• 专利附录
  • 专利说明
  • 权利要求
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  • 优先权
    • 专利摘要:
    The method of obtaining 6-hydroxy-2-
    公开号:SU1138028A3
    申请号:SU823417251
    申请日:1982-04-02
    公开日:1985-01-30
    发明作者:Кэтлин Питерз Мэри；Дэвид Джонз Чарльз
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    against the method of obtaining the acidula
    but
    ABOUT
    OCHzCHjNFiRg
    OH of a metal, such as sodium chloride, methyl bromide, sodium iodide or lithium, taken in an amount of 1-2.2 moles per 1 mole of sulfur compound. The demethylation reaction is carried out at 15-30 seconds. A decrease in temperature below the lower limit leads to a slower reaction rate. Heating above 30 ° C has no advantage. Thus, the proposed method allows a simple and convenient synthesis of the acylated benzothiophenes of formula 1, which are of interest to medical practice. Example 1. Chlorohydrate-6-hydroxy 2- (4-hydroxyphenyl) (2-piperidinoethoxy) -benzoyl benzo b thiophene. A mixture of 3 g of 4- (2-piperidinoethoxy) benzoic acid hydrochloride, 2 drops of dimethylformamide, 2.5 ml of thionyl chloride and 40 ml of chlorobenzene is heated at 70-79 ° Fe for 1 h under a nitrogen atmosphere. The excess thionyl chloride and 15-20 ml of solvent are distilled off, the remaining suspension is cooled to ambient temperature and 100 ml of dichloromethane 2.7 g (0.01 mol) of 6-methoxy-2- (4-methoxyphenyl) benzo 1) are added to it. thiophene and 10 g (0.075 mol) of aluminum chloride. The solution is stirred for 1 hour, 7.5 ml (6.2 g, 0.01 mol) of ethanethiol are added and the mixture is stirred for another 45 minutes at the same temperature. Then 40 ml of tetrahydrofuran, 15 mp of 20% hydrochloric acid are added, the mixture is heated to the boiling point, 50 ml of water and 25 ml of a saturated aqueous solution of sodium chloride are added. The mixture is stirred and allowed to cool to ambient temperature. The precipitate is filtered off and successively washed with 30 ml of water, 40 ml of a 25% aqueous solution of tetrahydrofuran and 35 ml of WATER, are dried in vacuum at 40 ° C and 5.05 g of technical product are obtained, which is purified by the method described in the example, and 3 , 05 g of the desired product. Output 60% k.m. NMR spectrum (90 MHz, deuterochloro form), E m, d: 1.7 (6H, m, N (CHCH) C 2, -3.1 (2H, m, N SNL) 3.5-4.1 (4H, M, NCH2); 4.4 (2H, m, OCH) i 6.6-7.4 (9H, m, aromatic) J7.7 (2H, d, aromatic ) j 9.8 (2H, m, OH), 28 .4 Example 2. 6-hydroxy2- (4-hydroxyphenyl) -3-4- (2-piperidinoethoxy) benzoyl | benzo B3 thiophene hydrochloride. From 1.5 g of 4- (2-piperidinoethoxy) benzoic acid hydrochloride is obtained using the method described in npiwepe 1. 30 ml of dichloromethane, 1.35 g (0.005 mol) of 6-methoxy-2 (4-methoxyphenyl) benzo b, thiophene are added to the acid chloride and 5 g (0.037 mol) of aluminum chloride. The mixture is stirred at a temperature re-ambient for 2.5 hours and add 0.74 g (0.006 mol) of lithium iodide to it, mix again for 1 hour, add 0.68 g (0.011 mol) of ethanethiol, and stir for 30 min. 25-35 ° C. Then 25 ml of tetrahydrofuran, 5 ml of 20% hydrochloric acid and 50 ml of water are stirred overnight, the precipitate is filtered off, rinsed with 45 ml of water, 40 ml of diethyl ether and dried under vacuum. Obtain 2.18 g of the technical product, which is purified. Using 90 MHz, NMR analysis was determined, according to the method described in Example 1. 1.32 g (52%) of the desired product was obtained, which according to the PMR spectrum, was identical to the product of Example 1. EXAMPLE 3 6-hydroxy hydrochloride - (4-hydroxyphenyl) -3-4- (2-piperidinoethoxy) benzoyl benzo b1 thiophene. The process carried out in Example 2 is repeated, except that 0.95 g (0.011 g) is used instead of lithium iodide. mole) lithium bromide. Get the product identical synthesized in example 1, in the amount of 1.53 g, yield 62%. EXAMPLE 4, 6-hydroxy2- (4-hydroxyphenyl) 3-.4- (2-piperidinoethoxy) -benzoGH | benzo LZ thiophene hydrochloride. The process carried out in Example 2 is repeated. except that after adding aluminum chloride the mixture is stirred for 1.5 h and, without adding lithium iodide, 0.81 ml (0.67 g l of 0.011 mol) of ethanethiol is added and the mixture is stirred for 1.5 h. After the indicated time has elapsed, thin layer chromatography establishes that the reaction mass contains a large amount of an undemethylated intermediate. Another 0.81 ml of ethanethiol is added and the reaction mixture is stirred for 1 h, 25 ml of 0-tetrahydrofuran, 5 ml of 20% hydrochloric acid, 25 ml of water are added. The product is isolated as described in Example 2.
    Get 1.63 g (64%) of a substance identical to the product obtained in example 1.
    Example 5. 6-hydroxy2 (4-hydroxyphenyl) -3-4- (2-piperidinoethoxy) benzoyl 6-benzoylbenzoyl thiophene hydrochloride.
    The process described in example 2 is repeated, except that after adding aluminum chloride, the reaction mass is stirred for 1.5 hours, 1j13 g (0.011 mol) of sodium bromide, ri and 0.81 ml (0 , 67 g, 0.011 mol) ethanethiol. The mixture was stirred for 1.25 hours, tetrahydrofuran, hydrochloric acid and water were added, and the mixture was filtered and washed as described in Example 2. After purification of the technical product according to the method described in the example, 1.51 g (60%) of the desired product was obtained. , which was studied using thin layer chromatography and showed that it was identical to the product obtained in Example 1.
    Example 6: 6-hydroxy-2- (4-hydroxyphenyl) -3-C4- (2-piperidinoethoxy) benzoyl benzo III S thiophene hydrochloride. : The process carried out in Example 5 is repeated, except that 0.64 g (0.011 mol) of sodium chloride is used instead of sodium bromide. The mixture is treated as indicated in the examples above, 1.31 g (51%) of the desired product is obtained, the study of which, using thin-layer chromatography, showed that it is identical to the product obtained in Example 1.
    Example 7. 6-hydroxy-27- (4-hydroxy-1) -3-4-2-pyrrolidinoethoxy-benzoyl benzoyl thiophene hydrochloride.
    Chloride hydride is obtained from 2.85 g of 4- (2-pyrrolidinoethoxy) benzoic acid hydrochloride as described in Example 1. Excess thionyl chloride and a large part of the solvent are distilled off. 80 ml of dichloromethane, 2.7 g are added to the residue at ambient temperature. (0.01 mol) 6-methoxy-2 (4-methoxyphenyl) b thiophene and 10 g (0.075 mol) of aluminum chloride. The mixture is stirred for 45 minutes, 7.5 ml of ethanolol are added.
    Stir for 45 minutes. Then 5 ml of methanol, 35 ml of tetrahydrofuran, 20 ml of 20% hydrochloric acid, 40 ml of water and 50 ml of diethyl ether are added. The precipitation is filtered off, washed with water, diethyl ether, dried under vacuum at 80 C. Obtain 4.36 g of a technical product.
    1 g of the product is dissolved in 10 ml of hot methanol and filtered. The filtrate is concentrated to a volume of 5 ml. While cooling, 10 ml of diethyl ether was slowly added to the mixture. The precipitated crystals are filtered off, washed with diethyl ether, dried at 100 ° C under vacuum. 0.9 g of the expected product is obtained. M.p. 226-227 ° C.
    PMR spectrum (90 MHz, DMSO), 8, ppm: 1.9 (m, 4H, N (CH2CH2) 2); 3.0-3.7 (m, 6H, CH, M (CHOCH,) -, 4.3-4.5 (m, 2H, OCHjCH b 6.6-7.8 (m, NH, aromatic) i 9.87-9.88 (m, 2H, OH).
    EXAMPLE 8 Chlorohydrate 6-hydroxy-2- (4-hydroxyphenyl) (2-piperidinoethoxy) benzoyl benzo benz thiophene.
    1.5 g of 4- (2-piperidinoethoxy) benzoic acid hydrochloride is converted to the acid chloride as described in Example 1, the excess volatile matter is removed under vacuum.
    At ambient temperature, 1.35 g (0.005 mol) of 6-methoxy-2- (4-methoxyphenyl) benzo B thiophene, 30 ml of dichloromethane and 5 g (0.0376 mol) of aluminum chloride are added to the acid chloride. The mixture was stirred for 30 minutes and 3.1 g (0.05 mol) of dimethyl sulfide was added to it. After stirring for 20 minutes, the reaction mass is cooled to 10 ° C and 25 ml of tetrahydrofuran is added to it. The mass is then heated to 25-30 seconds and 5 ml of 20% hydrochloric acid and 25 ml of water are added. Then the mixture is heated to 35 ° C, cooled, stirred overnight, the precipitate is filtered off and washed successively with 60 ml of water and 30 ml of diethyl ether, dried under vacuum.
    5 After purification of the technical product, carried out analogously to example 7, 1.6 g (63%) of the desired product is obtained, identical (according to ton 7 CWL chromatography and 1 H NMR) to the substance obtained in Example 1. Example 9. 6-ox-2-hydrochloride 2- (4-hydroxyphenyl) -3-4- (2-piperidinoethoxy) -benzoyl benzo 1) thiophene. The process carried out in Example 8 was repeated, except that the amount of dimethyl sulfide used was 1.6 ml (1.36 g, 0.021 mol) and after adding dimethyl sulfide, the mixture was stirred at ambient temperature for 75 minutes. The reaction mass is processed as described in Example 8. 1.54 g (61%) of the desired product is obtained, identical to the product obtained in Example 1. Example 10. 6-ox 2-(4-hydroxyphenyl) (2-piperidino-ethoxy) hydrochloride -benzoyl benzo b thiophene. A mixture of 1.5 g of 4- (2-piperidinoethoxy) benzoic acid hydrochloride, 20 ml of chlorobenzene, 3 ml of thionyl chloride and 2 drops of dimethylformamide is stirred at 75-79 ° C. for 2 hours to obtain the corresponding acid chloride. Volatile products are distilled off from the reaction mass under vacuum at a bath temperature of 65-90 ° C. 20 ml of chlorobenzene are added to the residue and the volatile components of the mixture are again distilled under the same conditions. The mixture is cooled, 15 ml of dichloromethane, 1.35 g (0.005 mol) of 6-methoxy-2- (4-methoxy phenyl) benzo benthiophene, 5 g (0.0375 mol) of aluminum chloride and 15 ml of dichloromethane are added successively. The reaction mass is stirred at 27-29 ° C for 90 minutes, 1.6 ml (1.33 g, 0.021 mol) of ethanethiol are added and stirring is continued while cooling, maintaining the temperature not higher than 35 ° C. After 30 min, the mixture is treated as indicated in Example 8, except that only 18 ml of tetrahydrofuran and water are used. After purification under the conditions of example 7, 1.6 g of the desired product are obtained, which is identical to the product (according to the PMR and those obtained) in Example 1. Example 11. 6oxy-2- (4-hydroxyphenyl) hydrochloride (2-piperi yinoethoxy) benzoyl benzoyl b of thiophene. The process carried out in Example 10 was repeated, except that 1.8 ml was used (1.49 g. of the reaction mass instead of tetanum of addition of zanethiol and the mixture was stirred for 30 min., 4 ml were added to it methanol (this is about 18 ml of water. The temperature of the mixture is maintained at about 25 ° C. The mass is stirred for 30 minutes, the dock is filtered off and treated, 1.54 g (61%) of the product, which, according to NMR analysis and thin layer obtained in example 1, lenminoethoxy) benzoyl benzoyl thiophene, leniminoethoxy) benzoic acid, is converted into the acid chloride, and the excess volatile products are removed under vacuum as described in example 10. To the residue were added 30 ml of dichloromethane, 5 g (0.0375 mol) of aluminum chloride and 1.35 g (0.005 mol) of 6methoxy-2- (4-methoxyphenyl) benzo b ′ thiophene. The mixture is stirred for 90 minutes at 27-29 ° C, cooled, 1.8 ml (1.49 g. O, 023 mol) of zanethiol are added and stirred for 30 minutes at 32-34 cV. The mixture is then cooled, added 18 ml of tetrahydrofuran, 5 ml of 20% hydrochloric acid, 18 ml of water and stirred overnight at ambient temperature. The precipitate is filtered, washed and dried under vacuum, as described in the above example. From 2.4 g of the technical product, after recrystallization from methanol, 0.94 g of the expected product is obtained. M.p. (with decomposition). Mass spectrum, p / e: 487. hydroxy-2- (4-hydroxyphenyl) -3-14- (2-dimethyl aminoethoxy) benzene Zbenzo U thiophene. methylaminoethoxy) benzoic acid, 2.5 ml of thionyl chloride, 20 ml of chlorobenzene and one drop of dimethlformamide are stirred at 75-79 ° C for 3 hours to obtain the acid chloride. 28 0.023 mol) ethytiol and methanol is used in the treatment of hydrofuran. It leads to a rapid evolution of gas and an increase in temperature), it is cooled to 30 ° C, 6 ml of methanol are added again, then 5 ml of 20% hydrochloric acid as indicated. After purification, the complete chromatography is identical to the product, Example 12. H. 6-hydroxy-2- (4-hydroxyphenyl) (2-hexameti1, 6 g 4- (2-hexamethi hydrochloride) Example 13. Hydrochloride 6Mix 1.3 g 4- (2-di-hydroxy-hydrochloride after distillation of the excess thionyl chloride as described in example 9, cooled, 30 ml of dichloromethane, 5 g (0.0375 mol) of aluminum chloride and 1.35 g (0.005 mol) of 6-methoxy-2- (4-methoxy phenyl) benzo 1) thiophene are added to it The reaction mixture is stirred for 90 minutes at 27-29 ° C, cooled, 1.8 ml of ethanethiol is added, and then the stirring is continued at 32-34 ° C for 30 minutes. The reaction mixture is processed as described Example 12. This gives 2.0 g of a technical product, from which 1.3 g of the desired product is recovered after recrystallization from methanol containing 1% of water, mp 136 ° C (with decomposition). : 433. Example 14. 6oxy-2- (4-hydroxyphenyl) (2-pyrrolidinoethoxy) benzoyl | benzo BZ hydrochloride thiophene A mixture of 5.71 g of 4- (2pyrrolidinoethoxy) benzoic acid hydrochloride, 10 ml of thionyl chloride, 4 drops of dimethylformamide and 4 ml of chlorobenzene is stirred at 75-79 ° C for 2 hours, the excess thionyl chloride is distilled off in vacuo, as described in step 10. The residue is cooled, 120 are added. l of dichloroethane, 5.4 g (0.02 mol) of 6-methoxy-2- (4-methoxyphenyl) -benzo b thiophene and .20 g (O, 15 mol) of aluminum chloride .. The mixture is stirred at 27-29 ° C for 90 minutes, cool, add 7.4 ml (6.2 g, 0.01 mol of ethanethiol) at 25 ° C and stir at 32-34 for 45 minutes. The treatment of the reaction mass is carried out by adding 100 ml of tetrahydrofuran, 20 ml of 20% hydrochloric acid and 100 ml of water. The mixture was stirred overnight, the precipitate was filtered and washed successively with water and diethyl ether. Get 9, technical product, So pl. 202 s (with decomposition), from which, after recrystallization from methanol and water, 5.45 g (55%) of the desired product was extracted. According to the PMR analysis, this product contains 0.5% methanol and is identical to the product obtained in Example 7. EXAMPLE 15 6-Oxy2- (4-hydroxyphenyl) (2-piperidinoethoxy) benzoylZbenzo1, thiophene hydrochloride . 200 g of 6 oxy-2- (4-hydroxyphenyl) (2-piperidinoethoxy) benzoyl benzoyl thiophene technical hydrochloride, a product of Example 10, is added to 4400 ml of methanol and 60 ml of deionized water. The mixture is heated to boiling point, with the result that most of the technical product goes into solution. The insoluble material is filtered off. A distillation head is then attached to the flask. The solvent is distilled off from the filtrate until the volume of the remaining solution is 1800 ml. This solution is cooled very slowly overnight with constant stirring. The crystalline product is filtered off, washed with cold (below) methanol, (100 ml-2) and dried at vacuum. 140 g of anhydrous product are obtained, which is mixed with 3000 ml of methanol and 42 ml of water, heated to the boiling point and cooled very slowly. The precipitate is filtered and dried as above. Obtain 121 g of the product, so pl. 259-260 ° C.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining 6-hydroxy-2- (4oxyphenyl) -3- (4-aminoethoxybenzoyl) benzo [b] thiophenes of the general formula 1 about
    —G “ with οα1 : σι ί 1, κ Λ:
    BUT where R ^ and R 2 are each alkyl with 1-4 carbon atoms or together form polymethylene with 4-6 carbon atoms, the group is (CH g ) 2 O (CH 2 ) 2 - or -CH 2 CH (CH ^) CH 2 CH 2 ~, or their salts, by acylation of 6-methoxy-2- (4-methoxy phenyl) benzo [B] thiophene with a compound of formula II where Rj and Rg have the indicated meanings under the Friedel-Crafts reaction in the presence of excess aluminum chloride in inert organic solvent, such as dichloromethane, dichloroethane or chlorobenzene, at 15-30 ° C followed by demethylation, characterized in that, in order to simplify the process, demethylation It is carried out by adding to the reaction mixture a compound of the formula ΙΠ
    Χ5Ύ, where X is alkyl with 1-2 carbon atoms •,
    Y is hydrogen or methyl, taken in excess from 2.2 to 10 mol at 15-35 ° C.
    Priority by signs:
    04/03/81 - R, and together form pentamethylene.
    12.16.81 ~ Rj and R2 each alkyl with
    1-4. Carbon atoms or together form polymethylene with 4-6 carbon atoms, the group - (CH 2 ) 2 O (CH 2 ) 2 or —CH 2 CH (CH 5 ) CH 2 CH 2 -.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US24633381A| true| 1981-04-03|1981-04-03|
    US06/331,046|US4380635A|1981-04-03|1981-12-16|Synthesis of acylated benzothiophenes|
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