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    • 专利摘要:
    The method of producing derivatives of trisubstituted imidazodes of the general formula A-AZ, where R and Rj are phenyl, each substituted by lower alkoxy; A is lower alkylene or lower alkylidene R is carboxy, lower alkoxycarbonyl or carbamoyl, or where one of the residues R and R is pyridyl or 1-oxide-pyridyl, and the other is phenyl or substituted lower alkoxy, hydroxy or halogen; . A - lower alkylene, lower alkylidene, lower alkenylidene or cyclopentylidene - .. Rg - carboxy, lower alkoxycarbonyl or lower alkanoyl oxoxy shcoxycarbonyl; or where one of the residues R and R is pyridyl or 1-oxide-pyridyl, and the other is thienyl; . A is lower alkylidene, R, j is lower alkoxycarbonyl with the condition that if A is methyl, and Rj is carboxy or carbamoyl, both residues R and R cannot simultaneously mean p-methoxyphenyl, -OR or their salts with bases , it is tl by the fact that the compound of the general formula N H N O O CO of ate where and A. have the indicated values are NO, dehydrogenate 2, 3-dichloro-5,6-dicyano 4. -1,4-benzoquinone or 2,3,5,6-tetrachloro-p-benzoquinone or p-benzoquinone or palladium on carbon and in free form or in the form of salts with bases or if R "is carboxyl, if desired are isolated in the form of esters or in the form of amides, or, if one of the residues R and R. is pyridyl, if desired, made in the form of pyridine-L-oxide.
    公开号:SU1169534A3
    申请号:SU823468675
    申请日:1982-07-30
    公开日:1985-07-23
    发明作者:Саллманн Альфред
    申请人:Циба-Гейги,Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of novel trisubstituted imidazoles which can be used in medicine as anti-inflammatory agents. Imidazole derivatives are known to have, in position 2 of the imidazole ring, mainly alkyl or cycloalkyl substituents that exhibit anti-inflammatory properties and are intended for systemic use 1. However, these compounds are not intended for external use. The known method of dehydrogenating heterocyclic systems in the presence of palladium on carbon or benzoquinone derivatives is heated by heating in an organic solvent medium (2J. The purpose of the invention is to develop a goal based on the known method of producing new trisubstituted imidazoles with valuable pharmacological properties. a method of producing derivatives of trisubstituted imidazoles of the formula N. where R and R are phenyl, each substituted lower alkoxy A is lower alkylene or lower alkyl Lidene R3 carboxy, lower alkoxycarbonyl or carbamoyl, or where one of the residues and pyridyl or 1-oxidiridyl, and the other - phenyl or substituted lower JKOKCH al, oxy or halogen phenyl; A - lower alkylene, lower alkyl: iden, lower alkenylidene or cyclopentylidene RJ is carboxy, lower alkoxycarbonyl or lower alkanoyloxy lower alkoxycarbonyl-, or where one of the residues R and RJ is pyridyl or 1-oxide-pyridyl and the other is thienyl A is lower alkylidene; RJ is lower alkoxycarbonyl with the condition that if A is ethylidene and K is carboxy or respectively carbamoyl, both residues R and R cannot simultaneously mean n-methoxyphenyl, or their salts with bases, a compound of the general formula: H TSI, nf /) where and A have the indicated meanings, they are dehydrated with 2,3-dichloro-5,6-dicyano-1. A-benzoquinone or 2,3,5,6-tetrachloro-p-benzoquinone or fi-benzoquinone or palladium on carbon and isolated in free form or as salts with bases or if R, is carboxyl, if desired, is isolated as esters or amides, or if one from residues R. and R - pyridyl, if desired, isolated as pyridine-N-oxide. Pyridyl is 3- or 4-pyridyl, 1-oxide-pyridyl is 1-oxide-3-pyridyl or 1-oxide-4-pyridyl. Phenyl substituted with lower alkoxy is 3-or 4-methoxy-phenyl or 3,4-dimethoxyphenyl. Halogen is, for example, icnop. Lower alkoxy is methoxy-totoxy. Lower alkylene is, for example, methylene, ethylene, 1,3-propylene. Lower alkylene is, for example, ethylide, n, 2,2-propylidene. Lower alkylene is butenylidene. The salts of the compounds of the formula I in the case of K-carboxy are salts with bases. Compounds of formula I are obtained by dehydrogenating a compound of formula II A-R and, if desired, the Free compound obtained according to the invention is converted into a salt or the salt obtained according to the invention is converted into the free compound. The dehydration of compounds of the formula II is carried out by a known method, as a rule, at elevated temperature, for example, in the temperature range of SO-ZOO C, using a dehydrating agent. As such agents, palladium on carbon or p-benzoquinones are used, for example, tetrachloro-p-benzoquinone or 2,3-dichl -5,6-dicyano-p-benzoquin6n. The compound obtained according to the invention can be converted in a usual manner to another compound of Form I. Thus, according to the invention, compounds of formula I obtained according to the invention can be free and esterified carboxyl groups Rj can be transformed one into another. . The free carboxyl group of R may, for example, in the usual manner, in the presence of an acidic catalyst, be esterified into an esterified carboxyl group of R ,. The etherified carboxyl group can, in turn, be converted to a free carboxyl group or the corresponding base metal salt. Further, compounds with an esterified carboxyl group may be. be prepared by treating the corresponding alkali salts with dialkyl sulfate in dimethylformamide. Compounds with carbamoyl can be converted to the corresponding compounds with Rg-carboxy-alkaline hydrolysis. Alkoxyaryl compounds can be cleaved to the corresponding aromatic alcohols by hydrolysis in the presence of Lewis acids, such as boron tribrimide. The novel compounds of the formula I and their pharmaceutically used salts, when applied locally, have a pronounced anti-inflammatory effect. viy. Thus, anti-inflammatory properties can be proved, for example, by suppressing croton oil-induced rat ear edema in normal rats in the dosage range of 1-100 MG / ML. A decrease in the intensity of inflammation may also appear in the test of inhibition of dermatitis by ultraviolet rays. guinea pigs using the dermatitis inhibition test caused by croton oil on rabbits, review the circumstances in the dosage area of 0.011, 0% g / g with a local application of the corresponding solution. Further, the compounds according to the invention in a test of inhibition of hyperplasia in guinea pigs show a pronounced inhibitory effect in the dosage range of 0.01-1.0% g / g when applied locally. In addition, substances were tested for activity in humans. In the solution test of the skin constriction of the vessels in the dosage area of 1-10 1-10g / g, a significant effect of vasoconstriction could be established. In addition, the compounds differ in their effect against certain viral strains. For example, in experiments on guinea pigs that were charged with HVH2 / Angelotti, after two times daily intravaginal application after 5 days, a 0.1 m gel with a 6.2% concentration was established to rapidly regress the symptoms caused by Herpes genitalis. Therefore, the compounds of the formula I can be used as therapeutic agents, especially external (local) skin-inflammatory agents for the treatment of inflammatory dermatitis of skin origin, as in mild skin irritations, contact dermatitis, burns, as well as anti-inflammatory drugs mucous membranes for treating inflammations of the mucous membranes, e.g. eyes, nose, lips, mouth, genital and anal areas. Further, the compounds can be used as a sunscreen, as well as an antiviral agent, for example, an anti-lightening agent. Pharmacological studies of new compounds yielded (in experimental rats) during the experiment with ear edema, the following values, mg / ml: Ethyl ester 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole-2 -sh1 / -2-methyl-propanoic acid 18 2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridyl) -imidazol-2-yl / 2-methylpropionic acid ethyl ester13 Ethyl ester 2- / 4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridsh1) -imidazol-2-sh1 / -2-methylpropionic acid18 2- / 4 (5) -phenyl-5 (4) -. - (3-pyridyl) -imidazol-2-yl / -1-carboxycyclopentane21 ethyl ester 2- / / 4 (5) - (p-chlorophenyl) -5 (4) - (1-oxide-3-pyridyl) -imidazole -2-yl / -2-methylpropionic acid 20 Et-ester 2- / 4 (5) -fensh1-5 (4) - (3-pyridyl) -imide 3ol-2-yl / -2-allyl-oxVCnic acid15 Ethyl ester 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-IL-acetic acid17 Pivaloyloxymethyl ester 2- / 4 (5) - (3-pyridyl) -imidazole-2 -yl / 2-methylpropionic acid12 2- / 4,5-bis- (h-methoxyphenyl) -imidazol-2-yl / -2 -2-methylpropionic acid ethyl ester 25 2- / 4 (5) - (2- ethyl ester) Tiensh1) -5 (4) - (3-pyridyl) -imidazap-2 - yl / -2-metsh1propionic acid you 31 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -acetic acid 25 Example 1. A mixture of 1.8 g of 2- / trans-4,5- (p-Methoxyphenyl) hydroimidaeolin-2-yl / -2-methylpoly acid and 2.0 g of 2,3-dichl-dicyan-1,4-beisoquinone in 60 m of aqueous dioxa are heated at paiType reflux distilled for 5, filtered, and concentrate the filtrate under reduced pressure to 40c until dry. The residue is taken up in 50 MP of ethyl acetate. This solution is washed with 20 ml twice with 2N 20 ml carbonate solution and again with 20 ml in dried over magnesium sulfate. Filtrate through a layer of silica gel under normal pressure and evaporate to dryness. The 2- [4,5-bis- (p-methoxyphenche1) -imidaeol-2-yl / -2-methylpropionic acid amide crystallizes from ethanol-water. Yield 0.3 g (18%). The original compound is obtained as follows. A solution of 2.7 g of d-1-1, 2-bis- (4-methoxyphenyl) -ethi-diamine and 1.6 g of monoamide of dimethylmalonic acid monoethyl ester in 40 ml of diphenyl ether is heated for 3 hours to 150 ° C. Ethyl alcohol formed is distilled off. Then it is cooled, poured onto 100 ml of water and the oil which has been precipitated is extracted twice with 100 MP of ether. The combined organic phases are washed with 50 ml of water, dried over magnesium sulphate and at 11 Torr and evaporated to dryness and at 0.1 Torr and freed from residual diphenyl ether. The 2- / trans-4,5- (p-methoxyphenyl) -4,5-diHydroimidaeol-2-yl / -2-methylpropionic acid amide is obtained as an oil and immediately reacted. Example 2. Analogously to Example 1, the following compounds are obtained. Ethyl ester 2- / 4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid, so pl. 126-128 C. 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid ethyl ester, m.p. 134-136 0, yield 0.5 g (27%). This 2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridsh1) -imidazol-2-yl / -2-methyl 1-propionic acid ester, m.p. 82-85 ° C, yield 0.5 g (15%). 2- / 4 (5) -phenyl-5 (4) -3-pyridyl) -imidazole-2-Sh1 / -PROPIONIC acid ethyl ester, T.PL.131PZ C, yield 0.6 g (19%). 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl] -acetic acid ethyl ester, m.p. 126-129C, yield 0.95 g (31%). 2- / 4 (5) - (m-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid ethyl ester, m.p. 135-137 0, yield 0.4 g (25%). 2- [4 (5) - (3,4-dimethoxyphenyl) -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid ethyl ester, m.p. 144-146 C, yield 0.5 g (27%). 2- / 4 (5) - (p-chlorofensh1) -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid ethyl ester, mp 161163 C / yield 1.46 g (79%). Ethyl
    2- [4 (5) -phenyl-5 (4) -. (A-pyridyl) -imidazol-2-yl] -methylpropionic acid ester, mp. 210-212С, yield 1.27 g (38%). 2- / 4 (5) -phenyl-5 (4) - (3-pyricyl) -imidazole-2-sh1 / -pro-5 pyoic acid ethyl ester, mp, 131-133 C, yield 2.8 g (87%). 2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridyl) -imidazol-2-yl / -2-methylbutyric acid ethyl ester, m.p. .1-10-10 ° C, yield 2.6 gO (74%). 2- [4 (5) -bis-01-methoxyphenyl) -imidazol-2-yl] acetic acid ethyl ester, m.p. 131-132 ° C, yield 0.27 g (14%). 2- [4 (5) -6] (p-methoxyphenyl) -imidazol-2-yl (15) -2-methyl-propionic acid ethyl ester, m.p. 128-132 ° C, yield 1.3 g (68%). Sodium salt of 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -mylazol-2-yl / -2-methylpropionic acid, as a hydrate, so pl. 273-20, yield 2.7 g (82%). Sodium salt of monohydrate of 2- / 4,5-6is- (p-methoxyphenyl) -imidazol-2-yl / -acetic acid, so pl. 187-190 ° C, yield 0.34 g (18%). 2- / 4 (5) -phenyl-5 (4) - (1-25-oxide-3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid, so pl. 178-180 ° C, yield 2.9 g (91%). Methyl ester of 2- / 4 (5) -phenyl-5 (4) - (Ioxido-3-pyridsh1) -imidazol-2-yl / -2-methyl-30 propyl acid, as the monohydrate, so pl. 96-98 ° C, yield 2.96-g (88%). 2- [4 (5) -phenyl-5 (4) - (1-oxide-4-pyridyl) -imidazol-2-yl] -2-methylpropionic acid ethyl ester, j, mp 164-166 C, yield 1.38 g (79%). Ethyl ester-hemihydrate-g2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridyl) -imidazole-2-sh1 / propionic acid, so pl. US-tAB C, yield 1.98 g, (59%). 1- / “O / 4 (5) -phenyl- (5 (4) - (1-oxide-3-pyridsh1) -imidazol-2-yl / -1-carbethoxypypopengan, mp 153-156 C, yield 0.4 g (23%). Ethyl ester of 2- / 4 (5) - (n-x-yarn) -5 (4) - (1-oxide-3-pyridyl) -im-4S dazal-2-yl / - 2-methylpropionic acid, mp. 137-140 Ci yield 1.5 g (79%). 2- / 4 (5) - (p-hydroxyphene 1) -5 (4) - (3) -pyridyl ethyl ester - casting sol-2-Sh1 / -2-methylpropionic acid, 50 m.p. 186-187 s, yield 2.4 g (68%). 2- / 4,5-bis- (p-methoxyphenyl) -imidazo-l-2-yl / propionic acid nonyl ester, m.p. 124-127 ° C, yield 1.5 g (84%). 2- / 4 (5) -phenyl-55 -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid lethyl ester, mp.158162C, yield 2.3 g (74 %). Pivaloyloxymethyl ester of 2- / 4 (5) -fensh1-5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid, so pl. 143-145 ° C. The yield of 1.8 g (87%). 2- [4,5-bis- (p-methoxyphenyl) -imkdazol-2-yl] acetic acid, IR (KBg): 3500 (broad), 1760 cm-, m.p. 159-161 C, yield 1.2 g (75%). Amide 2- / 4,5-bis- (p-methoxyphenyl) -imidazol-2-yl / -acetic acid, IR (KBg): 1670 cm, so pl. 119-121 0, yield 1.8 g (53%). 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -acetic acid, so pl. 129131 With, the yield of 1.9 g (69%). Amide 2- / 4 (5) -bis- (p-methoxyphenyl) -imidazol-2-yl / 2-methylpropionic acid, IR (KBr): 1670 cm, so pl. 128-130s, yield 1.5 g (83%). 2- / 4 (5) - (2-thienyl) 5 (4) - (3-pyridsh1) -imidazol-2-yl / -2-methylpropionic acid ethyl ester, m.p. 134-135С, yield 1.0 g (62%) 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -2-allyl-acetic acid ethyl ester, t .pl. 106-108 C. 1- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -carbz tox-cyclopentane, m.p. 115-117 ° C.
    Example 3. A solution of 2- / 4 (5) -phenyl-5 (4) - (3-pyridsh1) ethyl ester 1-imidazol-2-yl / -2-methylpropionic acid (3.32 g) in 20 ml of methanol is mixed with 40 ml 0.5 n. caustic soda solution. The solution is stirred for 4 hours at room temperature and evaporated under reduced pressure and at. The residue is mixed with 50 ml of methylesloride and yellowish crystals are filtered off. The sodium salt of 2- / 4 (5) -phenyl-5 (4) - (3-pyridkp) -imidazole-2-W1 / -2-methylpropionic acid (as a hydrate) melts at 273-276 C.
    In a similar way, yinhydrate of 2- (4 (5) - (p-methoxyphenyl) -imidazol-2-yl / acetic acid) sodium salt is obtained, mp 187-190 s, starting from 2- / 4 ethyl ester (5 ) -bis- (p-methoxyfennl) -imidazol-2-yl / -acetic acid.
    Example 4. A solution of 0.9 g of ethyl 2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridyl) -2-yl / -2-methylpropionic acid in 10 MP of methanol with stirring mixed with 3.0 ml of t n, sodium alkali solution. The solution is stirred for 15 hours at room temperature and at 11 mm Hg. and at 40 ° C free from methanol. The residue is mixed with 20 ml of water and the yellow solution is extracted with 20 MP of chloroform. The aqueous phase is then separated and when acidified with 2N hydrochloric acid solution. The clear solution is again extracted with 10 ml of chloroform. Then the aqueous phase at 11 mm Hg. and when evaporated to dryness. The white crystalline residue is dried at 0.1 Torr and at room temperature for 20 hours. 2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridyl) -imidazol-2-yl / - 2-methylpropionic acid melts at 178-180 ° C. Example 5. A solution of 5.9 g of ethyl 2- / 4 (5) -phenyl-5 (4) - (3-pyridylimidazol-2-yl / -2-methylpropionic acid) in 120 ml of methylene chloride is cooled to 0-5c and mixed with 3.5 g / and-chloroperbenzoic acid. The mixture is stirred at room temperature for 24 hours. Then the yellow solution is washed twice with 2 HI solution of potassium bicarbonate 20 ml each and with 30 ml of water, dried over magnesium sulfate at 40 ° C and concentrated under reduced pressure. The residue is dissolved in a small amount of methanol. After adding water, 2- / 4 (5) -phenyl-5 (4) - (1-oxy-3-pyridyl) -im ethyl ester crystallizes izol-2-yl / -2-methyl-propionic acid in the form of monohydrate. Mp. 82-85 C. In the same way receive. These catch ether 2- / 4 (5) - (2-thienyl) -5 (4) - (1-oxide-3-pyridyl) -nmidazole-2-Sh1 / / -2-methylpropionic acid, mp 134-135 p. 2- / 4 (5) -phenyl-5 (4) methyl ester monohydrate - (1-oxide-3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid, mp 96-98 0 (from methanol-water mixture). 2- / 4-ethyl ester (5) -phenyl-5 (4) - (1-oxide-4-pyridnp) -imidazol-2-nl / -2-methylpropionic acid, so pl. 164-166 With (from ethyl acetate), starting from ethyl 2- / 4 (5) -phenyl-5 (4) - (4-pyridyl) -imidazole-2-IL / -2-methylpropionic acid. 2- / 4 (5) -phenyl-5 (4) - (1-oxide-3-pyridin-1) -imidazol-2-yl / -propionic acid ethyl ester hemihydrate, oil, starting from 2- / 4 ethyl ester (5) -phenyl-5 (4) - (3-pyridyl) -imidazole-2-Sh1 / -propionic acid. Calculated,%: C 63.79; H 5.38 N 11.43. With an IP of 1 / 2H20. Found,%: C 64.07; H 5.76, N 11.77. 1- / 4 (5) -phensh1-5 (4) - (1-oxide-3-pyridyl) -imidazole-2-id / -1-carbethoxycyclopentane, oil yield 1.3 F (69%) (initial product 1 - / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -1-carbethoxy-cyclopentane). Calculated,%: C 69.19 H 6.68; N 11.0; HjG 0.64. C jHjjNjO ,. Found,%: C 68.9 N 6.4; N 10.5; 6. Ethyl ester of 2- / 4 (5) - (p-chlorophenyl) -5 (4) - (1-oxide-3-pyridyl) -imidazol-2-IL / -2-methylpropionic acid, so pl. 137-140 ° C (from methylene chloride-petroleum ether mixture) yield 1.5 g (77%), starting from 2- / 4 (5) - (p-chlorophenyl) -5 (4) - (3-pyridyl ethyl ether ) -imidazol-2-yl / -2-methylpropionic acid. Example 6. A solution of 1.3 g of ethyl 2- / 4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid ethyl in 50 im methylene chloride under nitrogen atmosphere with stirring and at -70c dropwise for 3 minutes, mixed with a solution of 4.7 g of boron tribromide in 20 ml of methylene chloride. The mixture was stirred at −70 ° C. for 30 minutes. 3aTej remove the cooling bath and mix until the temperature reaches 25 ° C. After that, the white suspension is poured onto 50 ml of ice-water mixture and stirred. The aqueous phase is separated, extracted twice with methylene chloride, 20 ml each and from 2N. The pH of the sodium carbonate solution is adjusted to pH 8. The precipitated crystals are extracted twice with 30 ml of ethyl acetate. The combined ethyl acetate phases are dried over magnesium sulphate and evaporated under reduced pressure to dryness. The residue is crystallized from ethyl acetate-ether. Obtain 0.3 g (30%) of ethyl ether 2- / 4 (5) - (p-hydroxyphenyl) -5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid, t. square 186-187C. Example 7. 100 MfT of anhydrous methanol saturated with hydrogen chloride gas is mixed with 5.0 g of 2- (4,5-bis - ((l-methoxyphenyl) -imidazol-2-yl / -propionic acid. The mixture is heated for 15 h at boiling, cooled and evaporated to reduced residue under reduced pressure. The residue is mixed with 10 ml of water and made alkaline with an aqueous concentrated ammonium solution. Extracted with 40 ml of ethyl acetate twice and washed with 5 ml of potassium bicarbonate and 20 ml of water at 5 It is dried over MgSO4 and concentrated under reduced pressure. pressure to dryness. 3.3 g (65%) of 2- / 4 (5) -bis- (g1-methoxyphenyl) -imidaeol-2-yl / propionic acid methyl ester, (ether-petroleum ether) of T.Sh1 are obtained . 124-127 ° C. P. i. M 8. Solution of 3.52 g of potassium salt of 2- / 4 (5) -phenyl-5 (4) (3-pyridyl) -imidazol-2-yl (-propionic acid in 30 ml of anhydrous dimethylformamide at 80 ° C and with stirring mixed with 3.0 g of diethyl sulfate. The mixture at 80 ° C is stirred for 15 minutes, cooled and injected onto a mixture of ice and water. The precipitated oil is dissolved in ethyl acetate and the organic phase is extracted twice with 2N. potassium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure to dryness. Ethyl ester of 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / propionic acid is crystallized from ether, so pl. 158162С, yield 2.7 g (79%). Example 9. A suspension of 3.5 g of sodium monohydrate 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid sodium monohydrate in 30 ml of anhydrous dimethylformamide by passing nitrogen and stirring at room temperature are mixed with 2.5 g of simethyliodide with drop by drop. The mixture is stirred for 15 hours at room temperature and then at 11 mm Hg. evaporated to dryness. The residue is partitioned between 20 MP of water and 50 ml of ethyl acetate. The organic phase is separated, dried over magnesium sulphate and at 11 Torr, concentrated to dryness. The residue is chromatographed on 300 g of silica gel. Fractions 1-15, eluted with a mixture of chloroform-ethyl acetate (95: 5), 300 ml each, are discarded. Fractions 16-26, eluted with a mixture of chloroform-ethyl acetate (80:20), 300 mp, are combined and evaporated to a dry residue at 11 Torr. The residue is crystallized from a mixture of ether-petroleum ether to obtain 1.1 g (25%) of pivaloyloxymethyl 3412 ether 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol-2-yl / -2- methylpropionic acid, so pl. at 143-145C. PRI me R 10. A solution of 5.0 g of amide 2- / 4 (5) -bis- (c-methoxyphensh1) -imidazol-2-yl / acetic acid and 5.0 g of potassium hydroxide in 100 ml of ibutanol heated for 8 hours at boiling. Then cooled and at 0.1 mm Hg. “Evaporated to dryness. The residue is dissolved in 200. ml of water. The solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. Precipitated crystals of 2- / 4 (5) -bis- (p-methoxyphenyl) -imidazol-2-yl / -acetic acid using filtering (IR (KBr): 3500 (br), 1760 cm, pl. 159-161 ° C, yield 3.0 g (60%). . The source material can be obtained as follows. 11.1 g of 2- [4 (5) -bis- (p-methoxyphenyl) -oxazol-2-yl] -acetic acid ethyl ester are heated in an autoclave with 97.0 g of liquid ammonia and 64 g of formamide for 5 hours to 200 ° C (pressure is 185 ag). Cool and pour the reaction mixture into 300 ml of water. Dissolved oil is extracted with 150 ml of ethyl acetate. The organic phase is separated, washed with 30 ml of saturated sodium chloride solution and water, dried over magnesium sulphate and evaporated under reduced pressure to a dry residue. The 2- [4 (5) -bis (p-methoxyphenyl) -imidazol-2-yl] -acetic acid amide crystallizes with methanol. IR {KBX): 1670 cm Example 11. A mixture of 3.5 g of 2- / 4 (5) -phenyl-5 (4) - (3-pyridyl) -4 (5) -dihydroimidazolin-2-yl / -2 ethyl ether -methylpropionic acid and 2.2 g of G1-benzoquinone in 50 ml of anhydrous dioxane, through which nitrogen is passed, are heated for 7 hours at boiling. After cooling, it is filtered and evaporated under reduced pressure to dryness. The residue is dissolved in 50 ml of ethyl acetate, washed with water and dried over magnesium sulphate. After removal of the solvent and recrystallization from the ester, 2- / 4 (5) -phene1-5 (4) - (3-pyridyl) -imidazol-2-yl / -2-methylpropionic acid ethyl ester, m.p. 274-276 C. Yield 0.4 g (12%). In a similar manner, dehydrogenation can be carried out with 5.2 g of 2,3, 5,6-tetrachloro-p-benzoquinone. Example 12. 3.5 g of 2/4 (5) -phenyl-5 (4) - (3-pyridyl) -4, 5-dihydroimidazolin-2-yl / -2-methylpropionic acid ethyl ester was dissolved in 75 ml of dioxane and 10 g of palladium carbon (10%) are added. The reaction mixture is heated with stirring to 250 C. 5 After 2 hours, cool and filter, and the solvent is evaporated under reduced pressure. After recrystallization from the ester, 2/4 (5) -phenyl ethyl ester is obtained;: - 5 4) - | (3-pyridyl) -imide- O sol-2-yl / 2-methylpropionic acid, mp 274-276 0 The yield is 0.77 g (23%). Example 13. 1.8 g of the sodium salt of (5) -bis- (p-methoxyphenyl) -imidazol-2-yl / acetic acid is dissolved in 30 MP of water and 20 MP of concentrated ammonia solution are added. The reaction mixture is heated at reflux for 3 hours. After cooling, it is evaporated and dissolved in 25 ml of methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and filtered. The solvent is removed under reduced pressure. In this way, 2- [4 (5) -bis- (p-methoxyphensh1) -imidazol-2-yl] -acetic acid amide is obtained, m.p. 119-121С with a yield of 1.1 g (68%).
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of trisubstituted imidazoles of the general formula where R., and R 2 - phenyl, each substituted with lower alkoxy;
    A is lower alkylene or lower alkylidene;
    R 3 is carboxy, lower alkoxycarbonyl or carbamoyl; or where one of the residues R ^ and R 2 is pyridyl or 1-oxo-pyridyl, and the other is phenyl or substituted with lower alkoxy, hydroxy or halogen phenyl; ·
    A is lower alkylene, lower alkylidene, lower alkenylidene or cyclopentylidene. ..
    R 3 is carboxy, lower alkoxycarbonyl or lower alkanoyloxin lower shkoxycarbonyl; or where one of the residues R ^ and R 2 is pyridyl or 1-oxidopyridyl, and the other is thienyl;
    A is lower alkylidene; R 3 is lower alkoxycarbonyl with the condition that if A is ethylidene and R 3 is carboxy 'or carbamoyl, respectively, both R ^ and R 2 residues cannot simultaneously mean η-methoxyphenyl, or their salts with bases, other the fact that the compound of the general formula where R ^ -Rj and A have the indicated meanings, 2, 3-Dichloro-5,6-dicyano.-1,4-benzoquinone or 2,3,5,6-tetrachloro-p-benzoquinone are dehydrated or η-benzoquinone or palladium on charcoal and is isolated in the free form or in the form of salts with bases, or if Rj is a carboxyl, if desired, isolated in the form of esters or in the form amides, or, if one of the residues R ^ and R 2 is pyridyl, if desired, alkali in the form of pyridine-L-oxide.
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    法律状态:
    优先权:
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