration time. The product is isolated by crystallization and adequate filtration. The catalyst used can be reused several times without loss of activity. ** - ** -'- • * - • - *** - - • •• áM ^ ÉÍIF? IlMtÉ ^ M EXAMPLES EXAMPLE 1 Production of 4-r (2-butyl-5-formyl-1 H-imidazo-1-yl) methanolbenzoic acid 900 mg (3 mmol) of 4 - [(2-butyl-5-hydroxymethyl-1 H-imidazo-1-yl) methyl] benzoic acid methyl ester, 8 ml of caustic soda solution (1 M), 0.5 ml of methanol and 107 mg of 5% platinum and 5% bismuth on activated carbon containing 60% water are placed in a 25 ml flask at room temperature and heated to 60 ° C. 0.8 g (4.6 mmol) 20% of an aqueous H 2 O 2 solution was added to this suspension at 60 ° C for 30 minutes and the mixture was then reacted with HPLC. Another 0.2 g (1.1 mmol) aqueous solution to 20% H2O2 were then added for 10 minutes. Then 0.2 g (5 mmoles) of 20% NaOH was added. The reaction solution was heated for 2 hours at 100 ° C. The mixture was cooled to room temperature.

The catalyst was filtered over celite and washed with 5 ml of water. After acidification of pH 5.0 with HCl (15%), the product was precipitated. It cooled to 2 ° C, it was filtered, washed with 2 x 5 ml of water and dried at room temperature at 15 mbar. 410 mg (48%) of yellow 4 - [(2-butyl-5-formyl-1 H-imidazo-1-yl) methyl] benzoic acid (96% content by HPLC) was obtained. Melting point: 144-146 ° C.

^ Mu M mi 1H NMR (DMSO-d6, 400 MHz) d 12.9 (1H, s), 9.65 (1H, s), 7.94 (1H, s), 7.90 (2H, d), 7.11 (2H, d) , 565 (2H, s), 2.63 (2H, t), 1.54 (2H, pent), 1.36 (2H, hex), 0.79 (3H, t). í ^^^^^^^ - --- ^ a ^ l? ^^ - ^ - ^^^^^^^^ l ^^^^ í?

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of formylimidazoles of the general formula wherein R1 represents an alkyl group, by the catalytic oxidation of hydroxymethyldimidazoles of the general formula 3 in which R1 has the above-mentioned meaning, in the presence of a noble metal catalyst, characterized in that the catalytic oxidation takes place in the presence of a peroxide in an alkaline medium. g »- *! ^ £ ^ g

2. The process according to claim 1, further characterized in that R1 is a butyl group.

3. The process according to any of claims 1 or 2, further characterized in that the noble metal catalyst is a platinum / bismuth catalyst or a platinum / lead catalyst.

4. The process according to any of claims 1 to 3, further characterized in that the peroxide is hydrogen peroxide.

5. The process according to any of claims 1 to 4, further characterized in that the alkaline medium was obtained by the addition of an alkali metal hydroxide, an alkali metal carbonate or an alkali metal acetate to the reaction mixture .

6. The process according to any of claims 1 to 5, further characterized in that the catalytic oxidation was carried out in the presence of water, a solvent miscible with water, or a mixture thereof, in an alkaline medium.

7. The process according to any of claims 1 to 6, further characterized in that the reaction was carried out at a temperature of 20 ° to 120 ° C.