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    • 专利摘要:
    A process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo. Said process involves dehalogenation of a 6-halo or 6,6-dihalo derivative of penicillanic acid 1,1-dioxide or ester thereof readily hydrolyzable in vivo or a carboxy protected derivative thereof (e.g. by hydrogenolysis). The 6-halo and 6,6-dihalo derivatives of penicillanic acid 1,1-dioxides, esters thereof readily hydrolyzable in vivo, and carboxy protected derivatives thereof are novel intermediates. Penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, are known compounds which are useful as beta- lactamase inhibitors and for enhancing the effectiveness of certain beta-lactam antibiotics (e.g. the penicillins) in the treatment of bacterial infections in mammals, particularly humans.
    公开号:SU1192626A3
    申请号:SU802889601
    申请日:1980-02-27
    公开日:1985-11-15
    发明作者:Шилдс Мур Бернард；Д.Кэрролл Ронни；Альфред Волкманн Роберт
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    "
    This invention relates to a method for producing penicillanic acid 1,1-dioxide or its ester, which is easily hydrolyzed in the body.
    A method is known for producing 1, peicicillanic acid oxide and its ester from 6 bromopenicillanic acid or its ester by removing bromine to form penicillanic acid or its ester, followed by oxidizing it to penicillan ACID 1,1-dioxide penicillanic acid and its ester easily hydrolyzed. in the body, used as β-lactamant inhibitors and as agents that enhance the efficacy of certain β-lactam antibiotics, when the latter are used to treat bacterial infections in mammals, especially in humans,
    By a known method, the yield of 1,1-dioxide or its ether, which is easily hydrolyzed in the body, is small (on the order of 27-35%). .
    The aim of the invention is to increase the yield of a valuable product.
    The goal is achieved by the fact that to obtain a compound of the formula
     (I)
    rj- ::
    SS
    -NO
    QOOR
    where R is hydrogen or pivaloyloxymethyl
    compound of formula
     H S F M-1 ™
    .
    COOK
    where at least one of the atoms X and Y is bromine, and the other is hydrogen or bromide;
    .R - hydrogen or pivaloyloxymethyl contact with a chemical reagent selected from the group including alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids (step a), then the resulting product is contacted with hydrogen in an inert solvent at a pressure of from 1 to iOO kg / cm , Tempo, ature from O to 60 С pH of the medium from 4.
    26262
    to 9 in the presence of a hydrogenolysis catalyst (step 5).
    The catalyst for hydrogenolysis is usually
    . used in quantities of from 0.01 to
    5 2.5% by weight, preferably from 0.1 to 1.0% by weight, based on the compound obtained after the embodiment of step a. In penicillanic acid derivatives
    0 substituent to. bic.clic, another dotted line indicates that the substituent is located behind the plane of the core, i.e. it is in the oi configuration. In contrast, the addition of a substituent to a bicyclic other by a continuous line indicates that the substituent is in front of the core plane. This latest configuration is called ft-config 2Q guration. Thus, the group X. has -configuration, and group Y has -configuration in the formula
    (Ii)
    When the target product of formula (I) is 25; in which R is
     ether-forming residue (pivaloyloxymethyl), easily hydrolyzed in arganism, exposed to blood or mammalian tissue,
    A compound of formula (I) in which R is hydrogen is readily formed.
    Step a of the process involves the oxidation of the sulfide moiety of the compound of formula (II) to the sulfone group. For this process, a variety of oxidizing agents can be used to oxidize sulfides to sulfones. Preferred reagents are alkali metal permanganates, for example sodium permanganate and CAL; alkaline earth metal permanganates such as calcium permanganates and barium and organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid.
    When a compound of formula (II), in which X, Y, and R have the indicated meanings, is oxidized to the corresponding compound using metal permanganate, this reaction takes place.
     This is usually carried out by treating the compound of formula (II) from about 0.5 mol. eq. (preferably from 1 to 4 molar equivalents of permanganate in a suitable reaction-inert 55 solvent system. A reaction-inert dissolving system is such a system that does not adversely affect either 3 starting materials or products; water is used as a solvent. A solvent can be added which is miscible with water but does not react with permanganate, for example tetrahydrofuran. The reaction can be carried out at a temperature ranging from -30 to 50 ° C and preferably from -10 to 10 ° C. At a temperature of about The reaction is usually almost complete within a short period (within 1 hour). Although the reaction can be carried out under neutral basic or acidic conditions, it is respectful to work at a pH in the range of about 4 to 9, preferably 6-8. conditions in which decomposition of the ring system of the 5-lactam does not proceed. It is necessary to keep the pH of the reaction mixture neutral with a buffer. The product is isolated according to standard procedures. The excess permanganate is decomposed using sodium bisulfide and then, if the product is not contained in solution, it is isolated by filtration. It is separated from manganese dioxide by extraction with an organic solvent, followed by evaporation of the solvent. If the product is contained in diluent at the end of the reaction, then it is isolated by the usual solvent extraction procedure. When a compound of formula (II), in which X, Y, and R have the indicated meanings, is oxidized to the corresponding compound using peroxycarboxylic acid, the reaction is usually carried out by treating the compound of formula (II) in a reaction-inert organic solvent of approximately 1-- 5 mol eq. (preferably about 2.2 mol. equiv.) oxidant. Typical solvents are chlorinated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; and% esters. for example, diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. Typically, the reaction is carried out at a temperature of from -30 to 50 ° C and preferably from 15 to 30 ° C. At a temperature of 25 ° C, the reaction time is 2 to 16 hours. The product is separated by removing the solvent by evaporation in vacuo. The reaction product can be purified by known methods or can be used directly in the step without the following purification. 26 Step 6 of the process is a dehalogenating reaction. One method of performing this conversion is to stir or shake the solution of the compound obtained in step q under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenolysis catalyst. Solvents for the hydrogenolysis reaction are those that substantially dissolve the starting compound and which themselves are not subjected to hydrogenation or hydrogenolysis, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; low molecular weight esters, such as ethyl acetate and butyl acetate; tertiary amides, such as S, K-dimethylformamide, S, H-dimethyl-acetamide and N-methylpyrroldon; water and mixtures thereof. In addition, buffer is added to the reaction mixture in order to maintain the pH between 4 and 9, preferably between 6 and 8. Borate and phosphate buffers are used. The introduction of hydrogen gas into the reaction medium is accompanied by carrying out the reaction in a closed vessel containing the compound obtained at the stage and, a solvent, a catalyst and hydrogen. The pressure inside the reaction vessel can vary from 1 to 100 atm. When the atmosphere inside the reaction vessel is substantially pure hydrogen, the preferred pressure range is from 2 to 5 at. Hydrogenolysis occurs at a temperature of from 0 to 60 ° C and preferably from 25 to 50 ° C. When using preferred: temperature ranges and pressures, hydrogenol usually takes several hours, for example, from 2 to 20 hours. The catalyst used in this hydrogenolysis reaction is which is ferrous metals, for example nickel, palladium, platinum and rhodium. Typically, the catalyst is present in an amount of from 0.01 to 2.5 wt.% And preferably from 0.1 to 1.0 wt.% Based on the compound obtained in step a. It is often convenient to apply the catalyst on an inert carrier (palladium supported on an inert carrier such as carbon).
    . s h
    Lp H1) | .forcemental removal of haposen from the compound obtained in the step and other methods can be used. For example, X and Y can be removed using a reducing system with a solution to tsegos metal, such as zinc dust in acetic acid, formic acid or phosphate buffer solution. Otherwise, stage o can be carried out using tin hydride, such as trialkyltin hydride, such as tri-n hydride butyl tin.
    Thus, the proposed method involves oxidation followed by dehalogenation of b-halide or 6.6 di-halo derivatives of penicillanic acid with a free carboxyl group in position 3.
    The compounds of the above formulas (I) and (II) as well as the compound obtained in step a, in which R is hydrogen, are acids and can form salts with basic reagents. These salts can be prepared by standard methods such as contacting the acidic and basic components, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium. They are then filtered by filtration, precipitated with a non-solvent, followed by filtration, evaporation of the solvent, or in the case of aqueous solutions by lyophilization. The main agents that are appropriately used in salt formation are of organic and inorganic type and they include ammonia, organic amines, alkali metal hydroxides, carbonates and biocarbonates, alkali metal hydrides and alkoxides, as well as hydroxides, carbonates, hydrides, and alkoxides. Metaplov.
    I The compounds of formula (I) in which R is hydrogen and their salts are active antimicrobial agents of moderate intensity as. outside and inside the body, and the compounds of formula (I) in which R — the ether-forming residue, easily hydrolyzed inside the body — are active antimicrobial agents of moderate strength in the body. Table 1 shows the values of the minimum inhibitory concentrations (MIC) of 1,1-dioxide ne9; b (.6
    nicillan clues against some micro;) 1 anisms.
    Mik,
    Microorganisms µg / ml
    100
    Staphylococcus aureus Streptococcus faec.alis 200 100 Streptococcus pyogenes Eschericliia coli
    50 Pseudomonas aeruginosa 200 5 Klebsiella pneuimoniae
    50 Proteus mirabilis 100 Proteus inorgani 100 Sulmonella typhitnurium
    50 Pasteurella multocida
    50
    Serratia marcescens 100
    25 Enterobacter aerogenes 100 Enterobacter elocae Citrobacter freundii
    50 Providencia 100
    Staphylococcus epidermis 200 Pseudomonas putida 200 Hemophilus influenzae
    50 0.312 Neisseria gonorrhoeae
    due to antimicrobial activity in the body, a compound of formula (I) in which R is hydrogen and its salts can be used, for example, in treating water, regulating sticky sludge, protecting paints and wood, and also for appropriate use as a deodorant . When using these compounds, the active ingredient is mixed with a non-toxic carrier, such as vegetable or mineral oil, or a softening cream. Similarly, it can be dissolved or dispersed in liquid carriers or solvents such as water, alkanols, glycols, or mixtures thereof. The concentration of the active ingredient at from 0.1% to 10% by weight, based on the entire composition.
    The activity in the body of compounds of formula (I), in which R is hydrogen or an ether-forming residue, is easy to hydrolyze; Leu makes them suitable for the suppression of microbial infections in humans, including humans, when administered orally or parenterally. These yoga compounds are used to suppress infections caused by susceptible microbes in the human body, for example, infections caused by Neisseria Crpoggoyeae strains. In the therapeutic use of a compound of formula (I) or a salt thereof for mammals, in particular a human, this compound may be administered alone or in a mixture with pharmaceutically acceptable carriers or diluted. tel mi. It may be administered orally or parenterally, for example, intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected based on the intended route of administration of the compound. For example, when procially administered, the compound can be used in the form of tablets, capsules, lozenges, polyhedra, powders, syrups, tinctures, aqueous solutions and suspensions. The proportional ratio of the active component to the carrier can depend on the chemical nature, solubility and stability of the active component as well as on the intended dosage. Pharmaceutical compositions containing antimicrobial agents of formula (I) can contain from 20% to 95% of the active component. In the case of tablets for peroral use, carriers commonly used include lactose, sodium citrate and phosphoric acid salts. Different pills, such as starch type dispensers and lubricating agents, such as magnesium stearate sodium lauryl sulfate and talc, are commonly used in tablets. For cereoral administration in the form of a capsule, useful diluents are lactose and high molecular weight polyethylene glycol. When aqueous suspensions are required for oral use, the active ingredient may be combined with emulsifying and suspending agents, sweetening and flavoring agents may be added. For parsteral administration, which includes intramuscular, intraperitoneal, subcutaneous, and intravenous administration, sterile solutions of the active component are usually prepared, and the pH of the solutions is adjusted and stabilized with appropriate buffers. For intravenous use, it is necessary to control the total concentration of the solute in order to prepare an isotonic solution of the Compound of formula (I) in which. R is hydrogen or ether-forming. A residue that is easily hydrolyzed in the body, or their salts enhance the antimicrobial efficacy of β-lactam antibiotics in the body. They reduce the amount of antibiotic that is needed to protect mice from other lethal inoculants of certain. β-lactamase producing bacteria,. This ability provides the value of these compounds when co-numbered with f5-lactam antibiotics in the treatment of bacterial infections in mammals, especially in humans. In the treatment of bacterial infections, the indicated compound of formula (I) can be mixed together with the 3-lactam antibiotic, so both agents are administered simultaneously. The compound of formula (I) may be administered as a separate agent during the treatment with the β-lactam antibiotic. In some cases it is advantageous to pre-dose the compound-to the patient. ly (I) before proceeding with treatment with a / 3-lactam antibiotic. When penicillanic acid 1,1-dioxide, its salt or., Ether, which is easily hydrolyzable in the body, is used, in order to increase the effectiveness of the knots of the lactam antibiotic, it is administered in a ready-made formulation along with a conventional pharmaceutical carrier or diluent. The formulation methods considered for the use of 1,1-dioxide penny cyplyotic acid or its ester, easily hydrolyzed in the body, as the only antimicrobial agent can also be used in the case of co-administration of this compound with another prescribed UZ-lactam antibiotic. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a UZ-lactam antibiotic and 1,1-dioxide penicillanic acid or its easily hydrolyzed ester, usually
    may contain from 5 to 80% of the pharmaceutical carrier by weight.
    When using 1.1 penicillanic acid dioxide or its ether, which is easily hydrolyzable in the body, the sulfone can be administered orally or parenterally (intramuscularly, subcutaneously or intraperitoneally) in combination with another 3-lactate antibiotic.
    Typical lactam antibiotics that can be co-administered with penicillanic acid 1,1-dioxide and erp ether readily hydrolyzed in the body are: 6 (-2-phenylacetamido) penicillin a. New acid, 6- (B-2-a; mino-2-phenylacetamido) pencycillanic acid, 6- (2-carboxy-2-fensh1-acetamido) penicillanic acid, and 7- (2 - (. 1-tetrazolyl / acetamido) -3- (2/5 -methyl-1,3,4-thiadiazolyl / -thiomethyl) -3-deacetoxymethyl-cepherasporic acid.
    Typical microorganisms against which the antimicrobial activity of these USS-lactam antibiotics is enhanced are: StaphyloCOCCUS .aureus, Hapmophilus influenzae Klebsiella pneuiraniae and Bacteroides fragilis.
    Some 5-lactam compounds are effective for oral or parenteral administration, while others are only effective for parenteral administration. When 1,1-dioxide penicillanic acid is its salt or. Ether, easily hydrolyzed; in the body, it is necessary to use at the same time (i.e., in bold) suz-lactam antibiotics, which are effective only for parenteral administration, then it may be necessary to combine them. recipe suitable for parenteral use. When penicillanic acid 1,1-oxide or its ester must be used simultaneously (in a mixture) with an ultrasound-lactam antibiotic that is effective orally or parenterally, combinations suitable for oral or parenteral administration can be prepared. In addition, oral administration of preparations 1, penicillanic acid I or its salt, or ester is possible, and parenteral / 3-lactam antibiotic is additionally prescribed. In addition, the administration of penicillanic 1,1-dioxide preparations
    acid or its salt, - or ester and additionally administered orally by a J-lactam antibiotic. . Infrared Spectra (IR) Does potassium bromide tablets
    (KBr), and the characteristic absorption bands are given in wavenumbers (cm). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl), perditeroacetone (CDjCOCDj), perdateriodimethylsulfoxide (DMSO-d), or dihydrogen (Deutterimeter). B, 0), and
    The 5 positions of the peaks were expressed in millionnuple (ppm) in the direction of decreasing the floor from tetramethylsilane or sodium-2, 2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for peak shape were used: c. - singlet, d. - doublet, t. - triplet, к - quartet, m. - multiplet ..
    Example 1. 6-alpha-Bromopenicillanic acid, 1,1-dioxide.
    5 To a stirred mixture of 560 ml of water, BOO of ml of dichloromethane and 56.0 g of 6-alpha-bromopenicillanic acid were added 4 n. sodium hydroxide solution until a constant pH of 7.2 is established. 55 ml of sodium hydroxide is required for this. The mixture is stirred at pH 7.2 for 10 minutes, then it is filtered. The salts are separated and the organic phase is discarded. Then,
     while stirring quickly, the water is poured into the oxidizing mixture, which is prepared in advance as follows.
    . In a 3-liter flask, 63.2 g of potassium permanganate, 1 l of water and 48.0 g of acetic acid are mixed. This mixture is stirred for 10 minutes at 20 ° C. and then cooled to.
    After adding the 6-alpha-bromopenicillanic acid solution to the oxidizing mixture, the reaction mixture is cooled with a cooling bath (-15 ° C). The internal temperature of the mixture rises to 15 ° C and then lowered to within 20 minutes. AT
    this time, with stirring, 30.0 g of sodium metabisulfite is added over 10 minutes at approximately 10 ° C. After an additional 15 minutes, the mixture is filtered and the filtrate is acidified to a pH of 1.2 by adding 170 ml of 6N. hydrochloric acid. Wod11
    This phase is extracted with chloroform and then with ethyl acetate. The chloroform and ethyl acetate extracts are dried using anhydrous sulfa magic, and then the extracts are evaporated in vacuo. The chloroform solution contains 10.0 g (16% yield) of the indicated compound. The ethyl acetate solution yields 57 g of an oil, which is triturated under heptane, until a white substance appears. This material was filtered to give 41.5 g (yield 66%) of the title compound, mp. (Decomp.).
    Calculated,%: C 30.78; H 3.23; Br 25.6; K 4.49; S 10.27.
    CgHjoBrNO S
    Found,%: C 31.05; H 3.24; j Br 25.54; N 4.66; S 10.21.
    Example 2. 1,1-Dioxide 6g-beta-bromopenicillanic acid.
    To a solution of 255 mg of sodium 6-beta-bromopenicillanate in 5 ml of water is added with a solution obtained from 140 mg of potassium permanganate, 0.11 MP of 85% phosphoric acid and 5 MP of water at 0-5 ° C. During the addition, the pH of the mixture is maintained in the range of 6.0-6.4. The reaction mixture at pH 6.3 was outweighed for 15 minutes, and then the purple solution was poured with ethyl acetate. The mixture was acidified to pH 1.7 and 330 mg of sodium bisulfite was added. After 5 minutes, the layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried over magnesium sulfate and evaporated in vacuo. 216 mg of the title compound are obtained as white crystals. The NMR spectrum (c) showed absorption at 5.78 (d, 1H, J 4.7 Hz). 5.25 (d, 1H, J 4 Hz), 4.20 (s, 1H), 1.65 (s, ZN) and 1.46 (s, ZN) ppm
    Example 3. Pivaloyloxymethyl-6-alpha-6-bromopenidillanate 1,1-dioxide.
    To a solution of 394 mg pivapoyloxymethyl-6-alpha-bromopenicillanate in 10 MP of dichloromethane, 400 mg of 3-chloroperbenzoic acid are added while the reaction mixture is stirred at 0-5 ° C for I h and then at 25 s for 24 h. the mixture is evaporated to dryness in vacuo to give the title compound.
    92626
    Example A. 1,1-Dnoxide penncillanic acid.
    To 100 ml of water, 9.4 g of b-alpha-prompenipicanoic acid 1,1-dioxide are added with and then a sufficient amount of 4N sodium hydroxide solution in order to establish a stable pH value of 7.3. To the resulting solution was added 2.25 g.
    IQ catalyst (5% palladium on carbon) and then 6.9 g decaliphosphate trihydrate. This mixture is then shaken under a hydrogen atmosphere at a pressure varying from 3.5 to 1.8 at. After
    15 by stopping the absorption of hydrogen, the solid is separated by filtration and the aqueous solution is covered with 100 ml of ethyl acetate. The solution is slowly acidified from pH 5.0 to 1.5 with 6N hydrochloric acid. Layers
    20 are separated, and the aqueous phase is further extracted with ethyl acetate. The combined ethylacetate layers were washed with brine, dried using anhydrous magnesium sulphate and evaporated in vacuo. The residue was triturated under ether and then the solid was separated by filtration. 4.5 g (yield 65%) of the title compound are obtained.
    Example 5. 1,1-Dioxide of pivaloyloxymethylpenicillanate.
    To a solution of 1.0 i; pivaloyloxymethyl-6-alpha-bromopenicillanate in 10 ml of methanol add 3 mp of M solution
    35 sodium bicarbonate and 200 mg of catalyst (10% palladium on carbon). The reaction mixture is vigorously shaken under a hydrogen atmosphere at a pressure of about 5 atm until the uptake of hydrogen ceases. The mixture is then filtered and the mass of methanol is removed by evaporation in vacuo. Water and ethyl acetate are added to the residue and the pH of the solution is adjusted to 8.5. Separate the layers, and wash the organic layer with water, dry with sodium sulfate and vacuum in vacuum. Get the specified connection.
    PRI and 1 P 6. 1,1-Dioxide of beer50 Looyloxymethyl-6-alpha-bromopenicillanate. An oxidizing solution is prepared by mixing with 4.26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water. The mixture is stirred
    55 for I h and then slowly add, when so far from 5 to 20 minutes, to a stirred solution of 5.32 g of piBaloyloxymethyl-6-alpha-1) -Ormmyan llanate in 70 ml of acetone and 10 Ml of water . The mixture was stirred at J C B for 30 minutes and 100 ml of ethyl acetate was added. After a further 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water is added over 15 minutes at a temperature of about 10 ° C. Stirring is continued for an additional 30 minutes at 5 ° C, and then the mixture is filtered. The organic phase is separated and washed with a saturated solution of sodium chloride. The dried organic layer was evaporated, yielding 5.4 g of the title compound as an oil, which slowly crystallized. Absorbances at 5.80 (k, 2H), 5.15 (d, H), 4.75 (d, 1H), 4.50 (s, 1H), 1.60 (s, EN) are noted in the NMR spectrum , 1.40 (s, 3N), 1.20 (s, 9H) ppm Example 7. 1,1-Dioxide of pivaloyloxymethylpenicillanate. A solution of 4.4 g of 1, -) pivalonloxymethyl-6-alpha-bromopenicillanate dioxide in 60 ml of tetrahydrofuran is added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution is shaken in a hydrogen atmosphere in the presence of 2 g of palladium (5%) on coal at a pressure of 3.3 to 3.6 at. Then the reaction mixture is fed and the residue is washed with 100 ml of ethyl acetate and 25 ml of water. The combined filtrate and washings were separated. The organic layer is washed with a saturated sodium chloride solution and dried over magnesium sulfate, and evaporated to give the title compound in the form as an oil. This oil was dissolved in ethyl acetate (20 mp was slowly added to the solution with 100 mp hexane and the precipitate was filtered off. Kc 2.4 g. In the NMR spectrum (in flMCO-d), absorbances at 5.75 (k, 2p), 5 , 05 (m, W), 4.40 (s, W), 3.95-2.95 (m, 2H) ,, 1.40 (s, JHJ, 1.25 (s, GD) and 1, 10 (s, 9H) ppm Example 8. 1, -Dioxide-6,6- -dibromoponitshshanic acid. To a solution of 6,6-dibromopenicillanic acid in dormethane from preparation B, add 300 ml of water and then add dropwise 105 Mil 3 and the sodium hydroxide solution are maintained for 30 minutes, the p11 solution is kept equal to /, 0. The aqueous layer is removed, and the organic the layer is extracted with water (2 pa- -ii, 100 np each). The combined aqueous Bop-uf is added at -5 ° C with a pre-mixed solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml water until the pink color of the permanganate appears. The addition operation takes 50 minutes and 550 ml of oxidant. Then add 500 ml of ethyl acetate and then acidify the mixture to pH 1.23 by adding 105 ml of 6N. hydrochloric acid. Then, 250 mp of 1 M sodium bisulfite solution is added at 10 ° C over 10-15 minutes. During the addition of sodium bisulfite solution, the pH of the mixture is maintained at 1.25-1.35 using 6N. hydrochloric acid solution. The aqueous phase is saturated with sodium chloride and the two phases are separated. The aqueous solution is extracted with an additional amount of ethyl acetate (2 times 150 ml each time) and the combined acetate solutions are washed with brine and dried over magnesium sulfate. A solution of 1,1,6-dioxide 6,6-dibromopenicillanic acid in ethyl acetate is obtained. 6,6-Dibromopenicillanic acid 1,1-dioxide can be isolated by removing the solvent in vacuo. The sample thus isolated from a similar preparation had a melting point of 20lc (decomp.). In the NMR spectrum (CDClI / DMSO-dg), absorbances at 9.35 (s, III), 5.30 (C, 1H), 4.42 (s, 1H), 1.63 (s, 3N) and 1 , 50 (s, ZN) ppm In the IR spectrum (KBG tablet), absorption is noted at 3846-2500, 1818, 1754, 1342 and 1250-1110 cm. Example 9. Penicillanic acid 1,1-Dioxide. A solution of 1,1,6-dioxide 6,6-dibromopenicillanic acid in ethyl acetate from Example 8 was combined with 705 ml of saturated sodium bicarbonate solution and 8.88 g of catalyst (5% palladium on carbon). The mixture was shaken under a hydrogen atmosphere at a pressure of about 5 atm. For about an hour. The catalyst was separated by filtration, the aqueous phase of the filtrate was acidified to pH 1.2 with 6N. hydrochloric acid. The aqueous phase is saturated with sodium chloride. Separate the layers and extract the aqueous phase with additional ethyl acetate (3 times 200 ml each time). The combined ethyl acetate solutions were dried over magnesium sulfate and evaporated in vacuo to yield 33.5 g (yield from 6-aminopenicillanic acid) 1,1-dioxide penicillanic acid. This product is dissolved in 600 ml of ethyl acetate, the solution is decolorized using activated carbon, and the solvent is removed by evaporation under vacuum. The product is washed with hexane. A pure product yield of 31.0 g is obtained. Example 10. 1.1-Pivaloyloxymethyl Dioxide -6, 6-dibromopenyl laneate. To a solution of 4.73 pivaloyloxymethyl-6, 6-dibromopenica llanate in 15 ml of dichloromethane was added 3.80 g of 3-chloroperbenzoic acid at 0-5 ° C. P-reaction mixture is stirred at 0-5 ° C. for 1 hour and then at 25 seconds for 24 hours. The filtered reaction mixture is evaporated to dryness in vacuo, and the residue is partitioned between ethyl acetate and water. The pH of the aqueous α-phase is adjusted to 7.5, and the layers are separated. The ethyl acetate phase is dried with sodium sulphate and upper. vacuum, get the specified connection. Example P. 1,1-Dioxide pivaloyloxymethyl nicyllanate. To a solution of 1.0 g of 1,1-dioxide pyvapoyloxymethyl-6,6-dibromopenicillanate in 10 ml of methanol was added 3 MP of 1 M sodium bicarbonate solution. and 200 mg of catalyst - 10% palladium on coal. The reaction mixture was shaken vigorously under a hydrogen atmosphere at a pressure of about 5 atm until the uptake of hydrogen ceased. The mixture is then filtered and the mass of methanol is removed by evaporation in vacuo. Water and ethyl acetate are added to the residue, the pH of the mixture is adjusted to 8.5. The layers are separated, and the organic layer is washed with water, dried over sodium sulfate, and evaporated on an aqueous vacuum. This gives pivaloyloxymethylpenicyl lanate 1,1-dioxide. Example 12. 1,1-Dioxide pivaloshtoksimetil-b, 6-dibromopenicilla nata, ..: Cool the stirred solution of 3.92 g of 1,1 - dioxide 6,6-dibrompenicillanic acid in 20 ml of K, H-dimethyl formamide to m. O C and then 1.29 g of diisopropylethylamine are added. 1.51 g of chloromethyl pivalate is then added. This reaction mixture was stirred at 0 ° C for 3 hours and then at room temperature for 16 hours. The reaction mixture was diluted with 25 ml of ethyl acetate and 26 ml of ode. Separate the layers and extract the aqueous layer with ethyl acetate. The combined ethyl acetate layers are washed with cold 5% sodium bicarbonate solution, water, and brine. Then the ethyl acetate solution is treated with Darko (activated bone charcoal), dried with magnesium sulfate and evaporated in a vacuum to brown oil, which weighs 2.1 g. This oil is chromatographed over 200 g of silica gel using dichloromethane as an eluant. The fractions containing the desired product are combined and chromatographed on a silica gel once more to obtain 0.025 g of the title compound. In the NMR spectrum (CDClg), absorption is noted at 6.10 (k, 2H), 5.00 (s, 1H), 4.55 (s, W), 1.60 (s, 3N), 1.50 (s , ZN) and 1.15 (s, 9H) ppm Example 13. 1,1-Dioxide pilsiloxymethylpenicillanate. To a stirred solution of 60 mg i 1,1-dioxide pivaloyloxymethyl-6,6-. -dibrompenicillanate in 5 mp of benzene. 52 µl of tri-N-butyltin hydride is added and then a catalytic amount of azobisiobutyronitrile. The reaction mixture is cooled to approximately 5 ° C and then irradiated. ultraviolet radiation for 1 hour. The reaction mixture is drunk in 20 ml of cold, 5% sodium bicarbonate solution and stirred for 30 minutes. Ethyl acetate is added and the pH of the aqueous phase is adjusted to 7.0. Separate the layers and further extract the aqueous phase with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is dried under high vacuum for 30 minutes. 70 mg of a yellow oil are obtained, which, as shown by NMR spectroscopy, contains the indicated compound, together with certain impurities containing n-butyl groups. Example 14. 1,1-Dioxide 6,6-dibromopenic acid To a solution of 359 mg of 6,6-dibromopenicillanic acid in 30 m dichloromethane was added 380 mg of 3-chloroperobenzoic acid at. Reactions
    The mixture was stirred for 30 minutes and then at 25 ° C for 24 hours. The filtered reaction mixture was evaporated in vacuo to give the product.
    Preparation B. Pivaloyloxymethyl-b-alpha-bromopenica anat.
    To a stirred mixture of 11.2 g of 6-apf-bromopenicillanic acid, 3.7 g of sodium bicarbonate and 44 ml of N, K-dimethylformamide, 6.16 g of chlorometshivalate are added dropwise over 5 minutes at room temperature. Stirring is continued for 66 hours and then the reaction mixture is diluted with 100 ml of ethyl acetate and 100 ml of water .: Separate; the layers, and the ethyl acetate layer was washed successively with water, a saturated sodium bicarbonate solution, water, and a saturated sodium chloride solution. The decolorized ethyl acetate solution is dried over magnesium sulfate and evaporated to dryness in vacuo. 12.8 g (yield 80%) of the title compound are obtained.
    Preparation F. Pivaloshloxymethyl-6, o - dibromopenicillanate.
    To a stirred solution of 3.59 g of 6,6-dibromopenicillanic acid in 20 ml of H, N-dimethylformamide is added 1, 30 g of dyisoproxyethylamine and. then 1.50 g of chloromethyl pivalate at about 10 ° C. The reaction mixture is stirred for approximately 30 minutes and then at room temperature for 24 hours. The reaction mixture is diluted with ethyl acetate and water, and the pH of the aqueous phase is adjusted to 7.5. . The ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. Then, the ethyl acetate solution is dried using anhydrous sodium sulfate and evaporated in vacuo to give the title compound.
    When carrying out the proposed method, in particular when combining the specified examples of 1 and 7, 9 and 10, 11 and 12, the total yield of the target product is 53-63%, which is approximately 2 times higher than the yield by the known method.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PENICYLANIC ACID OR ITS ETHER 1,1-DIOXIDE of the general formula, where R is hydrogen or pivaloyloxymethyl, from 6-halogen-penicillanoic acid or its ester, which is identical to that, in order to increase the yield of the target product, first, a compound of the general formula wherein at least one of the .atom * ”X and Y is bromine and the other is hydrogen or bromine;
    R is hydrogen or pivaloyloxymethyl, is contacted with a chemical reagent selected from the group consisting of alkali metal permanganates, alkaline earth metal permanganates and organic nadoxycarboxylic acids, then the resulting product is contacted with hydrogen in an inert solvent at a pressure of 1 to 100 kg / cm, temperature - from 0 to 60 ° Cj pH of the medium from 4 to 9 in the presence of a hydrogenolysis catalyst.
    -SU .and 192626 ί
    类似技术:
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    SU1192626A3|1985-11-15|Method of producing 1,1-dioxide of penicillanic acid or ether thereof
    US4420426A|1983-12-13|6-Alpha-halopenicillanic acid 1,1-dioxides
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    同族专利:
    公开号 | 公开日
    DK166353C|1993-09-06|
    LU82215A1|1980-09-24|
    DD149367A5|1981-07-08|
    DK92680A|1980-09-06|
    BG33292A3|1983-01-14|
    RO80112A|1982-10-26|
    NL180317C|1987-02-02|
    IN153685B|1984-08-04|
    CH644608A5|1984-08-15|
    FR2450836B1|1986-03-21|
    FI800661A|1980-09-06|
    PL125197B1|1983-04-30|
    UA6342A1|1994-12-29|
    DE3008257A1|1980-09-11|
    DK145690A|1990-06-14|
    EG14437A|1984-09-30|
    IL59515A|1983-02-23|
    NO823127L|1980-09-08|
    SG55884G|1985-03-08|
    SE8603309L|1986-08-04|
    CS215130B2|1982-07-30|
    AR225031A1|1982-02-15|
    FI70024B|1986-01-31|
    IL59515D0|1980-06-30|
    AU522572B2|1982-06-17|
    DK145690D0|1990-06-14|
    ES8103094A1|1981-02-16|
    FR2450836A1|1980-10-03|
    KR850001339B1|1985-09-19|
    PL222448A1|1981-01-02|
    KE3464A|1984-10-12|
    YU58580A|1983-02-28|
    NO800618L|1980-09-08|
    GR67234B|1981-06-25|
    DK166353B|1993-04-13|
    IE800429L|1980-09-05|
    AT366693B|1982-04-26|
    SE449103B|1987-04-06|
    MY8500319A|1985-12-31|
    GB2045755A|1980-11-05|
    YU42328B|1988-08-31|
    HU186304B|1985-07-29|
    FI70024C|1986-09-12|
    NL180317B|1986-09-01|
    SE8000512L|1980-09-06|
    DK159852B|1990-12-17|
    IE49535B1|1985-10-16|
    NL8001285A|1980-09-09|
    DE3008257C2|1984-03-01|
    DK159852C|1991-05-06|
    HK66587A|1987-09-25|
    SE8603309D0|1986-08-04|
    IT1130300B|1986-06-11|
    MX6032E|1984-10-04|
    PT70897A|1980-04-01|
    ES489185A0|1981-02-16|
    ATA119080A|1981-09-15|
    GB2045755B|1983-01-26|
    IT8020367D0|1980-03-05|
    AU5610480A|1980-09-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    IN149747B|1977-06-07|1982-04-03|Pfizer|
    CA1158639A|1978-12-11|1983-12-13|William H. Koster|6-bromopenicillanic acid sulfone|
    DE3068390D1|1979-01-10|1984-08-09|Beecham Group Plc|Penicillin derivatives, process for their preparation and pharmaceutical compositions containing certain of these compounds|
    IE49881B1|1979-02-13|1986-01-08|Leo Pharm Prod Ltd|B-lactam intermediates|IN159362B|1981-03-23|1987-05-09|Pfizer|
    US4419284A|1981-03-23|1983-12-06|Pfizer Inc.|Preparation of halomethyl estersof penicillanic acid 1,1-dioxide|
    PT76526B|1982-04-19|1986-01-21|Gist Brocades Nv|Preparation of 6-alpha-bromo- and/or 6,6-dibromopenicillanic acid 1,1-dioxides|
    IT1190897B|1982-06-29|1988-02-24|Opos Biochimica Srl|PROCEDURE FOR THE PREPARATION OF THE 1-ETHOXYCARBONYLOXYETHYL ACID ACID 6-- ALPHA AMINOALPHA-PHENYLACETAMIDE) -PENICILLANIC|
    US4606865A|1982-09-20|1986-08-19|Astra Lakemedel Aktiebolag|Methods for the preparation of α-bromodiethylcarbonate|
    EP0139047A1|1983-10-18|1985-05-02|Gist-Brocades N.V.|Process for the preparation of 6,6-dibromopenicillanic acid 1,1-dioxide|
    EP0139048A1|1983-10-18|1985-05-02|Gist-Brocades N.V.|Process for the dehalogenation of 6,6-dibromopenicillanic acid 1,1-dioxide|
    US4596677A|1984-04-06|1986-06-24|Bristol-Myers Company|Anhydropenicillin intermediates|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US1781079A| true| 1979-03-05|1979-03-05|
    US1780879A| true| 1979-03-05|1979-03-05|LV931229A| LV5515A3|1979-03-05|1993-11-15|Contribution to the penicillan coupling of 1,1-dioxide or its esters|
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