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    公开号:SU973023A3
    申请号:SU792742798
    申请日:1979-03-21
    公开日:1982-11-07
    发明作者:Грингль Херфрид；Фойдль Габриэле
    申请人:Фармасьютикал Лайсенсиз Компани Лтд (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING DERIVATIVES OF BENZOOURANE OR THEIR SALTS
    The invention relates to a new process for the preparation of new compounds: formula (I): where R is a carboxyl group or a -CH-CH-CH group, R is a hydrogen or methyl atom, substituted by an oxy group, or, if necessary, an eiino group, which is substituted by one or two lower alkyl groups or a lower carboxyalkyl group, R is methyl, only if R is a carboxyl group as a salt with an amine or R is a dimethylaminoethyl group, a substituted phosphate group or a hydrogen atom, or their salts. These compounds have active properties and can be used to treat liver disease. The known compounds are chemically related to dilignols or ligno-like compounds, which are formed as intermediate products formed during the production of lignin, which are obtained by dehydrogenating in vivo or in vitro g-cumar coniferalel sinapine alcohol, which are compounds from class derivatives of styrene flj. The purpose of the invention is a new method of obtaining new compounds of formula (I) with valuable pharmacological properties. This goal is achieved by the fact that isoeugenol is subjected to oxidative dimerization in the presence of ferric chloride in an aqueous alcohol medium at О®С and the target product of the formula, where R is a hydrogen atom, is obtained in free form or as a salt, or is converted into a compound of the formula (I), where R is methyl, by the action of dimethyl sulfate in the presence of caustic potassium in ethanol, or into a compound of the formula (|), where R is a 2-dimethylaminoethyl group, by the action of M, M-dimethyl-2-chloroethylaminohydrochloride in toluene in the presence of potassium hydroxide at 80 ° C, or Compound of formula (1), where R is a phosphate mono-substituted phosphatyl phosphorus in toluene in the presence of N, M-dimethylaniline at boiling, or a compound of formula (I), where R-CH CH-CHj, is converted into of formula (I), where R is a carboxyl group, by the action of potassium permanganate in acetone medium, or a compound of formula (I) where R is a hydrogen atom, is converted into a compound of formula (1), where R is methyl substituted by hydroxy group by solution hydroxymethyl formalin in the presence of potassium hydroxide when, or translated into a compound of the formula (1), d e R is methyl substituted by an amino group which is substituted by one or two lower alkyl groups or two lower alkyl groups or ONE lower alkyl and one lower oxyalkyl or lower carboxyalkyl group, by action of the corresponding amine in solution. formalin or paraformaldehyde in ethanol at elevated temperatures and increased the desired product in free form or in salt form. As salts of the compound of formula (I) with acidic groups, salts of alkali metals, in particular lithium, sodium or potassium, can be used. or alkaline earth metal salts, in particular calcium or magnesium, as well as salts of physiologically tolerable amines, such as N-methylglucamine, glucamine, dimethylaminoethanol, diethylaminoethanol, diethanolamine, ethanolamine hydroxyethylamine piperazine, these lendiamine or choline, or with acetylminamine, or arh, or arh, diamidine, or ethylenamine hydrochloride, ethylenediamine ethanolamine, diethyl amino ethanol, ethanolamine hydrochloride; ornithine, lysine, carnitine or betaine. Compounds with major groups can be used as salts with organic acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric, or with physiologic oglyclic acid, glycolic acid, dairy, ethanol, ethanol, ethanesulfonic, ethylene sulfonate, asparagine, and glycolic acid or thiazolidine boom. The valuable pharmacological properties of 4ts1 ligno-like compounds of formula (I), which are used as active substances in the therapeutic treatment of liver diseases, can be proved by means of pharmacological studies. The standard test methods for pharmacological action in experimental liver dysfunction are the hexabarbital sleep test, galactosamine and BC-amanitin tests. In the hexabarbital sleep test, the effect of the dil-like compound trans-2, .3-dihydro-, 2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- (E) -propenylbenzofuran (dehydrodiisoevgenol) with with similar known therapeutic npenapatoM for treating liver with isilimarin. For this purpose, groups of rats of 15 animals each receive intraperitoneally 100 mg / kg of the test compound in carboxymethylcellulose and after 90 min through a stomach probe in O, 3 ml / kg of carbon tetrachloride. yes in olive oil. After 48 h of 1 rat, intraperitoneal administration of 70 mg / kg of hexabarbital is anesthetized and the duration of sleep is then determined, min: Carbon tetrachloride without compound of formula (I) Control (hexobarbital only) Trans-2,3-dihydro-2- (4 -oxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- {E) -prope NILb enosofuran (dehydrodiisoeugenol) Silymarin Effect of trans-2,3-dihydro-2- (4-hydroxy-3-methoxyphenyl ) -7-methoxy-3-methyl-5- (E) -propenylbenzofuran (dehydrodiisoevgenol) is highly significant (, 01), the effect of the compared compound Xi imarina statistically significant. The 3 galactosamine experiments in rats are given orally in groups of 15 animals each in 100 mg / kg of the test compound N-g (trans-2,3-dihydro-7-methoxy-3-methyl-5- (E) -propenylbenzofuran 2-yl) -2-oxy-3-methoxyphenylmethyl-M- (2-hydroxyethyl) -N-methylammonium chloride and for comparison with silymarin as a tragic suspension and 350 mg / kg galactosamine hydrochloride are taken after one hour after 24 h blood samples for determining the enzyme swot GOT. and GPT Galactosamine hydrochloride without a test compound Control M- (3) -tra s-2, 3-dihydro-7-methoxy 3-methyl-5- (E) -propenylbenzofuran-2-yl (2) -oxy-3-methyroxyphenylmethyl-R-2-oxyethyl) -N-methyl vlmoniumchloroid422 185 Silymarin794 225 Especially in the 6PT enzyme, the action of the rotated compound of formula (I) is highly reliable (, 01) and is particularly distinct compared with the action of silymarin.
    In the (5-aminitin test), groups of 20 animals each received 50 mg / kg (trans-2,3-dihydro-7-methoxy, -3-methyl-5- (E) -propenylbenzofuran-2-yl) - 2-hydroxy-3-methoxyphenyl-methyl-J-N- (2-hydroxyethyl) -N-methyl ammonium chloride and for comparing silyharin, and an hour later - 0.7 mg / kg ot-amantine intraperitoneally Mortality is observed after 7 days. Silymarin does not provide for prevention of cases mortality compared with the control group, in (trans-2,3-dihydro-7-methoxy-3-methyl-5- (E) -propenylbenzofuran-2-yl) -2-hydroxy-3-methoxyphenylmethyl -M- (2 -oxyethyl) -N-methylammonium chloride pr The mortality rate, in contrast to the first compound, is only 20%.
    Toxicological studies have shown that the compounds of formula (I) are well tolerated.
     For example, the lethal dose of LDjo in rats given by oral administration of trans-2, 3-digidro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- (E) -propenylbenzofuran (dehydrodiisoevgenol) is higher 16 g / kg, and the same indicator for N-f5- (trans-2,3-dihydro-7-methoxy-3-methyl-5- (E) propenylbenzofuran-2-yl) -2-hydroxy-3 -methoxyphenylmethyl -M- (2-hydroxyethyl) -N-methyl ammonium chloride is in the range of 4-16 g / kg. The compounds of formula (I) are highly effective active preparations for the treatment of liver disease.
    Pharmaceutical preparations containing the compounds of formula (I) as active substances are highly effective drugs against diseases or diseases of the liver and prophylactic agents for their prevention. The dosage of the active substance depends on the circumstances of each particular case, in particular on the type of disease and the method used, but the daily dose, as a rule, is in the range of 10-1000 mg, 30-500 mg, preferably 25-250 mg of the active substance. . The pharmaceutical preparations contain the compounds of formula (I) in free form or in the form of their salts, especially in the form of therapeutically tolerable salts, usually in a mixture with suitable for enteral or parenteral, especially oral, rectal or intravenous administration with the corresponding pharmaceutical inorganic or organic carrier materials. As similar substances, substances that do not react with active substances, for example, water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, propylene glycol, petroleum jelly and others can be widely used. known substance carriers. Pharmaceutical preparations can be presented in the form of tablets, dragees, capsules, for example gelled, suppositories or in liquid form in the form of solutions (for example, measures, elixirs or syrups), suspensions or emulsions. If necessary, they may be sterilized and / or contain auxiliary substances, such as preservatives, stabilizing, wetting or emulsifying agents, dissolving agents or salts to alter the osmotic pressure or buffers. They may also contain other therapeutically active substances. Pharmaceutical preparations are obtained in the usual way.
    five
    The method is illustrated by the following examples.
    Example 1. 80 g of phosphoric oxychloride, 14.5 g of N, N-dimethylaniline and 30 g of trans-2,3-dihydro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-50 - ( E) Propenylbenzofuran (dehydrodiisoeugenol) is kept in 400 ml of absolute toluene for 12 hours at room temperature and then for 3 hours at, after cooling.
    5, the precipitated hydrochloride of N, N-dimethylaniline is separated and all volatile phases are carefully removed under vacuum at low concentrations. The remaining viscous oil is treated with 400 ml distilled
    Water and sodium carbonate in solid form are added in portions, while constantly balancing in portions, until the formation of carbon dioxide has ceased. The solution is cooled to room temperature and, by adding 2N sodium hydroxide solution, the pH of the solution is adjusted to 8.5. After that process with vigorous stirring 2 l of 96% alcohol, and again
    O a white flocculent precipitate is formed, which is immediately separated from the mother liquor and dried under vacuum over. By repeating this reprecipitation, 33 g of disodium 5 -4- (trans-2, 3-dihydro-7-methoxy-3-methyl-5 (E) propenylbenzofuran-2-yl) -2-methoxyphenyl phosphate are obtained in the form of fine, hygroscopic crystals m.p. 185-187 With (destruction).
    Found: C, 52.91; H, 4.92; P, 6.43; Ma, 10.02.
    SodNpOLRNa (450, 16).
    Calculated,%: C 53.34) H.4.70, P 6.87, Na 10.21.
    Getting the source material
    To solution. 100 g of (E) -isoevgenol in 1.3 l of 75% ethanol are added 150 g of ferric chloride in 400 ml of water; and allowed to stand at 0 ° C for 24 hours. The precipitate formed is filtered and recrystallized from ethanol, yielding 53 g of trans-2,3-dihydro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- (EO-propyylbenzofur 1a (dehydrodiisophal) in the form of colorless crystals. m.pl 132-133 C.
    Prim, ep 2. 5 g of trans-2,3-diHYDRO - 2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- (E) -propenylbenp. Zolfuran (dehydrodiisoevgenol) I 1 , 36 g of M-methylglycine is kept in 50 ml of ethanol after treatment with 1.2 ml of a 35% formalin solution for 16 hours with a reverse outflow, and after 12 hours the same amount of N-methylglycine and formalin solution is added again . After cooling, the precipitate was separated and, after crystallization from methanol / water, 4.1 JP (tranc-2,3-dihydro-7-methoxy-3-methyl-5 (E) -propenylbenzo-furan-2-yl) - 2-Aoxy-E.-methoxy-phenyl-methyl-M-methylglycine / small white crystals with m.p. 140.5141, 5 ° C (destruction).
    Found,%: C 67.13; H 6.73, N 3.21.
    f uA 19 ° 6 Calculated,%: C 67.40, H 6.86,
    N 3.28.
    Example 3. 5g trans-2,3-dihydro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- {E) -propenylben, zolfuran (dehydrodiisoeugenol) 0.9 g of paraformaldehyde and 2.3 g of methylaminoethanol is kept in 60 ml of absolute ethanol for 48 hours; at 65 ° C, the solvent is removed by the subpodum and after recrystallization from methylene chloride / petroleum ether (b.p. 6080 F., 4 g are obtained (trans-, 3-dihydro-7-methoxy-3-methyl-5 -lle) -propenylbenzofuran-2-yl) -2-oxy-3-methoxyphenylmethyl N-hydroxyethyl-N-methylamine in the form of fine colorless crystals, so pl. 101-103c.
    Found%: C 69.59, H 7.51 J N 3.17. .
    . ,
    Calculated,%: C 69.63, H 7.58, N 3.3.9.
    EXAMPLE 4 To obtain the hydrochloride of the compound obtained in Example 3, drop by drop, 5 g of trans-2,3-dihydro-7-methoxy-3-5- (E) -thopenylbenzofuran-2-yl are poured into the solution. - (2-hydroxy-3-methoxyphenylmethyl -N- (2-hydroxyethyl) -N-methylamine in 60 ml of absolute ether is an equimolar amount of ethereal hydrochloric acid. The precipitate is sucked out and washed with absolute ether. 8.8 g of N-f5- are obtained (Trace-2,3-dihydro-7-methoxy-3-methyl-5- (E) -propenylbenzofuran-2-yl) -2-hydroxy-3-methoxyphenylmethyl} -H- (2-hydroxyethyl) -N-methyl ammonium 5 chloride in the form of small, slightly yellow. hygroscopic crystals, mp. (destruction).
    Found,%: C 63.79 / N. 7.13, Ct 7.77; M 3.02.
    0 C3.4H42. ClNOg; 449.77).
    Calculated,%: C 64.03, H 7.19, C t 7.88, N 3.11.
    To prepare aspartate to a solution of 1 g of N-C5-TpaHc-2,3-dihydro-7-methoxy-3-methyl-5- (E) -propenylbenzofuran-2-yl) -2-hydroxy-3-methoxnphenylmethyl -N- (2-hydroxyethyl) -N-methylamine in 25 ml of ethanol was added 0.32 g with (, - aspartic acid in 15 ml of hot water, held for
     2 hours at 70 ° C and then the solvent is removed by means of a p-vaporizer. taveypor. After drying under a wa; Kuum gives a slightly brown amorphous DOS-NJ 5- (trans-2, .3-di5 hydro-7-ethoxy-3-methyl-5- (E) -prope nilbenzofuran-2-yl) -2-hydroxy-3-labels . syphenylmethyl 3-M- (2-hydroxyethyl) -N-methyl ammonium aspartate.
    To obtain the liponic acid salt to a solution of 1 g of (trans-2,3-dihydro-7 methoxy-3-methyl-5- (E) -propenylbenzofuran-2-yl) -2-hydroxy-3-methoxyphenylmethyl -M- (2 α-oxyethyl) -Y-methylamine in 50 ml of ethanol was added 0.5 g of liponic acid, stirred for 2 hours to ensure complete α-homogenization, and after evaporation of the methanol and drying under vacuum, light brown was obtained.
    Q is an amorphous residue.
    Example 5. Dissolve 3.9 g of ornithine in 200 ml of water and treat with a solution of 10 g of trans-2,3-dihydro-2- (3,4-dimethoxyphenyl) -7-methoxy-3-methyl-benzofuran-5-carboxylic acid in 2 ml of ethanol. The first transparent solution, after about 30 minutes, begins to grow cloudy and a bulky precipitate falls out, which after 2 hours
     aspirated, washed with 95%
    . alcohol and dried. . After recrystallization from a mixture
    water and acetone, 10 g of colorless crystals of L-ornithine-trans-2, .3-dihydro-2- (3,4-dimethoxyphenyl) - / are obtained.
    5 -7-methoxy-3-methylbenzofuran-5-carboxylate with so pl. 192-193 C (destruction).
    Found,%: C 60.19, H 6.66, N 5.79.
    Ci.4Hii 4 ° 8).,. ,
    Calculated,%: C, 60.46; H, 6.79; 5 N, 5.88.
    Getting the source material.
    40 g of trans-2,3-dihydro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- (E) -propenylbenzo-10 furan are treated in 800 ml of 96% ethanol 30 ml of dimethyl sulfate, and then treated in portions with shaking 48 ml of 30% potassium hydroxide solution, and the temperature should not exceed 5. After that, it is stirred for another 12 hours at room temperature and then diluted to 1 liter with water. Image: The precipitate is sucked off and washed with water. After recrystallization from ethanol, 34.8 g of trans-2, 3-dihydro-2- (3,4-dimethoxyphenyl) -7-methoxy-3-methyl-5-E) -propenylbenzofuran, mp. 25
    To 15 g of this methylated product in 300 ml of absolute acetone, with stirring, add 21 g of potassium permanganate under ice cooling for 16 hours in small portions, evaporate the acetone under vacuum on a rotavapor evaporator, suspend the residue in 600 ml of water and pass sulfur dioxide until the solution turns yellow, and pyrolusite goes into solution and a new 35-flaky osschk falls out. This precipitate is crushed, washed with water, separated by means of 600 ml of 10% sodium hydroxide solution, separated in a centrifuge from insoluble fractions, and sediment 40 is separated several times with 200 ml portions of water. United water the alcoholic phases are acidified with dilute hydrochloric acid and, after recrystallization, first from a mixture of acetic acid ester and petroleum ether (bp 60–8.), then 6.4 g of trans-2, 3– dihydro-2- (3,4-dimethyl-hydroxyphenyl) -7-methoxy-3-methylbenzofuran-5 carboxylic acid with so pl. 135136 S.
    To isolate L-ornithine, the corresponding hydrochloride is fed to the exchange column with amberlite 120 in the form of "NHjj, then washed with 5% ammonia solution and all volatile fractions are removed by evaporation.
    To obtain the salt of L-arginine, 5.1 g of L-arginine is treated in 200 ml of water with 10 grams of trans-2,3-dihydro--2- (3,4-dimethoxyphenyl) -7-methoxy-3-methylbenzofuran-5 -carboxylic acid in 500 ml of 95% ethanol. It is heated for 2 hours at and then the solvent is removed under vacuum, 5
    and a slightly yellow crystalline precipitate of L-arginine-trans-2, 3-dihydro-2- (3,4-dimethoxyphenyl) -7-methoxy-3-methylbenzofuran-5-carboxylate monohydrate is obtained with a melting point of mp. 130135С.
    Found,%: C 55.56) H 6.82.
    . ) Calculated,%: C 55.93, H 6.78. To obtain the choline salt, 4.1 g of choline chloride is treated with 150 ml of absolute ethanol with stirring, 1.6 g of KOH in 6 mi of water, after 2 h, filtered from the precipitated CC and washed with absolute ethanol. To this solution, 10 g of trans-2,3-dihydro-2- (3,4-dimethoxyphenyl) -7-methoxy-3-methylbenzofuran-5 carboxylic acid in 500 ml of absolute ethanol is added dropwise to this solution and for 1 h at. Thereafter, evaporation under vacuum is carried out and by adding diethyl ether, 13 g of chintrans-2, 3-dihydro-2- (3, 4-dimethoxyphenyl) -7-methoxy-3-methylbenzofuran-5-carboxylate monohydrate are obtained, m.p. 163-165C.
    Found,%; C 61.84, H 7.48. , (465.38). Calculated,%: C, 61.89; H, 7.59. Example 6. Under nitrogen, dissolve 10 g of trans-2, -3-dihydro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5-CE-propenylbenzofuran in 400 ml of 2 M caustic potassium and treated with 37 ml of 35% formalin solution. After that, it is kept at 75 ° C for 24 hours and once again during this time it is treated with equal (the same) amounts of formalin. After cooling with dilute hydrochloric acid, it is acidified to pH4, extracted with ether, washed with ether and water and dried over sodium sulfate. The oil obtained after removal of the ether crystallizes from a mixture of methylene chloride and petroleum ether (b.p. 60-80 0, after which 7 g 5- (trans-2,3-dihydro-7-methoxy-3-methyl-5- (E ) -propenylbenefuran-2-yl) -2-hydroxy-3-methoxybenzyl alcohol with mp 117119 ° C.
    Found,%: C 70.92 / H 6.67.
    GUI Datasheets (356.24).
    Calculated,%: C, 70.74; H, 6.80.
    Example 7. When dissolved, 15 g of trans-2, 3-dihydro-2- (4-hydroxy-3-methoxyphenyl) -7-methoxy-3-methyl-5- (E) -propenylbenzofuran (dehydrodiisoeugenol) in 150 ml of absolute toluene and 9.3 g of M, M-dimethyl-2-chloroethylamine hydrochloride and 15.5 g of KOH in solid form are added. After 6 hours at 80 ° C, the ipacTBop is cooled, decanted from the residue of solid KOH, the toluene solution is washed with water until the solution is completely removed, and after drying over sodium sulfate, the solvent is removed under vacuum. After crystallization of the residue under vacuum, the remaining part of the non-precipitated substance is transferred with gasoline into solution. I get with 11.2 g of M-2-4-trans-2,3-dihydro-7-methoxy-3-methyl-5- (E) -propenylbenzofuran-2-yl) -2- (2-methoxyfenox ethylJ-N , N-dimethylamine, small, weak-yellow crystals with mp 58bo; V Example 8. To obtain the gyrochloride of the compound obtained from 7, to a solution of 10 g (4-trans-2, 3-dihydro-7-methoxy- 3-meth-5- (4E) -propenylbenzofuran-2-yl- (2-methoxyphenoxy) -ethyl-N, M-dimethylamine 200 ml of absolute ether is added dropwise an equimolar amount of ethereal hydrochloric acid. this is partly not in crystalline form, the precipitate crystallizes within 24 hours, the mixture is completely sucked off and washed with absolute ether. 10.0 g (4-trans-2, 3-dihydro-7-methoxy-3-m-tyl-5- (E) -propenylbenzofuran-2-yl (2-methoxyphenoxy) are obtained. -ethyl-N, N-dimethylammonium chloride in the form of small weakly, more yellow hygroscopic crystals with mp 135.5-137.0 ° C. Found,%: C 66.20; And 7, 36; N 3, 2 °; cr 8.31. Sod H,., C N0, (433, .78). Calculated: T%: - C 66.39; H 7.45, N 3.23-, C1 8.17 D D and measure 9. Preparation of 110,000 tablets, each containing 50 mg of each substance, components, g: Trans-2,3-dihydro-2- (4-hydroxy-3-methoxyphenyl) - 7 - labels si - 3 -methyl-5- (E) -propenylbenzofuran Mo sugar Sujuruz starch PrlietilenglyTalc powdered magnesium tearate Method. The powder components are sieved through a sieve with a particle size of 0.6 mm. The active substance is then mixed in an appropriately suitable blender with milk sugar, talc, stearato, magnesia, and half of the starch. The other half of the starch is suspended in .50 ml of water, this suspension is added to a solution of polyethylene glycol heated to 80c in 190 ml of water. The similarly obtained paste is mixed with powdered components, then granulated, if necessary with the addition of some water. The granule is dried for 12 hours at a time, passed through a 1.2 mm sieve and pressed into tablets of 7 mm diameter. Preparation of 10,000 capsules with the content in each 100 mg of active veg: first effects of the following components, g; (trans-2,3-dihydro) label of si-3-methyl-5- (E) -propenylbenzofuran-2-IL-2-OXI-3-methoxy- Nilmethyl-N- (2-hydroxyethyl) -N-methylamine 1000 Milk: 2700 Talc powdered 200 Method. The powder components are sieved through a sieve with openings of 0.6 mm. The active substance is then homogenized with talc and then with milk sugar in a suitable mixer. By using a filling machine, gelatin capsules of corresponding sizes with a capsule weight of 400 mg of the mixture are obtained. Preparing 10,000 portions of injection solutions for packaging in ampoules. The content of the components, g:, trans-2, 3-dihydro-7-methoxy-3-methyl-5- (E) -prrphenylbenzofuran-2-yl -2-ckg: and-3-methoxyphenylmethyl-M-2-hydroxyethyl 3- N-methyl ammonium chloride. 600 Sodium chloride 10 Water for injections. Tsiido 10,000 ml. Way After the components are dissolved, filtration is carried out through a glass suction filter with apertures or passages of Q 3 capacity and then filled into ampoules in a nitrogen atmosphere for subsequent intravenous injection of 2 ml each. When applied, the effect is packaged in 5 ml ampoules.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method for preparing benzofuran derivatives of general formula {I)
    a substituted phosphate group or a hydrogen atom,
    or their salts, characterized in that isoeugenol is subjected to oxidative dimerization in the presence of iron chloride in an aqueous alcohol medium and the desired product of formula (I) is isolated, where R is a hydrogen atom, in free form or in the form of a salt, or compound of formula I; where R is methyl, by the action of dimethyl sulfate in the presence of caustic potassium in ethanol, or into a compound of formula (I), where R is a 2-dimethylaminoethyl group, by the action of N, M-dimethyl-2-chloroethyl 1-MHH hydrochloride in toluene in the presence of potassium hydroxide at, or to the compound of formula (I), where R is monosubstituted. phosphate, a group by the action of phosphorus oxychloride in toluene in the presence of N-, N-dimethylaniline at reflux, or a compound of formula (1), where -CH H CH 3 CH 3, is converted into a compound of formula (I), where R is a carboxyl group, by the action of potassium permaganganate in acetone with, or the compound of formula (I), where R is a hydrogen atom, is converted into a compound of formula (1), where R is methyl, substituted by hydroxy,
    5 by hydroxymethylation in a formalin solution in the presence of caustic potassium at, or translate it into a compound of formula (I), where R2 is methyl, substituted by an amino group, which is substituted by one or two - lower alkyl groups or one lower alkyl and one lower oxygen or. the lower carboxyalkyl group, the action of the corresponding amine in a formalin or para5 formaldehyde solution in ethanol at elevated temperature and the desired product is isolated in free form or as a salt.
    0
    Sources of information taken into account in the examination
    T. Freude.nberg K. Neuere Beitrage zur Bitdung und Konstitution des Lignins Brerinstoff Chemie, 1963 CC, s. 328.
    five
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    同族专利:
    公开号 | 公开日
    ES478795A1|1980-02-16|
    EP0004522A2|1979-10-03|
    DE2812664A1|1979-09-27|
    NZ189899A|1982-05-25|
    IL56901A|1983-12-30|
    DD143611A5|1980-09-03|
    CA1144557A|1983-04-12|
    GR66978B|1981-05-15|
    PT69377A|1979-04-01|
    IE790920L|1979-09-22|
    HU182913B|1984-03-28|
    JPS54138530A|1979-10-27|
    AU4519079A|1979-09-27|
    AT379593B|1986-01-27|
    EP0004522A3|1979-10-31|
    CS223875B2|1983-11-25|
    IE48904B1|1985-06-12|
    EP0004522B1|1982-06-23|
    US4304785A|1981-12-08|
    ZA791137B|1980-07-30|
    PL214270A1|1980-03-10|
    AU526814B2|1983-02-03|
    PL119289B1|1981-12-31|
    ATA153179A|1985-06-15|
    YU67679A|1983-02-28|
    DK115379A|1979-09-23|
    IL56901D0|1979-05-31|
    NO790948L|1979-09-25|
    DE2963141D1|1982-08-12|
    FI790945A|1979-09-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1199040A|1966-11-26|1970-07-15|Egyt Gyogyszervegyeszeti Gyar|Diisoeugenol Derivatives|AT371453B|1978-11-15|1983-06-27|Plc Pharma Licences|METHOD FOR PRODUCING NEW DERIVATIVES OF TRANS-2,3-DIHYDRO-2--7-METHOXY-3-METHYL-5--PROPENYLBENZOFURANE|
    JPH0552812B2|1987-02-09|1993-08-06|Sato Pharma|
    US4873241A|1988-10-31|1989-10-10|Fisons Corporation|2-amino-N-acetamides useful as anti-epileptics|
    JP4568527B2|2004-04-22|2010-10-27|ポーラ化成工業株式会社|Benzofuran derivative and external preparation for skin containing the same|
    US7919519B2|2005-11-23|2011-04-05|Epix Pharmaceuticals Inc.|S1P receptor modulating compounds and use thereof|
    WO2007061458A2|2005-11-23|2007-05-31|Epix Delaware, Inc.|S1p receptor modulating compounds and use thereof|
    KR100858357B1|2006-10-02|2008-09-11| 디지탈바이오텍|Composition comprising benzofuran type derivative for treating and preventing cognitive dysfunction|
    BR112012025740B1|2010-04-08|2017-12-26|Symrise Ag|Cosmetic preparation, and use of dihydrodesidrodi-isoeugenol|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19782812664|DE2812664A1|1978-03-22|1978-03-22|USE OF DILIGNOLS AND DILIGNOL-LIKE COMPOUNDS AS ACTIVE INGREDIENTS OF LEBERTHERAPEUTICA|
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