• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:

    公开号:SU818487A3
    申请号:SU792707651
    申请日:1979-01-15
    公开日:1981-03-30
    发明作者:Ли Томпсон Джеральд
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing dimeric 4-deacetylindolehydroindoles of the formula not described in the literature
    CrH5 total
    their salts possessing pharmacologists
    or activity. 25 ~ There is a known method of producing oxy compounds, which consists in alkaline hydrolysis of acetic acid esters £ 1]. The purpose of the invention is the expansion of the range of pharmacologically active dimeric indole dihydroindoles or 30.
    their salts due to the use for their preparation of a known method.
    This goal is achieved by the fact that in the method for producing dimeric 4-deacetylindole dihydroindoles of the general formula (1), where R is hydrogen, and R * 2 is methyl or formyl, go to their salts, which consists in the fact that the compound of general formula (1 ), where R is acetyl, and R ^ has the above meanings, is hydrolyzed in the presence of a base in a solvent.
    Sodium carbonate is preferably used as the base, and anhydrous methanol is used as the solvent. ,
    When using sodium carbonate in methyl alcohol, the process is preferably carried out at the temperature of singing. Of the bases, potassium tert-butylate, sodium or potassium methylate or ethylate, pyridine, triethylamine or other> tertiary amines, urea in polar organic solvents such as lower alcohols can be used. Diluted potassium or sodium hydroxide solutions, for example, c. May also be used. methyl alcohol, bases such as sodium or lithium hydride in benzene, ether, tetrahydrofuran or dimethyl sulfoxide sodium salt in dimethyl sulfoxide, and the process is carried out at a temperature of from room temperature (25 ° C.) to the boiling point of the solvent.
    Example 1. Obtaining 4-dee- $ hydroxy-4-deacetyl-1-formyllerosidine. ·.
    900 mg of chromium trioxide are dissolved in 10 ml of acetic acid and 1 ml of water. This solution was added dropwise, θ was added over 5 minutes to a stirred solution of 794 mg of 4-deoxyvinoblastin B in 95 ml of acetone and 50 ml of glacial acetic acid at a temperature of about -50 ° C.
    The reaction mixture was stirred '5 at this temperature for about 30 minutes, then cooled to -64 ° C. At this temperature, 19 ml of 14-aqueous ammonium hydroxide was added. Then the reaction mixture was poured into the mixture. 20 ice and water and the aqueous layer are extracted three times with 240 ml of chloroform. The organic layers are combined and the combined layers are washed with dilute aqueous sodium bisulfate, separated, 25 dried, 648 mg of a yellow solid are obtained. Thin layer chromatography of the residue obtained immediately after oxidation of the mixture before its purification shows the presence of a large ed and a small spot and the presence of traces of other components. Recrystallization of the residue from anhydrous ethanol gives a pure crystalline substance, which is separated and washed with cold ethanol.
    Chromatography of the obtained crystalline free base on g of silicon dioxide using a solvent system consisting of a mixture of dichloromethane and ethyl acetate in a 1: 1 ratio containing 20.30.45 and 60 vol.% Methanol as the mobile phase is carried out as follows:
    System
    1: 1 (20%) 1: 1 (30%) 1: 1 (45%) 1: 1 (60%) and get fractions:
    number
    200
    100
    100
    400
    The volume of the eluate, ml
    160
    100
    120
    120 fractions 4-7 are combined and obtained
    597 mg of a brownish-colored 60 residue, which gives 435 mg of white crystalline 4-deoxy-1-formylleurosidine) (ethyl alcohol !.
    Mass spectrum (m / e): 808 (M t ), 806, 777, 775.336, 138, 136; 05
    IR spectrum, chloroform, cm **: 3470, 1743, 1690, 1222.
    UV spectrum, alcohol, nm: 210, 222, 254, 290, 298,
    NMR spectrum at 100 MHz, methyl singlets: 3.87, 3.65 and 2.07 cP.
    pKa = 9.0 and 4.9 (66% dimethylformamide).
    The sulfate of this compound is obtained by dissolving 435 mg of the free base in 10 ml of hot ethanol and adding 1.5 mp 2% sulfuric acid in ethanol. Crystalline 4-deoxy-1-formylleurosidine sulfate precipitated upon cooling.
    About 744 mg of 4-deoxy-1-formylleurosidine is mixed with 10 ml of anhydrous methanol and the mixture is heated at boiling point, the compound is dissolved and gives a clear solution. 200 mg of solid sodium carbonate’s was added to the reaction mixture and stirred for 7.2 hours. Thin layer chromatography of the reaction mixture showed complete disappearance of the starting 4-deoxy-1-formylleurosidine. The solvent was evaporated, and the residue containing 4-deoxy-4-deacetyl-1-formylleurosidine was treated with dichloroethane and water. The organic layer was separated, dried, the solvent was evaporated, and 506 mg of a solid was obtained, which was pure 4-deoxy-4-deacetyl-1-formylleurosidine.
    Mass spectrum (m / e): 766 (M + ), 764, 735, 254, 252, 205, 138;
    IR spectrum, chloroform, cm *: 3450, 1734, 1680, 1596, 1495, 1456, 1434, Corresponding sulfate salt is formed, as in the previous example, using acetone as a solvent and 0.26 mp 2% sulfuric acid acids in ethyl alcohol. Other solvents may be used, but it is preferable to use a solvent in which the base is readily soluble and the sulfate salt is essentially insoluble.
    4-Deoxy-4-deacetylvincristine and its sulfate are obtained in a similar manner from 4 deoxyvincristine.
    Example 2 Preparation of 4-Deoxycetyl-Leurosin
    A reaction mixture is prepared containing 1.48 g of 4-deoxyvinblastin B, 1 g of sodium carbonate and 100 mp methanol and heated at boiling temperature in a nitrogen atmosphere. Thin-layer chromatography of the reaction products after 2 h shows that the hydrolysis reaction with the removal of the 4-acetyl group is half completed. After holding the reaction mixture overnight at room temperature, it is heated at the boiling point for 8.5 hours. Thin layer chromatography of the reaction mixture using a mixture of solvents from
    81848 ether, diethylamine, toluene in a ratio of 20: 1: 1 indicates that the reaction is complete. The solvent was evaporated from the reaction mixture, and the resulting residue was dissolved in a mixture of dichloromethane and water. The dichloromethane phase is separated and dried. After 9 evaporation of dichloromethane, a residue is obtained whose thin layer chromatography indicates the presence of a very polar substance and the expected 4-deoxy-4-deacetyl-leurosin. The residue (1.33 g) is dissolved in benzene, the polar substance is separated by filtration. The filtrate was evaporated to dryness and the residue (500 mg) was chromatographed on silica gel using a solvent system of ether, diethylamine and toluene in a 20: 1: 1 ratio (with increasing amounts of methanol) as the mobile phase. 20 thin layer chromatography was performed and the fractions containing 4-deoxy-4-deacetyl-leuroeidine were combined and, after evaporation of the solvent, the yield of the free base was 348 mg. The remainder of 06-25 work 1.28 ml of 2% sulfuric acid in methanol, the resulting solution is filtered. The yield of 4-deoxy-4-deacetylleurosidine sulfate was 315 mg.
    Mass spectrum (m / e); 752 (m), 750, 693, 691, 555, 338, 240, 138; w
    IR spectrum, chloroform, cm * ^: 3455, 1724, 1610. 1497, 1457, 1431. Compounds of the general formula (1) exhibit high antitumor activity. 35
    权利要求:
    Claims (2)
    [1]
    tetrahydrofuran or sodium dimethyl sulfoxide in dimethyl sulfox de, and the process is carried out at a temperature from room temperature () to a point of solvent point. Example 1. Preparation of 4-deoxy-4-deacetyl-1-formyl-leroyoidin. . . . . 900 mg of chromium trioxide are dissolved in 10 ml of UNIFICATION acid and 1 ml of water. This solution is added dropwise over the course of 5 minutes to a stirred solution of 794 mg of 4-deoxy-vinblas B in 95 ml of acetone and 50 ml of glacial acetic acid at a temperature of about 50 ° C. The reaction mixture is stirred at this temperature for about 30 minutes, then cooled to -64 ° C, with this TewiepaType 19 ml of 14-aqueous ammonium hydroxide is added. Then the reaction mixture is poured into a mixture of ice and water and the aqueous layer is extracted three times with 240 ml of chloroform. The organic layers are combined and the combined layers are washed with dilute aqueous sodium bisulfate, the section is dried, and 648 mg of yellow solid are obtained. A thin layer chromatograph of the residue obtained immediately after the oxidation of the mixture prior to its purification shows the presence of a large and small spot and the presence of traces of other components. By recrystallizing the residue from anhydrous ethanol, a pure crystalline substance is obtained, which is separated and washed with cold ethanol. Chromatography of the resulting crystalline free base on 50 g of silica with the use of solvent systems consisting of a mixture of dichloromethane and ethyl acetate in a ratio containing 20,30,45 and 60% by volume of methanol as the mobile phase is carried out as follows: KoJiH4ecTBO system (20%) 200 1: 1 (30%) 100 1: 1 (45%) 100 1: 1 (60%) and get shares: Eluate volume, m 160 100 fractions 4-7 are combined and get 597 mg colored brown residue, which gives 435 mg of white crystalline 4-deoxy-1-formillin rosidin) (from ethyl alcohol X. Mass spectrum (t / e): 808 (MM, 306 777, 775. 336, 13 &136; IR spectrum, chloroform, 3470, 1743, 1690, 1222. UV spectrum, alcohol, nm: 210, 222, 254, 290, 298, NMR spectrum at 100 MHz, methyl singlets: 3.87, 3.65, and 2.07 s R. pKst 9.0 and 4.9 (66% dimethylformamide). The sulfate of this compound is obtained by dissolving 435 mg of the free base in 10 ml of hot zanol and the addition of 1.5 MP of 2% sulfuric acid in ethanol.Crystalline 4-deoxy-1 sulfate - formlelerosidine is precipitated upon cooling. About 744 mg of 4-deoxy-1-formyl-lerosidine is mixed with 10 ml of anhydrous methanol and the mixture is heated at boiling point, the compound dissolves and gives a clear solution. 200 mg of solid sodium carbonate are added to the reaction mixture and mixed with 7.2 parts of it. Thin-layer chromatography of the reaction c Mecji shows the complete disappearance of the starting 4-deoxy-1-formyl-lerosidin. The solvent is evaporated, and the residue containing 4-deoxy-4-deacetyl-1-formyl-lerosidin is treated with dichloroethane and water. The organic layer is dried and the solvent is evaporated to give 506 mg of a solid, which is pure 4-deoxy-4-deacetyl-1-formyl-lerosidin. Mass spectrum (t / e): 766 (M), 7b4, 735, 254, 252, 205, 138 IR spectrum, chloroform, cm: 3450, 1734, 1680, 1596, 1495, 1456, 1434, Relevant sulfate salt It is formed as in the previous example, using acetone as a solvent and 0.26 ml of 2% sulfuric acid in ethyl alcohol. Other solvents may be used, but it is preferable to use a solvent in which the base is easily soluble and the sulphate salt is essentially insoluble. 4-Deoxy-4-deacetylvincristine and its sulfate are obtained in an anesthetic manner from 4 deoxyvincristin. Example 2. Preparation of 4-deoxycetyl-leurrzin. A reaction mixture containing 1.48 g of 4-deoxyvinblast B, 1 g of sodium carbonate and 100 ml of methanol is prepared and heated at boiling point under nitrogen atmosphere. A thin layer chromatography of the reaction products after 2 hours shows that the hydrolysis reaction with the removal of the 4-acetyl group is half complete. After keeping the reaction mixture overnight at room temperature, it is heated at boiling point for 8.5 hours. Thin layer chromatography of the reaction mixture {: mixture using a mixture of direct diethyl amine ether, toluene in a ratio of 20: 1: 1 shows that the reaction is running out. The solvent was evaporated from the reaction mixture, and the resulting residue was dissolved in a mixture of chloromethane and water. The dichloromethane phase is separated and dried. After evaporation of the dichloromethane, an "ESTC" is obtained, the thin layer chromatography of which indicates the presence of a very polar substance and the expected 4-deoxy-4-deacetyl-le Yeroein. Residue (1.33 g) {dissolved in benzene, the polar substance is separated by filtration. The filtrate is evaporated to dryness, and the residue (500 mg) is subjected to an Hc1 silica gel with a solvent system and ether, diethylamine and toluene in a ratio of 20: 1: 1 (with increasing amounts of methanol) as the mobile phase. Thin-layer chromatography and Fractions with 4-deoxy-4-deacetyl-leurozidine are carried out, combined, and after using a solvent, the yield of the free base is 348 mg. The residue is worked up with 1.28 ml of 2% sulfuric acid in methanol, the resulting solution is filtered. The output of sulphate 4-deoxy-4-deacetinlerosidna 315 mg. Mass spectrum (t / e) j 752 {m1, 750 693, 691, 555, 338, 240, 138; IR spectrum, chloroform, cm: 3455, 1724, 1610. 1497, 1457, 1431. The compounds of general formula (1) exhibit high antitumor activity. Claim 1. Method for producing dimeric 4-dezacetyl-diol-dihydroindoles by the formula CjHs R - hydrogen R - methyl or their salts, characterized in that the compound of general formula (1), where R has the above values, and R - acetyl, is subjected to hydrolysis in the presence of a base in a solvent followed by isolation of the desired product in its free form or as a salt.
    [2]
    2. The method according to claim 1, is different and with the fact that / as sodium carbonate is used as the base, and anhydrous methanol is used as the solvent. Sources of information taken into account during the examination 1. Voigand-Hilgetag. Method | s experiment in organic. 1968, p. 365. Chemistry
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US76059577A| true| 1977-01-19|1977-01-19|
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