CS262059B1 - Process for preparing imidazole and 4 (S) -methylimidazole - Google Patents

Abstract

The solution concerns a method for preparing imidazole and 4(5)-methylimidazole by reacting chlorine with ethanol or n-propanol, treating the resulting mixture of chlorination products with formamide and cyclizing to the final product. The prepared substances serve as raw materials for the synthesis of compounds with physiological activity.

Description

The present invention relates to a process for the preparation of imidazole and its 4 (S) -methyldilvate of formula I (I) wherein R is hydrogen or methyl.

Imidazole is also known by the trivial name glyoxalin and is prepared by treating ammonia with glyoxal, which is obtainable by oxidizing ethanol with nitric acid at a temperature of about 20 ^° C. This method is associated with the first preparation of glyoxaline (Debus H .: Ann. 102, 20, 1857; Ann. 107,199,1858).

Another method utilizes the condensation of ammonia with formaldehyde and glyoxal (Radziewski B .: Ber. 13, 645, 1882). These condensation methods have remained the basis of imidazole production to this day.

4 (S) -methylimidazole, also called methylglyoxaline, was prepared by heating the aminoacetone with potassium rhodanide in an acidic medium and subsequent oxidative degradation of the thiol group by heating with dilution. nitric acid [Gabriel S .: Ber. 26, 2197, 1893 j. However, since the beginning of the century (Windaus A .: Ber. 38, 1161, 1905) to date (Jeo I: Chem. Rumors 17, 865, 1963) it has been prepared by reacting glucose or other sugar with ammonia in alkaline in an aqueous environment, in a number of treatments optimizing pressure, temperature, metal ion effect, and method of product isolation. Also in these methods, the presence of formaldehyde is an advantage, which increases the yield of the product (Jezo I .: Chem. Rum. 17, 865, 1963).

Synthetic processes for the preparation of methylglyoxaline are based on acetone, from which chlorination yields chloroacetone further reacted in an alcoholic medium with potassium acetate to acetol. It further forms, with an ammoniacal cupric chloride solution, methylglyoxal condensing with ammonia and formaldehyde to methylglyoxaline (Madelung W .: Ber. 63, 940, 1932) in a yield not exceeding 40% (Weidenhagen R .: Ber. 68, 1961, 1935).

Another route of methylglyoxaline synthesis utilizes the ability of formamidine to form this product directly by reaction with chloroacetone (Grimmet M. R., Advances in Heterocyclic Chemistry, 12, 120, 1970). A certain drawback is the more complicated way of preparing formamidine, which binds the released hydrogen chloride and therefore has to be used in an amount of 2 moles per mole of chloroacetone. ’

It has now been found that both imidazole and 4 (S) -methylimidazole can be prepared by reacting ethanol or n-propanol (II) with chlorine and then reacting a mixture of chlorination products (III) with formamide followed by heating so as to form by cyclization to formic acid cleavage product as shown in equations 1 to 3.

R-CH 2 CH 2 OH (clay)

R-CH-CH-OY II Cl X r-CH-CH-OY Cl X _(I ')

R-O CH-NH-CHO 1 H-CHO (V (Z) (III)) - OCH-NH-CHO

-hcoqh _> r- _|

C3)

NH-CHO

In the equations, R is hydrogen or methyl, X is chlorine or hydroxyl, and Y is hydrogen or CH 2 CH 2 R.

The mixture of chlorination products (III) provides a condensation product with excess formamide. The liberated alcohol is distilled off and the residue is heated at 160-200 ° C for 2 to 8 hours.

The advantage of this preparation method is that it is possible to start from commercially available alcohols, the synthesis is easy to carry out and shows good yields without the need to isolate individual intermediates.

Both imidazole and 4 (S) -methylimidazole are substances that serve as a raw material for the synthesis of other valuable compounds, many of which have physiological activity, particularly of the antihistaminic type.

Example 1

To 75 ml of ethanol in a 250 ml reaction flask was fed a nitrogen-fed tube with 71 g of chlorine pre-metered in a weighed condenser. The reaction flask was placed in a cooling bath and the chlorine feed rate was controlled by evaporation rate by cooling the condenser so that the temperature in the reaction flask did not exceed 50 ° C. After the necessary chlorine was introduced, nitrogen was fed for an additional hour. The chlorination solution was added dropwise to 240 mL formamide in a stirred 1000 mL reaction flask and heated in a 150 ° C bath. Fraction 75-60 was distilled off

100 ° C containing ethanol and further heated to 170-180 ° C for 6 hours. After cooling, 70 g of potassium carbonate in a saturated aqueous solution was added, filtered and evaporated to dryness in a vacuum rotary evaporator from a water bath, extracted with anhydrous acetone, the product precipitated with acetic acid oxalic acid, filtered by imidazole oxalate and washed with acetone. potassium carbonate. This solution was extracted with ether, the extract dried with potassium carbonate and the ether distilled off. Imidazole was obtained as an oil with a boiling point of 263 ^DEG C. and a weight of 13.2 g (35.3%). Example 2

To 90 ml of n-propanol in a 250 ml reaction flask was added nitrogen to the bottom, to which 71 g of chlorine was gradually added so that the temperature of the reaction mixture did not exceed 50 ° C. After the necessary amount of chlorine was introduced, nitrogen was fed for an additional hour. The solution after chlorination was added dropwise to 200 ml of formamide in a stirred 1 OOOml reaction flask and heated at a bath temperature of 150 DEG C. were distilled ^Q fractions 85 to 100 ° C, containing n-propanol and further heated at 16-180 ° C for 8 hours . After cooling, 70 g of potassium carbonate in a saturated aqueous solution was added, filtered, evaporated from a water bath on a vacuum rotary evaporator, the residue extracted with anhydrous acetone, and the product in the form of oxalate was precipitated with acetic acid solution of oxalic acid. 35.3 g of 4 (S) -methylimidazole were obtained as the oxalate salt (41.0%) with a melting point of 205 ° C.

Claims (2)

SUBJECT A process for the preparation of imidazole and 4 (S) -methylimidazole of the general formula I (O wherein R is hydrogen or methyl), characterized in that ethanol or n-propanol is treated with chlorine, the resulting mixture of chlorination products is treated with formamide and then the mixture is cyclized to the final product by heating at 160 to 200 ° C for 2 to 8 hours. 2. The process of claim 1 wherein the molar ratio of formamide to chlorine used in the reaction is 1.5-6.