SU904295A1 - Process for producing 3-(amidazo(1,2,a)benzimidazolyl-3)acryl acids - Google Patents

Description

The invention relates to a new process for the preparation of new 3- (imidazo / 1, 2-a / benzimidazolyl-3) acrylic acids of the general formula

.sn snsoon

to

R (i;,

where R is lower alkyl;

R is methyl, phenyl or 4-bromophenyl,

intermediates in the synthesis of pharmacologically active compounds, for example histamine-like or hypoglycemic substances.

A known method for producing hetarylacryl acids by reacting hetaryls containing a methyl group with mobile hydrogen atoms, with ssorale and subsequent saponification of the intermediate haloalcohols l.

This method is not applicable to imidae / 1,2-a / benzimidazole derivatives, since chloral does not react with the methyl groups of 2-methyl- and 3-methyl-substituted imidazo / 1, 2-a / benzimidazoles.

Methods for the preparation of acrylic acids starting from aldehydes 2 are also known.

However, the use of 3-formylimidazo / 1, 2-a / benzimidazole as the starting product does not produce the desired product t3j.

The aim of the invention is a method of producing new 3- (imidazo / 1,2-a / benzimidazolyl-3) acrylic acids of general formula (1), which can be used in the synthesis of biologically active compounds with, for example, histamine-like or hypoglycemic properties.

Pr: the goal is achieved by ifeM, that the compounds of general formula (I I) or (III)

.If (g;

where r and

Claims (3)

have the indicated values. I subject to interaction with propiolovoy acid in the environment of polyphosphoric acid. The reaction can be carried out by heating the starting compounds in polyphosphoric acid at a temperature. 65-75 ° C. At a lower temperature, the reaction proceeds much slower, and an increase in temperature above 75 ° C leads to a decrease in the yield of acids of formula (1) due to undesirable side processes. The progress of the reaction is monitored with the help of those and its completion is judged by the disappearance of the spot of the original imidazo / 1,2P / benzimidazole on the chromatogram. The use of imines of formula (Ml J in the synthesis of compounds of formula (1) is possible due to their easy cyclization under the reaction conditions to imidazo / 1,2q / 6eH derivatives of imidazole of formula (P). The structure of the obtained compounds of formula (I) is confirmed by elemental analysis data IR and PMR spectra, their chemical properties. In the PMR spectra recorded in trifluoroacetic acid, the absorption of the methyl protons of the acrylic acid residue is manifested as two doublets in the regions 6,1-6,4 ppm and 7.6-7.85 ppm Acids obtained by this method of formula (I) have a trans configuration, as evidenced by the presence in their IR spectra, apart from the bands characteristic of the imidazo / 1.20 / benzimidazole core and carboxyl group, the absorption bands of out-of-plane and planar deformation vibrations of hydrogen atoms of the vinyl group in regions 965-970 and 1315 -1320 In addition, methyl 3- (9-methyl-2-phenylimidazo / 1/2-a / benzimidazolyl-3) acrylic acid, obtained from the corresponding acid of formula (1), is identical to the ester synthesized earlier by the Wittig reaction by the interaction 3 -formyl-9-methyl-2-phenylimidazo / 1,2 -0 / benzimidazole with resonance-stabilized carbalkoxymethylene triphenylphosphorane, and it is known that when using resonance-stabilized phosphoranes, the formation of trans-isomers of fl is usually observed. Example 1. . B A well stirred mixture of 2.47 g of (10) -methyl-2-phenyl. imidazo / 1,2-a / benzimidazal and 25 g of polyphosphoric acid, heated to, add 1.4 ml (20 mol) of propiolic acid and continue to be heated at this temperature until the reaction is complete, as judged by the disappearance of tn of the starting compound on TLC (eluent chloroform or benzene). The reaction time is 20 hours. Then the reaction mixture is poured into 100 ml of vigorously stirred cold water. The resulting suspension is neutralized with a 22% ammonia solution to a pH of 5-6. The crystalline yellow precipitate is filtered off, washed thoroughly with water and air dried. The dried precipitate (3.05 g) is repeatedly treated with benzene and 2.1 g (66.2% of theoretical) acid is obtained, which dissolves well in ammonia and alkali solutions. , in butanol and dioxane - when heated т. mp.187188 C (decomposition, from butanol). Found,%: C 71.7; H 5.0; N 13.3. units of GS1Calculated,%: C 71.9; H 4.8; N 13.2. Methyl ester of trans-3- (9-methyl-2-phenylimidazo / 1,2-c1 / benzimidazolyl-3) acrylic acid. To a suspension of 0.32 g (1 mol) of the above-described acid. 0.1 ml of thionyl chloride is added to 5 ml of absolute benzene and the mixture is boiled on a water bath for 40-50 minutes, and then 1.5- 2 ml of absolute methanol and heat for another 15-20 minutes. After this, the solvent is evaporated and the oily residue is treated with a dilute ammonia solution. The precipitate is filtered off, washed twice with water and dried in air. Purify the resulting ether first by chromatography on a column of A12.0z (eluent benzene), collecting the lemon-yellow fraction, and then by crystallization from alcohol. Lemon yellow needles with mp. 161-162s, easily soluble in most organic solvents. Yield 0.25 g (71.4%). IR spectrum (SNSC), 1180, 1260 (C-O-C), 1705 (C-0). Found,%: C 72.4; H 5.0; N 12.8. fyif7% 0i Calculated,%: C 72.5; H 5.2; N 12.7. The compound is identical to the ether obtained by the reaction of 9-methyl-2-phenyl-3-formylimidazo / 1, 2-a / benzimidazole with resonance stabilized carboxymethymethyltriphenylphosphorane. Example 2. 3- (2,9-Dimethylimidazo / 1, 2-o / benzimidazolyl-3) acrylic acid. A mixture of 1.85 g (10.; L "ol) 2,9-dimethylimidazo / 1, 2-a / benzimidazole, 1.4 ml (20: mol) of propiolic acid and 25 g of polyphosphoric acid is heated at 8-8 ° C for 15 hours. Then the reaction mixture is cooled to; 45-50 ° C and poured in a thin stream with vigorous stirring in 75 ml of cold water. The resulting solution is neutralized with a 22% at / zlc solution. to pH 5-6. The precipitated yellow precipitate is filtered off, washed thoroughly with water and air dried. The mother liquor solution is made alkaline with a solution of NdOH to pH 8, the precipitated crude precipitate is extracted with chloroform, and chloroform is evaporated, while 0.75 g of unmixed 1,2-o / benzimidazole is recovered. The isolated yellow precipitate (1.45 g, 96% of the imidazo / 1,2-a / benzimidazole reacted) is poorly soluble in alcohols, dioxane, acetone, chloroform, water, well soluble. When heated in dilute acetic acid, in icy acetic acid and ammonia solution dissolve in the cold. For purification, the precipitate is sequentially treated with acetone, chloroform, and benzene ether, and then crystallized from a large amount of butanol, from which the acid precipitates as a fine-crystalline bright yellow precipitate. The yield of pure acid is 1.15 g (76 calculated on the reaction of 2,9-dimethylimidazo / 1, 2chz1 / benzimidazole, mp = 212 ° C (decomposition). IR spectrum (vaz.maslo), 1675 (), 2200-2800 (OH), Found,%: C 65.8; And 5.4; N 16.5, 0., 0;. Calculated,%: C 65.9; And 5.1; N 16, Example 3. (.4-Bromophenyl) -9-methylimidazo / 1,2-O / benzimidazolyl-3-acrylic acid. A mixture of 1.63 g (5-mole) 2- (4-bromo-phenyl) -9-methyl-imidazo / 1, 2-a / benzim azole, 0.7 ml (10 mol) propiol acid and 15 g of polyphosphoric acid are heated for 15 hours and then the mixture is poured into 50 ml of water, neutralized with ammonia solution. The precipitate is filtered off, washed with dry and air. The dry residue (1.98 g) is repeatedly treated with boiling acetone and then washed with benzene and chloroform. 1.44 g (72.7%) of the acid is obtained, which does not dissolve in water and most organic solvents, insoluble in ammonia, but soluble in alkali solutions. Light yellow crystals with mp 203-204 ° C (decomposition). IR spectrum (vaz.oil), cm: 1685 (), 2400-3300 (OH ), Found,%: C 57.5; H 3.3; Br 20.0; N 10.7. . Calculated,%: C 57.6; H 3.5; 1 Vg 20.2; N 10.6. Example 4. 3- (2-Phenyl-9-ethylimidazo (1,2,2 h) / benzimidazolyl-3) acrylic acid. A mixture of 1.4 g (5 mol) of 2-imino-1-ethyl-3-phenacylbenzimidazoline and 15 g of polyphosphoric acid is heated up to 15 to 20 minutes at this temperature, then the temperature is lowered to 65-70 s, 0 , 7 ml (10 mol) of propionic acid and continue | heating at this temperature until complete reaction (control - TLC). The isolation of the acid is carried out as described in Example 1. A yield of 70%. Light yellow crystals with m.p.185186 ° C (decomposition). IR spectrum (vaz.maslo), cm: 1690 (), 2400-3400 (OH). / Found,%: C 72.3; H 5.0; N 12.9. Calculated,%: C 72.5; H 5.2; N 12., 7. Thus, the proposed method allows to obtain new 3- (imidazo / 1, 2-a / benzimidazolyl-3) acrylic acids of general formula 1, which can be used in the synthesis of biologically active substances. Claims 1. Method for preparing 3- (imidazo / 1,2-C1 / benzimidazolyl-3) acrylic acids of the general formula I, where R is lower alkyl; R is methyl, phenyl or 4-bromophenyl, characterized in that the compounds of the general formula 1 or HI. Po., N II R where R and R are as defined above, $ 7 a42958 subjected to interaction With propio-chwe 3- (i-m & tl-benzimipisop p) - left acid in the environment of polyphosphoric acrylic acids and their derivatives, acids with the release of the target product-Hem. Heterocycle. Soed.1970, 11, that p.1566. 2. The method according to claim 1, is different. 2. Bksher K., Pearson D. Organic and with the fact that the process is carried out 5 such syntheses. M., World, 1973, Part 2, at b5-75.s. s.260-262. Information sources, 3. Anisimova V.A., Avdyunina N.I., taken into account in the examinationSimonov A.M. et al. Synthesis and pharmaco1. Popov II, Simonov A.M., Co-logical activity of acetylene boat S.N. Studies on imidazo / 1,2-v / benzimidazoto compounds of benzimidazoA derivatives. Sin-la. Chem.Farm.ZH ,, 1978, 12, pp.40-45.