• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention relates to heterocyclic compounds, in particular to the preparation of 1-oxyalkyl-5-nitron-imidazoles in the form of aij-C N-CH iC (NOj) -N- - (CH (j) n-OH, where n 2 or 3, The purpose of the invention is to increase the yield of the target product. The preparation is carried out by the reaction of alkylene sulfate with nitroimidazole, in the form of CH3-C NC (NO) CH-NX, where X is acetoxymethyl, at 80-120 ° C, organic solvent. The resulting product is hydrolyzed with water in the presence of a strong acid selected from HgSO or HCl, or subjected to alcohol with an alcohol selected from methanol or ethanol, and the desired product is isolated.
    公开号:SU1657060A3
    申请号:SU894613302
    申请日:1989-01-13
    公开日:1991-06-15
    发明作者:Массонно Вивиан；Мюльхаузер Мишель；Бюфорн Альбер；Мандард-Казин Бурнадетт
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to an improved process for the preparation of 1-oxyalkyl-5-nitroimidazoles, which have valuable therapeutic properties.
    The purpose of the invention is to increase the yield of the target product.
    The goal is achieved by the fact that alkylene sulfate of the general formula
    (CH2) n 0
    :about
    about
     ,
    about
    where n 2 or 3,
    are reacted with nitroimidazole of the general formula
    N02
    NVN-X CH3
    where X is acetoxymethyl, at a temperature of 80-120 ° C, if necessary, in an organic solvent medium, such as glycol di-acetate or xylene, the resulting product is hydrolyzed with water in the presence of a strong acid chosen from sulfuric or hydrochloric acid, or subjected to alcoholysis with an alcohol selected from methanol or ethanol and the desired product is isolated.
    Example 1. In a flask equipped with a stirrer, 2 g (0.01 mol) of 1-acetoxymethyl-2-methyl-4-nitro-im I were added.
    3
    ABOUT
    about

    with
    3165
    dazole, 2.6 g (0.02 mol) of ethylene sulfate and 5 cm 5 of ethylene glycol diacetate, then heated for 4 hours to 80 ° C. The white precipitate formed is separated by filtration and washed with 2 times 5 cm of methyl acetate. After drying, 3.4 g of a white solid are obtained.
    Analysis of the filtrate by high resolution liquid chromatography (HPLC) indicates that it contains 98.6 mg of α-acetoxymethyl-2-methyl-4-nitroimidazole, the conversion of which is 95%, and the mixture of imidazole derivatives is formed from 98.5 % acetoxymethyl-2-methyl-4-nitroimidazole and 0.5% 2-methyl-4- (or 5) -nitroimidazole.
    1.705 g of the obtained bw is added.
    logo solids in a solution of I cm of concentrated sulfuric acid in L cm of water. The resulting solution is heated to 80 ° C for 10 minutes and then basified to pH 10 with sodium alkali. The precipitate formed is separated by filtration, then dried. This gives 0.685 g of a product containing 95% metronidazole (dosage by HPLC method with an internal standard).
    The yield of isolated metronidazole is 76.1% relative to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    Analysis of the filtrate shows that it contains 69.6 mg of metronidazole and 11.3 g of methyl 2-4 (or 5) -nitroimidazole. The total yield of metronidazole is 84.2% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 89% with respect to the converted I-acetoxymethyl-2-methyl-4-nitroimidazole.
    Example 2. It is operated as in Example 1, but using 2 g of 1-α-acetoxpmethyl-2 methyl 4-nitroimidazole (0.01 mol) and 1.3 g of ethylene sulirate (0.01 mol). After heating for 4 hours to 80 ° C, the precipitate formed is filtered off and dried. 2.85 g of white product are obtained.
    Analysis of the filtrate by the method of HPLC after alkalization to pH 10 shows that it contains 315 mg of 2-methyl-4 (or 5) -nitroimidazole. The conversion of 1-acetoxymethyl-2- -methyl-4-nitroimidazole is 75%.
    five
    0
    five
    0
    five
    0
    five
    0
    five
    The mixture of imidazole derivatives present in the solution is formed from 96% 2-methyl-4 (or 5) -nitosimidazole and 1.5% metronidazole (dosage by HPLC method with internal standard).
    0.57 g of the obtained white product in 5 cm of ethanol is added. The mixture is heated under reflux of ethanol for 4 hours until a homogeneous solution is obtained. After diluting the reaction mixture, 201 mg of metronidazole was detected.
    The yield of metronidazole is 59% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 81% with respect to the converted, 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    The mixture of imidazole derivatives present in the solution is formed from 94.8% metronidazole and 4.1% 2-methyl-4 (or 5) -nitroimidazole.
    Example 3. 0.57 g of the white product obtained in Example 2 was added to a solution of 0.2 cm of concentrated sulfuric acid in 2 cm of water. The resulting solution is heated to 80 ° C for 1 hour 30 minutes, then basified to pH 10 by addition of sodium alkali. B obtained solution is detected by the method of HPLC 260 mg of metronidase ol.
    The yield of metronidazole is 71.6% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 95% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    The mixture of imidazole derivatives present in the solution is formed from 92.8% metronidazole and 2.5% 2-methyl-4 (or 5) -nitroimidazole.
    Example 4. Work as in Example 2, using 0.603 g (0.003 mol) of 1-acetoxymethyl-2-methyl-4-nitroimidazole and 0.372 g (0.003 mol) of ethylene sulfate in 3 cm of chloroform. The mixture is heated to chloroform for 5 hours. The precipitate formed is separated by filtration and washed with chloroform. After drying, 0.56 g of a white solid is obtained.
    The filtrate is analyzed by HPLC with an external reference and 270 mg of 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 7.35 g of 2-methyl-4- (or 5) -nitroimidazole are detected in it.
    51
    The mixture of imidazo derivatives in the filtrate is formed from 94.6 l of 1-acetoxymethyl-2-methyl-4-nitroimidazole and 3.4% 2-methyl-4 (or 5) -nitroimidazole.
    The resulting white solid (0.56 g) was added to 6 cm of ethanol. The mixture is heated for 4 hours to reflux temperature of ethanol. After dilution of the reaction mixture, a 193 mg metnidazole and 16.5 mg 2-methyl-4 (or 5) -nitroimidazol were detected by HPLC.
    The yield of metronidazole is 38% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 76% with respect to the converted 1-acetoxymethyl-2-methyl 4-nitroimidazole.
    The conversion of 1-acetoxymethyl-2-methyl-4-nitroimidazole is 49%.
    The mixture of imidazole derivatives in solution is formed from 89.1% metronidazole and 9.6% 2-methyl-4 (or 5) -nitroimidazole.
    Example 5. Work as in example 2, but using 0.208 g (0.01 mol) of 1-acetoxymethyl-2-methyl-4-nitroimidazole and 0.156 g (0.0012 mol) of ethylene sulfate in 2 cm of xylene. Heat to 4 hours, then add 3 cm of ethanol and heat under reflux for 3 hours. In the resulting solution, 103 mg of metronidazole and 44 mg of 2-methyl-4 (or 5) -nitroimidazole are detected.
    The mixture of imidazole derivatives in solution is formed from 65.2% metronidazole and 33.5% 2-methyl-4 (or 5) -nitroimidazol.
    The conversion of 1-acetoxymethyl-2-methyl-4-nitroimidazole is 67%.
    The yield of metronidazole is 58% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 87% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidaeol.
    Example 6. Work according to Example 5, using methyl isobutyl ketone (2 cm3) as a solvent. After 4 hours of heating, a sticky precipitate appears. 3 cm3 of ethanol is added and the mixture is heated under reflux for 4 hours.
    570bO6
    Found in the resulting solution
    46.8 mg of metronidazole and 94.9 mg of 2-methyl-4 (or 5) -nitromidazole.
    The conversion of 1-acetoximetethyl-2-4-nitroimidazole is 28%.
    The yield of metronidazole was 26% with respect to the initial 1-acetoxymetl-2-methyl-4-nitroimidazole and 93.5% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    Example 7. Work as in example 5, using as a solvent (2 cm5).
    . io ow 3
    ten
    15
    20
    25
    thirty
    35
    40
    45
    50
    55
    Heated in
    l acetonitrile
    within 4 hours to 80 ° C. A white precipitate appears. 3 cm of ethanol is added, then heated under reflux for 4 hours.
    57.7 mg of metronidazole, 30.2 mg of 1-acetoxy-methyl-2-methyl-4-nitroimidazole and 58.3 mg of 2-methyl-4 (or 5) -nitroimidazole are detected in the solution.
    The conversion of 1-acetoxymethyl 2-methyl-4-nitroimidazole is 41%.
    The yield of metronidazole is 32.5% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 79% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    Example 8. A flask equipped with a stirrer; 0.573 g (0.00283 mol) of 1-acetoxymethyl-2-methyl 4-nitroimidazole and 0.4 g (0.00322 mol) of ethylene sulfate were introduced. The reaction mixture is heated for 1 hour to 90 ° C, then 5 cm-ethanol is added and heated under reflux for 4 hours.
    After dilution, 393 mg of metronidazole and 23.7 mg of 2-methyl-4 (or 5) -nitroimidazole are detected in the resulting solution.
    The mixture of imidazole derivatives in solution is formed from 6.9% 2-methyl-4 (or 5) -nitroimidazole and 91% metronidazole.
    The conversion of 1-acetoxy--2-methyl-4-nitroimidazole is 93.5%.
    The yield of metronidazole is 80% with respect to the initial 1-acetoxy-2-methyl-4-nitroimidazole and 85.3% with respect to the converted 1-acetoxy-methyl-2-methyl-4-nitroimidazole.
    Example 9. In a flask equipped with a stirrer, 130 mg of 2-methyl-4 (or 5) -nitroimidazole (0.001 mol), 130 mg of ethylene sulfate (0.001 mol) and 0.53 cm glycol diacetate are introduced. Heat to 1 hour. A precipitate forms. Add. 30 µl of sulfuric acid (d 1.83), then the reaction mixture is heated to 120 ° C for 4 hours. After cooling, a solution of 0.2 cm of concentrated sulfuric acid in 1 cm of water is added. Heat the resulting solution to 80 ° C for 1 hour and 30 minutes.
    After cooling, the reaction mixture is diluted. 70 mg of metronidazole and 29 mg of 2-methyl-4 (or 5) -nitroimidazole were detected by high-resolution liquid chromatography.
    The conversion of 2-MSTIL-41- (or 5) -nitroimidazole is 77%.
    The yield of metronidazole is 41% with respect to the starting 2-methyl-4 (or 5) -nitroimidazole and 53.2% with respect to the converted 2-methyl-4 (or 5) -nitroimidazole.
    Example 10. In a flask equipped with a stirrer, 131 mg of 2-methyl-4 (or 5) -nitronmidazole (0.001 mol) and 130 mg of ethylene sulfate (0.001 mol) are introduced
    heated for
    and 2 cm of xylene,
    4 hours to 80 ° C, then 5 cm of ethanol is added and heated under reflux for 4 hours.
    In the resulting solution, 25 mg of metronidazole and 100 mg of 2-methyl-4 (or 5) -nitroimidazole were detected by HPLC.
    The conversion of 2-methyl-4 (or 5) -nitroimidazole is 23%.
    The yield of metronidazole is 14% with respect to the starting 2-methyl-4 (or 5) -nitroimidazole and 60% with respect to the converted 2-methyl-4 (or 5) -nitroimidazole.
    Example 11. In a flask equipped with a stirrer, 130 mg of 2-methyl-4 (or 5) -nitroimidazole (0.001 mol) and 130 mg of ethylene sulfate (0.001 mol) are introduced. Heat the reaction mixture for 4 hours to 90 ° C, then
    flow
    add 5 cm of ethanol and heat under reflux for 4 hours.
    After dilution of the reaction mixture, it was detected by HPLC 42.4 mg
    0
    five
    0
    five
    metronidazole and 76.2 mg of 2-methyl-4 (or 5) -nitroimidazole.
    The conversion of 2-methyl-4 (or 5) -nitroimidazole is 42%.
    The yield of metronidazole is 24% with respect to the starting 2-me. Tyl-4- (or 5) -nitroimidazole and 58% / relative to the converted 2-methyl-4 (or 5) -nitroimidazole.
    Example 12. In a flask equipped with a stirrer, 12 g (0.06 mol) of 1-acetoxymethyl-2-methyl-4-nitroimidazole, 10 g (0.072 mol) of propylene sulfate and 40 cm of xylene are introduced. The reaction mixture is heated to 110 ° C for 5 hours. From the very beginning of the heating, a sticky precipitate appears. Then add 20 cm of water and 1.5 cm of concentrated sulfuric acid (0.028 mol) and heat under reflux for 4 hours.
    The reaction mixture is cooled to 20 ° C, the separated xylene phase is extracted with 90 cm3 of water. In the combined aqueous phases, 4.32 g of secnidazole, 0.33 g (1-hydroxy-2-methyl) -1-ethyl-2-methyl-5-nitroimidazole and 3.1 g 2-methyl-4 ( or 5) -nitroimidazole.
    The conversion of 1-acetoxymethyl-2-methyl-4-nitroimidazole is 59%.
    The yield of secnidazole is 39% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitroimidazole and 64% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    Example 13. In a flask equipped with a stirrer, 4.65 g (0.025 mol) of 1-acetoxymethyl-4-nitroimidazole, 4.16 g (0.0325 mol) of ethylene sulfate and 30 cm of xylene are introduced. The mixture is heated for 6 hours to 80 ° C, then 30 cm-water and 20 cm of concentrated sulfuric acid are added. The biphasic reaction mixture is heated under reflux for 4 hours.
    Analysis of the aqueous phase by HPLC with an external standard indicates that the conversion of 1-acetoxymethyl-4-nitroimidazole is 86%; the yield of 1-hydroxyethyl-5-nitroimidazole is 73.7% relative to the converted 1-acetoxymethyl-4-nitroimndazole.
    0
    five
    0
    0
    five
    Example 14. In a flask equipped with a stirrer, 2 g (0.01 mol) of 1-acetoxymethyl-2-methyl-4-nitroimidazole, 1.8 g (0.013 mol) of propyl sulfate and 10 g of xylene are introduced. The mixture is heated for 6 hours to 100 ° C, then 10 cm3 of water and 1 cm of concentrated sulfuric acid are added. The reaction mixture is heated at reflux for 3 h.
    Analysis of the aqueous phase by high resolution liquid chromatography (HPLC) with external ethanol indicates that the conversion of 1-acetoxymethyl-2-methyl-4-nitroimidazole is 43%; the yield of 1- (3-hydroxy-propyl) -2-methyl-5-nitroimidazole is 95% relative to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 1-oxyalkyl-5- -nitroimidazole General formula
    NYN- (CH2VOH CH,
    where n 2 or 3,
    based on a nitroimidazole derivative characterized in
    that, in order to increase the yield of the product, the alkylene sulfate
    formulas:
    (CH2) P
    Yu
    SG
    ABOUT
    about
    where n 2 or 3,
    are reacted with nitroimidazole of the general formula
    u
    CH3
    where X -1 is acetoxymethyl, at a temperature of 80-120 ° C, if necessary, in an environment of an organic solvent, such as glycol diacetate or xylene, the resulting product is hydrolyzed with water in the presence of a strong acid chosen from sulfuric or hydrochloric acid, or subjected to alcoholysis with an alcohol selected from methanol or ethanol, and the desired product is isolated.
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    同族专利:
    公开号 | 公开日
    MX169604B|1993-07-14|
    NO172798B|1993-06-01|
    AU2845289A|1989-07-20|
    CA1310326C|1992-11-17|
    PT89443A|1990-02-08|
    NO890157D0|1989-01-13|
    FI890186A|1989-07-16|
    DK14889A|1989-07-16|
    PT89443B|1993-09-30|
    US4925952A|1990-05-15|
    ZA89307B|1989-10-25|
    DE68900582D1|1992-02-06|
    FI890186A0|1989-01-13|
    AU608933B2|1991-04-18|
    HUT49586A|1989-10-30|
    AT70831T|1992-01-15|
    HU200447B|1990-06-28|
    EP0324691A1|1989-07-19|
    GR3003445T3|1993-02-17|
    NO172798C|1993-09-08|
    ES2028444T3|1992-07-01|
    FR2625998B1|1990-06-08|
    YU7289A|1990-12-31|
    YU46997B|1994-11-15|
    IL88944D0|1989-08-15|
    FR2625998A1|1989-07-21|
    DK14889D0|1989-01-13|
    JPH01216976A|1989-08-30|
    CN1023318C|1993-12-29|
    KR890011855A|1989-08-22|
    EP0324691B1|1991-12-27|
    CN1035288A|1989-09-06|
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    FR1427627A|1963-10-10|1966-02-11|Rhone Poulenc Sa|New imidazole derivatives and their preparation|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8800415A|FR2625998B1|1988-01-15|1988-01-15|PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 METHYL-2 NITRO-5 IMIDAZOLES|
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