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    • 专利摘要:
    1. METHOD FOR OBTAINING SUBSTITUTED AURONES of general formula I O D where Rj, R2, RR, R, and R are the same or different and each is hydrogen, halogen, alkyl C (-C4, metric, cyclohexyl, trifluoromethyl, acetamido, isopropylcarboxamido, amino, dimethylamino , cyan, hydroxy, carboxyl or —CH — CHClS; or RJ and Rg together form a group of the formula —CH — CH — CH — CH— with the proviso that at least one of R, R2, R, R4, RJ and Rg is carboxyl or -CH HCl, characterized in that the benzaldehyde of the general formula II R, onc where R, R5 and Rg have the indicated values, is subjected to en interaction with benzofurano of the general formula III O, where R, R2 and R - have the indicated values or with C-substituted acetophenone of the general formula IVQ CHjX I 3 where R., Re-name given values, X denotes a readily selected group selected from the halogen or toluenesulfonyl groups , in a solvent at 0-150s.
    公开号:SU1138027A3
    申请号:SU792816201
    申请日:1979-09-12
    公开日:1985-01-30
    发明作者:Ричард Бейкер Стефен；Джеймс Росс Вилльям；Боуфи Джеймисон Вилльям
    申请人:Лилли Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new substituted aurones of the general formula "Where Ri-R are the same or different and each is hydrogen, halogen, alkyl, Si labels, cyclohexyl, trifto methyl, acetamido, isopropylcarboxamido, amyo, dimethylamino, cyan, oxy, carboxyl or -CHN, or R.HR, taken together as a group of formulas -CH CH-CH CH, provided that at least one of them denotes carboxyl or -CH CHSOE possessing pharmacological activity, Disodium salt 1,3bis is known (2 -carboxychromon-5-yloxy) -2oxypropane, which is used in Treatment of asthma and possesses anti-allergic activity of flj. Compounds of general formula I are obtained based on the well-known reaction 2 by reacting benzal of dehydration formula where, have the indicated values with benzofuran of the general formula where they have the indicated values or with CO -substituted acetophenone of the general formula R O CHjX IV 272 where Rj-Rj have the indicated meanings; X - denotes an easily leaving group selected from the halogen or toluenesulfonyl group, in a solvent at 0-150 s. Suitable solvents for this reaction include ether solvents, such as dioxane and tetrahydrofuran, and liquid alkanols, such as ethanol. In general, temperature is not critical and only determines the rate of reaction. The reaction can proceed at any temperature from ambient temperature to the reflux temperature of the reaction mixture, e.g. 25-150 ° C. The reaction is preferably carried out in the presence of an acidic or basic catalyst. K-suitable acid catalysts include mineral acids, such as hydrochloric acid, and strong organic acids, such as AND-toluenesulfonic acid, and suitable inorganic or organic basic catalysts include alkalis, such as caustic soda, caustic potassium, sodium carbonate or triethylamine. In accordance with another embodiment, the process for the preparation of compounds of the formula I consists in the reaction of the CO-substituted acetophenone of the formula IV with the corresponding benzaldehyde of the formula III. Suitable solvents for this reaction include ether solvents, such as dioxane and tetrahydrofuran, and liquid alkanols, such as ethanol. In this case, the reaction is preferably pro-. water in the presence of a base catalyst using, for example, caustic soda, caustic, potassium, or sodium carbonate. The reaction can be carried out at 0-150 C. It has been found that aurones of formula I are useful in the prophylactic treatment of asthma in mammals. The activity is shown on guinea pigs using the Herzheimer test or the chopped lungs of the guinea pig. Herzheimer test. based on allergic bronchospasm caused in guinea pigs, which is very similar to an asthma attack in humans. The mediators causing bronchospasm are very similar to the mediators released when they are administered with sensitized human sensitized lung tissue. Compounds according to the invention show activity on the Herzheimer test at doses of 25-200 mg / k
    The compounds of the formula I can be administered in various ways, for which formulations are prepared in various forms, but they are effective when given orally. The compounds can be administered orally, rectally, topically, parenterally, for example, by injection, in the form of tablets, lozenges, tablets, tongue, eilatok, elixirs, suspensions, aero sol, ointments containing, for example, up to 10% by weight of the active compound in the approach Fushay basis, soft and hard gelatin capsules, suppositories, solutions and suspensions for injection in a physiologically acceptable medium and sterile powders in the package, adsorbed by the carrier, for the preparation of solutions for injection.
    Example 1. (7.) - 4-Carboxyl-2-benzyliden-5-methyl-benzenefuran-3 (2H) -one.
    U-Chloro-2-hydroxy-5-methylacetophenone (8.73 g, 0.05 mol) and 4-carboxybenzaldehyde (7.5 g, 0.05 mol) are dissolved in ethanol (100 ml) and the mixture
    heat to 60 ° C. Then, sodium hydrochloride (4 g, 0.1 mol) in water (20 ml) is slowly added to the mixture with stirring, the mixture turns dark red. After soaking at 60 ° C for 1 hour, a pale yellow precipitate forms, which is heated with reflux for 1 hour. The suspension thus obtained is then cooled to O C and acidified with hydrochloric acid (5M). The obtained pale yellow solid is filtered off, washed with water, dried under reduced pressure and recrystallized from dioxane, the case compound in the form of pale yellow needles, so pl. 288-290 ° С (decomposition), yield 34%.
    Examples 2-5. The following compounds were prepared similarly using the corresponding benzaldehyde and chloroacetophenone.
    (Z) -2 -Carboxyl-2-benzylidene-2methylbenzofuran-3 (2I) -one; m.p. 187189 ° С, yield 35%.
    (Z) -2 -Carboxyl-2-benzylidene-6-methylbenzrfuran-3 (2H) -one, m.p. 196198 With (decomposition.), The output of 67%.
    (Z) -2 -Carboxyl-2-benzylidene-naphtho- (2,1-b) furan-3 (2H) -one, m.p. 207-208 С, yield 28%.
    (Z) -4-Carboxyl-2-benzylidene-5-isopropyl-benzofuran-3 (2H) -one, m.p. 262-263 ° C, yield 38%.
    Example 6. (Z) -3-Kapoboxyl2-benzylidene-5-methoxybenzofuran3 (2H) -one.
    5-Methoxybenzofuran-3 (2H) -one (6.0 g, 0.036 mol) and 3-carboxybenzaldehyde (5.4 g, 0.036 mol) were dissolved in dioxane (50 ml) and concentrated hydrochloric acid (10. ml) The resulting yellow solution is then heated with reflux for 2 hours. After cooling and adding water (20 ml), a yellow precipitate is formed. After recrystallization of this substance from acetic acid, the compound is obtained in the form of yellow needles, so pl. 252-254s, yield 58%.
    Examples 7-36. Analogously to Example 6, but with a corresponding change in the starting benzofuranone and benzaldehyde, the following compounds were obtained.
    (Z) -2 -Carboxyl-2-benzylidene-6methoxybenzofuran-3 (2H) -one, m.p. 217-220 ° C (decomposition), yield 40%.
    (Z) -3-Carboxyl-2-benzylidene-6methoxybenzofuran-3 (2H) -one, mp 258-260 ° С (decomposed), yield 70%.
    (2) -4-Carboxyl-2-benzylidene-6methoxybenzofuran-3 (2H) -one, m.p. 2J3-275 ° C (decomposition), yield 70%.
    (Z) -3-Carboxyl-2-benzylidene-5-methylbenzofuran-3 (2H) -one, m.p. 264265 ° C, yield 68%.
    (Z) -3-Carboxyl-2-benzylidene-6-methylbenzofuran-3 (2H) -one, m.p. 263264 ° C, yield 51%.
    (Z) -4-Carboxyl-2-benzylidene-6-methylbenzofuran-3 () -one, m.p. 288289s, yield 57%.
    (Z) -3-Carboxyl-4-hydroxy-2-benzyl-6-methylbenzofuran-3 (2H) -one, mp. 290-29l C, yield 62%.
    (Z) -3-Carboxyl-4-hydroxy-2-benylidenebenzofuran-3 (2H) -one, m.p. 268-270 ° C, yield 56%. (Z) j4-Carboxyl-2-bezylidenebenzofurang-3 (2H) -one, tt.t. 274-275 yield 83%. . (g) -3-Carboxyl-2-6enzipiden-6chlorobenzrfuran-3 (2H) -one, m.p. 278280 ° C, yield 58%. . (Z) -2-Carboxyl 2-benzylidene-5chlorobenzofuran-3 (2H) -one, m.p. 205206 ° C, yield 32%. (Z) -3-Kap6oKCHfl-2-6eH3HflHfleH-9chlorobenzofuran-3 (2H) -one, so pl. 286288C, yield 72%. (Z) -4-Carboxyl-2-benzylidene-5-chlorobenzofuran-3 (2H) -one, m.p. 300 C yield 57%. (Z) -3-Carboxyl-2-benzylidene-5ethylbenzofuran-3 (2H) -one, so pl. 25A yield 34%. (Z) -3-Carboxyl-2-benzylideneben zofuran-3 (2H) -one, i.e. 259-260 ° C, yield 57%. {Z) -4-E-Carboxivinyl-2-benzylidene-5-methylbenzofuran-3 (2H) -one, t.TTL. 275-276 ° C, yield 90%. (Z) -3-Carboxyl-2-benzylidene-5cyclehexylbenzofuran-3 (2H) -one, m.p. 252-253 ° C, yield 49%. (Z) -4-Carboxyl-2-benzylidene-6-chlorobenzofuran-3 (2H) -one, m.p. 300 ° C, yield 70%. (Z) -2-Carboxyl-2-benzylidene-6-chlorobenzofuran-3 (2H) -one, m.p. 184 With an exit 51l. (Z) -4 (E) -2 Carboxivinyl -2-benzylidene-6-hydroxybenzofuran-3 (2H) -o so pl. 300 C decomposition.), 57% yield. (Z) -3-Kapboksil-2-benzylidene-6oxybenzofuran-3 (2H) -one, t „pl. 320 (decomposed), yield 49%. (Z) -2-Carboxyl-2-benzylidene-6019 sibenzofuran-3 (2H) -one, m.p. 282283 ° C, yield 52%. (Z) -4 - (E) -2-CarboxivinylZ-2-benzylidene-5, 7-dichlorobenzofuran-3 (2H it, mp. 300 ° C, yield 30%. (Z) -3- (E) -2-Carboxivinyl -2-benzylidene-5, 7-dichlorobenzofuran3 (2H) -one, mp, 47% yield. (Z) -3 - (E) -2-Carboxivinyl -2 "benzylidene-6-hydroxybenzofuran-3 (2H) -one T.nJi. 300 C, yield 72%. (Z) -3- (E) -2-Kapboxoxivinyl -2, benzylidene-5-methoxybenzofuran-3 (2H) it, mp. 242 C , yield 71%, (Z) -3 -Carboxyl-2-benzylidene naphtho (1,2-b) furan-3 (2H) -one, mp 276-278 ° C, yield 48%., (Z) -3 - (E) -2-Carboxivinyl -2benzylidene naphtho (1,2-b) furan-3 (2H) -one, mp 280 ° C, yield 49%. (Z) -3-Carboxyl-2- Beisylidene-4oxybenzofuran-3 (2H) -one, mp 285287 ° C, yield 32%. Example 37. (Z) -4- (5-TeTpa-. Zolyl) -2-benzylidene-5-chlorobenzofuran3 (2H) -one. 4-Cyanbenzaldehyde (13.1 g, 0.1 mol), ethylene glycol (6.2 g, 0.1 mol) and toluene-4-sulfonic acid (19.0 g, 0.1 mol) are heated with refpux in benzene (1 BO ml) for 8 hours using a Dean and Stark apparatus. Then benzene is distilled off to dryness and 4-cyano (2-1,3-Dioxolan) benzene as a waxy, colorless solid (m.p. 4445 C), used without further purification. Said dioxolane (17.1 g, 0.1 mol), sodium azide (6.5 g, 0.1 mol) and lithium chloride (6.5 g, 0.15 mol) are heated with reflux in 2-methoxyethanol (100 ml) over. 8 h. Then the suspension is poured onto ice and hydrochloric acid (5M). After standing in white, white crystals of 4- (5-tetrazol-1) benzaldehyde are formed, m.p. 200 C, yield 83%, which is reacted with 5-chlorobenzofuran-3 (2H) -one according to the procedure of Example 6, and a compound is obtained that is recrystallized from dimethylformamide, mp. 260 ° C (decomposition), yield 68%. Examples 38-41. Similarly, the following compounds were prepared using the corresponding cyanbenzaldehyde and benzofuranone. (Z) -3- (5-Tetrazyl) -2-benzylidene-5-methoxybenzofuran-3 (2H) -one, so pl. 278-280 ° C, 75% yield. (Z) -3 - (5-Tetrazolyl) -2-benzylidene-6-hydroxybenzofuran-3 (2H) -one, m.p. 300 C (decomposed), yield 78%. (Z) -4 - (5-Tetrazolyl) -2 benzylidene-5-methoxybenzofuran-3 (2H) -one, m.p. 268-270 C (decomposition), yield 62%. (Z) -3- (5-Tetrazolyl) -2-benzylidene-5, 7-dichlorobenzofuran-3 (2H) -one, m.p. 283-285s (decomposition), yield 54%. Example 42. (Z) -3- (5-TeTpasol1) -2-benzylidene-5-ethylbenzofuran-3 (2H) -one. 5-Ethylbenzofurak-3 (2H) -one (3.4 g, 0.02 mol) and 3-cyanbenzaldehyde
    (2.62 g, 0.02 mol) was dissolved in dixan (100 ml) and concentrated hydrochloric acid (5 ml) was added. The resulting yellow solution is heated with reflux for 2 hours. After cooling, yellow needles (Z) are formed. 3-cyan-2-benzylidenebenzofuran-3 (2H) aa, mp. , which are separated by iltration. Aura (0.5 g, 0.0018 mol) and trimethylsilyl azide (1 g, 0.086 mol) are heated together with reflux in dimethylformamide for 6 hours. The cooled solution is poured onto ice and hydrochloric acid. Then the suspension is heated to 70 ° C for 5 minutes in 30 minutes and after cooling, the precipitate is filtered off. It is established by chromatography that this yellow solid is the title compound 20 m.p. 242-243 ° C, yield 48%.
    Example 43. (Z) -2-Carboxyl 2-benzylidene-5-carbomethoxy-6-amine benzofuran-3 (2H) -one.
    Methyl 3-acetyl-4-hydroxy-6-aminobenzoate (8.0 g, 0.038 mol) in dichloromethane (250 ml) was added to trifluoroacetic anhydride (16 g, 0.076 mol) and the solution was stirred at room temperature for 15 minutes. | 1. 30 After evaporation of the pale yellow solution, 3-acetyl-4-acetoxy-6-trifluoroacetamido-benzoate is obtained, m.p. 130131 ° C, yield 98%.
    Copper (II) bromide (17.0 g, 35 0.076 mol) is suspended in ethyl acetate (300 ml) with rapid stirring. The resulting benzoate (11.5 g, 0.038 mol) is added to this suspension as a solution in ethyl acetate (200 ml ) 40 and the resulting mixture is stirred and heated with reflux for 3 hours. After cooling, the resulting pale green copper (I) bromide is separated by filtration, the solution is evaporated and a pale yellow solid is obtained, which after recrystallization from the mixture (petroleum ether, 40-60 ° C) is methyl-3- bromoacetyl-4-acetoxy-6-tri-50 fluoroacetamido benzoate. in the form of white crystals, so pl. 260-261 ° C, yield 72%.
    Then this compound (1.9 g, 0.005 mol) and 2-carboxybenzaldehyde 5 (0.75 g, 0.005 mol) in methanol (100 ml) is heated to 60 ° C.
    Sodium hydroxide (0.6 g, iO, 015 mol) in water (20 ml) was added. The resulting red solution is heated with reflux for 3 hours and then poured onto ice and hydrochloric acid (5M). The yellow solid thus formed is filtered off and dissolved in 10% aqueous sodium bicarbonate solution at 50 C. The pH of this solution is adjusted to 7 and amberlite 1PA-401 ion exchange resin is added in hydroxyl form. Then, the resin is filtered and washed first with water, then with glacial acetic acid. After evaporation of the acetic wash solution, the compound is obtained in the form of yellow prisms, mp. 280 C (decomposed), yield 48%.
    Example 44. (Z) -3-Carboxy2-benzylidene-5, 7-dibromo-4-hydroxybenzofuran-3 (2H) -one.
    .one
    Finely ground copper bromide
    (Ii) (88 g, 0.4 mol) is suspended in a 50:50 mixture of ethyl acetate and chloroform (200 ml). To the mixture was added 2,6-dioxy-Cethophenone (10 g, 0.0657 mol) in chloroform (20 ml) and then stirred with reflux for 8 hours, during which hydrogen bromide was released. After cooling, the copper (I) bromide obtained during the reaction is filtered and the solution is evaporated to dryness to obtain 3,5-dibromo-2,6-dioxyCO-bromoacetophenone, m.p. 150 C. Sh-Bromoacetophenone (8.2 g, 0.21 mol) and sodium acetate (20 g) are heated with reflux in 90% ethanol (100 ml) for 15 minutes. After cooling and then adding water (100 ml) from the yellow solution, a greenish solid precipitate was separated which was recrystallized from a mixture of ethanol and water to form 5,7-dibromo-4-hydroxybenzofuran-3 (2H) -one, mp. 185 С (decomposed),
    t
    Benzofuran-3 (2H) -one is reacted with 2-carboxylbenealdehyde in Example 6 to form the title compound, m.p. 300 C (decomposed), yield 56%.
    Examples 45-46. Analogously to Example 44, the following compounds are prepared using the proper
    benzaldehyde. about
    (2) -4-Carboxyl-2-benzylidene5, 7-dibrrm-4-hydroxybenzofuran-3 (2H) it m.p. (decomposed), yield 68%.
    (Z) -2-Karboksh1-2-benzylidene5, 7-di6rom-4-hydroxybenzofuran-3 (2H) - 5 it, so pl. 258-260 ° C, yield 60%.
    Example 47. (Z) -4-t (E) -2Carboxyvinyl -2-benzylidene-6-amino5-cyanobenzofyran-3 (2H) -on.
    4-amino-5-cyano-2-oxyacetophenone is converted to 4-trifluoroacetoamide-51iano-2-oxyacetophenone (mp. 214 ° C) using the method of Example 43, 98% yield.
    Acetophenone is reserved using copper (II) bromide according to Example 44 to form 4-trifluoroacetamido-5 cyano-2-hydroxy-bromoacetophenone, mp. , yield 58%.
    M-Bromoacetophenone (3.8 g, 0.011 mol) was dissolved in ethanol 50 ml and excess sodium acetate (10 g) was added along with water (10 ml). The mixture is then heated with reflux for 20 minutes and, upon cooling, an orange precipitate is formed, which is recrystallized from ethanol / water to form orange plates of 6-amino-5-cyanobenzofuran3 (2H) -one, mp. 270 ° С (decomposition), output- 30 stroke 60%.,
    The benzofuran is then reacted with (E) -4-forms of Coric acid using the method. Example 6, while receiving the target 35 compound in the form of orange crystals, t, pl. 7, yield 72%.
    Example 48. (g) -z-Carboxyl2-benzylidene-5-cyclohexybendofuran3 (2H) -one. 40
    Cyclohexylphenol (88 g, O, 5. mol) and acetyl chloride (39 g, 0.5 mol) are heated together at 170 ° C for 3 hours. The light liquid thus obtained is then cooled 45 to 100 ° C and aluminum chloride is slowly added (133 g, 1.0 mol). The brown viscous oil is then heated at 130 ° C for 5 hours. After cooling, ice is added and this acid is added to 50% hydrochloric acid and phenol is extracted with chloroform. Then this extract is evaporated to dryness, the residue is distilled off with steam and 2-acetyl-1-4-cyclohexylphenol is obtained. in the form of a clear oil. 55 Then, the phenol is reacted with copper (II) bromide as described in Example 43. The reaction yields 2-bromoacetyl-4-cyclohexylphenol as a yellow oil. This oil was dissolved in ethanol (100 ml) and sodium acetate (44 g) and water (20 ml) were added.
    Then, the resulting solution is heated in reflux for 10 minutes, cooled, and water is added to precipitate a brown oil, which is extracted with chlorine form. After evaporation of the chloroform extract to dryness, 5-cyclohexylbenzofuran-3 (2H) -one is obtained, which is reacted with 3-carboxybenzaldehyde according to the method of example 6, to give the compound as yellow crystals, t, pl. 252-253 ° C.
    Example 49. (g) 3, 4, 5 Trimethoxy-2-benzylidene-5-carboxybenzofuran-3 (2H) -one.
    L. Methyl4-acetoxybenzoate (126 g, 0.65 mol) and aluminum chloride (220 g, 1.63 mol) are mixed thoroughly and reacted with. The crude solid obtained after the acid treatment is mixed with a saturated sodium bicarbonate solution and the mixture is filtered. The filtrate is carefully acidified and 3-acetyl-4-hydroxybenzoic acid is obtained, which is filtered off, washed with water and dried. M.p. 232 ° C.
    The undissolved solid remaining after extraction with sodium bicarbonate is dissolved in dilute sodium hydroxide solution (2N) and carefully acidified with dilute hydrochloric acid (5N) to give methyl 3-acetyl-4-hydroxybenzoate, which after filtration, washing with water and drying has 1pl. 90-92 C. C. D-acetyl-4-hydroxybenzoic acid (24.0 g, 0.133 mol in dioxane (400 ml) is dissolved at 40 ° C. And bromine (7.2 ml, 0.14 mol) ./ Soon the color disappears and after 45 transparent layers of insoluble matter are decanted and evaporated, a light straw-colored solid, 3-bromoacetyl-4-hydroxybenzoic acid, mp 22bc is obtained.
    C. The product obtained according to example 49B is dissolved in a mixture of ethanol water, sodium acetate (30 g) is added and the solution is stirred at Yu min. The resulting dark orange-red solution is cooled to, stirred, and carefully acidified with 5N hydrochloric acid. The resulting bright yellow pacTBo is diluted with an equal volume of water and stored in the refrigerator overnight. A solid yellow crystalline substance is filtered off, washed with cold water, dried and 5-carboxybenzofuran3 (2H) -ln is obtained, m.p. (decomposed). D. Dissolve 5-carboxybenzofuran-3 (2H) -one (3.56 g, 0.02 mol) and 3,4,5-trimethoxybenzaldehyde (3.92 g, 0.02 mol) in warm dioxa ( 50 ml), concentrated hydrochloric acid is added on the steam bath for 15 minutes. After cooling and addition of an equal volume of water, the solid yellow crystalline substance is filtered off and washed with water and dried. After recrystallization from glacial acetic acid, the compound is obtained, m.p. 290c, yield 3.1 g (44% Examples 50-60. The following compounds were prepared analogously with measure 49. (Z) -2-Benzylidene-5-carboxybenzofuran-3 (2H) -one, mp. 280 ° C, yield 54%. (E) -4-Chloro-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, mp 300 ° C, yield 61%. (G) -2-Chloro-4-dimethylamine- 2-ben zilide-5-carboxybenzofuran-3 (2H) it, mp 275 C (decomposition) yield 24 (g) -4-Butyl-2-benzylidene-5-carboxy-furan-3 (2H) -one, mp 252 C, 51% yield. (Z) -4-Dimethylamine-I-benzsh1idencarboxybenzofuran-3 (2H) -one, t, rd, 295 ° C, yield 42%. (Z) -4-Methoxy- 2-benzylidene-5-boxybenzofuran-3 (2H) -one, mp, 300 ° C, yield 40%. (G) -4- (E) -2-Carboxivinyl -2benzylidene -5-carboxybenzofuran3 (2H) -one, m.p., yield 45%. (2) -3-Carboxyl-4-hydroxy-2-berzyl iden-5-carboxybenzofuran-3 (2H) -one, m.p. , yield 41%. (g) -4-Acetamide-2-benzylidene-5carboxybenzofuran-3 (2H) -o, mp 300 ° C, yield 29%. (Z) -3-Trifoftropylethyl-2-benzyliden 5carb6xybenzofuran-3 (2H) -one, mp 264 ° C, 46% yield. (Z) -3- (N-Isopropylcarbacamide) -2benzylidene-5-carboxyb8nzofuran-3 (2H) it, mp. 300 C, yield 44%. Example 61 5-carboxyl-6-oxybenzofuran-3 (2H) -one. A.5-Acetyl-2,4-dimethoxybenzoic acid (21.1 g, 0.094 mol) was stirred in dioxane (200 ml) at room temperature and bromine (5 ml, about O, 1 mol) was added dropwise. The color of bromine gradually disappears within 30 minutes, then the mixture is gently heated on the steam bath for 30 minutes, cooled and the dioxane is distilled off under vacuum. The solid product is treated with boiling ethyl acetate, filtered while hot, the filtrate is evaporated and 5-bromoacetyl-2, 4-dimethoxy-benzoic acid is obtained, m.p. 236 ° C. B. The product obtained according to Example 61A (21.6 g, 0.071 mol) was stirred in dichloromethane (250 ml), cooled in an ice bath, and boron tribromide (25 ml) was added over time. Then the solution is heated with reflux in a water bath for 4 hours :. The mixture is cooled and poured into ice (1 kg). . After removal of dichloromethane, the resulting pink solid is filtered, washed with water, evaporated to dryness and dissolved in ethanol-water (200/80 ml). Sodium acetate (25 g) is added and the solution is warmed at 30 minutes. After cooling and removal of the ethanol under vacuum, more water (150 ml) is added. The solution is cooled in a food bath and a solution of hydrochloric acid (5N) is added dropwise while stirring to pH 2. After storage} overnight in the refrigerator, a pale yellow crystalline solid is removed, crushed with water, dried. and get benzofuranone, so pl. 21bs, yield 11.8 g (86%). Example 62. (2) -3-Carboxyl-benzylidene-5-carboxyl-6-hydroxybenzouran-3 (2H) -one. Dissolve 5-carboxy-b-hydroxybenofuran-3 (2H) -one (5.82 g, 0.03 mol) dioxane (75 ml), add 3arboxybenzaldehyde (4.50 g, 03 mol), then concentrate
    hydrochloric acid (15 ml). The solution is gently agitated on the steam bath for 30 minutes with occasional stirring. The solid mixture is cooled, diluted with an equal volume of water and stored in a refrigerator for 1 hour. The product is filtered, washed with water and dried. After recrystallization from dimethylformamide, the product is obtained; (decomposed), yield 4.5 g (46%) ..
    Examples 63 and 64. The following compounds were prepared according to the method of Example 62.
    (g) -3-Carbox 1-hydroxy-2-benzylidene-5-carboxyl-6-hydroxybenzofuran 3 (2H) -one, so pl. 332 ° C (decomposition) j yield 47%.
    (g) -4- (Tetrazol-5-yl) -2-benzylidene-5-: arboxyl-6-hydroxybenzofuran3 (2H) -one, m.p. 327-328С. (decomposed), yield 59%. .
    Example 65. (2) -3-Carboxyl2-benzylidene-5-methoxycarboxybenzofuran-3 (2H) -one. . : Methyl-3-acetyl-4-hydroxybenzoate (5.39 g, 0.028 mol) was stirred in dioxane (200 ml) at 40 ° C and bromine (1.5 ml) was added dropwise. After 45 minutes, the colorless solution was extruded and a straw oil was obtained, which was dissolved in ethanol / water (75/15 ml). Sodium acetate (6.0 g) was added and the solution was stirred at room temperature for 5 minutes. The red solution is poured on ice (100 g) and extracted with chloroform. After evaporation of the chloroform extract, 5-methoxycarbonylbenzrfuran-3 (2H) is obtained as an orange-red oil (65% purity as determined by NMR). The product is dissolved in dioxane (50 ml), 3-carboxybenzaldehyde is added ( 4.5 g, 0.03 mol, then concentrated hydrochloric acid (10 ml) and the solution is heated on a steam bath for 15 minutes. Auron, mp, 280 ° C, is recirculated from dimethylformamide and recrystallized from dimethylformamide. yield 2.0 g (22%).
    Example 66. (g) -3-Carboxyl-2-benzylidene-6-acetamide-bezofur-1 (3H) -one.
    A. 3-Aminofenol (54.5 g, Q, 5 mol n acetic anhydride (200 ml) is stirred and heated on the steam bath for 2 hours. The straw-colored liquid is evaporated under vacuum and a viscous oil is obtained, which is heated to 110-120 s. with the gradual addition of aluminum chloride (170 g, 1.27 mol) with stirring. After 30 min, the solid product is slightly cooled and carefully decomposed by mixing water with ice (approximately 500 g), then added hydrochloric acid (200 ml), mix well and heat gently on a steam bath. After cooling
    the crystalline solid is filtered off, rinsed with water, dried and get 2-hydroxy-4-acetamide-acetophenone, so pl. 140 C.
    B. The product, as described in Example 66A (14.0 g, 0.072 mol), is dissolved in ethyl acetate (200 ml) and added to a stirred suspension of copper (II) bromide (32.0 g, 0.143 mol) in ethyl acetate (100 ml). The mixture is heated with reflux for 4 hours, then filtered while hot and the filtrate is evaporated in vacuo to give an oil, which crystallizes. This solid is converted to benzofuranone and reacted with 3-carboxybenzaldehyde (as in Example 65). However, during the course of this reaction, the product is partially diacylated and is further reduced.
    in contact with acetic anhydride (20 ml). c. reflux for complete conversion to the acetylated compound .. The reaction mixture is vortexed into ice (100 g) and an excess of acetic acid.
    anhydride is hydrolyzed .. Received
    the solid is filtered off, recrystallized from; ice / acetic acid / water mixture (50% volume / volume) to obtain (Z) -3-carboxyl-2-benzylidene-6-acetamido-benzo-Furan-3 (2H) -one, mp. 305 ° C (decomposition), yield 1.4 g (6%).
    Example 67. (Z) -4-Xnop-2benzsh1Iden-5-n-butoxycarbonsh1benzofuran-3 (2H) -one.
    (Z) -4-Chloro-2-benzylidene-5-carboxylbenzofuran-3 (2H) -one (3.0 g, 0.01 mol) is suspended in n-butanol (50 ml), concentrated sulfuric acid is added dropwise acid
    (1.5 ml) with stirring and the mixture of Na1 is refluxed for 5 hours. From the obtained yellow solution after cooling, yellow fluffy needle-shaped crystals of the required n-butyl ether precipitate. The crystals are filtered, washed with cold n butanol, then with diethyl ether and dried. M.p. , yield 2.7 g (76%). Example 68. (E) -4-Chloro-2benzylidene-5-n-butoxycarbonylbenzofuran-3 (2H) -one. (g) -4-Chloro-2-benzoliden-5-n-bucket Sicarbonylbenzofuran-3 (2H) -one (1.0 g) is dissolved in benzene (800 ml) and irradiated in 1 liter of Hanovig photochemical reagent for 15 h. The solution is evaporated in vacuo to give 1.0 g of a solid with m.p. about 130 ° C and the ratio of isomers E / Z 75/25 (definitely by NMR and liquid chromatography). 500 mg of this solid are chromatographed on a sorbsil silica gel column (Sorbs11) (200 g) using benz & a as the developer, and fractions containing the more mobile (E) -isomer are collected. The collected fractions are expelled and the yellow crystalline substance, yield 350 mg with So pl. 142 C and the ratio of isomers E / Z 88/12. 200 mg of this solid is recrystallized from a mixture of dichloromethane / petroleum ether (40-60 ° C) (1/3 by volume) and obtain 130 mg of a crystalline solid with m.p. 142 C and the ratio of isomers E / Z 92,5 / 7,5. Characteristics of the compounds obtained are presented in table. 1. The compounds demonstrate activity in studying the separated guinea pig lung, which is an in vitroj experiment commonly used to determine anti-allergic activity. When examining a separated guinea pig lung, direct measurement of a slowly responding substance in anaphylaxis (SRS-A), obtained in response to a call, is made. SRS-A demonstrated relief of asthmatic effects on the human lungs. The numbers in the table. 2 indicate a percentage reduction in the production of SRS-A after exposure to solutions containing 10 | 11 g / kp of the compounds under study. At the same time, the disodium salt of 1.3bis (2-carboxychromon-5-yloxy) -2-goxy-ipropane at a concentration of 10 µg / ml does not cause a reduction of SRS-A. Table 1
    (Z) -2 -Karboxy-2-benzshididen-g 5,7-dibromo-4-hydroxybenzofuran3 (2H) -one
    (Z) -3-Kabbksi-2-benzylidene-5,7 dichlorobenzofuran-3 (2H) -one
    (Z) -4 -Carboxy-2-benzylidene-6oxybenzofuran-3 (2H) -one
    43.6743.42
    440 С Н
    58-260
    1,832.07
    36.3235.98 Вг
    57,3.458,10
    335 C H C1.
    300
    2,412,35
    21,1621,72
    68.0967.83
    282 С Н
    300
    3,573.59
    Continued table. one
    Continued table. one
    Continuation of table 1
    Continued table. one
    (Z) -3-Carboxyl-2-benzylidene-5-carboxyl-6-hydroxybenzofuran3 (2H) -one
    4-hydroxy-2-benzyl-6-hydroxybenzofuran-5-yl) -2-benzyl-6-hydroxybenzo (Z) -3-Carboxy-2-benzylidene-5 methoxycarboxybenzofuran-3 (2H) -one
    (Z) -4-Chloro-2-benzylidene-6-acetomeido-isobene 3-furan-3 (2H) -one
    (Z) -3-Carboxy-2-benzylidene-5-n1-butoxycarbonylbenzofuran-3 (2H) -one
    (E) -4-Chloro-2-benzylidene-n-butoxycarbonylbenzofuran-3 (2H) -one
    . Continued table. one
    335 (different)
    332 (different)
    327-528 (decomp.)
    280
    C 66.66 67.01 H 3.73 3.89
    154
    130
    nn nn nn nn
    H
    n n
    snsnc: nn
    nn nn nn nn nn nn nn
    , nn nn nn nn nn
    , |
    n n n
    n n n
    table 2
    31 30 58 36 64 55 47 29 64 60 45 44 41 36 59 62 27 38
    nn nn nn nn nn nn nn nn nn nn nn
    nn nn nn nn. n
    4-OH 4-OH
    nn nn nn
    n n n
    n n n
    70 42 45
    n
    70 64
    n
    n
    n
    29 N H w 7-C1 H 7-C1 H N H 5 -OCH H H 5,6-CH CH-CH CH5, 6-CH H CH CH HH H 5-Br 7-Br H N H N H H N H 7-C1 H 5-C, H, H, H 5-0-CO-CH. b-NP H 5-Vg 7-Vg 5-Vg 7-Vg 5-Vg 7-Vg b-HH, H 5-cyclo C, Hi. H N about
    thirty
    1138027
    Continued table. 2 HH 2-UNHN35 4-CH CH-UNPHIN52 / 3-CH CH-COOH. HH40 3-CH HF-UNAH5 3 3 CH HH-UNHH 20 3-UNHIN 36 3-HH H-HOOHH 39 3-UNHONH 2-CHOHNH56 4 -Tetrizolyl-BH.42 3-TetrazolylHH50 4-TetrazolylHH63 4-TetrazolylHH46 3-TetrazolylH. H35 3-Tetrazolyl H39 2-UNTG38 3-COOHN41 4-COOHN53 2-COOH HH56 4-CH CH-COOHI21 3-UNHIN42
    n n n n n
    n n
    n n
    n n
    6-OH 6-OH N
    $
    n n n n

    Continued table. 2
    39 54 19 36
    4-och 5-och
    W-Bsnn n
    H
    H
    4-C1
    2-C1
    4- N (CH) 2
    22
    n
    H
    , 4-CH CH57 35
    n
    -soon
    4-OH
    3-COOH 49 n
    H
    4-NH-COCHj
    49 50
    n n
    H
    3-CF

    n
    3-NH-CO and S.N.
    A3 62 53 38 25
    nn and n
    nn nn nn
    3-COOH 3-COOH.
    3-COOH
    4-C1
    4-C1
    权利要求:
    Claims (1)
    [1]
    1. METHOD FOR PRODUCING SUBSTITUTED AURONS of the general formula I where Rf, R 2 , R
    R 4 , R 'and R ° are the same or different and each hydrogen, halogen, alkyl C (-C4, methoxy, cyclohexyl, trifluoromethyl, acetamido, isopropylcarboxamido, amino, dimethylamino, cyan, hydroxy, carboxyl or -CH = CHGOOH;
    or R | and Rj together a group of the formula —CH═CH — CH══CH—, with the proviso that at least one of R ^, R 2 , R ^, R 4 , R is carboxyl or —CH = UNCHS, characterized in that 'benzaldehyde of the general formula II where R 4 , R $ and Rg have the indicated meanings, is they reacted with benzofuranone with common acetophenone, or do I have a V-substituted formula IV indicated values, X denotes
    SU and 38027>
    an easily leaving group selected from halogen or toluenesulfonyl groups in a solvent at 0-150 ° C.
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    同族专利:
    公开号 | 公开日
    YU222079A|1983-02-28|
    IE791729L|1980-03-13|
    EG14105A|1983-03-31|
    AT376968B|1985-01-25|
    AR226210A1|1982-06-15|
    PL124296B1|1983-01-31|
    PH15712A|1983-03-14|
    SE447382B|1986-11-10|
    ATA598079A|1984-06-15|
    HU181450B|1983-07-28|
    BG43187A3|1988-04-15|
    GR71200B|1983-04-11|
    JPS5540692A|1980-03-22|
    FI792850A|1980-03-14|
    AU5078079A|1980-03-20|
    CH644603A5|1984-08-15|
    NZ191556A|1981-03-16|
    KR830001919B1|1983-09-23|
    IL58229D0|1979-12-30|
    CA1202309A|1986-03-25|
    IT1162395B|1987-03-25|
    MX6232E|1985-01-14|
    ES484115A1|1980-04-16|
    CS214806B2|1982-06-25|
    BG40315A3|1986-11-14|
    AU535369B2|1984-03-15|
    SE7907532L|1980-03-14|
    DK382579A|1980-03-14|
    AR228020A1|1983-01-14|
    ZA794836B|1981-03-25|
    PT70170A|1979-10-01|
    DD146046A5|1981-01-21|
    IL58229A|1984-05-31|
    PL218277A1|1980-07-14|
    IT7950245D0|1979-09-12|
    USRE32196E|1986-07-01|
    IE48824B1|1985-05-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    AT277985B|1967-11-14|1970-01-12|Schering Ag|Process for the preparation of new nitro-furan, -thiophene or -pyrrole derivatives|
    US4115567A|1973-12-27|1978-09-19|Carlo Erba S. P. A.|6-Carboxy-2--chromones and esters thereof|
    US3975380A|1974-06-03|1976-08-17|Smithkline Corporation|Substituted aurones|
    US4067993A|1975-09-24|1978-01-10|Riker Laboratories, Inc.|Antimicrobial 2-nitro-3-phenylbenzofurancarboxylic acids|
    US4143145A|1977-01-12|1979-03-06|Carlo Erba S. P. A.|Substituted 2-vinyl-chromones and process for their preparation|
    FR2396756A1|1977-07-06|1979-02-02|Inst Nat Sante Rech Med|NEW BENZYLIDENE-2-BENZOFURANNONES-3, THEIR OBTAINING AND THEIR APPLICATION AS MEDICINAL PRODUCTS|
    IT1093805B|1978-01-31|1985-07-26|Erba Carlo Spa|DERIVATIVES OF 2H-BENZOFURAN-3-ONE AND PROCEDURE FOR THEIR PREPARATION|
    US4143055A|1978-03-27|1979-03-06|Gruppo Lepetit S.P.A.|2,4,6-trisubstituted-2,3-dihydro-benzofuran derivatives|AU1709897A|1996-01-26|1997-08-20|Phytera, Inc.|Antimicrobial aurone derivatives|
    US6307070B1|1996-01-26|2001-10-23|Phytera, Inc.|Substituted aurone derivatives|
    JP2001510801A|1997-07-25|2001-08-07|フィテラインク．|Substituted aurone derivatives|
    JP2003524648A|2000-01-28|2003-08-19|メルクパテントゲゼルシャフトミットベシュレンクテルハフトング|Formulations for protection against oxidative stress containing benzofuranone derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7836705|1978-09-13|
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