PL214104B1 - Ionic liquids hexahydrothymol derivatives and process for the preparation of ionic liquids hexahydrothymol derivatives - Google Patents

Description

Description of the invention

The subject of the invention are ionic liquids derived from hexahydrotimol from the group of protic imidazolium liquids showing fungicidal properties and a method of producing ionic liquids derived from hexahydrotimol.

A method for producing optically active (-) - menthol from geraniol, nerol and mixtures thereof is known from the US patent No. 7709688.

From the Polish patent application PL 388448 A1 are known chiral bis (trifluoromethylsulfonyl) imidki 1-alkoxymethyl-3 - [(1 R, 2 S, 5 ^/:) - (-) - mentoksymetylo] imidazolium comprising component (1 ?, F 2S, 5F?) - (-) - menthol, the production method of which consists in that 1-alkoxymethyl-3 - [(1F?, 2S, 5 / ^z ?) - (-) - menthoxymethyl] imidazolium chloride is subjected to reaction with lithium bis (trifluoromethylsulfonyl) imide in a molar ratio of 0.8-1.5 at a temperature of 273 to 373K in the presence of a polar organic solvent or in water. These compounds have been tested as disinfectants in the form of 0.1 to 10% aqueous solutions of 1-alkoxymethyl-3 - [(1F ', 2S, 5 / ^: ') - (-) - menthoxymethyl] imidazolium chloride.

Ionic liquids of hexahydrotimol derivatives of the general formula 1, containing in the cationic part (1S, 2F ', 5S) - (+) - menthol, connected to the nitrogen atom of the imidazole pyrrole type in the N-1 position with a methylene group and a hydrogen atom at the nitrogen atom of the type of pyridinium in the N-3 position, while in the anionic part marked with the symbol X an organic anion with significant biological activity, such as: salicylate, acetylsalicylate, ibuprofen or L - (+) - lactate.

The new protic imidazolium ionic liquids containing the (1S, 2F ', 5S) - (+) - menthol component and the biologically active anion that are the subject of the invention have not been described in the literature so far.

The structures of the new junctions are characterized by three chiral centers that are located on the cation. In the case of 1- (1S, 2R, 5S) - (+) - menthoxymethyl-3- (7-imidazolium) lactate, the fourth center of symmetry is located on the anion.

The method of obtaining liquid ionic hexahydrotimol derivatives of the general formula 1, containing in the cationic part (1S, 2F ', 5S) - (+) - menthol, connected to the nitrogen atom of the imidazole pyrrole in the N-1 position with a methylene group and a hydrogen atom at a pyridinium nitrogen atom in the N-3 position, while in the anionic part, an organic anion with significant biological activity marked with the symbol X, such as: salicylate, acetylsalicylate, ibuprofen or /.-(+)- lactate, according to the invention is chiral an amine in the form of 1- (1S, 2F?, 5S) - (+) - menthoxymethylimidazole, of the general formula 2, is reacted with biologically active organic acids selected from the group consisting of: salicylic acid, acetylsalicylic acid, 2- ( p-isobutylphenyl) propionic ibuprofen or L - (+) - lactic acid, used in an equimolar ratio, preferably 0.85 to 1.4, at a temperature of 273 to 373K, in the presence of an organic solvent or in water. The organic solvent is selected from the group consisting of: primary alcohols with carbon atoms from 1 to 4, toluene, diethyl ether, hexane, heptane, methylene chloride, THF - tetrahydrofuran, ethyl acetate, chloroform, acetone, DMSO - dimethyl sulfoxide or DMF - dimethylformamide.

The method according to the invention enables the preparation of new tertiary imidazolium salts containing in the cationic part a hexahydrotimol derivative in the form of (1S, 2F?, 5S) - (+) - menthol and a biologically active anion in the reaction 1- (1S, 2F?, 5S) - (+) - menthoxymethylimidazole with the corresponding organic acid in high yield. They are ionic liquids with a low vapor pressure at room temperature, stable over a wide temperature range, belonging to chiral ionic liquids which are liquid over a wide temperature range. Viscosities of the obtained compounds, determined at the temperature of 303K, are in the range of 570 to 660 mm ² / s. The chiral liquid tertiary imidazolium salts dissolve organic compounds well.

The new structures of chiral ionic liquids according to the invention, additionally containing a biological anion component, show significant biological activity. This feature was checked by determining the fungicidal properties of the obtained salts. The tests were performed against the Candida albicans strain. From 1 g of the respective tertiary imidazolium salt, an aqueous solution was prepared and treated with the strain Candida albicans. The values of the minimum fungicidal concentration were determined. The fungicidal activity against this strain is similar, and in some cases higher, than the standard benzalkonium chloride used.

The subject of the invention is illustrated in the preparation of the new compounds.

PL214 104 Β1

Example 1

To prepare 1- (1S, 2R, 5S) - (+) - menthoxymethyl-3- (7-imidazolium) salicylate represented by the formula 3, 0.65 moles of 1- (1S, 2F?, 5S) are dissolved in the three-necked flask. ) - (+) - menthoxymethylimidazole in 20 cm ^{3 of} chloroform. Wherein 1- (1S, 2R, 5S) - (+) - menthoxymethylimidazole is obtained by equimolar reaction of triethylamine and chloromethyl ether [1S, 2R, 5S) - (+) - menthol] in the presence of toluene as the solvent, and then 30 minutes, a stoichiometric amount of imidazole is added at 353K.

To the chloroform solution of 1- (1S, 2F ', 5S) - (+) - menthoxymethylimidazole, while stirring vigorously, 0.70 mol of salicylic acid previously dissolved in an organic solvent, preferably in primary alcohol, is added. The reaction is carried out at the temperature of 303K. After 3 hours, the process is terminated and the reaction mixture is kept aside overnight. The product of the reaction, i.e. imidazolium salicylate. obtained as an ionic liquid after filtration from unreacted starting materials and removal of the solvent under reduced pressure. The chiral reaction product, in the form of a transparent ionic liquid, is dried in a vacuum desiccator. The reaction yield is 96%.

The reaction is similarly carried out using ethyl acetate as the solvent - the yield of the reaction is 95% or THF - the yield of the reaction is 90%.

Elemental CNH analysis and nuclear magnetic resonance spectroscopy identified the product obtained.

Elemental analysis (%) for C ₂ H ₃₀ N ₂ O ₄ (374.53): theoretical values: C 67.34; H 8.09; N 7.48; experimental values: C 67.30; H 8.08; N 7.50.

¹ H NMR spectrum salicylate 1- (1 S, 2 R, 5 S) - (+) - mentoksymetylo-3- / 7-imidazolium (CDCl3, 25 ° C) δ [ppm] = 0.47 (d, J = 6.9 Hz, 3H); 0.89 (m, 9H); 1.26 (m, 2H); 1.62 (m, 2H); 1.97 (m, 2H); 3.19 (td, J ¹ ' ³ = 10.5 Hz, J ¹ ' ² = 4.1 Hz, 1H); 5.40 (m, 2H); 6.88 (m, 1H); 6.92 (m, 1H); 7.16 (s. 1H); 7.30 (s. 1H); 7.41 (m, 1H); 7.94 (m, 1H); 8.31 (s. 1H); 11.09 (m, 2H); ¹³ C NMR (CDCl 3, 25 ° C) δ [ppm] = 15.5; 20.8; 22.1; 22.9; 25.5; 31.5; 34.1; 40.0; 47.9; 75.1; 78.3; 114.7; 117.1; 118.9; 125.8; 130.8; 134.8; 136.5; 161.9; 174.1.

Example 2

The method of producing 1- (1S, 2F?, 5S) - (+) - menthoxymethyl-3- (7-imidazolium) acetylsalicylate represented by the formula 4 consists in introducing 0.75 moles of 1- (1S, 2R, 5S) - (+) - menthoxymethylimidazole and 50 cm ^{3 of} DMF. Then 0.90 mol of acetylsalicylic acid, previously also dissolved in DMF, is slowly added dropwise. The reaction is carried out at the temperature of 373K. After 24 hours the solvent is evaporated off and the obtained ionic liquid is dissolved in toluene to get rid of any starting materials. The solvent is evaporated again and the resulting chiral liquid is dried at room temperature in a vacuum desiccator. The reaction yield was 91%.

The reaction is carried out in a similar manner using DMSO as the solvent - the yield of the reaction is 90%.

DMSO - the yield of the reaction is 90%.

Elemental CNH analysis confirmed the structure of the synthesized compound.

Elemental analysis (%) for C ₂₃ H ₃₂ N ₂ O ₅ (416.57): theoretical values: C 66.31; H 7.76; N 6.72; experimental values: C 66.41; H 7.72; N 6.66.

The content of imidazolium acetylsalicylate in the product, determined by two-phase titration according to EN ISO 2871-2: 1994, was 97.5%.

Example 3

The method of producing ibuprofen 1- (1S, 2R, 5S) - (+) - menthoxymethyl-3- / 7-imidazolium, represented by the formula 5, consists in introducing 0 into a two-necked flask equipped with a magnetic dipole and a thermometer, 55 moles of 1- (1S, 2F?, 5S) - (+) - menthoxymethylimidazole and 35 cm ^{3 of} methanol. Then 0.55 mole of 2- (p-isobutylphenyl) propionic acid-ibuprofen, previously dissolved in primary alcohol or in water, is added. The reaction is carried out at the temperature of 298K. After 24 hours the solvent is stripped off and the resulting ionic liquid is dissolved in toluene to get rid of any starting materials. After re-evaporating the solvent, the resulting chiral liquid material is dried in a vacuum desiccator. The reaction yield was 95.5%.

PL214 104B1

The reaction is carried out in a similar manner using the solvent in the form of ethanol, the yield of the reaction is 97%, the yield of propanol is 95% and the yield of butanol is 91%.

Elemental CNH analysis confirmed the structure of the synthesized compound.

Elemental analysis (%) for C14H25BF4N2O (324.21): theoretical values: C 51.86; H 7.79; N 8.64; experimental values: C 51.93; H 7.88; N 8.59.

The content of imidazolium ibuprofen in the product, determined by two-phase titration according to EN ISO 2871-2: 1994, was 94%.

Example 4

The method of producing ibuprofen 1- (1S, 2F?, 5S) - (+) - menthoxymethyl-3- / 7-imidazolium, represented by the formula 5, consists in introducing into a glass reactor equipped with a magnetic dipole, a thermometer and a mechanical stirrer 0.70 mole 1 - (1 S, 2R, 5S) - (+) - mentoksymetyloimidazolu and 45 cm ³ of acetone. Then 0.80 mol of ibuprofen 2- (p-isobutylphenylpropionic acid, previously dissolved in toluene, was added dropwise). The reaction was carried out at 273K. After 2 hours, the reaction was complete and the reaction mixture was allowed to stand overnight. The solvent was stripped off. and the resulting ionic liquid was dissolved in toluene to get rid of any starting materials, After the solvent was evaporated again, the resulting chiral liquid was dried in a vacuum desiccator The yield of the reaction was 97%.

The reaction is carried out in a similar manner using methylene chloride as the solvent, the yield of the reaction is 98%.

Elemental CNH analysis of the obtained imidazolium ibuprofen is described in Example 4.

Example 5

The method of producing 1- (1S, 2R, 5S) - (+) - menthoxymethyl-3- (7-imidazolium) lactate represented by the formula 6, consists in dissolving 0.55 moles of 1- (1S, 2 / ^z ?, 5S) - (+) - menthoxymethylimidazole in 30 cm ^{3 of} hexane. Then 0.65 mol of L - (+) - lactic acid, previously dissolved in hexane, is added with vigorous stirring. The reaction is carried out at the temperature of 288K. After 24 hours, the protonation reaction product is obtained. The solvent was removed under reduced pressure and the reaction product was dissolved in chloroform. After separation from the possibly unreacted starting material, the solvent is evaporated again. The chiral reaction product, in the form of a solid, is dried in a vacuum desiccator. The reaction yield is 98%.

The reaction is carried out in a similar manner using diethyl ether as the solvent, the yield of the reaction is 99% or heptane - the yield of the reaction is 96%.

Elemental CNH analysis and nuclear magnetic resonance spectroscopy identified the product obtained.

Elemental analysis (%) for C ₁₈ H ₂₉ N ₃ O ₅ S (399.60): theoretical values: C 54.10; H 7.33; N 10.52; experimental values: C 53.93; H 7.30; N 10.49.

¹ H NMR spectrum lactate 1- (1S, 2R, 5S) - (+) - mentoksymetylo-3- / 7-imidazolium (CDCl _3, 25 ° C) δ [ppm] = 0.46 (d, J = 6.9 Hz, 3H); 0.89 (m, 9H); 1.27 (m, 2H); 1.28 (d, J = 6.9 Hz, 3H); 1.60 (m, 2H); 1.97 (m, 2H); 3.17 (td, J ¹ ' ³ = 10.6 Hz, J ¹ ' ² = 4.2 Hz, 1H); 4.10 (qw, J = 6.9 Hz, 1H); 5.40 (m, 2H); 7.18 (s. 1H); 7.30 (s. 1H); 8.29 (s. 1H); 10.08 (s. 1H); 11.10 (m, 1H).

Example 6

A method for preparing lactate 1- (1S, 2R, 5S) - (+) - mentoksymetylo-3- / 7-imidazolium chloride represented by the formula 6, consists in the fact that to a glass reactor with a capacity of 250 cm ³ are introduced 0.45 mol 1 - (1S, 2R, 5S) - (+) - menthoxymethylimidazole and 30 cm ^{3 of} toluene. Then 0.46 mol of / - (+) - lactic acid is added with vigorous stirring. The reaction is carried out at the temperature of 293K. After 24 hours, the unreacted acid is filtered off and then the solvent is removed under reduced pressure. The reaction product is dried in a vacuum desiccator. The reaction yield is 90%.

Elemental CNH analysis and nuclear magnetic resonance spectroscopy of the obtained imidazolium lactate is described in Example 5.

Claims (4)

Patent claims 1. Ionic liquids of hexahydrotimol derivatives of the general formula 1, containing in the cationic part (1S, 2F ', 5S) - (+) - menthol, connected to the nitrogen atom of the imidazole pyrrole in the N-1 position with a methylene group and a hydrogen atom at the atom pyridinium nitrogen in the N-3 position, while in the anionic part marked with the symbol X, an organic anion with significant biological activity, such as: salicylate, acetylsalicylate, ibuprofen or L - (+) - lactate. 2. The method of producing liquid ionic hexahydrotimol derivatives of general formula 1, containing in the cationic part (1S, 2F ', 5S) - (+) - menthol, connected to the nitrogen atom of the imidazole pyrrole in the N-1 position with a methylene group and hydrogen at the nitrogen atom of the pyridinium type in the N-3 position, while in the anionic part marked with the symbol X an organic anion with significant biological activity, such as: salicylate, acetylsalicylate, ibuprofen or / _- (+) - lactate, characterized by the fact that 1- ( 1S, 2F?, 5S) - (+) - menthoxymethylimidazole, of the general formula 2, is reacted with biologically active organic acids selected from the group consisting of: salicylic acid, acetylsalicylic acid, 2- (p-isobutylphenyl) propionic acid - ibuprofen or L - (+) - lactic acid, in an equimolar ratio of 4, at a temperature of 273 to 373K, in the presence of an organic solvent or in water. 3. The method according to p. 2. The method of claim 2, characterized in that the organic solvent is selected from the group consisting of: primary alcohols with the number of carbon atoms from 1 to 4, toluene, diethyl ether, hexane, heptane, methylene chloride, THF - tetrahydrofuran, ethyl acetate, chloroform, acetone, DMSO dimethylsulfoxide or DMF for dimethylformamide. 4. The method according to p. The process of claim 2, wherein the molar ratio of 1- (1S, 2R, 5S) - (+) - menthoxymethylimidazole to the biologically active organic acid is 0.85 to 1.4.