• 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 substituted pyrrolidine, in particular the preparation of (R) -o (-eth t2-oxo-1-pyrrolidine acetamide, which has mnetic activity. The goal is to create a de-enantiomer of absolute R-configuration, which has high activity with low toxicity. Its synthesis lead from (K) -c-ethyl-2-oxa-1-pyrrolidine acetic acid, which is subsequently treated first with ethyl chloroformate and then with ammonia.The process is carried out in the presence of triethylamine in CH2Cl medium with stirring. mp 115-117 C; Co (, ace n); gross-f-la CgH. The mnesic activity is achieved at a dose of 0.17 mg / kg (in the racemate 1.7 mg / kg) and the toxicity of LDjQ is 5603 mg / kg (for the mouse) and 500 mg / kg (for rat). i CO C
    公开号:SU1417799A3
    申请号:SU3892951
    申请日:1985-05-14
    公开日:1988-08-15
    发明作者:Гобэр Жан；Журжа Корнели；Жерт Жан-Пьер；Бодзон Ги
    申请人:Юцб С.А. (Фирма)；
    IPC主号:
    专利说明:

    Nj
    ABOUT
    WITH

    cm
    20
     1417799
    The invention relates to a process for the preparation of a dextrorotatory enantiomer (C (ethyl-2-oxo-T-pyrrolidine acetamide), which has menesic activity.
    The purpose of the invention is to develop, on the basis of lime methods, a method for producing a dextro enantiomer having an absolute configuration of R Q and having a high pharmacological activity with low toxicity.
    The invention is illustrated by the following examples of iMH, 15 ethyl chloroformate, and not exceeding the example of A, A. Preparation of salt (S) - temperature, Stirred in c / methyl benzylamine (R) - (/ ethyl-2-oxo-1-pyrrapidine acetic acid.
    In a flask with a capacity of 4 l, 513 g (3 mol) of racemic (±) - (/ ETIHL-2-OXO-1-Pyrrolidine-H-ICE ICC) are suspended
    lots of 1.26 liters of anhydrous benzene. To this suspension is added a solution containing 181.5 g (1.5 mol) of (S) methyl benzylamine and 151.8 g (1.5 mol) of 25 (0.3-0.4 km) in the form of a powder. . Preparation of triethylamine in 2 l of anhydrous benzo-yut 11.2 g of (K) -o / -til-2-sco-1-pyrrolyl. The mixture is then refluxed until complete dissolution. The mixture is cooled and left to crystallize for several hours. The crystals are filtered off and washed twice with 400 mp of benzene. Thus, 337 g of the salt (S) -rf-methyl-benzylamine (R) -o (-ethyl 2-oxo 1-pyrrholedine of SULNA acid. Topl.
    145-149 ° C. Yield 76.9%.
    This salt can be purified by boiling under reflux for 4 hours in 3 liters of benzene; then cooled and filtered. Thus, g of the desired salt is obtained. M.p. 149-152 s, Yield 68% ...
    B, Preparation of (R) -oi -3Tmi 2 oKCo-1 pyrrolidine acetic acid.
    with magnesium and the solvent is evaporated. 170.5 g of (R) -c (, -this-2-o-c-co-1-pyrrolidine acetic acid) are obtained. Mp., ((), 3 (, acetone). Yield 98%.
    B. Preparation of (R) -o-ethyl-2-oco-1-pyrrolidine acetamide,
    17.1 g (0.1 mol) of (R) (y -3Tmi-2-oK-co-1-pyrrolidinacetic acid) are suspended in 100 MP of dichloromethane, cooled to -13 ° C. To this suspension will be dropped 13, 9 ml of triethylamine. To the resulting solution was added 9.56 ml
    within half an hour, then ammonia is passed through for about 2.5 hours.
    The temperature of the suspension is taken to: room temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off and the residue is crystallized from ethyl acetate in the presence of 10 g of molecular sieves.
    din acetamide. M.p. 11 5-11 7 ° C. (o /) jj +90.7 (, acetone). Yield 66%.
    Calculated,%: C, 56.45; H 8.29; N 16.46.
    C H
    Found,%: C 56.38; H 8.36;
    N 16.43.
    The synthesis used in this synthesis. Racemic (±) -o (-ethyl-2-oxo-1-yrrolidino-acetic acid) can be prepared as described.
    In a 20 L flask containing 3.65 kg (18.34 mol) of (ethyl) - (+) ethyl-2-oxy-1-pyropolydetate, for 2 hours at a temperature not exceeding .60 ° C5 a solution containing 788 g (19.7 mol) of sodium hydroxide in 4.35 l of water is added. Tempera-
    297.7 g of the mixture obtained in Example 1A was adjusted to 80 ° C and formed
    whether dissolved in 0.6 l of water. To this solution is slowly added 147.3 g of a 30% sodium hydroxide solution, pH of the solution. 12.6 and the temperature does not exceed 25 ° C. Stir the solution for an additional 20 minutes and inject the d-methyl benzylamine 7 times with 150 ml of benzene. The aqueous phase is then acidified to a pH of 1.1 by the addition of 188 ml. 6 N. hydrochloric acid. The mixture is stirred for 45 minutes and the acidic acid is extracted 5 times with 200 MP of dichloromethane, Organic. Kie phases are combined, dried them over L55
    the remaining alcohol is distilled off until the temperature in the medium reaches. 1.66 L (19.80 mol) of 12 N hydrochloric acid is added to cool for 2.5 h. The precipitate is filtered, washed with 2 l of toluene and recrystallized from isopropyl alcohol. Thus, 2.447 kg of racemic (±) -of-eth1-2-oxo-1-pyrrolidine acetic acid, melting at 155-156 ° C, are obtained. The yield is 78%.
     Calculated,%: C 56.12; H 7.65; N8,18
     ethyl chloroformate, and not over magnesium, and the solvent is evaporated. 170.5 g of (R) -c (, -this-2-o-c-co-1-pyrrolidine acetic acid) are obtained. Mp., ((), 3 (, acetone). Yield 98%.
    B. Preparation of (R) -o-ethyl-2-oco-1-pyrrolidine acetamide,
    17.1 g (0.1 mol) of (R) (y -3Tmi-2-oK-co-1-pyrrolidinacetic acid) are suspended in 100 MP of dichloromethane, cooled to -13 ° C. To this suspension will be dropped 13, 9 ml of triethylamine. To the resulting solution was added 9.56 ml
    are heated, stirred in
    (0.3-0.4 km) in the form of a slug. 11.2 g of (K) -o / -stil-2-sco-1-pyrrolite for half an hour are obtained, then a stream of ammonia is passed through for about 2.5 hours.
    The temperature of the suspension is taken to: room temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off and the residue is crystallized from ethyl acetate in the presence of 10 g of molecular sieves.
    (0.3-0.4 km) in the form of a slug. 11.2 g of (K) -o / -stil-2-sco-1-pyrrole are obtained.
    din acetamide. M.p. 11 5-11 7 ° C. (o /) jj +90.7 (, acetone). Yield 66%.
    Calculated,%: C, 56.45; H 8.29; N 16.46.
    C H
    Found,%: C 56.38; H 8.36;
    N 16.43. .
    Used in this synthesis. The racemic (±) -o (-ethyl-2-oxo-1-yrrolidino-acetic acid) can be obtained in the manner described.
    In a 20 L flask containing 3.65 kg (18.34 mol) of (ethyl) - (+) ethyl-2-oxy-1-pyropolydetate, for 2 hours at a temperature not exceeding .60 ° C5 a solution containing 788 g (19.7 mol) of sodium hydroxide in 4.35 l of water is added. Tempera-

    the remaining alcohol is distilled off until the temperature in the medium reaches. 1.66 L (19.80 mol) of 12 N hydrochloric acid is added to cool for 2.5 h. The precipitate is filtered, washed with 2 l of toluene and recrystallized from isopropyl alcohol. Thus, 2.447 kg of racemic (±) -of-eth1-2-oxo-1-pyrrolidine acetic acid, melting at 155-156 ° C, are obtained. The yield is 78%.
     Calculated,%: C 56.12; H 7.65; N8,18
    Found,%: C 55.82; H 8.10; N7.97.
    Pharmacological testing.
    Racemic o-ethyl-2-oxo-1-pyr rolidine acetamide (product A) and (R) -0 / -ethyl-2-OXO-1-pyrrolidine acetamide (product B) according to the present invention are subjected to pharmacological tests. Mona activity. The effect on memory is shown by the antagonism test of the amnesic effect of electric current.
    The principle of the test is as follows. A rat paw compression reaction is observed, under increasing pressure; The pressure at which the reaction occurs is referred to as the reaction threshold. The latter is expressed by the number of graduations read directly on the scale of the apparatus (UGO BASILE analgesimeter, Milan) and, therefore, corresponds to the minimum pressure that is applied to the paw of the animals, causes compression (training session) .. It takes 3 measurements in the interval of 30 minutes.
    The untreated animals, tested after 24 hours after completion of training, show natural retention of the previous reaction, which corresponds to a threshold of about 8–11 graduations. The amnesic effect is obtained by applying a temporary supermaximal shock (100 mA, 120 W, 0.2 s) to rats 15 minutes after the end of training. The amnesic effect caused by electroshock is released during the measurement of the delay after 24 h to increase the output threshold ( manifestations) which corresponds to that of inexperienced animals (without training), i.e. threshold 14-19 graduations.
    Dp each test product determine the minimum active dose
    (mg / kg), which, in animals, is subjected to electric shock, 24 hours after training, restores the normal threshold of 8–11 calibrations.
    Test products are administered as a 10% solution or suspension subcutaneously to groups of 10 rats (Wistar female rat weighing 150 g each) after 5 minutes
    after graduation. At the same
    The control group of 10 rats received only aqueous 0.9% sodium chloride solution.
    In this test, dextro enan-.
    Thiomer (product B) is 10 times more active than racemate (product A) to protect the animal from the amnesic effect of electroshock.
    Test product dose is active,
    mg / kg A1.70
    B0,17
    Toxicity. Below for products. A and B indicated P intravenous administration defined in males of mice and rats:
    Test product LD5o mg / kg: Mouse; Rat
    A1790 1500
    B5603. 5000
    From the data it follows that the legal enantiomer (product B) is three times less toxic than the racemate (product A).
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The half-student (K) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide method, which is based on the fact that (R) -apf-ethyl-2-oxo-1-pyrrolidine acetic acid, is subjected to the interaction sequentially with ethyl chloropharm and then with ammonia.
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    同族专利:
    公开号 | 公开日
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    FI80674B|1990-03-30|
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    PL257386A1|1986-10-07|
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    NO164535B|1990-07-09|
    AU574175B2|1988-06-30|
    JPS60255764A|1985-12-17|
    PT80461A|1985-06-01|
    EP0165919A1|1985-12-27|
    CY1568A|1991-12-20|
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    HK62692A|1992-08-28|
    PL253373A1|1986-05-06|
    GR851156B|1986-11-25|
    DE3572168D1|1989-09-14|
    GB8412358D0|1984-06-20|
    FI80674C|1990-07-10|
    EP0165919B1|1989-08-09|
    BG50272A3|1992-06-15|
    DK163500B|1992-03-09|
    PT80461B|1987-08-19|
    IE58393B1|1993-09-08|
    SU1428194A3|1988-09-30|
    FI851876A0|1985-05-13|
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    引用文献:
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    法律状态:
    2005-01-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20030515 |
    优先权:
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    GB848412358A|GB8412358D0|1984-05-15|1984-05-15|Pharmaceutical composition|
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