SU940647A3 - Process for producing 4,5-diaryl-2-nitroimidazoles - Google Patents

Description

3 R and Rrt have the indicated values, are nitrated with nitrogen tetroxide in the presence of H-butyl lithium, to isolate the desired product in free form, by alkylation or by acylation. Example 1. i, (-fluorophenyl) -2-nitroimidazole. A mixture consisting of 124 g (0.8 mol), 5-bis- (α-fluorophenyl) -imidazole, 8 g (1.0 mol) of dihydropyran, 20 g of boron trifluoride etherate and 1 g of ethyl acetate is heated to reflux temperature for 2 days Analysis by TLC (ethyl acetate) shows the presence of a certain amount of unreacted starting material, so that 20 g (-0.2 mol) of dihydro-pyran and 5 g of boron trifluoride etherate are added and the mixture is heated overnight. The mixture is then diluted with 1 L of ether and washed with sodium bicarbonate solution (3 x 1 L). The organic layer is dried and concentrated on a rotary evaporator. The solid residue is recrystallized from methylcyclohexane (removing the remaining insoluble starting material by filtration) to give 2 g (85%), 5-bis - (- fluorophenyl) -1- (2-tetrahydropyranyl) imidazole as white solid with so pl. F9-152. F-NMR purity of the product is determined: A smaller fraction is subjected to chromatography with the preparation of a pure material st. square 158-159 IR spectrum: 3.25 microns (CH); 3.38, 3, "9 microns (sat. CH), 6.22, 6.28, 6.41, 6.60, 6.69 microns (C-C and / or) 8.20 microns (CF) , area 9 microns (C-O-C). H-NMR m .: (1.4-2.1 s, 6H); m. (3.4sL 1H); m. (4.0o, 1H); m., (4 ,, 1Н); (6.6-7.5 sL. 8H); with .. (7.8 sl F). P-NMR: two multiplets (112, and 116, each separated into a singlet). To a mixture of 17.0 g (50 mmol) of 4,5-bi- (4-fluorophenyl) -1- (2-tetrahydropyranyl) imidazole, 6.4 g, (55 mol) of N, N, N, N-tetramethyldiamine and 200 ml of ether (cooled to –78 °) are added dropwise 35 ml (55 mmol of 1.6 M butyl lithium. After stirring for 15 minutes, a solution of 7.9 g (86 mmol) of nitrogen tetroxide in 50 ml is added dropwise ether. The reaction mixture is heated to room temperature, then partitioned between aqueous sodium bicarbonate and ether. The ether is dried and evaporated to give 21.7 g of an amber oil. The oil is heated with a mixture of 125 ml of ethanol and 10 ml of 1N aq. hydrochloric acid in a few minutes. The reaction mixture is concentrated in vacuo.The chromatography and recrystallization of the product from toluene yields 6.1 g, (- fluorophenium) -2-nitroimidazole with mp 245-2 + 6 C (decomposition) IR, NMR and F-flMP spectra correspond to a given structure. Found.%: C 60.21; H 3.03; N 13.55 Calculated: C 59.81; H 3.01; N 13.95 Example 2. A, (- methoxyphenyl) -2-nitromidazole. According to the method described in Example 1 (1st paragraph), 5-bis (-methoxyphenyl) imidazole is converted in 50% yield to i, (-methoxyphenyl) -1- (2-tetrahydropyranyl) imidazole is a white substance with m. square 123-125 ° C. IR spectrum: 3.26 microns (CH); 3.40, 3.53 microns (nos. CH), 6.17, 6.32, 6.58, 6.68 microns (and / or), 8.03 microns (aryl-o), 9.60 and 9.72 microns (C-O-C). H-NMR: m., (1.3-2.10 6H), two singlets (3.75-3.85o 6H), m., (3.2L, 2c 2H), tr., (4.85 1H), two quartets (6.7-7.6 8H), p. (7.85o 1H). Found,%: C 72,32; H 6.35; N 7.37 "SI Calculated: C 72.51; H 6.64; N 7.69. As in Example 1, 14.5 g of 4,5-bis- (4-methoxyphenyl) -1- (2-tetrahydropyranyl) -imidazole is converted to 4,5-bis- (4-methoxyphenyl) -2-nitroimidazole. Using chromatography get an analytical sample with so pl. 174 ° C (decomposition). The IR and NMR spectra confirm the structure found. Mass Found, 325.1030 Calculated, 325.10b2. Example 3- 4-1,4-fluorophenyl) l5 2-thienyl) -2-nitroimidazole. to a mixture of 100.0 g (0.65 mol) -fluorophenyl acetic acid and 2O, 0 thiophene (heated to) is added dropwise 150.0 g (0.71 mol) of trifluoroacetic anhydride. The reaction mixture is heated to reflux for 3 hours, cooled and then poured onto ice. The aqueous layer is brought to a basic state with sodium carbonate, and the product is extracted with ether. The combined ether extracts are washed with water and, after drying on anhydrous potassium carbonate, they are evaporated to give 150.5 g of oil. As a result of crystallization from methanol, 2- (4-fluorophenyl-1- (2-thienyl) ethanone) is obtained with a melting point of 60. Found, C b5, H, 0b C ijiHgFOS Calculated: C b5, H i, 09 K solution 9.1 g (0,) 3 mol) 2- ("-fluorophenyl) -1- (2-thienyl) ethanone; in 700 ml of ether, a solution of 65.0 g (o, mol) of bromine in 140 ml is added dropwise methylene chloride at room temperature and | stirring. The solvent is removed in vacuo to give 125.0 g of 2-bromo-2 - (- fluorophenyl) (2-thienyl) ethanone. A mixture of 2-brpm - (- fluorophenyl) -1- (2-thienyl) ethanone and b5 ml of formamide is heated to reflux in an air condenser for 2 hours. The reaction mixture is cooled to room temperature and as a result, the filtrate is collected 73.3 4- (-fluorophenyl) -5 - (2-thienyl) imidazole, m.p. 182189C. A sample for analysis is obtained by recrystallization from nitromethane, m.p. 200-202 C. H-NMR: m. (6.9-7.7sL, 7H), p. (7.8 (L, 1H). Found,%: C 63.3; H 3.82; N 11.56 Calculated,;: C 63.93; And 3, b9; N P, 48. Analogously to example 1 (first paragraph), 35.0 g of 4- (-fluorophenyl) -5- (2-thienyl) imidazole is converted into 56.6 g - (-fluorophenyl) (2-thienyl) -1- (2-tetrahydropyranyl) -imidazole As a result of chromatography on neutral aluminum (degree of activity according to Velm 1), 30.0 g of pure substance are obtained as a mixture of two isomers 76 H-NMR: m (1, 4-2.1 (L 6H-), m, (3, 1H), m. (k, 0d 1H), m. (4, 1H), m. (6.7-7.7t, 7H), 2 s. (7.9 sl, 1H). According to the method described in example 1, 30.0 g / 5 / (- fluorophenyl) -5 / + / - (2-thienyl) -1- (2-tetrahydropyranyl) imidazole is converted into -C-fluorophenyl) -5 (2-thienyl) -2-nitroimidazole. Purification is carried out by dissolving the crude product in aqueous (0.2 M) potassium hydroxide followed by filtration, then acidifying with acetic acid to precipitate the sample for analysis , mp 177,. The IR and NMR spectra correspond to the structure found. Mass for C j NjOij S: calculated 289; found 289 Found: C 5.5; H 2.8 "4; N C, HNPMZO, 15 Calculated,;: C 53.88; And 2.77; U, 53 Example, i- (A-ethoxyphenyl) (l-fluorophenyl) -2-nitroimidazole. A mixture, 4 g (86.5 mmol) of k- (k-ethoxyphenyl) -5 (-fluorophenyl) -imidazo a, 12.5 g (0.173 mol) of ethyl vinyl ether and 11.2 g (86.8 mmol) of dichloroacetic acid 175 ml of toluene is heated to reflux for several hours. After cooling to room temperature, the reaction mixture is stirred overnight with 85 ml of an aqueous solution of sodium hydroxide. The toluene layer is separated, washed several times with water, dried over low purity with anhydrous potassium carbonate, and then evaporated to give 21.6 g of 4/5 | - (4-ethoxyphenyl) -5M / - (-fluorophenyl) -1- (1-ethoxyethyl) imidazole in the form of oil. The oil is subjected to chromatography on neutral aluminum (degree of activity according to Velm 1), washed with chloroform to obtain 18.0 g of pure substance. H-NMR: m. (1.0-1.8 (P 9H), q. (3.2 (L.2H), q. (, 1 (Y 2H), q. (5.1sL, 1H) , m. (6.7-7.7 sP 8H), s. (7.8 eU 1H). According to the method described in Example 1, 8.5 g 4/5 / (-ethoxyphenyl) (4-fluorophenyl) -1 - (1-ethoxyphenyl) imidazole is converted to 4- (-ethoxyphenyl) -5 (-fluorophenyl) -2-nor-troimidazole. IR and NMR spectra confirm a certain structure of the substance. Chromatography on silica gel-AR chloroform followed by recrystallization from 1-chlorobutane is obtained sample for analysis with mp (decomposition). Mass for C-j calculated: 327; found 327. Found, C 62, A; H 4.33; -N 12, TstN14 zR02, “Calculated: C 62.39 ; H ", 28; N 12.8. Example 5. - (3, -dichlorophenyl) -5-phenyl-2-nitromidazole. A mixture of C- (3,4-dichlorophenyl) -5-phenyl imidazole (, S g, 50 mmol), ethyl vinyl ether (10 ml, 100 mmol) and dichloroacetic acid (4.2 ml, 50 mmol) in 100 ml of toluene is heated to reflux under Nq for 1 hour. The cooled mixture is treated with 50 ml of 20% aqueous NaOH solution, stirred overnight and then kept at room temperature for 2 days. The organic phase is washed with water, dried on and concentrated on a rotary evaporator to give 4/5 / - (3. Dichlorophenyl) -5 / "/ - phenyl-1- (1-ethoxyethyl) -imidazole as an oil. H-NMR: 1.13 (tr. L 7 Hz, ZN), 1, BZSL (d. 3 6 Hz, ZN), 3, ZSA (2 sq. Hz, 2H), 5.13cf (sq. L 6 Hz , III), 7.28-7, (M., 8H), 7.91 s / (s, 1H). Received (5) (3, -Dichlorophenyl) -5- Ct) -phenyl-1- (1-ethoxyethyl) imidazole (50 mmol) and N, N, N, N-tetramethylethylenediamine (7.5 ml 55 mmol in 200 ml THF is cooled to under Nn and treated dropwise to 1.6 m. (H-butyl lithium Ctl ml, B5 mmol). After stirring for 15 minutes, a solution of nitrogen trioxide (7 ml, 110 mmol) in 25 ml of ether (added dropwise) is added. The reaction mixture was stirred at -78 ° C. for 1 h, then warmed to room temperature. The dark mixture is poured into 300 ml of saturated aqueous NaHCOj and extracted with ether. The combined organic extracts are washed with brine, dried and divided into two portions (3: 1). The large portion is concentrated in a rotary evaporator, redissolved in 125 ml of ethanol, treated with 30 ml of 1N. HCE and heated to reflux for 10 min. The reaction mixture is cooled to room temperature and diluted with 35 ml of water. The crystals are collected, washed with 0.1 n. KOH and recrystallized from chloride. methylene to obtain 1.2 g of 4- (3i-dichlorophenip) -5-phenyl-2-nitroimidazole with so pl. 248-2 9 ° C (decomposition). The IR spectrum and the NMR spectrum coincide with a specific structure of the substance. Mass spectrum 333 (M +). Found,%: C 53.86; H 2, N 12.67 C. HgNjOrjCCr Calculated: C 53.91; H 2.71; N 12.58. Example 6. (-Oprophenyl) -5- (3-pyridyl) -2-nitroimidazole. A mixture of 82.0 g (0.6 mol) of methyl nicotinate and 81.0 g (0.6 mol) of p-fluorobenzyl cyanide was added dropwise to a solution of 0.9 mol of sodium ethoxide in 250 ml of ethanol at room temperature and stirring. The reaction mixture is heated to reflux overnight, cooled and then poured into ice water. The aqueous solution is washed with ether and then acidified with concentrated hydrochloric acid. The precipitate is collected by filtration and washed with water. A mixture of the solid with 350 ml of 48% hydrobromic acid is heated to reflux overnight with stirring. The reaction mixture is cooled to room temperature, the crystals are collected by filtration. The crystals are weighed in water, which is then brought to the ground state using concentrated ammonium hydroxide. The products are extracted with ether, which, after drying on anhydrous carbonate, is evaporated to give 77.9 g of fluorobenzyl-3 pyridyl ketone as colorless crystals with a mp. 64-b5 C; IR spectrum 6.0 m (). H-NMR: s. (k, 2H), m. (6.97, 6yy 5H), d. (tr.). (8.2) 1H), d / d (8.8s 1H), d. (9.3s 1H) . A solution of 12.3 (76.9 mmol) bromine in 120 ml of acetic acid at room temperature (with stirring) is added dropwise to a solution of 15.0 g (69.8 mmol) of fluorobenzyl-3-pyridyl ketone in 120 ml of acetic acid. . After stirring overnight, the precipitate — l8, t g of d-bromo-fluorobenzyl-3-pyridyl ketone hydrobromide is collected by filtration. A mixture of o1-bromo-fluorobenzyl-3 pyridyl ketone 9 hydrobromide with 150 ml of formamide is heated to reflux temperature with an air condenser under nitrogen for 2 hours. The reaction mixture is cooled to room temperature, then poured into water. The aqueous solution is basified with sodium carbonate and the product is extracted with ether. The combined ether extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried on anhydrous potassium carbonate and evaporated to give 7.5 ° C- (C-fluorophenyl) -5 (3-pyridyl) imidazole. Purified by chromatography on neutral aluminum (Belm activity, degree 1), washed with ethyl acetate (tetrahydrofuran, and crystallized using ether to obtain 2.2 g of pure imidazole, mp 15 + -15b c. H-NMR: m. (6.8-7, 5H, p. (7.6sL, 1H), d (tr. 7.8sL, 1H), d / d (B, 1H), d (8.7c /, 1H). Found: C 70.3; H ", 3; N 18, Calculated: C 70.29; H k M 17.57. In the variant method, a mixture consisting of 28.8 g of oL-br - -fluorobenzyl-3- hydrobromide pyridyl ketone and 0.0 g of potassium acetate in 50 ml of acetic anhydride are stirred overnight at room temperature. Then the reaction mixture is poured The ether layers are washed with water and then with an aqueous solution of sodium bicarbonate. The ether layer is dried on LIA carbonate and evaporated. The residue solution in 250 ml of 1 N. aqueous hydrochloric acid is heated to reflux temperature for 0 , 5 hours and after cooling down to a basic state with solid sodium carbonate. The product is extracted with ether and the combined ether extracts are evaporated, and after drying on anhydrous potassium carbonate, 16.5 rot-oxy-D-fluoro benzyl 3-pyridyl ketone is obtained. The resulting d-hydroxy-4-fluorobenzyl-3-pyrile ketone (16.5 g) is reacted with 12.5 ammonium thiocyanate in 1-propanol while heating to reflux temperature to give 11.3 g - (-fluorophenyl) -5 (3-Pyridyl) -1H-2-imide azolthiol, so pl. 335-338с (decomposition). 7 Compound t - (+ - fluorophenyl) -5 - (3-pyridyl) -1H-2-imidazolithiol (8.2 g) was added portionwise to a mixture of 30 ml of nitroacetic acid at room temperature. After stirring overnight, the reaction mixture is diluted with water and made basic with sodium carbonate. The product is extracted with ethyl acetate and, after drying over potassium carbonate, the latter is evaporated, yielding 5.3 g of i- (4-fluorophenyl) -5 - (3-pyridyl) imidazole. Analogously to Example 4 (first paragraph), 1.5 g of - ((- fluorophenyl) -5- (3 pyridyl) imidazole is converted into - (4-fluorophenyl) -5 / / - (3 pyridyl) -1- (1-ethoxyethyl) imidazole . As a result of chromatography on neutral aluminum (Belm activity, degree 1), eluting with tetrahydrofuran, a pure substance is obtained. H-NMR: tr. (, 2d ЗН), д. (1,6с ЗН), m. (З.О-З., 2Н), - sq. M. (5, 1H), m. (6.8-7.5d, 3N), mp. (7.7, 1H), p. (8,8c / J 1H), d / d (8 ,, 1Н), D. (8.7, 1Н). In a similar manner to Example 1, 1.0 g of tlSl - (-fluorophenyl) -5 + (3-pyridyl) - (1-toxyethyl) imidazole is converted to B + - (U-fluorophenyl) -5- (3 pyridyl) -2-nitroimidazole. R 0.19 / TLC, silica gel G: ethyl acetate, methanol) (90:10). Example 7-1-Benzoyl-4,5-bis (-methoxyphenyl) -2-nitroimidazole. To a solution of 4, (4-methoxyphenyl) -2-nitroimidazole (3 g, 9.2 mmol) and triethylamine (3.9 ml, 27.6 mmol) in 30 ml of THF at 0 ° C in NQ are added dropwise a solution of benzoyl chloride (1.2 ml of 10.1 mmol) in 5 ml of THF. The reaction mixture is stirred for 8 hours at 0 ° C, then kept in a refrigerator overnight, diluted with 30 ml of ether and filtered. The filtrate is concentrated on a rotary evaporator and chromatographed on Florasil. After recrystallization from methylcyclohexane, 1.89 g of 1-benzoyl, (4-methoxyphenyl) -2-nitroimidazole are obtained, m.p. 1b1-1b3 ° C, IR spectrum: 1745. H-NMR: 3.73 sl (p., 3N) 3.75 sl (p., 3N), 6, b7-7.83 s (m, 13H). Mass Spectrum:. (M +). Found: C 67.2; H “, 40; N 9.5 - ChdN N305

Calculated, /: C b7,12; H k,

N 9.7.

Example 8. 1-Ethoxycarbonyl-, (A-methoxyphenyl) -2-nitroimidazole.

To a solution of t, (4-methoxyphenyl -2-nitroimidazole (1.5 g, 6 mmol) in 25 ml of pyridine at 0 ° C under nitrogen atmosphere, ethyl chloroforiate (1.5 ml, 15b mmol) is added dropwise. After 5 hours, the reaction mixture is diluted with ethyl acetate, washed 3 times with 1N carried, 3 times with saturated NaHCO, once with brine, dried and concentrated on a rotary evaporator. Chlorisil chromatography gives 1 mg of ethoxycarbonyl, 87 mg (4 -methoxyphenyl) -2-nitroimidazole as an oil.

1795 IR Spectrum

H-NMR: 1, 21sz (tr., J = 7 Hz, 3N) 3.7oMs., 3N), 3.8sA (s., 3N), 3s / (apt. 3 7 Hz, 2H), 6 , 6-7.76 (2 kV AB, 3 8 Hz, 8H). Mass spectrum 397 (M +).

Example 9-1-Acetyl-, 5-bis (4-methoxyphenyl) -2-nitroimidazole

To a solution of i, 5-bis (4-methoxyphenyl -2-nitroimidazole (3.0 g, 9.22 mmol and triethylamine (7 ml, 51 mmol) in 30 ml of THF, under an atmosphere of nitrogen, is added a solution of acetal chloride (1.3 ml, 18, mmol) in 5 ml of THF. After 2 h at O-C, the reaction mixture is diluted with ethyl acetate, washed with 1N HCC, saturated with aqueous NaHCOn and brine, dried and concentrated on a rotary evaporator. After crystallization from about 600 mg of starting material is obtained from the ether. As a result of TLC mother liquor and crystallization from the ether, 1-acetyl-A, (methoxy phenyl) -2-n and a dazole, mp 1 + 6-1 51 ° C. Using H-NMR, the determined purity of the substance: 95-H-NMR: 2, (c., 3N), 3.8 secA (p., 3N), 6.73-7.5 bsL (2Q. AB, Hz, 8H).

Pr and measures 10. 1- (1-ethoxyethyl) -, (4-methoxyphenyl) -2-nitroimidazole.

A mixture of i, (-methoxyphenyl) -2-nitroimidazole (1 g, 308 mmol), ethyl vinyl ether (.1 ml, 6.16 mmol) and dichloroacetic acid (0.3 ml, 3.08 mmol) in 1 o ml toluene is heated to reflux at a nitrogen atmosphere for 1 hour.

The reaction mixture is cooled, 2 ml of ethyl vinyl ether is added and heating is continued overnight. The cooled reaction mixture is treated with 5 ml of 20% NaOH and stirred for 24 hours. The organic phase is washed with water, brine, dried on K, 2C02i is concentrated on a rotary evaporator. As a result of chromatography on Florisil, 178 mg of 1- (1-ethoxyethyl) -, 5- bis (+ methoxyphenyl -2-nitroimidazole as an oil.

H-NMR: 1.08 cA (t, 3 7H, 2. 1, b5cA (d., 3 6H, 3N), 3.4 ° C (KB., J 7H, 2H), - 3.73 s / (s. , ZN), 3.86sLs., ZN), 5.9sA (q, 3 6H, 1H), 6.6-7.36or (2 kV, AB, 8H). Mass spectrum 352 (M-OC, jf%), 325 (M-CrjHT OCrj Hj).

Application. In order to determine the anti-inflammatory activity of the proposed compounds and compare the latter with standard drugs, a test using a standard type of arthritis is used, the results of which give indications regarding the effect on the person. The standard type of arthritis is arthritis caused by the introduction of a special agent in rats. Male rats (weight 130-150 g) were subcutaneously injected into the foot area of the right hind paw with 0.1 ml of auxiliary agent, grown in Difco's nutrient medium, destroyed by heating, Lyophilized microorganism Musbacterium Butyricum, suspended in mineral oil, 5 mg (ml) . Experimental animals are kept for 2 weeks to allow arthritis to develop. The control animals in the 20 unaffected arthritis are injected with mineral oil. Then, the volume of the untreated left hind paw is measured, the animals treated with the agent are selected and grouped (10 rats of the same stage of the disease). Untreated control animals are divided into 2 groups of 10 copies each. The rats are orally administered with a compound or a mixture of 1% polyvinyl alcohol, gum arabic, 0, metal paraben (10 ml / kg) on this day and for the next 6 days. One day after the last dose, paw volume (untreated back left) was measured using a differential volume meter and

Claims (3)

SUMMARY OF THE INVENTION Method for the preparation of 4,5 “diaryl-2-nitroimidazoles of the general formula Connection proposed R ED ^ 0%, mg / kg 0.6 (1, s) 2,5 Indomethacin Phenylbutazone 0.3 to at least one of Ibuprofen Aspirin 100 305 Phenylquinone paws. The standard division and comparison of the analgesic activity of the compounds of these groups, which can be well compared with respect to their efficacy in humans, is the standard phenylquinone test for the reaction of the paw, which is modified appropriately. The test compound, weighed in 1% methylcellulose, is orally administered to non-fed (17–21 h) white female mice (5 ~ 20 animals in a double-blind test). Aqueous phenylquinone (0.01% phenyl-p-benzoquinone) is injected intraperitoneally after 24 minutes, 0.20 ml 30 minutes each. starting with the test subject's paths, 10 convulsive pain-caused by injected phenylquinone are observed. The effective analgesic 'dose for 50% of the mice (EDDD) is calculated by the moving average method. In addition, the time of the highest activity of movements for many of these compounds is determined. reaction test method for opren mouse. Through the administration of an oral compound, beyond the mymin on the nature of the movement of the paws, Order 4700/80 3S where what R and Rq are fluoro, chloro or coxy; hydrogen, fluorine, hydrogen, benzoyl, ethoxycarbonyl, ethoxyethyl, acetyl, characterized in that ^C G ^C 4 ^aL_ chlorine; o the compound of General formula where g P _g - 2-tetrahydropyranyl, 1-ethoxyethyl; R ₄ and R (j have the indicated meanings, nitrate with nitrogen tetroxide in the presence of n-butyllithium, with the isolation of the target product in free form, by alkylation or acylation.