• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    A process for preparing vindesine characterized by reacting a 4-desacetyl VLB C-3 carboxazide with trihydrocarbylphosphine to form 4-desacetyl VLB C-3 N-(trihydrocarbylphosphoranyl)carboximide and then decomposing said acyl iminophosphorane with acid to yield vindesine. The process for preparing a 4-desacetyl VLB C-3 N-(trihydrocarbylphosphoranyl)carboximide characterized by reacting 4-desacetyl VLB C-3 carboxazide with trihydrocarbylphosphine. The 4-desacetyl VLB C-3 N-(trihydrocarbylphosphoranyl)carboximide compounds are novel.
    公开号:SU906381A3
    申请号:SU802872553
    申请日:1980-01-14
    公开日:1982-02-15
    发明作者:Кросланд Пэшел Глория；Ли Томпсон Джеральд
    申请人:Эли Лилли Энд Компани (Инофирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to an improved method of preparation, vindesine (O-dezacetyl-Bincalecoblastin-C-carboxamide) having an antitumor effect. tviem .five
    A known method of obtaining vindesine by treating vincaleblastin with liquid ammonia in anhydrous methanol at 10 ° C for 60 hours, followed by separation of the target product by column chromatography on silica gel (yield 42%) G1.
    A known method for producing winde-. zine by treating vincalecoblastin jj with anhydrous hydrazine under nitrogen at 60 ° C for 24 hours, followed by isolation of the intermediate product and its reduction with Raney nickel in methanol at a boiling point of the reaction mixture for 7 hours. Total exit. preparative thin layer chromatography and crystallization of the target product 20% 2.25
     However, these methods are characterized by the complexity of the process and the rather low yield of the desired product.
    The closest to the present invention is a method of obtaining vindeein from o-deacetylvinvalecoblastin-C-carboxazide obtained by diazotization (1 / -desacetyl-vinine-lecoblastine-C -carboxyhydrazide with sodium nitrite in dilute acid during its treatment with anhydrous gaseous amniax in 18 hours 18 hours in dilute acid in 18 hours 18 minutes in dilute acid in treating it with anhydrous gaseous amniamax in 18 hours not specified) NW.
    Significant disadvantages of the process are the length of the process, as well as the difficulty of separating the target product from the reaction mixture due to the non-specificity of the process.
    The purpose of the invention is to simplify the process of obtaining vindesine.
    This goal is achieved by the fact that according to the method of obtaining win
    desiace from 4-desacetyl-vinca-lecoblastin-C - carboxazide, the starting product is treated with triphenylphosphine and the resulting intermediate product is decomposed with an acid, mainly hydrochloric.
    The initial O-distecyl-vinca-leukoblast-C-carboxase 1 is treated with triphenylphosphine at 0 ° C for 1 hour. Excess triphenylphosphine and its 10 oxides are removed by extraction after acid pedrolysis of the intermediate. For extraction, a solvent not miscible with water is used as a rule, chlorine methane 15. The desired product is usually isolated by liquid chromatography under high pressure with subsequent recrystallization.
    PRI me R 1. 77 mg of 0-dezacetyl-20 and 1-leucoblastin-C-carboxyhydraide are dissolved in 2 ml of 1N aqueous hydrochloric acid and the resulting solution is cooled to a temperature of about 0 ° C. Ribavl 8.4 M1 sodium nitrite and 25 the reaction mixture is stirred at about 0 ° C for 5 minutes. A cold aqueous solution of sodium bicarbonate was then added, and the resulting aqueous mixture was extracted with cold methienium chloride. The extract in methylene chloride is separated, dried over sodium sulfate, and methylene chloride is distilled off. The residue containing 4-deacetyl-vincal leucoblastic-1-C is arboxase; is dissolved in 7 ml of tetrahydrofuran, and an excess of triphenylphosphine in tetrahydrouran is added dropwise to the resulting solution. The reaction mixture is stirred for 1 hour after completion of the addition of triphenylphosphine. An excess of 1N hydrochloric acid aqueous solution is added to the tert-hydrofuran solution and the reaction mixture is stirred at room temperature for 30 minutes. By thin layer chromatography, it is established that the main product of the reaction is viidesin and the amount of by-products present is very small.
    PRI mme R 2. 76.8 mg of 0-dezacetyl in alaco-acryl-latin-C-carboxylate azide is dissolved in 1 ml of tetrahydrofluorine and 1 ml of acetic acid. The reaction mixture is cooled to O C; and 0.2 ml of a 10% aqueous solution (v / v) of n-butyl nitrite in tetrahydrofuran is added dropwise. This reaction mixture is stirred at 0 ° C & for 5 minutes Thereafter, 262 mg of triphenylphosphine in 2 ml of tetrahydrofuran are added dropwise and the resulting reaction mixture is stirred at 0 ° C for 30 minutes after completion of the addition of triphenylphosphine. Using thin layer chromatography, it was established that the reaction mixture contained 20%, vindesine, both starting materials, as well as 1 or 2 unknown substances.
    L.
    Example The 1O -desacetyl-vinca-lecoblastin-C-carboxyhydrazide is dissolved in 25kn of terrahydrofuran and the resulting solution is cooled to 0 ° C. 7.8 ml of 1N is added. an aqueous solution of hydrochloric acid, followed by the introduction of 2.6 ml of a 10% (v / v) solution of n-butyl nitrite in tetrahydrofuran (2 equivalents of n-butyl nitrite). The reaction mixture was stirred at 0 ° C for 5 minutes. Then, 3.4 g of triphenylphosphine in 25 ml of tetrahydrofuran (10 equivalents) were introduced and the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then heated to room temperature and diluted hydrochloric acid. The reaction mixture is extracted with three portions of methylene chloride of equivalent volume. After this, the solution is alkalinized by the addition of 5N. an aqueous solution of sodium hydroxide and the basic solution is extracted four times with equal volumes of methylene dichloride. The organic extracts are combined and the combined extracts are substantial. After evaporation of the reaction mixture, 946 mg of the residue containing vindesine are obtained. The yield of viidesin, established by liquid chromatography under high pressure, is 63.7%.
    PRI me R 4. 1.973 g of 0-dezacetyl-vinc lecoblast-C-carboxyhydrazide is dissolved in 50 ml of tetrahydrofuran and the resulting solution is cooled to stirring under nitrogen atmosphere. 15.6 ml of 1N is added. aqueous hydrochloric acid and then at one time 5.2 ml of 10% (volume / volume) solution of n-butyl nitrite in tetrahydrofuran. The reaction mixture was stirred at 0 ° C for 5 minutes after which n6 drops of 6.8 g of triphenylphosphine in 50 ml of tetrahydrofuran were added dropwise. After completion of the triphenyphosphine, the reaction mixture is stirred at 0 ° C for Jh and then 25 ml of water is added. The tetrahydrofuran is distilled off in vacuo. The remaining aqueous suspension is diluted with 1 and. aqueous hydrochloric acid and the acidic solution are extracted with two portions of methylene chloride. The pH of the aqueous solution of ammonium hydroxide and the resulting alkaline solution is extracted with three portions of methylene chloride. The organic extracts are combined and dried. After distilling off the solvent, 1.95 g of crude vindesine is obtained. After purification by liquid chromatography under high pressure, followed by recrystallization, I is obtained, 44 g of the free base, which corresponds to a 74.6% yield of pure vindesine.
    The advantage of the proposed method is a significant reduction. process time
    权利要求:
    Claims (3)
    [1]
    1.Barnett C.1., G.I. Gerzon K.jiHoytng R.S., Jones W.E. Newlon V / .M., Poore G.A. , Robison R.L. Sweeney M.I. and Todd G.C. Structure-Activity Relationships of
    , Dimeric Catharanthus Alkaloids. 1. Deacetylvinblastine Amide (Vindesine) sulfate. - J. Med. Chem., 1978, .2j (l), p. 90.
    [2]
    2. In the same place 90.
    [3]
    3. In the same place 91.
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    同族专利:
    公开号 | 公开日
    IT8019210D0|1980-01-14|
    GB2040934B|1983-03-09|
    IT1140506B|1986-10-01|
    IE49376B1|1985-10-02|
    ES8101611A1|1980-12-16|
    DK14780A|1980-07-16|
    RO77532A|1982-02-26|
    MY8500570A|1985-12-31|
    NZ192574A|1982-03-16|
    DD148779A5|1981-06-10|
    FR2446290B1|1983-06-24|
    GB2040934A|1980-09-03|
    IL59119A|1983-06-15|
    EP0014053A1|1980-08-06|
    BG33295A3|1983-01-14|
    PH15343A|1982-12-02|
    PL221359A1|1980-12-15|
    AU5452280A|1980-07-24|
    YU5680A|1983-02-28|
    ATA14080A|1982-10-15|
    KR830001961A|1983-05-21|
    AR223694A1|1981-09-15|
    DK148961B|1985-12-02|
    FR2446290A1|1980-08-08|
    ZA80157B|1981-08-26|
    ES487726A0|1980-12-16|
    CS214691B2|1982-05-28|
    ES8101612A1|1980-12-16|
    CA1148945A|1983-06-28|
    DK148961C|1986-05-20|
    JPS6332796B2|1988-07-01|
    PL124350B1|1983-01-31|
    FI800071A|1980-07-16|
    GR72464B|1983-11-10|
    HU182083B|1983-12-28|
    BE881078A|1980-07-10|
    CH645383A5|1984-09-28|
    IE800060L|1980-07-15|
    KR830002840B1|1983-12-27|
    EP0014053B1|1983-12-14|
    ES487682A0|1980-12-16|
    LU82079A1|1980-04-23|
    AT371127B|1983-06-10|
    JPS5598195A|1980-07-25|
    US4210584A|1980-07-01|
    DE3065852D1|1984-01-19|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/003,442|US4210584A|1979-01-15|1979-01-15|Vindesine synthesis|
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