SU948290A3 - Process for producing 1-alkylimidazoles or their salts - Google Patents

Description

The invention relates to a process for the preparation of new 1-alkylimidazoles of the general formupy-. where a is lower alkyl containing 1 carbon atom; a cycloalkyl and cycloalkenyl residue containing 4 to 9 carbon atoms, unsubstituted or substituted by methyl, provided that when A is methyl, R must not be unsubstituted cyclohexyl or to their salts, which may be used in medicine. It is known that alkylation in position 1 easily proceeds under the action of ordinary alkylating agents such as alkyl halides {| 1. The purpose of the invention is the synthesis of new compounds that possess unified pharmacological properties. This goal is achieved according to the method of obtaining compounds of the general formula based on the known alkylation reaction and the fact that the imidazole or its salt is subjected to interaction with the chemical agent of the formula 2 - A - R, where A and R have the values mentioned above, and Z is chlorine or bromine in the presence of an alkali metal alcoholate, to release the desired product in free form or in the form of a salt. Example 1. 1-Cyclo-octylmethyl-imidazole. Cyclooctane methyl bromide (5.5 g, 0.027 mol) is added dropwise to a solution of imidazole that is boiling under reflux temperature (2.0 g, 0.03 mol) in sodium solution. (0.7 g, 0.03 mol) and absolute ethanol (50 ml). Thereafter, the resulting mixture is boiled for an additional 15 hours under reflux. The solid was filtered and the filtrate was concentrated in vacuo. The residue is placed in 2n. hydrochloric acid (100 ml) and. rot out with ether (25 ml). The aqueous layer is alkalinized, 10 n is added. an aqueous solution of sodium hydroxide is then extracted with chloroform (3 x 50 ml). The combined extracts are dried over anhydrous magnesium sulphate and chloroform is distilled off under vacuum. The resulting oily residue was purified on a column of silica gel 5, eluting with ethyl acetate / methanol (9: 1), and the resulting product was distilled under vacuum. The boiling point is 120-122 ° C (at O, 2 mm Hg). Example 2. Preparation of 1- (cyclopentylmethyl) imidazole. A solution of sodium ethylate is prepared, a solution of sodium (2.3 g, 0.1 mol) in absolute ethanol (100 ml). Imidaeo (6.8 g, 0.1 mol) is added after this. The mixture is then heated at reflux temperature, after which cyclopentylmethyl bromide (16.3 g, 0.1 mol) is added dropwise. The reaction mixture was then heated under reflux for 16 hours. The resulting mixture was allowed to cool. After that, the solid product is filtered off and the filtrate is evaporated under vacuum. The residue was taken up in 2N HC1 (150 ml) and washed with ether (50 ml). The resulting solution is alkalinized with excess Yun. NaOH, -the resulting product is extracted with chloroform (3x50 gl). The combined extracts were dried over anhydrous MgSO4, and then chloroform was distilled off under vacuum, resulting in a yellowish oil. The crude product is purified on a silica gel column, eluting with EtOAc / MeOH (9: 1). The fractions of the product obtained are combined and evaporated under vacuum, leaving 1.9 g of a slightly yellowish oil. It is distilled under vacuum. Boiling point: 68-b9s / 0.125 g-1m Hg. Output 0.95g. Example 3. Getting 1- (3-cyclopentylpropyl) imidazole. A solution of sodium ethylate is obtained by a solution of sodium (0.34 g, 0.0148 mol) in absolute ethanol (30 ml). Then 1.0 g of imidazole is added. The resulting mixture was heated to reflux, 3-cyclopentylpropyl bromide (2.94 g, 0.0153 mole) was added dropwise. The reaction mixture is then refluxed for an additional 20 hours after the addition of the cyclopentylpropyl bromide. The mixture was allowed to cool. The solid is filtered off and the filtrate is evaporated under vacuum. The residue is taken up in 2B.HCl (50 ml) and washed with ether (25 ml). The resulting solution was basified with an excess of 10 H.NaOH, the product was extracted with chloroform (ml), the combined extracts were dried over anhydrous MgSOj, chloroform was distilled off under vacuum, resulting in 2.1 g of a golden-yellow oil. The crude product is purified on a silica gel column, eluting with EtOAc (MeOH) (9: 1). The resulting product fractions were combined and evaporated in vacuo to give 1.25 g of a slightly yellowish oil. This oil is distilled under vacuum. The boiling point of the product is 69-90 ° C (0.1 mm Hg). Yield 0.78 g. Example 4. Preparation of 1- (cyclopentylmethyl) imidazole. Potassium tert-butoxide 3.1 g 0.0277 mol Imidaeol 1.90 g, 0.0279 mol Cyclopentylmethyl bromide 5.3 g, 0.02775 mol n Butanol 50 ml Dry nitrogen Cyclopentylmethyl bromide dropwise m-add-yat (5.3 g, 0.2775 mol) to a mixture of potassium tert-butoxide (3.1 g, 0.0277 mol) and imidazole (1.9 g, 0.0279 mol) in dry n-butanol, the temperature of the oil bath being 120 ° C. After adding (after about 20 minutes) the temperature of the reaction mixture is raised to boiling, and refluxing with continuous stirring is continued for 7 hours, after which checking with TLC shows that the reaction is complete. The insoluble product is filtered off and the butanol is distilled off under reduced pressure, resulting in a light yellow oil. The resulting oil is dissolved in 100 ml of 2N HC1, the acidic solution is washed with ether (100 ml). The acidic solution is made alkaline with Na.NaOH and the resulting oil is extracted with chloroform (3-50 ml). The chloroform extracts are combined and dried. After evaporation of the chloroform solution, 2.0 g of a light yellow oil is obtained. Thin layer chromatography showed imidazole still present in the oil. The oil was introduced onto a silica gel column and eluted with EtOAc (NfeOH) (9: 1). After evaporation of the fractions containing pure 1- (cyclopentylmethyl) imidazole, 1.3 g of a light yellow oil is obtained. Distillation of the oil under reduced pressure gives a colorless oil. The boiling point is 92-94 ° C / / 0.1 mm Hg. , Yield 0.6.3 g. Example 5. (a) Preparation of 2-cycloooxtenium Methanol.

To a stirred suspension of paraformaldehyde (24 g, 0.64 mol) in 98% formic acid (100 Cg, cyclooctane (69 g, 0.64 mol) is added dropwise with stirring. After this addition, the resulting mixture is heated under reflux when peremeni vivi for 2 h. After adding water (100 CMJ and a simple

t.c.80 s / 24 mmHg

1 2 3 4 5 b

TP.80-110 ° C / 24 mm Hg

th.kip.110-130s / 0.5 mm PT.ST.

B. Kip. 110-116S / 0.3 mm Hg

bp.11b-130s / 0.3 mmHg

bp 130-170 ° C / 0.3 mm Hg

Fractions 1 and 2 are pooled and 10 g is treated with Claisen alkali GCON (10 g), MeOH / 31.2 cm of water (8 CM) J. The resulting mixture was heated under reflux for 2 hours, after which, according to TLC, there were no changes. The resulting mixture is cooled, poured on ice - so kip.

128 C / 23 mm Hg 128-130s / 23 mmHg

- bp 130-132 C / 23 mm Hg

- bp The NMR spectrum of fraction 9 showed the presence of a small amount of impurities: perhaps these were traces of cyclooctane methanol or hexamethylenedioxane. (b) Preparation of 2-cilooctylmethyl bromide. A solution of tribromide phosphorus (1.02 cm, 0.0105 m) in 40-60 seconds of petroleum ether is added dropwise to a solution of 2-cyclooctylcarbinol (2.8 g, 0.02 m) (fraction 9 above) and AR. A solution of pyridine (0.104 g, 0.0013 m) in petroleum ether (15 cm) is stirred and cooled to. After the addition, the mixture is allowed to warm to room temperature and at this temperature it is set for 2 days. The reaction mixture was treated with water (50 cm) and the organic layer was separated. The aqueous layer is extracted with petroleum ether in an amount of 40-60 cm (3 to 25 cm), after which the combined organic layer and petroleum extracts are washed with 2N-NaOH (25 cm) and water (25 cm) Petroleum extracts are combined and dried over anhydrous MgSu, and after removing the solvent under vacuum to obtain 2.3 g of the crude product. The crude product is distilled and obtain 0.7 g of pure product with a boil of 48-50 ° at 0.25 mm Hg (c) Preparation 1- ( cyclooctylmethyl) imidazole. The 2-cyclooctenyl bromide thus obtained (0.7 g, 0.0035 mol) is added dropwise at a boil reflux to an imidazole solution (0.24 g,

ether (50 cg, the mixture was separated. The ether layer was washed with a saturated solution of CaNOS3 (5-50 cm), water (2-50 ml) and dried over anhydrous MgSO4. The ether was removed under vacuum, and the resulting residue was distilled. The result six fractions and remains of A.

Combined by TLC Yield 21.5 g Combined by TLC Yield 45.3 g

water (50 cm) and extracted with ether (see the combined extracts dried over anhydrous ether are removed under vacuum, the result is a colorless oil (yield 8.1 g), which is distilled off under vacuum, resulting in the following fractions :

Combined by TLC Yield 6.7 g (0.0025 mol) and potassium t-butoxide (0.39 g, 0035 mol) in dry butanol under nitrogen. After the addition, the mixture is refluxed under stirring for 1 hour. A pure product is obtained as described in Example 4, b.p. 108-110s with 0.02 mm Hg Example 6. Obtaining 1- (4-methylcyclohexylmethyl) imidazole. 4-methylcyclohexylmethyl bromide (3.1 g, 0.0164 mol) is added dropwise to the boiling solution under reflux and idazole (1.12 g, 0.0655 mol) in a solution of potassium tert-butylate (1.85 g , 0,0165 mol) in N. butanol (50 cm). The reaction mixture is stored under nitrogen. After the addition, the mixture is heated at reflux for an additional 2 hours and allowed to stand overnight at room temperature. The thin layer chromatography method showed that the reaction was halved. The mixture is then refluxed for an additional 8 hours and left for 2 days at room temperature. Thin layer chromatography indicated that the reaction no longer proceeded. The insoluble product is filtered off and the solvent is distilled off in vacuo. The resulting residue is placed in 2N.HCl (100 cm) and washed with ether (50 ml). The aqueous layer was basified with an excess of 10 H.NaOH and extracted with chloroform (3V 50 cm). The combined extracts are dried over anhydrous MgSO4 and the solvent is distilled off in vacuo. The oily residue was introduced into a silica gel column and eluted with EtOAc (MeOH) 9: 1. 0.8 g of the product obtained on the column was distilled, giving 0.28 g of pure product with mp 80 C at 0.125. mm Hg

Example 7, Results of biological tests.

Differential centrifugation of horse blood was obtained from horse thrombocytes. Approximately 10 platelets were homogenized in j. Ml of 100 mm tris-buffer pH 7.4. Various concentrations of active compound were added, the reaction doses were incubated for 5 minutes at ambient temperature. Then, 20 {/ al erachidonic acid containing 10 (disintegrations per minute) of labeled zrahiddonic acid was added to each tube, and TyoLj was incubated for 3 min with a shaking water bath. After incubation, the radioactive products were extracted from the acidified aqueous phase with ethyl acetate, after centrifugation, separated by thin layer chromatography on silica gel, eluted with chloroform (methanol): acetic acid; water (90: 8: 1: 0.8) as a solvent solvent. The amount of thromboxane produced was measured by scraping the radioactive zone corresponding to thromboxane B and by evaluating the radioactivity in a scintillation fluid in a counter.

The concentration of the active compound was determined, which reduced the enzyme activity by 50% (EP. The results are shown in the table.

. I selectf-f +

f 4 4

Table continuation

13

1-Cyclohex-3-enylmethylimide +++ azole

50

4- + 125

+ 4 +

1-Cycloone 10, 5 +++ methylimidazole

1-Cycloheptyl4, 7 ++++ me1milimidazole

1- (4-Methylcyclohexylmethyl) b, 6 ++ 4 and. Shdazole

The selectivity of the active compounds was determined in a similar manner and the amounts of PGE, PGF and PCD generated were determined. The greater the selectivity, the more prostaglandins are produced, indicating a lower level of cyclooxygenase inhibition.

In the table (selectivity is given, and O means no selectivity; + means low selectivity; + 4 is average selectivity, ++ 4 is high selectivity and +444 is especially high selectivity.

Claims (1)

Invention Formula The method of obtaining 1-alkylimidazole of the General formula HN-A-R N where a - is lower alkyl; R is cycloalkyl or cycloalkenyl unsubstituted or substituted by methyl, provided that when A is methyl, R must not be unsubstituted cyclohexyl, whether their salts, characterized in that the imidazole or its salt is reacted with an alkylating agent of the general formula Z - A - R where A and R have the indicated meanings; Z - chlorine or bromine in the presence of an alkali metal alcoholate, with the release of the target pro9 94829010 duct in free form or in vmemethylcycloheptyl, cyclohexenyl, salt.cyclohaxyl, cyclobutyl. Priority featured: 01.02.78 with A - methyl; R - cyclo-Sources of information, hexyl, cyclohexenyl. 08.08.78 with A - methyl; R - cyclo-5 1. Elderfield R. Heterocyclic octyl, cyclopentyl, cycloheptyl, cue compounds. M., Foreign lycyclooctyl, methyl cycloheptenyl, teratura, 1954, P. 5, p.