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    • 专利摘要:
    Novel 7 alpha -methoxycephalosporin derivatives, their pharmaceutically acceptable salts, process for the preparation thereof, and antibacterial drugs involving the derivative or salt. The derivatives or salts are effective against the Gram-positive bacteria and the Gram-negative bacteria.
    公开号:SU1095879A3
    申请号:SU813226153
    申请日:1981-01-07
    公开日:1984-05-30
    发明作者:Матида Есимаса；Саито Исао；Номото Сеиитиро；Неги Сигето；Икута Хиронори；Кито Киосуке
    申请人:Эйсаи Ко., Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of novel cephalosporin derivatives or their pharmaceutically acceptable salts, which have antimicrobial activity and can be used as medicines in medicine. A known method for the preparation of biologically active cephalo sporin derivatives of the formula A SONH J Ogl SNGV-1CH ° C where R is 1-methyltetrazol-5-yl, 1-carboxymethyltetrazal-5-yl or 5-methyl-1, 3,4-thiadiazol-2 -yl RJ is a hydrogen atom or hydroxy groups Rj, R and RJ are each, a hydrogen atom or an hydroxy or acetoxy group, or their salts, which consists in the fact that a compound of the general formula B CH -SNG: G TShg (% 5 in which H and R have the indicated references, or a salt thereof, is reacted with a compound of the general formula B In which RJ, R and Rg have the above values, or its solution capable of derivative, and the process is carried out in an inert solvent at a temperature of from -50 to 50 ° C, followed by isolation of the target product in free form or in the form of salt I. The process is preferably carried out in the presence of a basic or silylating agent. cephalosporin antibiotics, which expand the arsenal of effects on a living organism. The goal is achieved based on a known reaction method of obtaining cephalosporin - the general formula I ssh-ns-sog ocHj. S JLi CHi-Rt soon where R is an acetoxy group or a tetrazol-5-ylthio group, is substituted in position 1 by methyl, etcht, carboxymethyl or methoxycarbonylmethyl Rj is hydrogen or hydroxy, Rj is independently from each other hydrogen or chlorine, methyl, hydroxy, acetoxy- , methoxy, benzyloxy, nitro, ethoxycarbonyloxy or trichloroethoxycarbonyloxy, and at least two substituents from EZ-RU are hydrogen, or their pharmaceutically acceptable salts, which is that the compound of formula II is CH-C01SH OCH3 b, -i where R. and RJ have the indicated meanings. or its salt or hydrate is reacted with a compound of formula III. where RJ-R have the indicated meanings, or with its reactive derivative, and isolate the desired product as the free acid or its pharmaceutically acceptable salt. The reaction is carried out in an inert solvent at a temperature of from -50 to
    50 C, preferably from -20 to 30 C in the presence or in the absence of a basic reagent or silylation agent.
    HHeptHbiMH solvents can be acetone, tetrahydrofuran, dimethylacetamide, dimethylformamide, dioxane, dichloromethane, chloroform, benzene, toluene, ethyl acetate, or mixtures thereof.
    The basic reagents can be, for example, alkali hydroxides, such as sodium or potassium hydroxide, alkali metal bicarbonates, such as sodium or potassium bicarbonate, amines, such as triethylamine, pyridine, dimethylaniline or N-methylmorpholine.
    Siliding agents can be, for example, N, 0-bis (trimethylsilyl) acetamide, hexamethyldisilazane or trimethylsilylacetamide.
    7 j (6,7-Dioxychromone-3-carboxamido) -2-phenylacetamido {-7a-methoxy-3- (1-carboxymethyl-5-tetrazoyl) thiomethyl-3-cephem-4-carboxylic acid.
    (6,7-Diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-7a-methoxy-3- (1-carboxymethyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    (6, 7-Diacetoxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamdo-7a-methoxy-3-5-carboxymethyl-2- (.1,3,4-thiadiazolyl) -thiomethyl-3-cephem- 4-carboxylic acid.
    (6,7-Diacetoxychromon-3-carboxamido) -2- (4-hydroxyfennl) acetamdo} -7a-methoxy-3- 5-carboxymethyl-2- (1,3,4-oxadiazolyl) thiomethyl-3-cephem-4 - carboxylic acid.
    The compounds of the formula X obtained by the proposed method show high antimicrobial activity and are effective against gram-positive and gram-negative bacteria. These compounds are especially effective against bacteria such as Pseudomonos aeruginosa, Serratia marcescens, and the like, which cause severe disease, as well as against bacteria producing p-lactamase.
    The test results are shown in the table.
    The magnitude of acute toxicity (dose, causing 50% mortality when orally administered to children) is higher
    5 g / kg for the following compounds prepared according to the invention:
    7A-; D-2- (6, 7-Dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) -acetamido | -76-methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    (6,7-Dioxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-7 (X-methoxy-3-5-methyl-2- (1,3,4-thiadiazolyl) thiomethyl-3-cephem- 4-carboxylic acid.
    The disodium salt of (6, 7-dioxychromone-3-carboxyamido) -2- (4-hydroxyphenyl) acetamido-76-methoxy-3- (1-carboxymethyl-5-tetrazolyl) timethyl-3-cephem-4-carboxylic acid.
    , 7-Bis (ethoxycarbonyloxy) chromone-3-carboxamido -2- (4-hydroxyphenyl) acetamido-7 ()-methoxy-3- (1-methoxycarbonylmethyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    7p - (, 7-Bis (2,2,2-trichloroxy-carbonyloxy) chromone-3-carboxamido} -2- (4-hydroxyphenyl) acetamido-7c | C-methoxy-3- (1-methyl-5-tetrazolyl ) Thiomethyl-3-cephem-4-carboxylic acid.
    , 7-Dioxychromone) -3-carboxamido -2- (4-hydroxyphenyl) acetamido-3-5-carboxymethyl-2- (1,3,4-thiadiazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    Example 1. (6,7-Diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido -7o (, methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    A. 6,7-Diacetoxychromone-3-carboxylic acid, acid chloride.
    A mixture of 18.4 g of 6,7-diacetoxychromone-3-carboxylic acid, 450 ml of benzene, 8.6 g of thionyl chloride and 3 ml of dimethylformamide is heated under reflux for 1 hour and then cooled to room temperature. 300 ml of hexane was added to the reaction mixture and the precipitate separated out was filtered by filtration. Thus, 17.6 g of the expected product are obtained.
    IR Absorption Spectrum (nudzhol): 1780, 1755, 1660, 1625.
    B. (6,7-Diacetoxychromone, -3-carboxamido) -2- (4-hydroxyphenyl) acetamidr -7 (-methyl-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4- carboxylic acid. 7H-o-2-amino- (4-hydroxyphenylacetamido-7o) salt (, methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (150 mg ) suspended in ethyl acetate. (7.5 ml). To the suspension, add K, 0-bis (trimethylsilyl) acetamide (417 µl) at 0 ° C and stirring, and after stirring for 15 minutes at 05 ° C add 78 , 2 mg of the indicated acid chloride (A) and the mixture is stirred at for about 1.5 hours. Into the reaction The solution is added with 100 ml of ethnyl acetate and the mixture is sequentially washed in portions: 20 ml each with 0.5N hydrochloric acid, twice distilled with water, and a saturated aqueous solution of sodium chloride. The resulting organic layer is separated and dried over magnesium sulphate. was removed by distillation, the residue was dissolved in acetone (15 ml) and left to stand overnight, the solvent was removed by distillation, and the residue was triturated with ethyl ether. The precipitate thus formed was filtered by filtration to obtain 150 mg of a crude product, which was purified by flash chromatography to obtain 79 mg. Mp. 175-185 With the target product (decomposition). T Elemental analysis for C C H. Calculated,%: 49.81 3.67 Found,%: 48.25 3.58 11.2 IR absorption spectrum, (cm, nudzhol): 1770-1790, 1715, 1670, 1620. NIR spectrum, (million Shares, dimethyl sulfoxide - d): 2.34 (3N, singlet 2.36 (3N, s); 3.40 (3N, 5), 3.34 (1H (3, 3 18H), 3.66 (1H , d, 3 18Hz.); 3.90 (ZN, 5), 4.12 (, 3 13Н7) -, 5.06 (1H, 5), 5.68 (1H, (3.3 8H2 :); 6.73 (2H, d, L 8,) 1 7.30 (2H, d, and 8.5 Hz) j7.86 (1H, 5), 8.02 (1H, 3), 9.03 (1H 5 ); 9.03 (1H, 5). Example 2. 7p- B- (7,8-Diaz toxichromon-3-carboxyamino) -2- (4-hydroxyphenyl) acetamido-76-methoxy-3- (1-methyl -5-tetrazolyl) -thiomethyl-3-cephem-4-carboxylic acid. A. 7,8-Diacetoxychromone-3-carbonyl chloride A mixture of 9.5 g of 7.8-diacetoxychromone-3-carboxylic acid, 2.6 ml of chloride thionyl, 0.1 MP of dimethylformamide and 300 ml of benzene are boiled for 1.5 hours under reflux, then 2.6 ml of thionyl chloride and 0.1 ml of dimethylformamide are additionally added. for 1 hour. After that, the solvent is distilled off during the distillation, the residue is triturated with n-hexane. The resulting solid powder was filtered. Thus, 9.3 g of the expected product are obtained. IR Absorption Spectrum (, nujol): 1780, 1770, 1670, 1620. B. (7,8-Diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-7c-methoxy-3- (1-methyl -5-tetrazolsh1) thiomethyl-3-cephem-4-carboxylic acid. Salt 7 | - p-2-amino-2- (4-hydroxyphenyl) acetamido-7dC-methoxy-3- (1-metsh1-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (150 mg) are suspended in 7.5 ml of ethyl acetate, N, 0-bis (trimethylsilyl) acetamide (417 µl) is added to it with stirring. The acid chloride (78.2 mg) that was obtained (A) was added to the mixture and the whole was stirred at C for 3 hours. The reaction solution after adding 100 ml of ethyl acetate to it was successively washed in 20 ml portions. , 5 n. hydrochloric acid, twice with distilled water and saturated sodium chloride solution. The residual residue, after removing the solvent from it during the distillation, is dissolved in 15 ml of acetone and left to stand overnight at room temperature. The solvent is distilled off from the solution, the residue is triturated with ethyl ether to obtain 98 mg of the crude product, which is washed with a mixture of ethyl ether, acetone and methanol in a ratio of 9: 0.5: 0.5, to obtain 69 mg of the desired product. M.p. 175-190 ° C. Elemental analysis for Cj, H / j, NjO, S2 Calculated,%: 49.81 Found,%: 49.24
    Infrared Absorption Spectrum (cm, nudzhol): 1770-1970, 1715, 1670, 1615 ..
    NMR spectrum (ppm, DMSO - (,). 2.37 (3H, 5) i 2.43 (3N, 5); 3.40 (3N. 5), 3.6 (2H, b); 3.89 (3H, S) i 4.16 (1H, a,: 13Hg :), 4.36 (1H, d, a 13H2) i 5.06 (1H, 5); 5.67 (1H, D BH-g), 6.73 (2H, 3, 3 8.5H4); 7.30 (2H, d, 3 8.5Hg), 7.55 (1H, a, 3 9H2); 8.10 (1H ,}, and 9)), 8.99 (1H, 5).
    Example 3. 7 | - 0-2- {6,7-№oxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamido2 -7o, methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4 - carboxylic acid.
    A. 6,7- Dioxychromone-3-carbon 1 Chloride.
    A mixture of 888 mg of 6,7-dioxychromone-3-carboxylic acid and 25 ml of thionyl chloride is heated under reflux for 1 hour. From the reaction mixture, all unreacted embossed chloride is then removed from the reaction mixture. Benzene is added to the residue and the mixture is distilled. The residue is triturated with dichloromethane to obtain 719 mg of the desired product.
    Infrared Absorption Spectrum (cm, nudzhol): 1780, 1765, 1645, 1625.
    B. 7 ((6,7-DioxychromontZ-carboxamido) -2- (4-hydroxyphenyl) acetamido3 -7C-methoxy-3- (1-methyl-5-tetrazolyl) thiometyp) -Z-cephem-4-carboxylic acid.
    Salt 7p-B-2-amino-2- (4-hydroxyphenyl) acetamido -7o1, methoxy-3- (1-methyl-5-tetrazol1) thiomethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (150 mg ) is suspended in 7.5 ml of ethyl acetate and added to the suspension at 0 ° C with stirring. 41) μl of S, 0-bis (trimethylsilyl) acetamide. The resulting mixture (A) of dioxychromone-3-carboxylic acid chloride (58 mg) was added to the resulting mixture while stirring at 0 ° C. Once again, 417 µl of N, O-Bic (trimethylsilyl) acetamide was added and the whole was stirred at 0 ° C for 3 hours. After adding 150 ml of ethyl acetate to the reaction solution, the mixture was successively washed with 30 ml of 0.5N hydrochloric acid. acid, twice with distilled water and brine. An organic layer is separated from the mixture.
    dried over magnesium sulfate and the solvent is distilled off. The semi-so-pure residue is dissolved in acetone (30 ml) and left overnight at room temperature. After removing a small amount of insoluble matter by filtration, the solvent is distilled off. Ethyl ether is added to the residue to triturate the residue. Thus, after filtration, a target substance (105 mg) is obtained. M.p. 160-185 C (. Decomposition). Elemental analysis for
    Calculated,%: 48.94 3.54 13.78% 46.42% found 3.38 10.38
    IR center (cm, nudzhol): 17701780, 1710, .1665, 1615,
    NMR spectrum (ppm, daCO - d): 3.40 (3N, 5); 3.89 (3N, 5) -, 4.11 (1H, s}, O 13HZ), 4.34 (1H, d, J 13Hg) J 5.04 (1H, 5); 5.64 (1H, d, Q SH-i); 6.73 (2H, d, D 8.5 Ig), 6.97 (1H,), 7.29 (2H,
    a, 3 8,5ng); 7.39 (1H, S);
    8.95 (1H, S).
    PRI me R 4. 7 ((7,8-daoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) -acetamido-7c / 1-methoxy-3, - (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    A. 7,8-Dioxychromon-3-carbonyl chloride.
    7,8-Dioxychromone-3-carboxylic acid (6.6 g) is boiled in a mixture of 25 mp of thionyl chloride for 1 hour. The unreacted thionyl chloride remaining in the reaction mixture is distilled off and after adding benzene to the residue, the mixture is again subjected to distillation. N-Hexane is added to the residue to triturate the residue in
    powder. After filtration, 7.2 g of the expected product are obtained. . Infrared Absorption Spectrum (nudzhol): 1775, 1660, 1620.
    B. 7/3- D- (7,8-Dioxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamido3 -7o (, -methoxy-3- (1-methyl-5-tetrazolyl) thiomersh-3- cephem-4-carboxylic acid.
    Salt of 7-Co-2-amino-2- (4-hydroxyphenip) acetamido3-7L-methoxy-3- (1-metsh1-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (150 mg) suspended in 7.5 ml of ethyl acetate. While stirring, 417 µl of H, 0-bis (trimethyl) acetamide was added to this suspension at O ° C and 58 mg of 7.8-dioxichromone-3-carbonyl chloride obtained at A ° C and stirring was added to the resulting mixture. An additional 417 µl of N, O-Bic (trimethylsilyl) acetamide was added and the whole was stirred at 0 ° C for 3 hours. 150 ml of ethyl acetate was added to the reaction mixture. The mixture is washed successively in portions of 30 ml of 0.5 and. hydrochloric acid, distilled water (twice) and the above saline solution. The separated organic layer is dried over magnesium sulfate, and then the solvent is distilled off from it during the distillation. The residue is dissolved in 30 ml of acetone and left to stand at room temperature for 4 hours. A small amount of the separated insoluble matter is removed by filtration and the solvent is distilled off from the filtrate. The remaining material was triturated with ethyl ether to obtain 88 mg of a crude product. The latter is dissolved in a mixture of ethyl ether, acetone and methanol in a 1: 1: 1 ratio by volume. After removal of the insoluble material by filtration, the filtrate is concentrated and the remaining substance is triturated with ethyl ether. The obtained solid is washed with a mixture of ethyl ether, acetone and methanol in a volume ratio of 8: 1: 1. 21 mg of the desired product is obtained. M.p. 170-200 ° C (decomposition).
    Elemental analysis for
    CjgHijN O Si
    С Н N
    Calculated,%: 48.94 3.54 13.78 Found, 43.08 3.26 9.03 IR absorption spectrum (nudzhol): 1770-1780, 1710, 1665, 1615
    NMR spectrum (ppm), DMSO - f-: 3.40 (3N, 5); 3.90 (3N, 5); 4.13 (2H, d, J 13H7:), 4.34 (1H, d, 3 13H2); 5.05 (1H, 5); 5.64 (1H, (, 3 7Hz); 6.73 (2H, d, and 8.5Hz), 7.04 (1H, d, 1 9Hz); 7.30 (2H, a, 1 8.5Ng ;); 7.51 (1H, s, G)
     9H7:) i 8.91 (1H, S).
    Example 5. 7 ((6,7-Dioxychromon-3-carboximido) -2-phenylacetamido3 -7o-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid and its sodium salt.
    A. (6,7-Dioxychromone-3-carboxamido) -2-phenylacetamido-7o, methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid.
    7p- (B-2-amino-2-phenylacetamido) -7C6-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid salt and three toroacetic acid (700 mg) are suspended in ethyl acetate (35 ml). 2.2 ml of M, 0-bis (trimethylsilyl) acetamide (2.2 ml) are added to this suspension while stirring at 0 ° C and stirring. After 10 minutes, 305.5 mg of the obtained (A) 6,7-dioxychromone-3-carbonyl chloride was added. The mixture is stirred for 1 hour at 0 ° C and then for 2 hours at 15 ° C.
    700 ml of ethyl acetate was added to the reaction mixture, and the entire amount was sequentially washed in portions of 140 ml of 0.5 and. hydrochloric acid, distilled water (twice) and a saturated aqueous solution of sodium chloride. The separated organic layer is taken up and dried over magnesium sulphate. The solvent was then removed from the mixture and the residue was dissolved in acetone (70 ml), and the solution was left at room temperature overnight. The solvent is distilled off, from the solution, the residue is ground to powder with ethyl ether. The solid mass is washed with a mixture of ethyl ether, acetone and methanol in a ratio of 9: 0.5: 0.5 by volume. 181 mg of the expected product are obtained. M.p. 200250 C (decomposition).
    Elemental, analysis for
    C HjjN-jO jS
    С Н N
     Calculated,%: 54.46 3.94 6.57 Found, 48.85 3.73 6.83 IR absorption spectrum (cm, nujol): 1780, 1730, 1710, 1665, 1635. NMR spectrum ( ml. shares, 7IMCO - d):
    2.00 (3N, 5); 3.18 (1H, d, 3 18Hz)
    3.41 (3N, 5); 3.52 (1H, d, J
     18H2); 4.60 (1H, d, 3 13H);
    4.90 (1H, d, J 13H2;); 5.11 (1H,
    3); 5.81 (1H, d, and 7.5 H-),
    6.98 (1H, 5); 7.1-7.6 (5H, 1p);
    7.40 (1H, 5) -, 8.86 (1H, 5).
    B. Natrium salt obtained (A)
    carboxylic acid. 11.10 The obtained (A) carboxylic acid (30 mg) is dissolved in 1.2 ml of tetrahydrofuran. 94 µl of a 0.5 M solution of 2-ethylhexanoic acid sodium salt in tetrahydrofuran is added to the solution with stirring. The precipitate formed is separated by filtration and washed with tetrahydrofuran. Thus, 24 mg of the desired product is obtained. Mp 200-230 ° C. (decomposition). Elemental analysis for C2, H24N NaO.S C H N Calculated,%: 52.65 3.66 6.35 Found,%: 48.84 3.56 5.60 IR absorption spectrum (cm, nujol): 1765, 1730, 1665, 1610,1630. NMR spectrum (ppm, DMSO-d,) 1.99 (3N, 5), 2.96 (1H, d, J 17H7;), 3.43 (3N, 5); 3.50 (1H, d 3 17Xx); 4.67 (1H, d,: 12H7) 4.86 (1H, d, J 12H2); 4.95 (1H, 5); 5.86 (1H, d, D 7.5H2); 6.97 (1H, 5), 7.37 (1H, S), 7.1-7.7 5H, gp); 8.83 (1H, 5). B. The disodium salt of the obtained (A) compound, i.e. sodium salt 7p) (6-hydroxy-7-sodium oxychromone-3-carboxamido) -2-phenylacetamido-7 (i-labels si-3-acetoxymethyl-3-cephem-4-carboxylic acid. Received (A) compound (30 mg) dissolved in 0.6 ml of dimethyl forms-i. 282 µl of a 0.5 M solution of sodium salt of 2-ethylhexanoic acid in dimethylformamide is added to the resulting solution with stirring. The resulting solution is dropwise added dropwise in 7 ml ethyl acetate The precipitate formed is filtered and washed with ethyl acetate to obtain 20 mg of the expected product. mp 200-230 ° C (decomposition). Analysis for C2qH28N Na20 2S CHN. Calculated,%: 50.95 3.39 6.15 Found, 47.17 3.78 5.34 IR absorption spectrum (cm, nudzhol): 1765, 1730, 1665, 1610-1630. NMR spectrum (ppm, DG-1SO-g): 1.98 (3N, 5), 2.92 (1H, d, O 17H), 3.38 (1H, d,: i 17 H2;); 3.42 (IH, 5) -,, 68 (IH, d .3 12H2 :); 4.82 (1H, d, :) 12H) V 4.92 (IH, 5) -, 5.84 (IH, d, 3, 8Hz); 6.04 (IH, S); 6.94 (1H.5) 7.2-7.7 (5H, Wo), 8.54 (1H, 6), 9 The compounds of examples 6-12 were prepared analogously to examples 1-5. Example 6. (7,8-Dioxychromone-3-carboxamido) -2-phenyl-acetamido-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid. Vkod 18%, so pl. 200-240 ° C (decomposition). Elemental analysis for C2C) C H Calculated,%: 54.46 3.96 6.57 Found,%: 52.75 4.01 6.23 IR absorption spectrum (cm, nujol): 1775, 1735, 1715, 1670 , 1620. uChMR spectrum (min. Lobes, DMSO -dj,): 2.00 (3N, 5), 3.19 (1H, d, J 18Ht); 3.42 (3N, 5); 3.52 (1H, d ,: 18a2); 4.6i (IH, d,: $ 13H2;); 4.88 (IH, d, :) i8fl); 5.11 (IH, 5); 5.81 (IH, d, 3 7.5H2); 7.03 (IH, d, 3 B, 5.Ez} 7.1–7.6 (6H, m); 8.93 (1H, 5). Example 7. (5-MeTOX psychromon-3-carboxyamido) - 2- (4-hydroxyphenyl) acetamido - 7a |, methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid. Yield 57%, mp. 170-195 C ( decomposition) Elemental analysis for cN Calculated,%: 50.77 Found,%: 48.78 IR absorption spectrum (cm, nujol): 1770, 1730, 1670, 1620. NMR spectrum (ppm, DMSO -dg ): 3.40 (3H, 5) J, 3.90 (6H, 5), 4.10 (1H, j, 11 13H), 4.36 (1H, d, 3 13Hz); 5.07 (1H , 5), 5.64 (IH, (3 L 7.5H) -, 6.75 (2H, d, 3 8.5 Ng); 7.08 (IH, d, 3 8H2), 7.20 ( IH, d, 3 8H) -, 7.30 (2H, d, J 8.5H2) i - 7.76 (IH, 1.0 8H2), 8.85 (IH, S). Example 8. Sodium salt 7A-b-2- (5-methoxychromon-3-carboxamido) -2- (4-hydroxyphenyl) ac tamido-7Ы methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid. 88% yield, mp 200-230 ° C (decomposition). Elemental analysis of СНN Calculated,% : 49.24 3.58 13.40 Found: 49.01 3.64 12.56 IR absorption spectrum (, nujol): 1760, 1670, 1610. NMR spectrum (ppm, DMSO-C3) 3.41 (ZN, b), 3.89 (ZN, 6), (ZN, S); 4.25 (2n, Tr., 6); 4.88 (1H, 5); 5.68 (1H, d, 3 7H2) v 6.75 (2H, d, L 8.5Hg), 7 ,, d, d), 7.21 (1H, d:}), 7.30 (2H , d, j 2.5Hg); 7.77 (1H, t,: j 8Hg), 85 (1H, S P p and m ep 9. (XpoMOH-3-carboxamido) -2- (4-hydroxyphenyl) ace tamido-7o-methoxy-3- ( 1-methyl-5-tetraeolyl) thiomethyl-3-cephem-4-carboxylic acid. Yield 34%, mp 175-200 ° C (dilution) Elemental analysis for CjHHj, S, .CHN Calculated,%: 51.24 3.71 14.73% found: 49, J2 3.90 11.62 IR absorption spectrum (cm, nudzhol): 1770-1790, 1710, 1665, 1615. 51 MM spectrum (ppm, D10-) 3.40 (3H, S); 3.90 (3N, 5); 4.13 (1H, d, 3 13Hg), - 4.36 (1H, ci, and 13H2), 5.06 ( 1H, 5), 5.68 (1H, d, L 7 Hz), 6.75 (2H, d, L 8.5 HZ); 7.31 (2H, d, J 8.5 H2); 7.4 -8.1 (3H, m), 7.18 (1H, kti, d, SHj), 9.04 (1H, S). Example 10. (6-Nitr Chromone-3-carboxamido;) - 2- Fensh1atseta DCH1 «® ° 3 ЗЦ ° ™ -cephem-4-carboxylic acid slots. C (Yield times 56%, mp 140-150) Elemental analysis for C2uHj NO Calculated,%: 52.50 Found,%: 52.01 IR absorption spectrum): 1775, 1740, 1720 , 1670, 1620. NMR spectrum (ppm, daCO -d) 2.00 (3N, 5); 3.21 (1H, d, 3 18H2), 3.43 (3H, S), 3.54 (W, d, 3 18Hz); 4.63 (IH, d, 3 13Hg), 4.92 (IH, d,; GZNd), 5.14 (IH, S), 5.86 (IH, d, L 7.5H); 7.2-7.7 (5H, Yn), 8.05 (IH, d, 3 - 9H2) -, 8.66 (IH, a., L 9Hg, 2.5 Hz); 8.87- (1H, jj,: i 2.5H), - 9.13 (IH, 5). Example 11. (7-Chloro-chromone-3-carboxamido) -2-phenylacetoimidoJ-7o (, methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid. Yield 41%, mp. 150-165 ° C ( decomposition) Elemental analysis for Cj H24C1N30, oS Calculated,%: 54.25 Found,%: 53.63 IR absorption spectrum): 1770-1790, 1730, 1710, 1700, 1670, 1605. NMR spectrum (million Shares, DMSO -.d): 2.01 (3N, S); 3.21 (1H, d, 3 18H2); 3.44 (3H, 5.) -, 3.53 (1H, d, 3 18H2); 4.64 (in, d, 3 1 st); 4.92 (1H, d, 3 13Нц); 5.13 (1H, 5), 5.84 (1H, d, 3 7.5H2); 7.1 - 7.9 (6H, m); 8.2 (lH, d, 3 2 Hz) i 8.20 (IH, d, a 8.5 H); 9.05 (IH, 5). Example 12. (7-Benzsh1oxy-8-methylchromone-3-carboxamido) -2-phenylacetamido) -7o (.- methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid. Yield 46%, so pl. 145 -170 ° C (decomposition) Elemental analysis for CjTH NjOllS CHN Calculated: 61.06 4.75.77 Found: 60.28 4.455.70 IR absorption spectrum (cm, nujol): 1780, 1740, 1725, 1705 , 1665, NMR spectrum (ppm,, TMSO-d): 2.01 (3N, 5); 2.34 (3N, 5) i 3.21 (1H, d 3 18H2); 3.44 (3N , 5), 3.54 (1H, d,: 18H2), 4.6D (1H, d, J PN ,;), 4.92 (1H, (3.3 13Hz) i 5.13 (1H, 5 ); 5.36 (2H, 5), 5.84 (1H, d, 3 7.5 HZ); 7.2 7, 7 (11H, m), 9.03 (IH, S): Example 13. 7 ((6,7-Dioxy-3-carboxamido-2- (4-hydroxy-1) -acetamido-7O6-methoxy-3-acetome simethyl-3-cephem-4-carb Novoic acid. 7y-P-2-amino-2- (4-hydroxy-fephenyl) acetamido-7o salt (, methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (680 mg) are suspended in tetrahydrofuran (25 ml). To this suspension was added 1.33 ml of H, 0-bis (trimethylsilyl} acetamide and the mixture was stirred at O - C. After 10 minutes, 1.51095 289 microns of 6.7-dioxychromone were added to the suspension 3H-carbonyl chloride as in Example 3 (A) and the suspension is further stirred for 2 hours at the same temperature. The reaction mixture is concentrated, s approximately to a volume of 10 ml, and the concentrate is drunk in 100 mp 0.5 n. hydrochloric acid at 0 ° C. The precipitate formed is collected by filtration and washed with water, dissolved in 100 ml of 10 tetrahydrofuran, and the solution is dried over magnesium sulfate. It is then concentrated to approximately 10 ml and poured into 100 ml of ethyl ether. The resulting precipitate was collected by filtration and dried, yielding 294 mg of the desired product. The solvent was removed from the filtrate by distillation and a mixture of tetrahydrofuran and ethyl ether (0.2: 9.8) 20 was added to the residue to triturate to obtain 102 mg of the intended product. Just get 396 mg of the target product. M.p. 250® C (decomposition). Elemental analysis for C ,, H25NjO, C H N Calculated,%: 56.33 3.58 5.97 Found, 51.78 3.90 6.22 IR absorption spectrum (n / h 301zhol): 1770, 1720, 1710, 1615-1650. NMR spectrum (ppm, DMSO-b): 2.01 (3N, 5); 3.21 (1H, Lg-, a, 3 18H2); 3.42 (3N, 5); 3.54 (1H, «i, 3 l8 Hz), 4.62 (1H, d, L 13H2g), 35 4.90 (1H, d, 3 13Hg); 5.10 (1H, 5); 5.67 (1H, d, 3 7.5Hz :); 6.74 (2H, 3, 3 9Hz)., 6.98 (1H, 5) i 7.31 (2H, (3. 3 9Hg); 7.40 (w, s) -, 3.86 (1H , S) .40 Example 14. (7,8-Dioxychromon-3-carboxyl-idb) -2- (4-hydroxyphenyl) acetamido-76-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid .45 Salt 7y- in 2-amino-2- (4-hydroxyphenyl) acetamido -7O1, -methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (230 mg) are suspended in 7 mg of tetrahydrofuran 50 and to this suspension is added 454 µl of H, 0-bis (tri-methylsnyl) acetade-HадаD are added with O C. stirring. After 10 minutes, 98 mg of the acid chloride obtained in Example 4 (A) are added and 55 mixing is continued until for 2 hours at the same temperature. The reaction mixture is concentrated to approximately 3 ml and the concentrate is added to 0.5N hydrochloric acid (30 ml) at about 0 ° C. The precipitate formed is collected by filtration, washed with water and dried. the powder is thus washed with a mixture of tetrahydrofuran and ethyl ether (0.2: 9.8), then with ethyl ether and dried, to give 153 mg of the desired product. M.p. 220-260 С (decomposition). Elemental analysis for C, H CsO, CZ c H N Calculated,%: 56.33 3.58 5.97 Found, 55.91 3.52 5.67 IR absorption spectrum (cm, nudzhol): 1770 , 1725, 1710, 1660, 1615. NMR spectrum (ppm, DMSO - dg) 2.00 (3N, 6); 3.42 (3N, 5); 4.61 (1H, d, 3 13Нг), 4.9С (1H, d, 3 ПН); 5.09 (1H, 5), 5.66 (1H, d, O 7.5Hg); 6.73 (2H, d, 3 8.5Hg); 7.04 (1H, d, 3 8.5К5;) ;. 7.30 (2H, d, D 8.5H2;); 7.51 (1H, a, 3 8.5 N). Example 15. (6,7-Dioxychroms-3-carboxam 1do) -2- (4-hydroxy- "phenyl) acetamide-7O6-methoxy-3- (1-methoxycarbonylmethyl-5-tetrazolsh1) -thiometnl-3-cephem- 4-carboxylic acid A. Lithium methylate (133 mg) is dissolved in 4 ml of methanol and 14 ml of tetrahydrofuran at room temperature under argon and the resulting solution is cooled to -74 ° C. 7 | 3-c-2-tert-Butoxycarboxamido- .- 4- ( 2-tetrahydropyrannl) oxyphenyl acetamide-3- (1-carboxymethyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid, dibenzhydryl ether (1.009 g) was dissolved in 3.5 ml of tetrahydrofuran and the resulting solution was added to the indicated lithium methylate solution under argon with stirring. The components are reacted for 15 minutes, at which time the temperature is maintained at -74 ° C, then 1 ml of acetic acid is added. The reaction mixture was added to 200 ml of chloroform and 50 ml of 5% aqueous sodium bicarbonate solution and stirred. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate, then with water and with a saturated aqueous solution of sodium chloride. This layer was dried over magnesium sulfate, and the solvent was removed by distillation. The residue is purified by chromatography on a column of silica gel, using an eluting solvent comprising ethyl acetate and benzene in the ratio of 15:85, to give 549 mg of the expected product. Infrared Absorption Spectrum (, nud, zhol):, 1750, 1680, 172P. B. Benzhydryl ether 7R-D-2- (tert-butoxycarboxamido) -2-34- (2-tetrahydropyranyl) oxyphenyl ac tamido -7o (, methoxy-3- (1-methoxycarbonyl-5-tetrazolyl) thiomethyl-3- cephem-4-carboxylic acid. Dissolve in 7 ml of methanol and 14 tetrahydrofuran, 239 mg of lithium methylate at room temperature under argon atmosphere. In 4.8 ml of tetrahydrofuran dissolve 1.595 g of the obtained compound (A) and add the solution for 1 min under argon into the resulting solution of lithium methylate, cooled to -75 ° C, with stirring. Then, dropwise with stirring, 2 79 µl of tert-butyl hypochloride Continue stirring for 15 minutes at -75 s, then t, 5 ml of acetic acid is added. The reaction mixture is added to 200 ml of chloroform and 50 ml of 5% aqueous sodium bicarbonate solution. The organic layer is washed With a 5% aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride. This layer is dried over magnesium sulphate and the solvent is removed by distillation. The residue is purified by chromatography on a column of silica gel, using an eluting solution comprising ethyl acetate and benzene in a ratio of 20:80. 872 mg of the expected product are obtained. Infrared Absorption Spectrum (cm, nudzhol): 1780, 1750, 1670-1720. B. Salt 7A-in-2-amino-2- (4-hydroxy-1) acetamido-7-C-methoxy-3- (1-methoxycarbonylmethyl-5-tetrazolyl) thiomethyl-3-cephem-4carboxy 6th acid and trifluoroacetic acid. , 150 mg of the obtained compound (B). To the mixture are added 2.5 ml of trifluoro 1188 hydrochloric acid and 1 ml of anisole cooled to C with stirring. Stirring is continued at 0 ° C for 4 hours and the reaction mixture is added to 50 ml of a mixture of ethyl ether and n-hexane (1: 1) with stirring. The precipitate formed is collected by filtration, washed with ethyl ether and dried, to give 118 mg of the desired product. Infrared Absorption Spectrum (cm, nudzhol): 1760, 1705, 1690, 1675, 1640, 1610. G. (6,7-Dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamideJ-7o - methoxy-3- (1-methoxycarbonylmethyl-5-tetrazolyl) -thiomethyl-3-cephem-4-carboxylic acid. The resulting (B) compound (21 mg) is suspended in 1 ml of tetrahydrofuran | And K, 0-bis (trimethylsilyl) acetamide is added to the suspension with stirring. After stirring for 10 minutes; 7.5 mg of the acid chloride prepared in Example 3 (A) and stirring is continued for another 2 hours. nprf 0 C. Then the reaction mixture is added to 10 ml of 0.5N. hydrochloric acid with OS. The precipitate formed is washed with water and dried. The powder formed is washed with a mixture of tetrahydrofuran and ethyl ether (0.2: 9.8) and then with ethyl ether and dried to obtain 20 mg of the target m.p. 200-230 0 (degraded product, ing). Elemental analysis for C N Accepted,%: 48.37 3.54 Found, 48.42 3.48 IR absorption spectrum (cm): 1765, 1720, 1705, 1666, 1615, 1609. NMR spectrum ( ppm LMSO-s): 3.40 (3N, 5); 3.71 (3N, 5); 4.14 (1H, d, L 12H2); 4.42 (1H, CI 12H), 5, C1 (1H, 5); 5.44 (2H, Dg, 5), 5.65 (1H, 3, 3 8H, j); 6.72 (2H, d, J 8Hz); 6.97 (1H, S); 7.28 (2H, d, 3 H) 7.39 (1H, 5)} 3.85 (1H, 6 Example 16. (6.7 Bis (ethoxycarbonyloxy) chromone-3-caroxamido) -2- (4-hydroxyphenyl ) acetamido) 7 ° C methoxy-3- (1-methoxycarbonylmethyl 5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid.
    A.6,7-Bis (ethoxycarbonyloxy) chromone-3-carbonyl chloride.,
    6,7-Bis (ethoxycarbonyloxy) chromone-3-carboxylic acid (1.1 g) was dissolved in 20 ml of benzene and 2 ml of thionyl chloride was added dropwise at room temperature while stirring. The mixture is then heated under reflux with stirring. The reaction mixture is concentrated and n-hexane is added to the concentrate in order to cause it to crystallize. The resulting crystals are collected by filtration, passed through with n-hexane and dried, to give 980 mg of the desired product. M.p. 89-92 S.
    B.7 (, 7-Bis (ethoxycarbonyloxy) chromone-3-carbox dimo-2- (4-hydroxyphenyl) acetamido T (-7 (1-methoxy- - (1-methoxycarbonylmethyl-5-tetrazolyl) thiomethyl-3-cephem-4 - carboxylic acid.
    The compound (34 mg) obtained in Example 15 (B) was suspended in 1 ml of tetrahydrofuran, and 56 µl of K, 0-bis (trimethylsilyl) acetamide was added to this suspension at 0 ° C and with stirring. After 10 minutes of stirring at 0 ° C, 19.2 mg of the obtained (A) acid chloride is dissolved in 1 ml of tetrahydrofuran and stirring is continued for another 2 hours at 0 ° C. Then the reaction mixture is concentrated to -O, 5 ml and the concentrated solution is poured into ice-cooled 0.5 n. hydrochloric acid (10 ml). The precipitate formed is isolated by filtration, washed with water and dried. The resulting material was dissolved in tetrahydrofuran (0.5 ml). This solution is added to 20 ml of ethyl ether with stirring. The precipitate formed is separated by filtration and washed with a mixture (2%) of tetra: hydrfuran-ethyl ether and then with ethyl ether, followed by drying j to obtain 32 mg (yield 73%) of the desired product. M.p. 140-170 ° C (decomposition) ..
    Infrared Absorption Spectrum (cm, nudzhol): 1750-1790, 1665, 1610.
    5GMR spectrum (ppm, DMSO-d): 1.34 (6H,., 3 THj); 3.42 (3H, S) 3.72 (3N, 5), 1-.5 (6H, W);
    5.00 (1H, 8); 5.40 (2H, Lg, S; 5.66 (1H, d,: J 6.5Hg), 6.72 (2H, (3.3 VH) -, 7.29 (2H, a, 3 8H. d);
    7.99 (1H, 5); 8.14 (1H, 5) $ 9.03 (1H, b).
    Example 17. Sodium salt of (6,7-bis (ethoxycarbonyloxy) chromone-3-carboxamido) -2- (4-hydroxyphenyl) -acetamido 3 -7-6-methoxy-3- (1-methoxycarbonylmethyl-5-tetrazolyl) -thiomethyl-3 cepheme-4-carboxylic acid.
    The compound (13 mg) obtained in Example 16 was dissolved in a mixture (0.4 ml) of tetrahydrofuran and ethyl acetate in a volume ratio of 1: 1. To this solution, 28 µl of a 0.5 M solution of sodium salt of 2-ethylhexanoic acid in tetrafidrofuran and then 2 ml of ethyl ether are added. The precipitate formed is isolated by filtration and washed with a mixture of ethyl acetate and ethyl ether in a 1: 1 ratio by volume and ethyl ether. After drying, 12 mg of the uie product is obtained. M.p. 170-210 ° C (decomposition).
    Infrared Absorption Spectrum (cm, nudzhol): 1730-1790, 1660, 1615.
    NMR spectrum (ppm), DMSO-J: 1.31 (6H, i, 3 7H2); 3.42 (311.6); 3.71 (3N, 5), 4.1-4.5 (6H,); 4.84 (1H, 5), 5.35 (.H, Zr, 5), 5.68 (1H, d, E 7Hz); G, 71 (2H, d, 3-8.5 HZ), 7.30 (2H, d, 3 8.5Hz), 7.97 (1H, 5); 8.14 (1H, 5); 9.02 (1H 5).
    Example 18. (6,7-Bis (ethoxycarbonyloxy) sromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-7C-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid.
    Sol 7 / i- | D-2-amino-2- (4-hydroxyphenyl) acetamido -7O6.-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (226 mg) are suspended in 7 ml of tetrahydrofuran. While stirring, the suspension is added at 0 C with 445 µl of S, 0-bis (trimethylsilyl) acetamide. After stirring for an additional 10 minutes at 0 ° C, 154 mg of 6.7-bis (ethoxycarbonyloxy) chromone-3-carbomyl chloride, dissolved in 4 ml of tetrahydrofuran, are added to the mixture, and the whole is stirred for 2 hours at comp. natal temperature. The reaction solution is concentrated to 3 ml and the concentrate is poured into 30 ml of 0.5 n. hydrochloric acid solution. The precipitate which separates out is separated by filtration, washed with water, dried and washed successively with ethyl ether, 2% tetrahydrofuran solution in ethyl ether and again with ether, followed by distillation. 261 mg of product are obtained (yield 82%). M.p. 220 C (decomposition). Infrared Absorption Spectrum (cm., Nujol): 1760-1780, 1660-1680 and 1615. Nuclear Magnetic Resonance Spectrum (mr.dol, DMSO -dfiOs f, 30 (6H, i, 3 7Hg) i 2.00 (NN, 5) 3.42 (3N, 9), 4.31 (2H, g-.a "AH, 4.32 (2H, d, 3 7H: i), 4.62 (1H, d, - ISH ,; ); 4.90 (1H, 3 3Нг :), 5.10 (1H, 5); 5.70 (I d, 3 7H2;), 6.74 (2H J, 3 7.5H2), 7, 31 (2H, d, L 7.5H), 8.04 (1H, 5)} 8.17 (1H, 5), .9.05 (1H, S). Example 19 (6 , 7-bis (2,2,2-trichloroethoxycaronyl)) chromone-3-carboxayado) -2- (4-hydroxyphenyl) acetamidoJ - 7 i6-Me current si-3 - (1-metip-5-tetrazolyl) thiomethyl- 3-cephem-4 carboxylic acid. A. 6,7-Bis (2,2,2-trichloroethoxycarboxypoxy) -chromone-3-carbonyl chloride. 57.3 mg 6,7-bis (2,2,2 trichloroethoc sicarbonyloxy) -chromone-3-carboxylic acids The solution is dissolved in tO ml of benzene. To this solution, 0.5 ml of thionyl chloride is picked up at room temperature and under stirring. The cia mixture is kept under reflux with stirring for 3 hours and the reaction solution is concentrated. To the concentrate is added 5 ml of n -hexane in order to induce crystallization of the reaction product. The resulting product is filtered and washed with n-hexane, then dried. Thus, 34.8 mg of the expected product is obtained. M.p. 140-142 C. B. (6,7-Vis (2,2,2-trichloro-ethoxycarbonshuksi) chromone-3-carboxasado) -2- (4-hydroxy-1) acetamidoZ. -methoxy-3- (1-methyl-5-tetrazol1) thio-methyl-3-cephem-4-carboxylic acid. Salt of 7B-Gv-2-amino-2- (4-hydroxyphenyl) adhetamido-7c-methoxy-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4gcarboxylic acid and trifluoroacetic acid (62 mg) is suspended in 2 ml of tetrahydrofuran. To the suspension thus obtained, 111 µl of H, 0-bis (trimethylsiyl) acetamide was added with O ® C under stirring. (The mixture was stirred at 0 ° C for another 10 minutes. To this mixture was added 1,922 obtained (A) solution of acid chlorohydride (59.1 mg) in 1 ml of tetrahydrofuran, and the whole was stirred at 0 ° C for 2 hours. The reaction solution was concentrated to 1 ml and poured into 20 ml of ice-cold 0.5 N hydrochloric acid. The precipitate was filtered in, washed with water and dried, the dry substance was washed with 2% tetrahydrofuran solution in ethyl ether, then with ethyl ether and dried again. 100 mg of the desired product are obtained (yield 94%). Mp. elemental analysis for C ,, 5S2 С H Calculated,%: 39.56 2.56 Found,%: 39.35 2.5P IR absorption spectrum (cm, nudzhol): 1740-1790, 1710, 1670, 1660, 1610. NMR spectrum (ppm, DMSO): s, 41 (3N, S)} 3.89 (3N, 5), 4.12 (1H, J-, 3 14H7); 4.36 ( 1H, 3, 14H2); 5.03 (1H, §);. (2H, Sfc); 5.09 (2n, 5); 5.67 (1n, j, 3, 6.72 (2H, d , L 8.5H);, 7.29 (2H, d, 3 8.5H2), 8.13 (1H, S), 8.28 (1H, 5); 9.05 (1H, 5). Example 20. 7 | -fD-2- 6,7- Bis (2,2,2-trichloroethoxycarbonyloxy) chromo n-3-carboxamides) / - 2-phen1-acetamido-76-methoxy-3-acetoxymethyl-3-cephem 4-carboxylic acid. Salt 7Y- (P-2-amino-2-phenylacetamUto) -7O1-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (22 mg) are suspended in 1 ml of tetrahydrofuran. To the suspension at 43 ° C, 43 µl of S, O-bis (trimethylsyl1) acetamide was added with stirring, which was continued for another 2 minutes. To this mixture was added 23.7 mg of 6.7-bis (2,2,2-trichloroethoxycarbontox) chromone-3-carbonyl chloride, dissolved in 0.5 ml of tetrahydrofuran, and the whole amount was further stirred for 2 hours at 0 ° C. Reaction solution concentrated to 0.5 ml and drunk in 10 ml of ice-cold 0.5 n. hydrochloric acid. The precipitate introduced is filtered, washed with water and dried. The dry precipitate is washed with 2% tetrahydrofuran solution in ethyl ether, then ethyl. ether and
    dried. 7 mg of the desired product is obtained. M.p. 160-240 0 (decomposition).
    IR (cm, nudzhol): 1780, 1710 ,. 1740, 1660, 1610.5
    NMR spectrum (ppm, DMSO-d): 2.00 (3N, 5), 3.41 (3N, 6 U-, 4.62 (1H, A, THHr), 4.90 (1H, d, 3 HH), 5.09 (5H, b, 5), 5.84 (1H, d, :) 7.5 Hz); 7.2-7.5 °
    (5n, m); 8.15 (1H, S); 8, zo (1H, S)
    9.06 (1H, 5).
    Additional compounds of Examples 21-23 were prepared analogously to Examples 16-20.5.
    Example 21. (6,7-Bis (2,2,2-trichloroethoxycarbonyloxy) chromone 73-carboxamido) -2- (4-hydroxyphenyl) acetamido-7-6-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid. T. pl. 210-230 ° C (decomposition).
    Elemental analysis for
    , сНеНЗО ,, 8
    Calculated,%: 41.77 2.70 4.18 Found,%: 41.72 2.70 4.36
    Infrared Absorption Spectrum (cm, nudzhol): 1780, 1765, 1660-1680, 1615.
    NMR spectrum (mpn. Share, DMSO-s}): 0
    2.00 (3N, 5); 3.41 (zn,); 4.62 (1h, s,: j - gzng); 4.90 (1H,
    (1.3 13Hg), 5.1 (5H, Lg, 5); 5.70 (1H, CJ, 3 7Hz) v 6.73 (2H, d. 3 g 8.5H2) -, 7.31 (2H, d, 3 8.5H2), 35 8.16 (1H, 5 ); 8.30 (1H, 5) i
    9.07 (1H, 5).
    Example 22. (6,7-Bis (2,2,2-trichloroethoxycarbonnepoxy) chromone-3-carboxamido) -2- (4-hydroxy-40 phenyl) acetamido-7o-methoxy-3- (1-methoxycarbonylmethyl-5- tetrazol1) thiomesh1-3-cephem-4-carboxylic acid. M.p. 155-180 with (decomposition).
      .. -. 45
    Elemental analysis for
    ..
    CHN
    Calculated,%: 39.86 2.61 8.75 Found, 38.91 8.17; IR absorption spectrum (cm, nudzhol): 1780, 1765, 1750, 1660.
    NMR spectrum (ppm, DMSO-Jg) 3.42 (3N, S.); 3.72 (3N, 5), 4.15 (1H, d, 3 1447.); 4.43 (1H, a. 3 14H); 5.00 (1H, 5 U; 5.06 (2H, S) -, 5.08 (2H, S); 5.39 (2H, Zr, S); 5.67 (1H, i, 3 7H) ; 6.72 (2H, d, 3 8.5H2); 7.30 (2H,
    c), 3 8.5H2), 8.12 (1H, 5),
    8.27 (1H, 6), - 9.05 (1H, 5). Example 23. (6,7-Bis (ethoxycarbonyloxy) chromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido3-7-methoxy-3- (1-carboxy-"tyl-5-tetrazolp) thiomethyl-3- cephem-4-carboxylic acid. M.p. 155 230 C (decomposition).
    Infrared Absorption Spectrum (cm, nudzhol): 1740-1790, 1665, 1610.
    NMR spectrum (ppm, DMSO-3); 1.32 (6H, i,: i 7H) i 3.42 (3N, 5); 4.05-4.55 (6H, m)} 5.00 (1H, 5);
    5.28 (2H, LP, 5); 5.67 (lH, d,
    : 6.5Hx) i 6.71 (2H, d., 3 "8Hg),
    7.29 (2H, d, -J - 8H); 7.99 (1H, 6) 8, 15 (1H, 5), 9.03 (1H. 5).
    Example 24. 7 | 5-yO-2- (6,7-Dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-7O1-methoxy- (1-ethyl-5-tetrazolyl) thiomethyl-3-cephem -4-carboxylic acid.
    Salt 7 | - B-2-a in72- (4-hydroxyphenylacetamido-Z-7o (, -methoxy-3- (1-ethyl-5-tetrazolyl) thioethyl 1-3-cephem-4-carboxylic acid and trifluoroacetic acid (127 mg)) are suspended in ethyl acetate 7. To the resulting suspension is added dropwise {1,0-bis (trimethylsilyl) acetamide (346 µl) at 0 C and stirring, which is continued for 20 minutes at. 48 mg of 6,7-dioxychromone are added -3-carbonyl chloride and the whole mixture is stirred for 2 hours at 0 ° C. To the resulting reaction liquid, 150 ml of ethyl acetate are added and the organic layer separated from the liquid, after washed with portions of 30 ml of 0.5 and hydrochloric acid and distilled water (3 times), dried over magnesium sulphate and the solvent removed from the organic layer by distillation. The remaining substance is dissolved in 30 ml of acetone and the solution is left in overnight. The solvent is distilled off from it and the residue is solidified by adding ethyl ether. The solid is collected, washed with a mixture containing ethyl, acetone and methanol (9: 1: 1). Upon drying, 41 mg of the desired product is obtained. M.p. 205207 С (decomposition).
    Infrared Absorption Spectrum (cm, nudzhol): 1760, 1660, 1610, 1515. Nuclear Magnetic Resonance Spectrum (mpd.dol, DMSO — dg): 1.38 (3N, i, :) SHj;); 3.42 (3N, S) 4.27 (2H, O,: 8H2); 5.02 (1H, 5) 5.66 (1H, d, 1 8Hz); 6.75 (2H, d, - 8Hj); 6.96 (1H, 5) J 7.32 (2H, cj, 3 - BHg); 7.39 (1H, 6); 8.82 (1H S). Example 25. (6,7-flH oxichromone-3-carboxamido) -2- (4-hydroxy-phenyl) acetamides-7C-methoxy-3- (1-carboxymethyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid . Salt 7A-B-2-amino-2- (4-hydroxyphenyl) acetamido-7C-methoxy-3- (1-carboxymethyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid and trifluoroacetic acid (301.2 mg) suspended in 15 ml of tetrahydrofuran. To this suspension, 503 µl of N, 0-Bis (trimethylsilyl) acetic acid at 0 ° C and stirring are added. The mixture is stirred for 20 minutes at room temperature, followed by cooling to 0 ° C. To this mixture is then added 109.1 mg of the acid chloride obtained in Example 3 (A), the Hj3ce amount is stirred at and for 2 hours. The reaction solution concentrated to approximately 7 ml and the concentrate is drunk in 50 ml of 1N. hydrochloric acid in a mixture with 100 ml of ice-cold water. The resulting precipitate was isolated by filtration, followed by washing with water. The product is dissolved in 100 ml of tetrahydrofuran and the solution is dried over magnesium sulphate. The solution is concentrated to approximately 5 ml. The concentrate is poured into 100 ml of ethyl ether. The precipitate formed was collected by filtration, followed by drying, in order to obtain 203.6 mg of the target product. In addition, 40.6 mg of the desired product is isolated from the indicated filtrate. The melting point, IR absorption spectrum and NMR spectrum of the compound were consistent with those for the compound of Example 15. I The compounds obtained in the examples were tested for antimicrobial activity in vitro. The results are shown in the table (the compound of Example 5 is selected and used as a free carboxylic acid, as in Example 5A).
    1.56
    0.4 3.13
    1.56 0.4
    3.13
    3.13 3.13
    3.13 0.8
    6.25 3.13
    0.4 12.5
    0.4 3.13
    3.13 1.56
    0.4
    6.25
    0.8
    3.13
    0.8
    50
    50 0.8 0.4
    27
    28
    1095879 Continuation of the table
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of cephalosporin of the formula I
    Rj 0Rj -CH-CORH OCHj $ f o tj ^ LcH r Ri R t COOK where Rj is an acetoxy group or tetrazole
    -5-ylthio group substituted at position t with methyl, ethyl, carboxymethyl or methoxycarbonylmethyl}
    R 2 is hydrogen or an oxy group ', R 3 - R & - independently from each other is hydrogen or chlorine, methyl, hydroxy, acetoxy, methoxy, benzyloxy, nitro, ethoxycarbonyloxy or trichlorooxycarbonyloxy, with at least two the substituent of Rj - R fe is hydrogen, or their pharmaceutically acceptable salts, characterized in that the compound of formula II where R t HR 2 have the indicated meanings, or its salt or hydrate is * reacted with a compound of the formula ΠΙ, where R - and 6 have the abovementioned meaning, / or a reactive derivative thereof and isolating the desired n odukt in free acid form or its pharmaceutically acceptable salt.
    Featured Priority
    03/04/80 when R t is an acetoxy group or tetrazol-5-ylthio group substituted at position I with methyl,
    R x is hydrogen,
    R 3 - R e - independently from each other, hydrogen or chlorine, methyl, acetoxy, methoxy, benzyloxy, or nitro, with at least two substituents from R 3 - R 6 - hydrogen. 07/08/80 when R, is an acetoxy group or tetrazol-5-ylthio group substituted at position I with carboxymethyl or methoxycarbonylmethyl;
    Rj is hydrogen or an oxy group;
    R 3 , R ^, Rj and Rg are independently of each other hydrogen or an oxy group, at least two substituents • from R, - are hydrogen.
    类似技术:
    公开号 | 公开日 | 专利标题
    US4468394A|1984-08-28|Cephalosporin compounds
    SU927119A3|1982-05-07|Process for producing derivatives of cephalosorin or their esters, ethers, or salts, or their hydrates, or ester hydrates, ether hydrates, or salts
    FR2512449A1|1983-03-11|CEPHALOSPORINE QUINOLINIUM-BETINES AND THEIR PHARMACOLIC APPLICATION
    SU1487814A3|1989-06-15|Method of producing 7-amino-3-/3-|-1-propene-1-yl/-3-cephem-4-carboxylate
    SU1095879A3|1984-05-30|Process for preparing derivatives of cephalosporin or their pharmaceutically acceptable salts
    SU1128838A3|1984-12-07|Method of obtaining cephalosporin derivatives or their salts with alkali metals
    CS247080B2|1986-11-13|Production method of cefemderivatives
    EP0264091A2|1988-04-20|3-Propenylcephem derivative, preparation thereof, chemical intermediates therein, pharmaceutical composition and use
    US4139618A|1979-02-13|Cephalosporin type antibacterials
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    US4094978A|1978-06-13|3-propenyl derivatives of cephalosporin, compositions and their use
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    IE45559B1|1982-09-22|Lactam antibiotics
    PL92491B1|1977-04-30|
    FR2476091A1|1981-08-21|
    DE2325065A1|1974-01-10|NEW DITHIOCARBONYLAMINOACETYLCEPHALOSPORINE
    US5373000A|1994-12-13|7Beta-|-2-iminoacetamido-3cephem compounds
    KR0135979B1|1998-04-25|Method for recovery of anti-biotics from mother liquors
    CA1104560A|1981-07-07|Pyrrole cephalosporin derivatives
    SE467782B|1992-09-14|THE DIERYTROMYCIN AND DICOLINE SALTS AV / 3S | / - 2 /// 1- | -2 - // 2,2-DIMETHYL-4-OXO-1- | -3- AZETIDINYL / AMINO / -2-OXOETYLIDE / AMINO / OXI / ACETIC ACID USEABLE IN TREATMENT OF BACTERIAL INFECTIONS IN MAMMALS AND PROCEDURES FOR PREPARING THEREOF
    EP0049309B1|1984-05-09|Cephem derivatives, process for producing thereof, and antibacterial agents comprising said compounds
    JPH0674276B2|1994-09-21|Novel crystal of 7- [2- | -2-hydroxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid |
    US4180660A|1979-12-25|Cephalosporin derivatives
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    同族专利:
    公开号 | 公开日
    KR830004316A|1983-07-09|
    NL8007011A|1981-10-01|
    HU183276B|1984-04-28|
    DE3048657A1|1981-10-01|
    AU6583080A|1981-09-10|
    SU1105117A3|1984-07-23|
    ATA630780A|1983-07-15|
    FR2477548B1|1983-06-10|
    DK548380A|1981-09-05|
    US4344944A|1982-08-17|
    ES508723A0|1982-11-01|
    GB2070589A|1981-09-09|
    PH17794A|1984-12-13|
    CH643850A5|1984-06-29|
    AT373895B|1984-02-27|
    ES8300773A1|1982-11-01|
    ES8205809A1|1982-06-16|
    SU1130569A1|1984-12-23|
    KR840002162B1|1984-11-24|
    SE8009049L|1981-09-05|
    FR2477548A1|1981-09-11|
    CA1165759A|1984-04-17|
    GB2070589B|1984-06-06|
    US4415567A|1983-11-15|
    IT8026965D0|1980-12-24|
    AU540042B2|1984-11-01|
    ES498145A0|1982-06-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4165429A|1976-06-28|1979-08-21|Yamanouchi Pharmaceutical Co., Ltd.|7α-METHOXY-CEPHALOSPORANIC ACID DERIVATIVES|
    US4150224A|1977-10-04|1979-04-17|Yeda Research And Development Co., Ltd.|7[[7 acetyl]amino]cephalosporin derivatives|
    US4124762A|1977-11-07|1978-11-07|Yeda Research And Development Co., Ltd.|7-[phenyl]acetamido-cephalosporin derivatives|
    JPS565487A|1979-06-26|1981-01-20|Eisai Co Ltd|Cephalosporin compound, its preparation, and antimicrobial comprising it|JPS5855491A|1981-09-29|1983-04-01|Eisai Co Ltd|4-carbamoyloxymethylcephem derivative and its preparation|
    US4546176A|1982-12-14|1985-10-08|Eisai Co., Ltd.|7-Carboxymethoxyphenylacetamido-3-cephem derivatives and antibacterial preparations containing the same|
    AU2002334987A1|2001-10-15|2003-04-28|The Regents Of The University Of Michigan|Systems and methods for the generation of crystalline polymorphs|
    US20070036950A1|2005-08-15|2007-02-15|Royal Brush Manufacturing, Inc.|Dry transfer lettering with separable units|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP2611280A|JPS56122384A|1980-03-04|1980-03-04|7alpha-methoxycephalosporin derivative, its preparation and antifungal agent comprising it|
    JP9219980A|JPS6366320B2|1980-07-08|1980-07-08|
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