DE3306196C2 - - Google Patents

Description

The present invention relates to new methods of manufacture of imidazolyl-benzaldehydes of the formula I.

wherein R¹ is hydrogen or a C₁-C₄ lower alkyl group.

Imidazolylbenzaldehydes of the formula I are valuable intermediates, among other things for the production pharmacologically effective substances.

L. M. Sitkina and A. M. Simonov [Khim. Heterotics Soedin. Akad. Nauk Latv. SSR 1966 (1), 143-5; C.A. 65 (1966), 13686e] describe the preparation of 4 (1-imidazolyl) benzaldehyde (R1 = H) by the Ullmann method by 30 hours Heating imidazole and 4-bromobenzaldehyde with potassium carbonate and catalytic amounts of copper (1) bromide in nitrobenzene to 200 ° C with a yield of 30%.

This method is also described in DE-OS 29 23 815, example 1, Method H, one being based on bromobenzaldehyde related yield of 40% is given. The of J. B. Polya (J. Chem. Soc. C. 1970, 85-91) for the preparation of 4- (1-imidazolyl) acetophenone from imidazole and 4-bromoacetophenone successfully used variant (48 hours Heat the two components in pyridine with potassium carbonate and catalytic amounts of copper (2) oxide, yield 82%)  delivers on transfer to imidazole and 4-bromobenzaldehyde only an unsatisfactory yield of approx. 10%. It is also known from the literature (M. R. Grimmett, Advances in Heterocyclic Chemistry, Vol. 27, 318 ff, Academic Press Inc., New York and London, 1980) that 2-methylimidazoles on the Methyl group are very reactive and - especially under basic Conditions - easy condensation reactions with Enter carbonyl compounds.

It has now surprisingly been found that the production of Imidazolylbenzaldehydes of the formula I are possible by 2 processes is, which are clearly superior to the previously known or 2-alkylimidazolylbenzaldehydes of formula I with R¹ = Make alkyl accessible for the first time at a reasonable cost.

In the first process, imidazole compounds of the formula II

wherein R¹ has the meaning given in formula I, with a Fluorobenzaldehyde of the formula III

in an aprotic solvent from the group Dimethyl sulfoxide, dimethylformamide and sulfolane in the presence an auxiliary base from the group of potassium carbonate, sodium carbonate, Magnesium oxide and calcium carbonate, at temperatures between 60 ° and 140 ° C, preferably at 100 ° -120 ° C, if necessary Protective gas atmosphere such as nitrogen, argon, carbon dioxide, implemented during 2-8 hours.

From molar amounts of imidazole, 4-fluorobenzaldehyde and potassium carbonate 4- (1-imidazolyl) benzaldehyde (formula I, R¹ = H) in yields of 75-85%, and 4- (2-methyl 1-imidazolyl) benzaldehyde in yields of 40-50%.  

In the second process, trimethylsilylimidazoles of the formula IV

wherein R¹ has the meaning given in formula I, with a Fluorobenzaldehyde of the formula III at temperatures of 100 ° - 180 ° C, preferably at 140 ° -180 ° C, optionally in one Autoclaves, implemented. From molar amounts of 2-methyl-1-trimethylsilylimidazole (formula IV, R¹ = CH₃) and 4-fluorobenzaldehyde are obtained after this procedure by heating in an atmosphere for 3-6 hours to 140 ° -180 ° C 4- (2-methyl-1-imidazolyl) benzaldehyde (Formula I, R¹ = CH₃) in yields of 45-55%.

The new processes are advantageous in several ways. The yields compared to the known processes are from 30-40% increased to 75-85% (for Formula I, R1 = H). The expensive 4-bromobenzaldehyde is replaced by the significantly cheaper one 4-fluorobenzaldehyde replaced. The high energy costs of the known methods with 18-48 hours Heating to 200 ° C are significantly reduced by Heating for 2-8 hours at 100 ° -120 ° C in method 1. Das Toxic nitrobenzene becomes physiologically essential through that harmless dimethyl sulfoxide replaced (method 1). Method 2 can be carried out without a solvent. 2-alkylimidazolylbenzaldehydes are by either method producible for the first time with reasonable effort.

The methods of the invention are illustrated by the following Examples explained. The melting points given were measured with a Büchi 510 melting point determination apparatus and are given in ° C as well as those given in ° C Boiling points not corrected. The IR spectra were recorded using the Perkin-Elmer 257 or Nicolet NIC 3600 and the mass spectra with the Varian device MAT-311-A (70eV) added.  

Example 1 4- (1-imidazolyl) benzaldehyde according to method 1

A mixture of 13.6 g imidazole, 24.8 g 4-fluorobenzaldehyde, 30.4 g potassium carbonate and 200 ml dimethyl sulfoxide is stirred for 8 hours at 100 ° -110 ° C in a nitrogen atmosphere. After cooling to 50 ° C, the reaction mixture is stirred into 500 ml of water. The solid which has precipitated out is filtered off with suction, washed with water and then recrystallized from 90% ethanol.
Yield: 26.6 g (77% of theory)
150 ° -151 ° C.

Example 2 4- (2-methyl-1-imidazolyl) benzaldehyde according to method 1

A mixture of 186 g of 4-fluorobenzaldehyde, 123 g of 2-methylimidazole, 228 g of potassium carbonate and 2 l of dimethyl sulfoxide is stirred at 100 ° C. in a nitrogen atmosphere for 6 hours. After cooling, the mixture is stirred into 4 l of water and brought to pH 2 by adding hydrochloric acid. The mixture is then extracted with chloroform and the water phase is adjusted to pH 9 by adding 20% sodium hydroxide solution. The water phase is extracted with chloroform, the chloroform phase is dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel / chloroform). 74 g of fluorobenzaldehyde (40%) are recovered from the chloroform extract of the acidic water phase by distillation.
Yield: 114 g (41% of theory).
Mp 107 ° -108 ° C.
IR (in KBr): 1695 cm -1.
MS [m / e]: 186 (M⁺, 100%), 157 (16%), 144 (20%), 130 (20%), 116 (14%).

Example 3 4- (2-methyl-1-imidazolyl) benzaldehyde according to method 2

77 g of 2-methyl-1-trimethylsilylimidazole (prepared by heating molar amounts of 2-methylimidazole, chlorotrimethylsilane and triethylamine in toluene, yield 84% of theory. Bp. 127 ° -131 ° C., 46.55 hPa) are obtained in 20 62 g of 4-fluorobenzaldehyde were added dropwise at 40 ° -60 ° C. with a gentle introduction of nitrogen. The mixture is then stirred at the reflux temperature for 6 hours, during which the temperature drops from 180 ° to 130 ° C. After cooling to 70 ° C., the reaction mixture is poured onto 300 g of ice. After acidification with 18% hydrochloric acid, the mixture is extracted with chloroform, the water phase is neutralized by adding 20% sodium hydroxide solution, the precipitated solid is filtered off with suction, washed with water and recrystallized from dilute alcohol and then dried.
Yield: 48 g (52% of theory).
106-108 ° C.

The following are prepared according to the processes described in Examples 1-3:
4- (2-ethyl-imidazolyl) benzaldehyde,
4- (2-propyl-imidazolyl) benzaldehyde,
4- (2-butylimidazolyl) benzaldehyde.

Claims (5)

1. Process for the preparation of imidazolylbenzaldehydes of the general formula I. wherein R¹ is hydrogen or a C₁-C₄ lower alkyl radical, characterized in that an imidazole compounds of formula II wherein R¹ has the meaning given in formula I, with a fluorobenzaldehyde of the formula III in an aprotic solvent from the group of dimethyl sulfoxide, dimethylformamide and sulfolane in the presence of a base from the group of potassium carbonate, sodium carbonate, magnesium oxide and calcium carbonate, at a temperature between 60 ° and 140 ° C. 2. The method according to claim 1, characterized characterized in that the reaction at a temperature between 100 ° and 120 ° C is carried out. 3. A process for the preparation of imidazolaldehydes according to claim 1, characterized in that a trimethylsilylimidazole of the formula IV wherein R¹ has the meaning given in formula I, with a fluorobenzaldehyde of the formula III at a temperature of 100 ° to 180 ° C. 4. The method according to claim 3, characterized characterized in that the reaction at a temperature in the range of 140 ° to 180 ° C. 5. The method according to claims 3 and 4, characterized characterized in that the reaction in an autoclave carries out.