• 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:

    公开号:SU1657059A3
    申请号:SU894613239
    申请日:1989-01-13
    公开日:1991-06-15
    发明作者:Vivian Massonno；Mishel Myulkhauzer；Alber Byuforn
    申请人:Rhone Poulenc Sante；
    IPC主号:
    专利说明:

    The invention relates to an improved method for producing 1-οκοηβ til-5-nitroimidazoles with valuable therapeutic properties.
    The purpose of the invention is to simplify the process.
    This goal is achieved by the fact that the imidazole derivative of the General formula
    ch 3
    where X is acyloxymethyl, in which
    the acyl part contains 1-4 carbon atoms,
    interact with concentrated sulfuric acid at 95140 ° С in the presence of glyco-2 diacetate
    in particular, the production of 1-oxyethyl-5-nitroimidazole derivatives that exhibit therapeutic activity. The goal is to simplify the process. Getting lead by the reaction of the derivative of imidazole F.
    XI-CH-C (IO C ) - Ν = ΰ-εΗ 3 , where X is acyloxymethyl, with concentrated H g 5C ^ at 95-140 ° C in the presence of glycerol diacetate, followed by hydrolysis with water or alcoholysis with alcohol (methanol or ethanol ) at a temperature of from 80 ° C to the boiling point of the reaction mixture. These conditions increase the degree of conversion to 92% and the yield of the target product to 85%.
    <o
    A and the resulting product is hydrolyzed with water or alcoholysis alcohol selected from methanol or ethanol at a temperature of from 80 C to the reflux temperature of the reaction mixture.
    Example 1. In a flask equipped with a stirrer, 0.9 g of ethylene sulfate (0.0083 mol), 0.2 g of 1-acetoxymethyl-2-methyl-4-nitro-imidazole (0.001 mol) and 60 microliters of concentrated sulfuric acid ( 8 = 1.83) (0.001 mol). The reaction mixture was heated to 120 C for 4 h. The hydrolysis is carried out by adding 60 .mu.l of a solution of sulfuric acid in 2 cm ^ of water, and then heating the resulting solution to 90 p C for 8h.
    After dilution, the reaction
    the mixture is analyzed by high resolution
    liquid chromatography (HPLC) with
    1657059AZ
    3
    1657059
    four
    external ethanol *, which detects 60 mg of metronidazole.
    The degree of conversion of 1-acetoxymethyl-2-methyl-4-nitroimidazole is 74%.
    The yield of metronidazole is <35% with respect to the initial 1-acetoxime-2-methyl-4-nitro-im, cnzol and 47% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
    Example 2. In a flask equipped with a stirrer, injected 0.46 g of 1-acetoxymethyl-2-methyl-4-nitro-imidazole (0.023 mol), 2.5 cm * glycol diacetate and 0.30 cm * concentrated sulfuric acid (P = 1.83) (0.0028 mol). ι The reaction mixture is heated to 140 ° C for 3 hours. Then hydrolysis is carried out by adding a solution of 0.15 cm3 of sulfuric acid in 2.5 cm3 of water, heating the resulting solution to 80 ° C for 4 hours.
    After dilution, the reaction mixture is analyzed by HPLC with external ethanol, which detects 0.218 g of metronidazole in the reaction mixture.
    The degree of conversion of 1-acetoxymethyl-2 ~ methyl ~ 4-nitroimidazole is 92%.
    The yield of metronidazole is 55% with respect to the initial 1-acetoxy.methyl-2-methyl-4-nitro-imidazole and 60% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
    Example 3. In a flask equipped with a stirrer, inject 0.334 g of 2-methyl-4 (or 5) -nitro-imidazole (0.0026 mol), 2.5 cm * glycol diacetate and 0.15 cm $ with concentrated sulfuric acid (8 = 1.83) (0.0028 mol). The reaction mixture is heated to 140 ° C for 3 hours. Then hydrolysis is carried out by adding a solution of 0.15 cm * of sulfuric acid in 2.5 cm ^ of water, heating the resulting solution to 80 ° C for 4 hours.
    After dilution, the reaction mixture is analyzed by HPLC with an external standard and 185 g of metronidazole is detected in the reaction mixture.
    The degree of conversion of 2-metzl-4 (or 5) -nitro-imidazole is 61%.
    The yield of metronidazole is 41% with respect to the starting 2-methyl-4 (or 5) -nitro-imidazole and 68% with respect to the converted 2-methyl-4 (or 5) -nitro-imidazole.
    Example 4. In a distillation apparatus, the receiver of which is immersed in a bath of acetone-dry ice, 4.38 g of ethylene glycol diacetate (0.03 mol), 2 g of 2-acetoxymethyl-2-nitroimidazole (0.02 mol) are injected,
    1.56 g of concentrated sulfuric acid (8 = 1.83) (0.016 mol) and 0.45 cm3 of acetic anhydride to remove the water present in sulfuric acid. Establish in the apparatus a pressure of 150 mm Hg. Art. (20 kPa), then load the reaction mixture for 8 hours to 95 C. During heating, 0.94 g of acetic acid is distilled off. The distillation apparatus is placed under atmospheric pressure, and after cooling the reaction mass, 15 cm 4 of ethanol are added to a boiler.
    The distillation apparatus is replaced by a refrigerator. The solution obtained after the addition of ethanol is heated under reflux for 4 hours.
    After cooling the reaction mixture, it is analyzed by HPLC with external ethanol and 1 g of metronidazole is detected.
    The degree of conversion of 1-acetoxymethyl-2-methyl-4-nitro-imidazole is 71%.
    The yield of metronidazole is 59% with respect to the initial 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 83% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
    Example 5. In a flask equipped with a stirrer, enter 12 g (0.06 mol)
    1-acetoxymethyl-4-nitro-imidazole,
    26 g (0.18 mol) glycol diacetate and 9.4 g (0.09 mol) of concentrated sulfuric acid. The mixture is heated for 6 hours at a pressure of 150 mmHg. (20 kPa). During heating, a mixture of acetic acid and glycol diacetate is distilled off. Add 30 cm ^ of water, then heat under reflux for 4 hours.
    After dilution of the reaction mixture, it is analyzed by HPLC with external ethanol. The results of the analysis show that the degree of conversion of 1-acetoxime-4-nitro-imidazole is 87.8%, the yield of 1 — oxymethyl — 5 — nitro — imidazole is 85% from 5
    1657059
    6
    V
    converted to 1-acetoxymethyl-4-nitro-imidazole.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives of 1-hydroxyethyl-5-nitronmtstsazola General formula
    N0 '
    N04 -CH 2 CH 2 OH CH 3
    ten
    based on an imidazole derivative, characterized in that, to simplify the process, an imidazole derivative of the general formula is used as an imidazole derivative
    0 2 Ν
    Ν-Χ
    CH 3
    15
    20
    where X is acyloxymethyl,
    in which the acyl part contains
    1-4 carbon atoms, which is reacted with concentrated sulfuric acid at 95-140 ° C in the presence of diacetate glycol and the resulting product is subjected to hydrolysis with water or alcoholysis with an alcohol selected from methanol or ethanol at a temperature from 80 ° C to the boiling point of the reaction mixture.
    类似技术:
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    同族专利:
    公开号 | 公开日
    DK14689D0|1989-01-13|
    NO890160D0|1989-01-13|
    AU608934B2|1991-04-18|
    ES2054036T3|1994-08-01|
    FI890188A|1989-07-16|
    DK14689A|1989-07-16|
    GR3007573T3|1993-08-31|
    FR2625999B1|1990-06-08|
    HUT49587A|1989-10-30|
    JPH01216977A|1989-08-30|
    AU2845389A|1989-07-20|
    HU200448B|1990-06-28|
    NO171911B|1993-02-08|
    PT89445A|1990-02-08|
    US4925951A|1990-05-15|
    IE890093L|1989-07-15|
    FI890188A0|1989-01-13|
    AT87913T|1993-04-15|
    EP0325513A1|1989-07-26|
    ZA89309B|1989-10-25|
    PT89445B|1993-09-30|
    IL88946D0|1989-08-15|
    CA1310328C|1992-11-17|
    CN1023220C|1993-12-22|
    MX169605B|1993-07-14|
    NO171911C|1993-05-19|
    IL88946A|1993-03-15|
    DE68905830T2|1993-09-23|
    YU7489A|1990-12-31|
    CN1035289A|1989-09-06|
    EP0325513B1|1993-04-07|
    NO890160L|1989-07-17|
    FR2625999A1|1989-07-21|
    KR890011857A|1989-08-23|
    DE68905830D1|1993-05-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR1212028A|1957-09-20|1960-03-21|Rhone Poulenc Sa|New derivatives of 5'-nitroimidazole and their preparation|
    US3178446A|1961-07-27|1965-04-13|Luso Farmaco Inst|Oxyethylation of imidazole compounds|
    FR1379787A|1963-10-18|1964-11-27|Rhone Poulenc Sa|Process for the preparation of imidazole derivatives|
    FR3270M|1963-12-30|Rhone Poulenc Sa|New imidazole derivatives and compositions containing them.|
    FR1545317A|1966-11-26|1968-11-08|Richter Gedeon Vegyeszet|Process for the preparation of imidazole derivatives|
    GB1277666A|1969-12-17|1972-06-14|Pfizer Ltd|Improvements in the n-alkylation of nitroimidazoles|
    IL88943A|1988-01-15|1994-05-30|Rhone Poulenc Sante|Process for preparing 1-alkyl-5- nitroimidazoles|
    FR2625998B1|1988-01-15|1990-06-08|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 METHYL-2 NITRO-5 IMIDAZOLES|IL88943A|1988-01-15|1994-05-30|Rhone Poulenc Sante|Process for preparing 1-alkyl-5- nitroimidazoles|
    FR2625998B1|1988-01-15|1990-06-08|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 METHYL-2 NITRO-5 IMIDAZOLES|
    CN100376559C|2006-05-22|2008-03-26|浙江苏泊尔制药有限公司|Method for preparing secnidazole|
    CN102321028B|2011-06-30|2013-12-25|湖北省宏源药业有限公司|Method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol|
    US10335390B2|2014-09-05|2019-07-02|Symbiomix Therapeutics, Llc|Secnidazole for use in the treatment of bacterial vaginosis|
    US11253501B2|2015-06-01|2022-02-22|Lupin Inc.|Secnidazole formulations and use in treating bacterial vaginosis|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR888800417A|FR2625999B1|1988-01-15|1988-01-15|PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 METHYL-2 NITRO-5 IMIDAZOLES|
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