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    公开号:SU1514245A3
    申请号:SU864028303
    申请日:1986-10-16
    公开日:1989-10-07
    发明作者:Piter Dzhejms Mechin；Dzhon Mervin Ozbond；Kristofer Rejmond Self；Keri Ernest Smizen；Brajen Piter Tong
    申请人:Hoffmann La Roche；
    IPC主号:
    专利说明:

    The invention relates to heterocyclic substances, in particular the preparation of oxazole or isoxazole derivatives of the general formula HeC-A-O-C (K,) (K 2 ) -C (OZHZ, where a. A - CH 7 ; K ^ K ^ CHZ ';
    -t-0
    K 3 -OH; HeC | [, at K 4 - H;
    at,
    'Ν
    - 4-chlorophenyl, or - CH 3 ; K. $ 4-chloro (fluoro or methylthio) phenyl; 3 chlorophenyl; 3,4-dichlorophenyl; CP 3 , or
    C g N 5 ; 8 5 - 4-chlorophenyl, or
    3,4-dichlorophenyl, 5-chlorothien-2-yl; b. K, = K 2 - CH 3 , H 3 - OH at A - -CH 2 CH 2 ~ HeC - 2- (4 ~ chlorophenyl) -3-methyloxazol-5-yl, 3- (4-chlorophenyl) isoxazol-5il or A is CH (CH 3 ), HeC - 3- (4-chlorophenyl) isoxazol-5-yl; VA -> CH 4 ,
    HeC - 2- (4-chlorophenyl) -3-methyloxaol-5-yl with E, - CH 3 , C, H 3 , K 2 - C 2 H 5 ,
    K 3 - OH or P, = P 2 -CH 3 , K 3 - OCH 3 , OC 2 H 5 , OYa, ΝΗ ,; A ~> CH 7 ; K, = = K 2 -CH 3 , HeC - 3- (4-chlorophenyl) isoxazol-5-yl, K 3 - ΝΗ 2 , YHCHN E , piperizino group, having anti-arthritic activity, which can be used in medicine. The goal is to create new, more active substances of the specified class. Synthesis of lead from the corresponding substituted oxymethyl (ethyl) oxazoles (isoxazoles), aliphatic ketones and CHC1 ъ or CC1 4 in an excess of aliphatic ketone at boiling. In the case of K 3 - OH, the product is esterified or converted into an amide-derived or salt with an alkali metal. New compounds have low toxicity and at a dose of 100 mg / kg (per day) reduce edema after inflammation by 41–84%, compared with the control. 2 tab.
    811 ,,,, 1514245 AZ
    1514245
    2
    The invention relates to a process for the preparation of new derivatives of oxazole and isoxazole derivatives or their pharmaceutically acceptable salts with alkali metal -. lamis with anti-arthritic activity 5 , which can be used in medicine for the treatment and prevention of arthritis.
    The purpose of the invention is to obtain new g derivatives of oxazole and isoxazole, with increased anti-arthritic activity in this series of compounds.
    Example 1. 6.9 g (30.8 mmol), 5 2- (4-chlorfepyl) -4-methyl-5-oxazolmethanol is mixed with 6.2 g (155 mmol) of powdered sodium hydroxide in 45 ml of acetone, after which The resulting suspension is heated to the boiling point. Then, 4.9 g (41.1 'mmol) of chloroform in 10 ml of acetone are added dropwise within 30 minutes, after which the resulting suspension is heated at boiling point for 4 hours. Then the solvent is removed by evaporation under reduced pressure, after which the residue is separated in phases with 150 ml of diethyl ether and 400 ml of water. Then the organic phase and the aqueous phase are separated, extracted twice with diethyl ether. The aqueous phase is acidified to pH 2 with concentrated hydrochloric acid and extracted three times with dichloromethane (50 ml). The collected dichloromethane extracts are dried with magnesium sulfate, filtered and evaporated to give 3.7 g of crude product. 8, recrystallization of 40 from znlcate gives 3.1 g (32.5%) of 2 - // 2- (4-hl o p (Fe and yl) -4-milli-5-o ks az o lil / methoxy / -2-methylpropionic acid with T „, 166-167 °. The same product is obtained in the case of using tetrachloroacetate carbon instead of chloroform and potassium hydroxide instead of sodium hydroxide,
    2- (4-Chlo-phosphate) -4-methyl-5-o xa and zolmethanol, used as the raw material, was prepared as follows.
    a.Solution 15.65 g (0.1 mol)
    4-Chlorobenzoic acid in 20 ml of DMF is added dropwise to a stirred suspension of 5.3 g (0.05 mol) of anhydrous sodium carbonate in 80 ml of dimethylformamidez (η, ι). Then the suspension is heated for * I h 80'C. then add a solution of 16.46 g (0.1 mol) of ethyl 2-chloroacetoethane in 10 ml of DMF. Then the suspension is heated for 6 h at 80 ° C and cooled overnight. The solvent is then removed by evaporation under reduced pressure, after which the resulting residue is separated in phases with 400 ml of water and 300 ml of diethyl ether. Then the organic phase is separated and washed twice with water (300 ml each). The organic phase is dried with magnesium sulfate, filtered and the solvent is removed by evaporation under reduced pressure to obtain 26.86 g (94%) of ethyl 2- (4-chlorobenzoyloxy) -3-oxobutyrate as a homogeneous oil (according to TLC)
    6.19.6 g (0.2 stranded) of concentrated sulfuric acid are added dropwise to 90 g (2 mol) of formamide for 10 minutes, while the temperature of the solution is maintained below external temperature by cooling by external cooling. Then 26.8 g (0.09 mol) of ethyl 2- (4-chlorobenzoyloxy) -3-oxo ~ eurate is added and the stirred solution is heated at 140 ° C for two hours. The cooled slurry is separated in phases with 400 ml of water and 300 ml diethyl ether. The organic phase is washed twice with 1N. hydrochloric acid (200 ml each) and once with water, after which they are filtered to remove suspended solids. ”The organic phase is then dried with magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a silica gel using 20% v / v ethyl acetate in hexane as solvent. After evaporation of the eluate, 13.3 g (50%) of ethyl 2 - ^ - chlorophenyl) ^ - methyl - 5-oxazole carboxylate with a melting point of 80-81 ° C are obtained,
    in 9.3 g (35.1 mmol) of ethyl 2- (4 chlorophenyl) -4-methyl-5-oxaeol carboxylate is dissolved in 40 ml of dry tetrahydrofuoane (TG'F). The solution thus obtained is added dropwise to the stirred suspension 1.75 g (46.1 mmol) of aluminum hydride in 10 ml of 60 mL of dry THF at 0 s C. during 10 minutes. The suspension is stirred for 1 h at 0 ° C and then 1, 5 h at room temperature. Excess lithium aluminum hydride is destroyed by adding dropwise a saturated aqueous solution of sulfa3 1514245
    that of sodium, followed by the addition of 100 ml of dilute aqueous sulfuric acid. The aqueous phase is extracted twice with dichloromethane. The collected extracts are washed once with water, after which they are dried with magnesium sulfate, filtered and evaporated. The residue is recrystallized from a mixture of chloroform and hexane to obtain 6.44 g (82%)
    2- (4-chlorophenyl) -4-methyl-5-oxazolmethanol with a melting point of 135 ° C.
    PRI mme R 2. In analogy to Example 1, out of 8.5 g (41.1 mmol) of 2- (4-fluorophenyl) -4-methyl-5-oxazolmethanol, after 5 recrystallizations of the crude product from ethyl acetate, 3.5 g are obtained ( 29%)
    2 - // 2- (4-fluorophenyl) -4-methyl-5-oxazolyl / methoxy / -2-methylpropionic acid with a melting point of 166.5 -> about 167.5 ° C.
    The 2- (4-fluorophenyl) -4-methyl-5oxazolmethanol (melting point 136 ° C) used as the starting material is obtained by analogy with the method described in Example 1a-c.
    Example As in Example 1, out of 13.5 g (57.9 mmol) of 2- (4-trifluoromethyphenyl) -4-methyl-5-oxazolmethanol, after recrystallization of the crude 30% product from ethyl acetate, 5.67 g (28.5%) are obtained 2 - // 2- (4-trifluoromethylphenyl) -4-methyl-5-oxazolyl / methoxy / 2-methylpropionic acid with a melting point of 156-157 ° C.
    The starting product, 2- (4-trifluoromethylphenyl) -4-metip-5-oxazolmethanol, melting point 141-142 ° C, was prepared in a manner similar to Example 1, ab,>
    EXAMPLE 4. In analogy to Example 40 1, of 4.25 g (20.3 mmol) of 2- (4-chlorophenyl) -5 ~ oxazolmethanol, after recrystallization of the crude product from ethyl acetate, 2.2 g (36.6% of ) *
    2 - // 2- (4-chloroethyl) -5-oxaolyl / methoxy / -2-methylpropionic acid with a melting point of 151.5-153 C.
    The 2- (4-chlorophenyl) -5-oxazole-methanol used as the starting material was prepared as follows.
    13.8 ml of 2.42 g (33.4 mmol) of a solution of n-butyl lithium in hexane are added dropwise over 5 minutes to a stirred solution of 6 g (33.4 mmol)
    2- (4-chlorophenyl) okeazol in 60 ml of dry ΊΤΦ maintained at -60 ° C in an argon atmosphere .. Then the resulting suspension is allowed to warm to -40 ° C for 30 minutes, after which 6.9 g (230 mmol) paraformaldehyde as a suspension in 15 ml of dry TG <then, the mixture is allowed to warm to room temperature for 1.5 hours, after which it is stirred for another 1 hour. Then 10 ml of a saturated aqueous solution of ammonium chloride are added to the mixture, after which the resulting suspension is separated in phases with 300 ml of water and 200 ml of dichloromethane. The organic phase is then separated and the aqueous phase is extracted twice with dichloromethane (200 ml each). The collected organic phases are dried with magnesium sulfate and filtered, after which the solvent is removed by evaporation under reduced pressure, resulting in an oil, which is chromatographed on silica gel using ethyl acetate (70 vol.%) As eluent. The resulting eluate is evaporated to give 4.25 g (60%).
    2- (4-chlorophenyl) -5-oxazolmethanol with a melting point of 115-116 C.
    Example 5, analogously to example 1, but using potassium hydroxide powder instead of powdered sodium hydroxide from 7.2 g (34.4 mmol) of 5- (4-chlorophenyl) -2-oxazolmethanol from the grains, after recrystallization of the crude product from ethyl acetate, 1.4 are obtained g (14%) 2 - // 5- (4-chlorophenyl) 2-oxazolyl / methoxy / ”2-methylpropionic acid with a melting point of 143-146 ° C.
    The 5- (4-chlorophenyl) -2-oxazolmethanol used as the starting material was prepared as follows.
    but. With stirring and periodic cooling, providing a temperature not higher than room temperature, 12.78 g (50 mmol) Ν - / (4-χπορbenzoyl) methyl / -2-ethoxyacetamide are dissolved in
    32.5 ml of concentrated sulfuric acid. The resulting mixture for
    It is kept at room temperature for 20 hours, after which it is poured onto 600 ml of ice and water and extracted three times with diethyl ether (150 ml each). The collected ether extracts are washed with 100 ml of saturated sodium bicarbonate solution, dried with magnesium sulfate, filtered and evaporated to give 10.55 g (89%) of 5- (4-chlorophenyl) -2-ethoxymethyl oxazole as a syrup.
    b. 7.5 ml of concentrated sulfuric acid is carefully added to the cool5
    1514245
    6
    suspended ice 1.4 g (5.9 mmol)
    5- (4-chlorophenyl) -2-ethoxymethyl-oxazole in 4.5 ml of water. The resulting solution is stirred and heated under reflux for 4 hours at 140 ° C. Then it is cooled and poured onto a 140 ml mixture of ice and water. The resulting mixture was extracted three times with dichloromethane (30 ml each). The collected dichloromethane extracts are washed with 50 ml of saturated sodium bicarbonate solution, dried with sodium sulfate, filtered and evaporated. After recrystallization of the crude product from toluene, 0.80 g (652!) Of 5- (4-chlorophenyl) 2-oxaolol methanol is obtained with a melting point of 100-103.5 ° C.
    EXAMPLE 6 Analogously to Example 1, from 16 g (76 mmol) 4- (4-chlorophenyl) -20 2-oxazolmethanol, after recrystallization of the crude product from toluene, 8.85 g (392!) 2 are obtained - 4 4 // // - (4-chlorophenyl) -2-ocosazolyl / methoxy / -2-methylpropionic acid with a melting point (5 of 115.5-118 ° C.
    The 4- (4-chlorophenyl) -2-oxazolmethanol used as the starting material was prepared as follows.
    and 40 g (0.41 mol) of concentrated sulfuric acid are added dropwise with stirring to 150 g (3.3 mol) of formamide, and the temperature of the solution is kept below 10 1 'C by cooling with ice. Then add 50 g (0.2 mol) (4-chlorobenzoip) methylethoxyacetate, then the solution is stirred and heated for two hours at 140 C. The mass is cooled, poured into 2 liters of water, acidified to pH 1 with concentrated hydrochloric acid and extracted once with toluene (500 ml) and twice with toluene (250 ml each). The collected toluene extracts are washed with water, dried with sodium sulfate, filtered and evaporated. Ostatoxyrope is extracted with 700 ml of hot gasoline (boiling point 60-80 ° C). The solution is evaporated to dryness, and the residue is dissolved in 150 ml of hot gasoline (boiling point 40-60 ° C). After cooling in a mixture of acetone and CO the product crystallizes, is quickly filtered off and dried, yielding 21.7 g of (477) 4- (4-chlorophenyl) -2-ethoxymethyloxazole as a soft solid with an undetermined melting point.
    b 181 ml of 1 M solution of trichloride boron in dichloromethane is added dropwise to the stirred solution
    21.5 g (90.5 mmol) of 4- (4-chlorophenyl) -2-ethoxymethyl-oxazole in 100 ml of dichloromethane. In this case, by cooling with ice, the temperature of the mass is maintained at a level below 10 ° C. At the end of the process the additive mass is stirred for another 2 hours at room temperature, after which it is poured into 500 MP of a mixture of ice and water. The dichloromethane phase is then separated. The aqueous phase is extracted with 100 ml of dichloromethane. The collected dichloromethane extracts are washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered and evaporated. After recrystallization of the residue from toluene, 15.7 g (83%) of 4- (4-chlorophenyl) -2-oxazolmethanol are obtained with a melting point of 68-71.5 ° s
    Example 7. Analogously to example 1 of 23.15 g (90 mmol) of 2- (4-trifluoromethylphenyl) -5 "methyl - 4-oxazolmethanol after recrystallization of the crude product from toluene, 8.0 g (26%) of 2 - // 2 - (4-trifluoromethylphenyl) -5-methyl-4oxazolyl / methoxy / -2-methylpropionic acid in the form of a cream-colored crystalline solid with a melting point of 146-147 ° C.
    The 2- (4-trifluoromethylphenyl) -5methyl-4-oxazole-methanol used as the starting material is prepared as follows.
    but. 34.8 g (0.20 mol) of 4-trifluoromethylbenzaldehyde and 20.2 g (0.20 mol)
    2,3-butanedionemonoxime is dissolved in 100 ml of glacial acetic acid. With stirring at room temperature, gaseous hydrogen chloride is passed through the mixture until a saturated solution is formed. Then the mass is stirred at room temperature overnight; after which it is treated with an excess of anhydrous diethyl ether. The colorless crystalline precipitate is filtered, using fresh anhydrous diethyl ether, the mother liquors are stripped off and then dried in vacuo to give 50 g (86%) of 2- (4-trifluoromethylphenyl) -4,5-dimetypoxazole-M-oxide acid hydrochloride with a melting point 175-177 ° C (with decomp.).
    b. 50 g of the indicated hydrochloride oxyde added to the suspension 14 g
    Ί
    1514245
    eight
    (O, 17 mol) of finely divided aqueous sodium acetate in 100 ml of acetic anhydride. The resulting mixture is stirred until the exothermic reaction subsides, after which it is heated for about 4 hours to a temperature of about 140 ° C. The mass is then cooled, and the inorganic precipitate is filtered off and washed with toluene. The collected organic solutions are concentrated in vacuo, and the residue is separated in phases using dichloromethane and an excess of aqueous 2Ν, sodium carbonate solution. The organic phase is then separated, washed twice with water, dried with magnesium sulfate, filtered through silica gel and concentrated in vacuo to give 30 g (60%) of crude 4-acetoxymethyl-2- (4-trifluoromethylphenyl) -5-, θ of metipoxazole as yellowish solid semi-crystalline substance, which according to TLC is homogeneous.
    in 30 g of the specified ester 25 is dissolved in 400 ml of ethanol. The resulting solution is treated with 300 ml of aqueous 2 n sodium hydroxide solution, after which the mass is stirred at room temperature overnight. Then, its θ is concentrated in vacuo, and the residue is separated in phases with dichloromethane and water. The aqueous phase is separated and washed with two additional portions of dichloromethane. The collected organic phases are washed twice with water, dried with magnesium sulfate, filtered and concentrated in vacuo to give 23 g (90%) of crude 2- (4-trifluoromethylphenyl) -5-methyl-4-oxazolmethanol as a yellow solid. Brown color. After recrystallization from cyclohexane in the presence of bleaching charcoal, pure 2- (4-trifluoromethylphenyl) -5-methyl-4-oxazole-methanol is obtained in the form of a cream-colored crystalline solid with a melting point of 9899 ° C.
    Sample Analogously to example 1, from 11.2 g (50 mmol) of 2- (4-chlorophenyl) -5-methyl-4-oxazolmethanol, after recrystallization of the crude product from toluene, 2.7 g (17.4%) of 2 - // 2- is obtained (4-chlorophenyl) -5-methyl-4-oxazolyl / methoxy / -2-methylpropionic acid as a colorless crystalline solid with a melting point of 123-124 C.
    The 2- (4-chlorophenyl) -5-methyl-4oxazolmethanol used as the starting material is obtained either by reducing the known 2- (4-chlorophenyl) -5-methyl-4-oxazolecarbonic CI 'slots using lithium aluminum hydride in a manner similar to that described in Example 1c, or from 2- (4-chlorophenyl) -4,5 dimethyloxazole-M-oxide, similar to the method described in examples 7b-c.
    By any of these methods, 2- (4-chlorophenyl) -5-methyl-4-oxazolmethanol is obtained with a melting point of 130—
    131 C (from cyclohexane).
    PRI me R 9. Similarly to example 1, from 6.5 g (31.4 mmol) of 2- (4-fluorophenyl) -5-methyl-4-oxazolmethanol, after recrystallization of the crude product from toluene, 1.5 g (17 %) 2 - // 2- (4-fluorophenyl) -5-methyl-4-oxazolyl / methoxy / -2-methylpropionic acid as a colorless crystalline solid with a melting point of 118-120 ° C.
    The 2- (4-fluorophenyl) -5-methyl-4oxazolmethanol used as the starting material is obtained in a manner similar to the method described in Example 8, by reducing the known 2- (4-fluorofe-, nyl) -5-methyl-4-oxazolecarboxylic acid with by lithium aluminum hydride or by rearrangement of 2- (4-fluorophenyl) -4,5-dimethyl-oksazol-N-oxide in acetic anhydride followed by alkaline hydrolysis in an aqueous-alcoholic medium. By any of these methods, 2- (4-fluorophenyl) —5 — methyl-4-oxazolmethanol with a melting point of 153–155 ° C (from cyclohexane) is obtained.
    Example 10. Analogously to the previous examples, 1.6 g (57%) of 2 - // 2- (4-chlorophenyl) -4-oxazolyl / methoxy / -2-methylpropionic acid with a melting point of 144.5-145 ° C are obtained.
    Example 11. Analogously to example 26, methyl-2 - // 3- (4-chlorophenyl) -5-isoxazolyl / -methoxy / -2-methipropionate is obtained in the form of a colorless oil with a purity of 99% (according to BJC).
    EXAMPLE 12 Analogously to the previous examples, 2- // 3- (4-chlorophenyl) -5-isoxazolyl / methoxy / -2-methylpropionic acid is obtained with a melting point of 130-134 ° C.
    PRI me R 13. Analogously to example 1, but using instead of the guide 151
    potassium sodium hydroxide potassium from
    5 g (24 mmol) of 5- (4-chlorophenyl) -3 ~ isoxaeol methanol after recrystallization of the crude product from a mixture of toluene and hexane to obtain 1.06 g (15%)
    2 - // 5- (4-chlorfepyl) -3-isoxazolyl / methoxy / -2-methylpropioic acid with a melting point of 115-118 ° C.
    The 5- (4-chlorophenyl) -3-isoxazolmethanol used as the starting material was prepared as follows.
    Ethyl 5- (4-chlorophenyl) -3-isokeazol carboxylate with a melting point of 124-126 C in the amount of 4.75 g (19 mmol) is dissolved in 30 ml of dimethyl ether under nitrogen atmosphere and a suspension of 1.05 g is added dropwise ( 48 mmol) lithium borohydride in 5 ml of ether "The resulting mixture is stirred for 15 minutes at 20 ° C, gradually heated to reflux and maintained at this temperature for 3.5 hours. Then it is poured into a mixture of ice and water, extracted with ethereal and the collected ether extracts are dried with magnesium sulfate, filtered and evaporated. Recrystallization of the residue from toluene yields 2.8 g (71%) of 5- (4-chlorophenyl) -3-neoxazole-methanol with a melting point of 93-95 ° C.
    Example 14. In analogy to example 1, instead of using potassium hydroxide instead of sodium hydroxide, from 5 g (22.4 mmol) 3- (4-chlorophenyl) -5 ~ ns oxazolium L-2-ethanol after recrystallization of the crude product from ethyl acetate- hexane receive 0.9 g (13%) of 2- / 2- / 3- (4-chlorophenyl) -5 isoxazolyl / -ethoxy / -2-methylpropanoic acid with a melting point of 98-100 ° C.
    The 3- (4-chlorophenyl) -5-nzoxazolyl-2-ethanol used as the starting material was prepared as follows.
    5.05 g (5 mmol) of triethylamine in 20 ml of distil ether at -10 ° C are added dropwise to a solution of 3.86 g (5.5 mmol) of 3-butyl-1-ol and 9.50 g (5 mmol) 4-chlorobenzene-M-hydroxycarboximidoyl chloride in 200 ml of dry diethyl ether. After 3 h, filter the reaction mass, evaporate the filtrate, and the residue is recrystallized from ethyl acetate-hexane to give 6.15 g (55%) of 3- (4-chlorophenyl) -5-isoxazolyl-2-ethanol with a temperature of
    4245 10
    melting at 65.5-67.5 ° C. after crystallization from ethyl acetate,
    PRI me R 15 "Analogously to Example 26, pure methyl 2 - // 35 (3,4-dichlorophenyl) -5-isoxazolyl / methoxy / -2-methylpropionate is obtained in the form of an oil.
    Calculated,%: C 52.34; H 4.39;
    N 4.07
    1 η С 15 Н, 5С1, N0 «
    Found,%: C 52.57; H 4.38;
    N 4.15
    PRI me R 16. Similarly to the previous examples, 2 - // 3- (3,4, $ dichlorophenyl) -5-isoxazolyl / -methoxy / 2-methylpropionic acid with a melting point of 129-131 ° C is obtained.
    Example 17. Analogously to example 1, but using instead of hydroxide
    20 sodium hydroxide powder
    potassium, from 5 g (22.4 mmol) of 3- (4-chlorophenyl) -5-isoxazolyl-1-ethanol after recrystallization of the crude product from a mixture of ethyl acetate and hexane receive
    25 0.7 g (10%) 2- / 1 (1 <5) ~ / 3 ~ (4-chlorophenyl) 5-isoxazolyl / -ethoxy / -2-megylpropionic acid with melting point 141-143 ° C.
    Re-dissolution of the indicated Ki30 slots K 8 is as follows.
    A mixture of 6.18 g (200 mmol) acid
    K8 and 3.32 g (200 mmol) (+) - ephedrine
    recrystallized from 20 ml of isopropanol "Then the crystals 6 times over with
    '· * Crystallized from isopropanol to obtain pure (-) - acid salt of ephedrine. Then the salt is separated in phases with 2 n. hydrochloric acid and distillate ether. The ether extract is then dried with sodium sulfate, filtered and evaporated to give (-) - 2- / 1- / 3- (4 ^ 5 chlorophenyl) -5-isoxazolyl / ethoxy / -2methylpropioic acid, after recrystallization from ethyl acetate-hexane, with a melting point 121-125 ° C; / s ^ / 5yz = -96.1 (c = 1% in ethanol).
    Similarly, but using instead
    50 (+) - ephedrine (-) - ephedrine, get (+) - 2- / 1- / 3- (4-chlorophenyl) -5-isoxazolyl-ethoxy / -2-methylpropionic acid with a melting point of 120— 124 ° C ; / c </ = + 94.7 ° (c = 1% in ethanol).
    40
    55
    589
    3- (4-Chlorophenyl) -5-isoxazolyl-1 ethanol, used as starting material, was prepared as follows.
    1514245
    Similar to the third paragraph of example 14, using 1.93 g (27 mmol)
    3-butyn-2-ol, after recrystallization from methylcyclohexane, 3.82 g (68%) of 3- (4-chlorophenyl) -5-isoxaolol-1-ethanol with a melting point of 63-65 ° C are obtained.
    Example 18. Similarly to the previous examples get 2 - // 3- (5-χπορ- | θ thien-2-yl) -5-isoxazol / methoxy / -2 methylpropionic acid with a melting point of 128-130 ° C
    Example 19. 1.3 g of oxalyl chloride is added dropwise to 3 g and
    (100 mmol) 2 - // 3- (4-chlorophenyl) -5isoxazolyl / -methoxy / -2-methylpropionic acid in 100 ml of diztile ester. After 4 hours at 20 ° C, diethyl ether is removed under reduced pressure, 20% and the acid chloride is dissolved in 75 ml of THF and added to a solution of THF saturated with ammonia gas. After 1.5 hours, the heavy white precipitate is removed by filtration, and the resulting 25 filtrate is evaporated. The result of 2.46 g (82%) 2 - // 3- (4-chlorophenyl) -5-isoxazolyl / methoxy / - 2-methylpropionamide, which is crystallized from ethanol with a melting point of 154-155 ° C .
    Example 20. Analogously to example 19, but using instead of a solution of THF methylamine in dry diethyl ether saturated with ammonia gas, after crystallization from ethyl acetate, 2- // 3- (4-chlorophenyl) -5-isoxazolyl / methoxy / -Ν, 2-dimethylpropionamide is obtained with a melting point of 93-94 ° C.
    EXAMPLE EXAMPLE 21 Analogously to Example dd about 19, but using 3- (4-chlorophenyl-5 instead of THF saturated with ammonia gas piperidine solution in dry diethyl ether, after crystallization from ethyl acetate-hexane - 1 // d-methane Tyl-1- (piperidinocarbonyl) ethoxy / -methyl / isoxazole with a melting point of 239-242 ° C.
    Example 22. Analogously to example 1 of 5.17 g (20 mmol) of 2- (3,4-dichlorophenyl) -4-methyl-5-oxazolmethanol -. barely recrystallizing the crude product from ethyl acetate-hexane, 1.69 g (24.6%) of 2 - // 2- (3,4-dichlorophenip) -4-methyl-5-oxazolyl / methoxy / -2- $$ methypropionic acid is obtained with a melting point of 130-131 C.
    2- (3,4-Dichlorophenip) -4-methyl-5oxazolmethanol with a melting point of 158-159 ° C, used as a starting material, is obtained by analogy to the method described in Example 1 a-B.
    II p and mep 23. Analogously to example 1, of 4.6 g (20.6 mmol) of 2- (3-chlorophenyl) -4-methyl-5-oxazolmethanol, after recrystallization of the crude product from ethyl acetate-hexane, 1.2 g are obtained (18.8%) 2 - // 2- (3-chlorophenyl) -4methyl - 5-oxazolyl / methoxy / -2-methylpropionic acid with a melting point of 117 ° C.
    2- (3-Chlorophenyl) -4-methyl-5-oxazolmethanol with a melting point of 123 C, used as a starting material, was prepared in a manner similar to Example 1a-c.
    EXAMPLE 24 Analogously to Example 1 from 5 g (21.3 mmol) of 4-methyl-2- / 4 (methylthio) phenyl / -5-oxazolmethanol, after recrystallization of the crude product from ethyl acetate-hexane, 0.4 g are obtained. (6%) 2-methyl-2 - // 4-methyl-2 / 4- (methylthio) phenyl / -5-oxazolyl / methoxy / -propionic acid with a melting point of 128 ° C.
    4-methyl-2- / 4- (methylthio) phenyl / -5oxazolmethanol with a melting point of 130 ° C, used as a starting material, is obtained analogously to example 1a-c,
    Example 25. 4,44 g (14.5 mmol) of 2 - // 2- (4-chlorophenyl) -4-methyl-5 ~ oxazolyl / -methoxy / -2-methylpropionic acid is dissolved in 40 ml of dry dichloromethane and add 1 a drop of dkf. Then, 1.96 g (16 mmol) of thionyl chloride is added, after which the resulting mixture is heated at boiling point for 4 hours. Then, the cooled solution of the acid chloride obtained is added with stirring to 70 ppm of an aqueous solution of ammonium hydroxide (specific weight 1.880) and crushed ice. After stirring for 16 h, the suspension is extracted with 200 mp of dichloromethane. Then the organic phase is separated and washed twice with water (100 ml each). The organic phase is then dried with magnesium sulfate and filtered, after which the solvent is removed by evaporation under reduced pressure. As a result of recrystallization of the crude solid, 2.2 g (49%) of 2 - // 2- (4-chlorophenyl) -4methyl-5-oxazolyl / methoxy / -2-methyl1514245 are obtained from ethyl acetate.
    proinonamide with a melting point of 177-178 ° C.
    II p and meper 26. 4,44 g of 14.5 mmol 2 - // 2- (4-chlorophenyl) -4-methyl-5-oxazolyl / methoxy „/ - 2-methylpropionic. $
    Acids are dissolved in 40 ml of dry dichloromethane, then 1 drop of DMF is added. Then, 1.9 g (16 mmol) of thionyl chloride is added, after which the mixture is heated for 4 hours at the boiling point. To a rendered solution of the acid chloride thus obtained at 70 ° C, 70 ml of ethanol are slowly added. The resulting mixture, 5, is stirred for 18 h, and then the solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using 17% by volume ethyl acetate in hexane for 20 elution. After evaporation of the nitrogen, 2.8 g (57.2 / 0 ethyl-2 - // 2- (4 chlorophenyl) -4-methyl-5-oxazolyl / methoxy / -2-methylpropionate with a melting point of 75-76 p. 75 are obtained. C. 25
    Example 27. In a manner similar to Example 1, from 2 g (8.4 mmol) of 2- (4-chlorophenyl) -4-ethyl-5-oxazolmethanol, after recrystallization from ethyl acetate-hexane, 1.09 g (40%) of 2 - // 2- 39
    (4-chlorophenyl) -4-ethyl-5-oxazolyl / methoxy / -2-methylpropionic acid with a melting point of 133.5-134.5 ° C.
    2- (4-Chlorophenyl) -4-ethyl-5-oxazolmethanol with a melting point of 135136 C, used as a starting material, is obtained from 4-chlorobenzoic acid and ethyl 2-chloro-3oxopentanoate in a manner similar to that described in Example 1a-c dd
    P II EXAMPLE 28. Similarly to the previous examples to give 2 - // 2- (4hlorfenil) -4-oxazolyl metn.1-5 / Methoxy / -2-ethylbutyric acid with a melting temperature of 157 C.
    II p and me R 29. Analogously to Example 1, from 5.5 g (23 mmol) of 2- (4-chlorophenyl) -4-methyl-5- (2-hydroxyethyl) oxazole after recrystallization of the crude product from ethyl acetate-hexane, 59 are obtained. 0.4 g (5.2%) of 2- / 2 - / 2- (4-chlorophenyl) -4 methyles-1-5-oxazolne / ethoxy / -2-methyl-propionic acid with a melting point of 114-115 ° C.
    EXAMPLE 30 Analogously to example 1, but using ethylmethyl ketop instead of acetone, from 3.5 g (15.6 mmol) 2 (4-chlorophenyl) -4-methyl-5-oxazolmethanol after recrystallization of the crude
    0.47 g (9.27%) of 2 - // 2- (4-chlorophenyl) -4-methyl5-oxazolyl / methoxy / -2-methyl-butyric acid with a melting point of 143144 ° C is obtained from the product from toluene.
    II p and mep 31 0 Analogously to Example 26, methyl 2 - // 2- (4-xporpenyl) -4-methyl-5-oxazolyl / methoxy / 2-methylpropionate with a melting point of 88-90 ° C is obtained.
    Example 32. 10.0 ml of a 1 M solution of sodium isopropanolate in isopropanol is added to a warm stirred solution of 3.09 g (10 mmol) 2 - // 2- (4-chlorophenyl) -4-methyl-5-oxazole il / sy labels (-2-methyl propionate in 30 ml of isopropanol). After slowly cooling the mixture, 3.0 g (90%) of 2 - // 2- (4-chlorophenyl) -4-methyl-5-oxazolyl / methoxy / -2-methylpropionate sodium are obtained in the form of a colorless crystalline solid with a melting point 277-278 ° C.
    The study of the biological activity of the compounds of formula (I).
    The compounds of formula (I) and the pharmaceutically acceptable salts of the compounds of formula (I), where K 3 is a hydroxyl group, with bases, possess valuable anti-arthritic properties, as manifested, for example, in the following case.
    Female rats were injected subcutaneously in the shaved back with an emulsion (10 7 - 0.1 ml) of type (II) collagen and Freund's incomplete adjuvant (PregensGester asychocab). Two weeks later, rats with flamed hind legs were treated with the test compound, administered orally as a daily dose for another two weeks. Then, paw volumes were measured plethysmographically with water displacement, and the activity of the active principle was expressed as average changes in paw volume compared to the volume of untreated paws. Statistical analysis was carried out using the ZbiDepb'z ipraggeDb Sezb test. The results of the anti-arthritic effect obtained using oxazole derivatives as test compounds are presented in Table. one.
    Inflammation was also caused in rats by subsurface injection.
    Bacteria MusobasSeggit Siegegs1-813
    in the right hind legs of groups of rats. The change in paw volume was measured based on
    15
    1514245
    oppression water paradise per day song of oral administration of the compound, the results obtained (anti-arthritic effect of oxazole derivatives and isoxaol) are presented in Table. 2. $
    The compounds of formula (I) and the pharmaceutically acceptable salts of the compounds of formula (I), where K 3 is a hydroxyl group, can be used with alkali metals as medicines, for example, in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions / emulsions or suspensions, or rectally, for example, in the reel of suppositories, or parenterally, for example, in the form of solutions for injections,
    Pharmaceutical preparations contain, as an active principle, compounds of formula (I) and pharmaceutically acceptable salts of such compounds, where Ks means a hydroxyl group, c. alkali metals.
    Tablets prepared in the usual way, contain the following ingredients, mg: 30
    Active principle '50 Lactose 120 Corn starch 75 Talc four Magnesium stearate one Tablet weight is 2 50 mg Capsules Cooked the usual
    contain the following ingredients, mg:
    Active principle 100 Lactose 150 Corn starch 20 Talc 5
    35
    40
    The weight of the contents of the capsule is 275 mg
    The compounds of formula (I) belong to a low-toxic category, for example, 2 - // 2- (4-chlorophenyl) -4-methyl 5-oxazolyl / methoxy / -2-methyl propionic acid did not adversely affect the rat ;: at doses up to 200 mg / kg / day.
    45
    > 0
    As can be seen from Table 2, new aqueous oxazole and isoxaolol reduce edema after inflammation by 41-847. 55
    and are promising! for their use in medicine as anti-arthritic drugs.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining oxazole derivatives or isoxaol general formula (I)
    V "
    He1-AOAC
    where A is C, -C, -alkylene;
    He1 - 2-phenyloxazol-4-yl or -5yl or 4- or 5-phenyl-oxazol-2-yl, monosubstituted in the phenyl ring by a halogen atom or trifluoromethyl- or methylthio or disame chlorine atoms in the phenyl ring and possibly C (~ C4-alkyl or He — 3 or 5-phenyl-isoxaol-5-yl or -3-yl in the oxyl ring, mono- or disubstituted in the phenyl ring by chlorine atoms, or chloro-islylisoxazole 2-yl;
    E, and K, independently of each other C, -C 4 -alkyl;
    K 3 - hydroxy-, C, -C 4 -alkoxy ~, amino-, C, -Sy-alkylamino or piperidino,
    or in the case when K e is a gtsroksgruppa, their pharmaceutically acceptable salts with alkali metals, characterized in that the alcohol of General formula (II)
    Heaven - A - OH,
    where A and Heaven have the indicated meanings, are reacted with an excess of ketone of the general formula (III)
    ""WITH
    II
    0
    where k, and have the indicated values, and chloroform or carbon tetrachloride in the presence of an alkali metal hydroxide at the boiling point of the reaction mass, the desired product is isolated, where K 3 is a hydroxy group, or it is reacted with C, -C 4 alkanol to obtain the desired product where K a is C, -C 4 alkoxy, either with ammonia or the corresponding amine to form the desired product, where K $ is amino,
    C 1 — Cd — alkylamino or pipercinol group, or the desired product, where the hydroxy group is transferred to its headlamps17
    1514245
    18
    An acceptable alkali metal salt.
    Priority for the p p from and a to and m:
    10/17/85, with A - methylene; HeC 2-phenyloxazol-4-yl or -5-yl or 4 or 5-fenpl-oxazol-2 ~ yl, monosubstituted in the feiil ring by a halogen atom and the trifluoromethide group or diatesubstituted in the feiil ring by chlorine atoms and possibly containing an oxazole nucleus C, -C 4 -alkyl or HeC '· 6 '
    3- or 5-feinl-isoxazol-5-yl or -3-yl, mono- or disubstituted in the feil ring with chlorine atoms; K, and K 2 are independently of each other C, -C alkyl; K 3 - hydroxy-,
    C, -C, is alkoxy, ayasho, C, -0, is an alkylamino group or, in the case of a hydroxy group, their pharmaceutically acceptable salts with alkali metals;
    07.17.86, nrp Λ - С, -С ^ -alkylene;
    11e (: - 2-phenyloxazol-4-yl or -5-yl or 4- or 5-phenyloxazol-2-yl, monosubstituted in the feiil ring by a halogen atom or trfluoromethyl- or methylthio group or disubstituted in the feiil ring by chlorine atoms and possibly containing in the oxazole ring C, -C ,, -Alcpp or Neb-3-or 5-phenyl-isoxazol-5-yl or -3-yl, mono-or disubstituted in the feiil ring by chlorine atoms, or chlorothenylnzoxazol-2-yl; K , and K, independently of each other, mean C, -C ,, - alknl; - hydroxy-, C, -C-alkoxn-, amino-,
    C, —C + —slknlamino — or piperidium, or in the case when K 3 is a hydroxy group, of their pharmaceutically acceptable salts with alkali metals.
    Table 1
    Compound,receivedby example Dosage mg / kg / day Paw volume, averagechange to1 1st day compared withthe first one 50 -0.29 + 0.005 * + ten 100 -0.47 + 0, About 4 " eight 100 -0.44 + 0.11 ** Control experience - + 0.13 + 0.12
    15 + p = 0.005;
    ++ p = 0.01 compared with control - experience of bezm). (in testing and 8bi8epb'z "b"Table 2Compound Dosage Reduction received ka, mg / kg / paw swelling in by example / day the period from the 1st to the 4th day compared tocontrolby animals one 100 81 ** ten 100 84 ** eight 100 67 ** nineteen 100 61 ** 20 100 44 * 21 100 41 * 25 100 61 * 26 100 71 **
    40 * p = 0.01;
    ** p = 0.001 compared with the control experiment.
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    同族专利:
    公开号 | 公开日
    CS741586A2|1987-07-16|
    DK470886A|1987-04-18|
    EP0220573A1|1987-05-06|
    US4774253A|1988-09-27|
    CA1287058C|1991-07-30|
    NO167284B|1991-07-15|
    FI864052A|1987-04-18|
    EP0220573B1|1991-12-11|
    DK470886D0|1986-10-02|
    CS255881B2|1988-03-15|
    PT83565B|1989-05-31|
    NZ217871A|1990-03-27|
    PH23022A|1989-03-03|
    IL80290A|1990-11-29|
    IL80290D0|1987-01-30|
    AU594382B2|1990-03-08|
    HU195792B|1988-07-28|
    PT83565A|1986-11-01|
    ES2010537A6|1989-11-16|
    DE3682873D1|1992-01-23|
    NO167284C|1991-10-23|
    AU6383886A|1987-04-30|
    ES2002420A6|1988-08-01|
    HUT44245A|1988-02-29|
    MC1770A1|1987-07-17|
    NO864128D0|1986-10-16|
    ZW19786A1|1988-05-18|
    NO864128L|1987-04-21|
    FI864052A0|1986-10-07|
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    US5380738A|1993-05-21|1995-01-10|Monsanto Company|2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858525578A|GB8525578D0|1985-10-17|1985-10-17|Heterocyclic compounds|
    GB868617503A|GB8617503D0|1985-10-17|1986-07-17|Heterocyclic compounds|
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