• 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 antibiotic 7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-1-propenyl]ceph-3-em -4-carboxylic acid (BMY-28100) forms imidazolidinone derivatives on reaction with ketones. These derivatives are useful in pharmaceutical dosage forms and as intermediates for separation thereof from mixtures containing the [(E)-1-propenyl]isomer of the antibiotic.
    公开号:SU1493110A3
    申请号:SU864028601
    申请日:1986-11-24
    公开日:1989-07-07
    发明作者:Артур Каплан Мюррей；Уинстон Ловелл Марк；Беллард Богардус Джозеф
    申请人:Бристоль Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing a new cephalosporin antibiotic derivative, specifically the sodium salt, 2-dimethyl-4- (4-oxyfeil) -5-oxo-1-rmidazolinyl-3-(Z) -propenyl-cef-3-e -4-carbonic ACID), representing interest as a semi-product in the process
    purification for the preparation of the antibiotic 7-B-2-amino-2- (4-ox phenyl) -acetamid-DoZ-3 - {(g) -1-propenyl-cef-3-em-4 -carboxylic acid (ant1biotic VIC - 28100) in (7) -configuration, which actually does not contain its (E) -isomer, and also as a precursor
    314
    tibiotics VMC-28100, easily hydrolyzed to it in the body.
    The purpose of the invention is to obtain a new derivative of the antibiotic VMTs-28100, allowing the degree of purification to be isolated when isolating the antibiotic VMTs-28100, and also suitable as a prodrug for dosage of pharmaceutical compositions of increased stability.
    Example 1. Imidazolidinone derivatives of ns acetone.
    The solid composition, consisting of ... of 83% crystalline monohydrate of the antibiotic VMC-28100 and 17% of its (E) isomer (antibiotic VMC-28167) weighing 102 g is mixed with 2 l a; 1 g: tone and the resulting paste the mixture is then heated with stirring to 40 ° C. With continuous stirring, 83.1 g (0.5 M) of sodium 2-eth1thexanoate are introduced as a powder with the addition of 1.2 liters of methanol. Within 5 min of continuous stirring at 40 ° C a clear solution is obtained. After 15 minutes, the sodium salt of the acetonimidazolidine derivative of the antibiotic indicated, namely, 3-dimethyl- -4- (4-hydroxyphenyl) -5-oxo-1-imidazo-LIN1-3-Cl (Z) -propylene, cef-3- The 4-sodium carboxylate is subjected to crystallization. After 1 hour, the mixture thickens and, to facilitate mixing, add 1 liter of a mixture of methanol and acetone in a ratio of 1: 1 v / v. After stirring for another 1 h at 40 ° C, the mixture is. is cooled to 15–20 ° C with mixing, and the insoluble product is then removed by filtration in vacuum filters. The wet filter cake is suspended in a mixture of 2 liters of acetone and 0.5 liters of methanol, then
    stirred for 1 h at 20 C. The resulting product is collected by filtration, washed on the filter with a mixture of 0.2 l of methanol and acetone in a ratio of 2: 8 v / v, and then with acetone, placed in a vacuum desiccator and you
    dried.
    The second process is obtained by concentration, {esuspended in 1 liter of a mixture of methanol and acetone in a ratio of 1: 5 v / v, then another 22.1 g of product is collected and dried to yield, which is similar in quality to the first collection. The total product yield is 86.1 g (93%).
    ten
    Product Formula
    CHS UN - 1-CH
    L I T. 6

     with jiH-iNgOjSNa - mol. mass 451.49).
    The product is obtained as crystalline hydrate.
    Elemental analysis:
    Calculated,%: C 55.85; H 4.91 N 9.31; S 7,10, -) -; ash content 5.09.
    Found,%: C 55.50; H 5.00; N 8.89; S 6.83; KG (H20) 4.58; ash content (as Na) 4.77.
    UV spectrum, 222 nm (E 14423).
    Data 5I fP: chemical displacement (relative to trimethylsilylpropane sulfonic acid O h, ppm with water elimination): 7.35 doublet 211 S (aromatic) n; 6.95 doublet 2H S (aromatic) 6.0 doublet 1H (vinyl) H, 5.75 multiplet 1H (vinyl) 5.25 singlet 2 (siglet) H, P, H, 4.78 singlet ZN З; 3.47 double doublet 1.65 doublet ZN B 1.50 singlet bN z 2 (CH).
    PRI mme R 2. Hydrolysis of the imidazolidinone derivative to an antibiotic,
    30 g of the imidazolidinone derivative obtained in Example 1 is added as a dry powder to 175 ml of water that has been preheated to 40 ° C and placed in a reaction vessel equipped with a stirrer, thermometer, dropping funnel and pH electrode. The pH of the reaction mixture rises as the acetone derivative dissolves and is kept in the range of 5.8-6.0 by adding dropwise 1 N. hydrochloric acid. After 15 minutes, a second portion of 30 g of imidazolidinone derivative is added, maintaining the pH in the range of 5.8-6.0. Similarly, approximately 15 minutes after the introduction of the second portion, the last portion of 26 g of imidazolidinone derivative is added, the pH is measured within 4, 5 hours, with this
    51
    maintain the enamel pH in the interpal 5.8-6.0 by adding 1 and. hydrochloric acid over the specified period. The mixture is then cooled to approximately O ° C and the pH is adjusted to 4.1 with the addition of 1 and. hydrochloric acid. After 20 minutes, the product is collected by filtration, the filter cake is washed with 100 ml of ice water and dried in vacuo. Product yield
    62.4g (83.6%).
    Analysis by PMR shows that the resulting product contains 1.5% by weight of the (E) -isomer, and when using HPL-C HPLC, the product consists of 94.9% by weight of the required (2) isomer of the antibiotic and 1, 78 wt.% (E) -isomer
    For high performance liquid chromatography of the raw material in Example 1 and the product in Example 2, the following system is suitable for the ratio of components (Z) and (E), (antibiotic VMU-28100) (E) -isomer 28167
    Operating conditions: chromatographic column: Lichrosorb C-18, category No. 218604.
    Mobile phase: pumping A 97 .5h. 0.1 MNH4H2P04., PH 4.4; 2.5 hours of acetonitrile, pumping B-acetonitrile.
    Gradient: from 100% A to a ratio of 75% A / 25% B for 25 minutes, the equilibrium state in the column for 10 minutes.
    Thinner - 25% mixture of acetonitrile and water.
    Injection volume. Consumption (feed rate) 1.0 ml / min.
    Detector - UV at 230 them.
    The sample is the composition of the antibiotic VMU-28100 at 2 mg / ml.
    Retention time:
    VMU-2810011 min
    VMU-2816713 min
    acetonide
    VMU-28100 17 min
    acetonide
    VMU-28167 19 min
    VMU-28167 19 min
    Example 3: Conversion of the sodium salt of an imidazolidinone antibiotic derivative using sodium bisulfite.
    125 mg of the product obtained in Example 1 is dissolved in 1 ml of water at 45-50 0. As the specified solution is stirred, 62.5 mg are added over 20 minutes (example
    five
    about
    about
    Q
    five
    five
    106
    but 2.5 mol ekp) of sodium bisulfite. At this stage it is expedient to add seed crystals, if any, but this is not necessary. The mixture is cooled to room temperature, stirring is continued for another half hour, and then the product is collected. The product yield is approximately 60% monohydrate antibiotic BMU-28100, containing 1.8% of its (E) -isomer.
    Suitability, 2-dimethyl-4- (4-oxyphenyl) -5-oxo-1-imidazolinyl-3- (Z) -1-propenyl J-cef-3-em-4-carboxylate sodium in the form of a finished drug the parenteral solution was demonstrated by preparing an aqueous solution containing 250 mg / ml and determining the concentration of the antibiotic in the solution at room temperature during storage for several hours. A solution with a pH of 7.2 is found to lose Failure activity by 10% after about 2 hours. This shows a much higher stability relative to the stability shown by the sodium salt of the antibiotic itself, which has a pH of 8.2 and loses its activity by 10% through 30 min. While a 10% loss of activity is considered acceptable, a so-called shelf life of not less is needed. 2 hours for an onsite antibiotic solution.
    The stability of the solid state of the specified substance is shown when storing its samples at different temperatures for different periods of time and measuring the purity of the sample at different intervals. The results obtained are tabulated.
    Thus, a new imidazolidinone derivative of the antibiotic VMC-. 28100 allows it to be isolated in a more pure form, and also has increased stability in both its solid state and aqueous solution for parenteral administration.
    Formula of the invention
    The method of obtaining the sodium salt of 7-C 2,2-dimethyl-4- (4-hydroxy-1) 75-oxo 1-imidazolinyl-3-l (2) -propenyl-j-csf-3-em-4-carboxylic acid form
    r1

    °° COiNa
    IyCHj
    characterized in that the mixture of the antibiotic 7-f (B-2-amino-2- - (4-hydroxyphenyl) acetamido -3-C (2) -1-propene-cef-3-em-4-carboxylic acid with its The (E) -isomer is reacted with a sodium salt-forming reagent, such as sodium 2.-ethylhexanoate, in the presence of acetone and methanol at 35-55 ° C, the resulting mixture of the sodium salt of an imidazolidinone derivative
     an antibiotic of formula and sodium salt of imidazolidinone derivative of (E) - isomer is suspended in a solvent in which the sodium salt of imidazolidinone derivative is dissolved
    eight
    (E) -isomer and in fact does not dissolve the sodium salt of the alkaline newest antibiotic derivative of the given formula, such as a 1: 1 mixture of methanol: acetone, thereby obtaining a suspension of the sodium imidazolidinone derivative of the antibiotic of the formula imidazole dinone sodium salt the derivative of the (E) isomer, and the insoluble sodium salt of the imidazolidinone derivative of the antibiotic form is isolated from the suspension. The forms are essentially free of the (E) isomer.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of producing sodium salt
    7-C 2,2-dimethyl-4- (4-hydroxyphenide) 75-ok1493110 co-1-imidazolinyl] -3- [ΐ (Ζ) -propenylJ-cef-Z-em-4-carboxylic acid of the formula
    A sn = sn characterized in that the mixture of antibiotic 7 - ((0-2-amino-2- (4-hydroxyphenyl) acetamido] -3 - ((Z) -1-propenyl} -ceph-3-em-4- carboxylic acid with its (E) -isomer is reacted with a sodium salt-forming reagent, such as sodium 2-ethylhexanoate, in the presence of acetone and methanol at 35-55 ° C, the resulting mixture of the sodium salt of an imidazolidinone derivative of an antibiotic of the formula and the sodium salt of the imidazolidinone derivative of the (E) ~ -isomer is suspended in a solvent in which the imidazolidinone sodium salt is dissolved of the original (E) -isomer and the sodium salt of the imidazolidinone derivative of the antibiotic of the Formula given, such as a methanol: acetone mixture in a 1: 1 ratio, thereby obtaining a suspension of the sodium salt of the imidazolidinone derivative of the antibiotic of the formula in a solution of the sodium salt of the imidazolidinone derivative (E) isomer, and the insoluble sodium salt of the imidazolidinone derivative of the antibiotic of the formula is substantially free of the (E) -isomer from the suspension.
    Time weeks Temperature,° C Retention% 4 37 100 4 45 102 4 56 98.6 1 70 94.0 1 day 100 80
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