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    • 专利摘要:
    The invention relates to substituted heterocyclic acids, in particular, 6- (substituted hydroxymethyl) penicillanic acids, or their salts with alkali metals, or their esters of the general formula @ where R 1 is H, alkali metal allyl pivaloyloxymethyl benzyl diphenylmethyl (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl or 1- (ethoxycarbonyloxy) ethyl R 2 -vinyl, pyridyl-2 (or -3, or -4), furyl-2 thienyl-2 4-methylthienyl-2 5-methylisoxazolyl-2 isothiazolyl-3 mono- or disubstituted methyl thiazolyl-2 4-phenylthiazolyl-2 benzoxazolyl-2 benzothiazolyl-2 6-methoxybenzothiazolyl-2 N-acetylpyrrolyl-2 imidazolyl-2 1-methylimidazolyl-2 4-phenylimidazolyl-2 1-mono-C 1 -C 3 -alkyl-benzimidazolyl-2 1-dimethyl-5 (or 6) -methoxybenzimidazolyl-2 1,5,6-trimethylbenzimidazolyl-2 2-phenyl-1,2,3-triazolyl-4 3-methyl-1,3,4-triazolyl-2 1,2,3-thiadiazolyl-4 5-methyl-1,2,4-oxadiazolyl-3 pyrimidinyl-2 (or -4) pyrazinyl-2, pyridazinyl-3 or quinoxalinyl-2 R 3 - H, ethoxycarbonyl, benzoyl, pyrazinyl-2-carbonyl or C 2 -C 4 -alkanoyl X - H or bromine N = 0 or 2, with antibacterial and β - lactamase inhibiting action, which can be used in medicine. The goal is to create more active substances of the specified class. Their synthesis is carried out by the reaction of allyl (or benzyl) -6,6-dibromopenicillanate with tert-butyl lithium or methyl magnesium bromide with aldehyde R 2 -CH = 0, where R 2 is above, in an inert solvent at (-78) - (- 68) ° C. The resulting alcohol ester of this acid is then, if necessary, treated with a) an acid anhydride R 4 -C (O) OH, where R 4 is as defined for R 3 (except hydrogen) in an organic solvent medium in the presence of an organic base at ambient temperature, or b) is subjected to hydrogenolysis in an inert organic solvent using tributyltin hydride at room temperature to boiling, or c) hydrogenated in the presence of a PD catalyst at ambient temperature. The selection of the target product are in the form of acid or its desired derivative. New substances actively inhibit β - lactamase, and their antibacterial action is manifested against a broad spectrum of microbes, including those resistant to the action of other antibiotics. 14 tab.
    公开号:SU1503683A3
    申请号:SU864027136
    申请日:1986-03-17
    公开日:1989-08-23
    发明作者:Лианг Чен Юхпинг
    申请人:Пфайзер Инк. (Фирма)；
    IPC主号:
    专利说明:

    the product is in the form of an acid or its desired derivative. New substances actively inhibit / Si-lactam-ae, and their antibacterial action
    appears against a broad spectrum of microbes, including those resistant to other antibiotics. 17 tab.
    This invention relates to a process for the preparation of new chemical compounds, namely, 6- (substituted hydroxymethyl) penicillanic acids or their salts with alkali metals, or their esters, which have antibacterial and beta -lactamase inhibitory influences that can be found application in medicine.
    The aim of the invention is the creation of new penicillin antibiotics, which make it possible to enhance the antibacterial action of known antibiotics against resistant strains of microorganisms.
    Nuclear Magnetic Resonance, Proton (IMP) and C spectra were measured at 60, 90, 250 or 300 MHz for solutions in deuterochloroform (SBS1 of deuterium oxide (), perdeuterated acetone (CDjCOCI) 3) or perdy dimethyl sulfoxide (DMCO-d ), the side of decreasing of the field is determined from tetramethylsilane.
    Example 1. Benzyl-6- (2-pyridyl) oxymethyl penicillanate.
    Benzyl-6-bromo-6- (2-pyridyl) oxymethylpenicillanate.
    A solution of 9.0 g (0.02 mol) of benzyl-6,6-dibromopenicillanate in 200 ml of freshly distilled toluene is cooled to -78 ° C and 9 ml of a 2.2 M solution of tert-butyl lithium in pentane is added dropwise. The resulting mixture was stirred for 30 minutes, 2.14 g (0.02 mol) of 2-pyridine-carboxaldehyde was added and stirring was continued for another 40 minutes. The reaction is quenched by adding dropwise a solution of acetic acid in toluene. After stirring for 1 hour, the cooling bath is removed, the mixture is heated to -10 ° C, diluted with 200 ml of toluene, washed 5 times with water and dried over anhydrous sodium sulfate. The toluene solution was loaded onto a Florisil column (1 kg) and eluted with a toluene: ethyl acetate 2: 1 mixture. Fractions with pro5
    0
    five
    0 5
    0 5 Q 5
    The product is combined and evaporated in vacuo to give 4.2 g of a brown syrup, which is used in the next step.
    The resulting brown syrupy compound (4.2 g) was dissolved in 50 ml of beisol and 2.65 g of tributyltin hydride was added. The mixture was heated under reflux for 2 hours, an additional amount (1.65 g) of tributyltin hydride was added and the boiling under reflux was continued overnight. The solvent is evaporated under vacuum, the residue is washed with hexane, loaded onto a column containing 500 g of silica gel, eluted with a mixture of toluene: ethyl acetate 2: 1, and 425 g of the title compound are obtained.
     H-NMR (AHSC) (5, ppm: 1.35 (s., ZN); 1.7 (s., ZN); 4.0 (d., 1H); 4.5 (s. , 1H); 5.1 (s., 2H); 5.2 (d, 1H); 5.4 (d, 1H) ;, 7.0-7.8 (m, 3N); 8 , 5 (m., 1H).
    Example 2. 1, 1-Dioxide-6- (2-pyridyl) oxymethylphenylsilane acid.
    Benzyl 6- (2-pyridyl) oxymethyl-1,1-dioxopenicillanate.
    To a solution of 0.40 g of benzyl-6- (2-pyridyl) hydroxymethylpenienespanate in 5 ml of methylene chloride was added 0.20 g of methane-chloroperbenzoic acid and the mixture was stirred at room temperature for 1 hour. thin layer chromatography shows that the mixture contains some sulfoxide. Additionally, 0.2 g of meta-chloroperbenzoic acid was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, successively washed with saturated sodium thiosulfate solution, water, and all sodium bicarbonate solution and the organic layer was concentrated under vacuum. Ethyl acetate was added to the residue, washed with sodium bicarbonate solution, water, brine and
    shat over anhydrous sodium sulphate. By evaporation of the solvent, 330 mg of the desired benzyl ester are obtained in the form of a brown oil, which is purified by chromatography on a column of silica gel, gelled with ethyl acetate: hexane 11: 9, and 60 mg of a yellow oil are obtained.
     H-NMR (COClS) (, ppm: 1.25 (s., ZN); 1.52 (s., ZN); 4.1 (d, 1H); 4.5 (s. , PO 4.72 (d, lH) j 5.5 (d, 2H); 5.8 (d, 1H); 7.1-8.0 (m, 3N); 8, 5 (m, 1H).
    A suspension of 118 mg of catalyst 10% Pd / C in 10 ml of tetrahydrofuran (THF) and 4 ml of water are pre-hydrogenated for 20 minutes under a hydrogen pressure of 3 atm. 130 mg of the obtained benzyl ester was added to this suspension in 4 ml of the same mixture of THF and water. The resulting mixture is hydrogenated at 3.5 kg / cm for 30 minutes. Additionally, 129 mg of 10% Pd / C was added and hydrogenation at 3.5 kg / cm was continued for 2 hours. The catalyst was removed by filtration, the solvent was evaporated under vacuum and the residue was treated with a mixture of water and ethyl acetate. The aqueous layer is freeze dried and receive 85 mg of the target acid.
     H-NMR (CDCl1) (ppm: 1.3 (s., 3N); 1.5 (s., 3N); 4.4 (s., 1H); 5.0-5, 35 (m, 2H); 5.9 (d, 1H).
    IR Spectrum (KBG): 1620, 1731, 3407.
    Reproduce the procedure described, but use meta-chloroperbenzoic, an acid in an amount that equals to 175 grams in total, an equimolar amount, and produce a product that is a mixture of the corresponding alpha and beta sulfoxides.
    Example 3. Allyl-6- (2-thiazolyl) acetoxymethyl-1,1-dioxopenicillanate.
    . Acylation of 0.5 g (1.29 mmol) of allyl-6- (2-thiazolyl) -oxymethyl-1,1-discsopenicillanate with the help of 0.396 g (3.88 mmol) of acetic anhydride and 0.307 g of pyridine in 5 ml of tetrahydrofuran wire t by stirring at room temperature for 4 hours. The mixture is then diluted with methylene chloride, washed with water until neutral (pH 6.0-6.5), the organic phase is dried over anhydrous sulfate
    0
    683
    sodium, the solvent is evaporated off and 0.68 g of the desired acetate is obtained. H-NMR (AHSC), ppm: 1.52 (s., ZN); 1.70 (s., NN); 2.35 (s., NN); 4.4-4.6 (m, 2H); 4.6-5.0 (m., ЗН); 5.2-6.4 (m., 3N); 6.65 (d, 1H); 7.4 (d, 1H); 7.8 (d, 1H). Allyl-6- (L-acetylpyrrol-2-yl) Q acetoxymethyl-1,1-dioxopenicillanate,
    Allyl-6- (K-acetylpyrrol-2-yl) - hydroxymethyl-I, 1-dioxypenicillanate (210 mg, 0.51 mmol) is dissolved in 3 ml of tetrahydrofuran, added
    g 0.16 ml of acetic anhydride and 0.2 ml of pyridine and the mixture is stirred at room temperature for 24 hours. The reaction is quenched with water, extracted with methylene chloride, the extracts are dried, concentrated and 171 mg (75%) of yellow crystals are obtained.
     H-NMR (CDCl,), ppm: 1.4 (s., 3N); 1.6 (s., NN); 2.15 (s, 1H); 2.55 (s., NN); 4.15-4.3 (d, 1H); 4.2
    25 (s, 1H); 4.6-4.8 (m., ЗН); 5.1-6.0 (m., 3N); 6.1-6.6 (m, 2H); 6.6-7.4 (m, 2H).
    Example 4. Using the approach of one aldehyde of the formula R CHO,
     according to the procedure described in Example I, compounds are obtained whose characteristics and yields are given in Table. one.
    Example 5. (b-alpha, 85) -6- - (pyrimidin-2-yl) oxymethyl-1,1-dioxopenicillanate potassium,
     To a solution of 300 mg (0.79 mmol) of the first eluted allyl-6-α-alpha- (pyrimidin-2-yl) oxymethyl-1,1-dioxopenicillanate isomer (prepared in Example 4) in 4 ml of ethnyl acetate was added 30 mg of tetrakis ( triphenylphosphine) palladium (O) and 30 mg of triphenylphosphine. The mixture was stirred under a nitrogen atmosphere until the reagents were dissolved (5-10 min) and 1.57 ml (0.79 mmol) of potassium 2-ethylhexanoate in ethyl acetate was added. After stirring at room temperature for 20 minutes, the mixture is filtered and the filter cake is washed with ethyl acetate, dried and 53 mg of a yellow solid are obtained. The filtrate is treated with diethyl ether to precipitate additional precipitate, 152 mg, total yield 69%.
     H-NMR (250 MHz, DMCO-dg) (, h /
    5 ppm: 1.33 (s., MN); 1.44 (s., NN); 3.77 (s, 1H); 3.95 (d, or dd, J 2, J 6, 1H); 4.89 (d, J 2, III); 5.1 (d, J 6, 1H); 6.33 (with ..
    Ih); 7, A8 (t., J 4, IH); 8.84 (d, J 4, 2H).
    (6-Alpha, 8K) -6- (hydroxycidium-2-yl) oxnemethyl-1,1-dioxopenicillanate potassium.
    A solution of 300 mg (0.79 mmol) of the second eluted isomer of allyl-6-al-fa- (griirimidin-2-yl) oxymethyl-1, 1-di15
    20
    thirty
    of oxopenicillanate obtained in the presence of P-P, 342 mg (43%) of target 4 is obtained, converted to its potassium salt by the described procedure and 236 mg (79%) are obtained.
    CMYR (250 MHz, DMCO-d), h / m: 1.30 (s., ZN); 1., 42 (s., 3Fi); 3.65 (s, 1H); 4.60 (d, J 2, J 8, I); 4.75 (d, J 2, IH); 5.15 (d, J 8, 1H); 7.47 (t, 1H); 8.85 (d, J 4, 2H).
    Example 6. Allyl- (6-alpha, 8S) -6- (pyrimidin-2-yl) acetoxymethyl-1, 1-dioxopepicillanate.
    To a solution of 785 mg (2.1 mmol) of elu-HpyeNsoro by the first isomer of the allyl-6-al-α- (1P1rimidin-2-yl) oxymethyl-1, 1-di-25 oxO1 en11C1 shlanat prepared in Example 4 in 4 ml 0.45 ml (5.6 mmol) of pyridine and 0.53 ml (5.6 mmol) of acetic anhydride are added to methylene chloride and the mixture is stirred at room temperature for 2.5 hours. The mixture is diluted with 30 ml of methylene chloride. extract with water (7x60 ml), dry over anhydrous magnesium sulphate and filter. By evaporation under vacuum, 813 mg (92%) of the compound are obtained.
    H-NMR (CDCl1) 5, ppm: 1.4 (s., 3N); 1.6 (s., NN); 2.2 (s., NN); 4.45 (s., ZN); 4.45 (dd., P1); 4.75 (m, 2H); 4.95 (d, 1H); 5.2-5.6 (m, 2H); 5.7-6.3 (m, 1H); 6.45 (d, 1H); 7.35 (t, PO; 8.85 (d, 1H).
    Allyl- (6-alpha, 8R) -6- (nirimidin--2-yl) acetoxymethyl-1,1-dioxopencyllanate.
    The acylation of the allyl-b-alpha- (pyrimidin-2- -yl) oximesh1-1,1-dioxopenicillanate eluted by the second isomer obtained in Example 4 was carried out as described above and the desired compound was obtained in 88% yield.
    CMR (CDCl), ppm: 1.4 (s., MN); 1.6 (s., NN); 4.45 (s, 1H); 4.5 (dd, L 1, J 8, 1H); 4.75. (m, 2H); 4.8 (d, J I, III); 5.25-5.6 (m, 2H); 5.7-6.3 (m, 1H); 6.4 (d, J 8, 1H); 7.35 (t, J 6, 1H); 8.8 (d, J 6,) H).
    35
    40
    45
    . 50
    55
    potassium salt, which is purified by preparative medium pressure liquid chromatography (LCSD), eluted with water: acetonitrile 9: 1, and 105 mg of product are obtained using high pressure liquid chromatography (HPLC) analysis, product purity 85% .
    (6-Alpha, 8K) -6- (pyrimidin-2-yl) - potassium acetoxymethyl-1,1-dioxopenicillanate.
    A solution of 666 mg (1.57 mmol) of allyl- (6-alpha, 8R) -6- (pyrimidine-2-Sh1) -acetoxymethyl-1,1-dioxopenicillan is reacted by the same procedure and a 339 mg (51%) of the crude product, which is purified by IHSD using water: acetonitrile to obtain 162 mg of the pure isomer.
    H-NMR (250 MHz, DMSO-de) S, h / m: 1.34 (s., 3N); 1.44 (s., NN); 2.17 (s., ZN); 3.65 (s, 1H); 4.15 (dd., J 2, J 8, IH); 4.97 (d, J 2, IH); 6.27 (d, J 8, IH); 7.50 (t, J 5, IH); 8.85 (d, J 5, 2H).
    Example 8. Using the starting compound (OH) -substituted-1,1-dioxopenicillan ester from Example 4 as described in Example 6, the corresponding (OCOH3) -substituted esters are obtained, the characteristics and yields of which are given in Table. 2
    Example 9. The 8-Acetoxy-3-carbonyloxyallyl esters prepared in Example 8 are converted to the corresponding potassium salts obtained according to the procedure of Example 5, the characteristics and yields of which are listed in Table. 3
    Example 10. Potassium 6- (Imidazol-2- -yl) hydroxymethyl-1,1-dioxopenicillanate.
    A mixture consisting of 141 mg (0.38 mmol) of allyl-6- (imidazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate (displaced isomers obtained in Example 7. (6-Alpha, 8S) -6- - (11irimidin-2-cl) acetoxymethyl-1,1-dioxopenica potassium.
    A solution of 789 mg (1.86 mmol), allyl- (6 alpha, 85) -6- (pyrimidin-2-yl) -acetoxymethyl-1,1-dioxopenicillanate in 4 ml of ethyl acetate is reacted by the procedure described in example 15
    20
    thirty
    i- P get 342 mg (43%) of target,
    - - 25 Yves-t); .
    t
    .,. , , ,eight
    35
    40
    45
    50
    55
    potassium salt, which is purified by preparative medium pressure liquid chromatography (LCSD), eluted with water: acetonitrile 9: 1, and 105 mg of product are obtained using high pressure liquid chromatography (HPLC) analysis, product purity 85% .
    (6-Alpha, 8K) -6- (pyrimidin-2-yl) - potassium acetoxymethyl-1,1-dioxopenicillanate.
    A solution of 666 mg (1.57 mmol) of allyl- (6-alpha, 8R) -6- (pyrimidine-2-Sh1) -acetoxymethyl-1,1-dioxopenicillanate is reacted by the same procedure and 339 mg (51%) of crude product is obtained, which is purified by IHSD using a mixture of water:: acetonitrile and 162 mg of pure isomer are obtained.
    H-NMR (250 MHz, DMSO-de) S, h / m: 1.34 (s., 3N); 1.44 (s., NN); 2.17 (s., ZN); 3.65 (s, 1H); 4.15 (dd., J 2, J 8, IH); 4.97 (d, J 2, IH); 6.27 (d, J 8, IH); 7.50 (t, J 5, IH); 8.85 (d, J 5, 2H).
    Example 8. Using as the starting compound (OH) -substituted-1,1-dioxopenicillan ester from example 4 according to the method of example 6, the corresponding (OCOH3) -substituted esters are obtained, the characteristics and yields of which are listed in Table. 2
    Example 9. The 8-Acetoxy-3-carbonyloxyallyl esters prepared in Example 8 are converted to the corresponding potassium salts obtained according to the procedure of Example 5, the characteristics and yields of which are listed in Table. 3
    EXAMPLE 10 Potassium 6- (Imidazol-2- -yl) hydroxymethyl-1,1-dioxopenicillinate.
    A mixture consisting of 141 mg (0.38 mmol) of allyl-6- (imidazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate (displaced isomers obtained at ISCM
    measure 4), 12 mg of tetraxp- (transfeplofosfii) palladium (O), 12 mg of triphenylphosphine, 0.76 ml (0, J8 mmol) of 2-ethylhexanoate potassium and 2 ml of echnyl acetate, stirred at atmosphere)) nitrogen for 1 hour. The precipitated product is isolated by filtration to give 143 mg (100%) of a yellow solid which contains two isomers according to the HPLC assay.
    IR spectrum (KBG),: 3382, 1780, 1728 and 1615.
    Example II Allyl-6-bromo-6- (2-thiazolyl) hydroxymethyl-1,1-dioxopenicillanate.
    A solution of 8.84 mg (20 mmol) of allyl-6,6-di6 r-1,1-dioxopenicillanate in 100 ml of dry tetrahydrofuran is cooled to -78 ° C, 7.02 ml (20 mmol) of methyl magnesium bromide is added and the resulting the mixture is stirred for 5 minutes. With a solution of 2.26 g of 20 mmol) thiazole-2-carboxaldehyde in 10 ml of the same solvent is added and the resulting mixture is stirred for 20 minutes. Acetic acid (1.2 ml) is added, the mixture is poured into water and extracted with ethyl acetate and chloroform. The combined organic layers are dried (and the solvent is evaporated in vacuo to give 8.5 g of a glassy crude product. The crude glass is purified by chromatography on a column of silica gel, eluting with chloroform: ethyl acetate in a ratio of 89:11 to form 6 , 2 g (72%) of pure product, which is one isomer.
    H-NMR (CDC1,), ppm: 1.4 (s., 3N); 1.6 (p. 311); 4.0 (bs, IH); 4.42 (s, 1H); 4.6 (d, 2H); 5.3 (s, 1H); 5.55 (s, 1H); 5.1-6.3 (m, 3N); 7.35 (d, 1H); 7.75 (d, 1H).
    Benzyl-6-bromo-6- (2-thiazolyl) hydroxymethyl-, 1-dioxopenicillanate.
    Using benzyl-6,6-dibromo-1,1-dioxopenicillanate instead of allyl ester, the title compound is obtained as an orange foam using the procedure described.
     H-NMR (CDCl,), hours / million: 1,3255
    (s., NN); 1.60 (s., NN); 4.5 (s, 2H); 5.2-5.8 (m, 411); 7.3 (d, 1H); 7.4 (s, 5H); 7.8 (d, 1H).
    5 o
    five
    five

    five
    one
    Aiia.iioiHMHO get. Spedinenm, characteristics and B1.1 going, 1 to the mountain are given in table. four.
    Example 12. Lps tylation of the compounds obtained in Example 11 according to the method of Example 6 leads to the synthesis of compounds whose characteristics and outputs are presented in Table. five.
    These compounds can also be prepared by carrying out the procedure of Example 11 by acetylating the reaction mixture before isolating the product, according to the following method.
    To a solution of 1.0 equivalent, 6-dibromopenidyl ester ester in tetrahydrofuran at -78 ° C, 1.3 equivalents of methyl magnesium bromide dissolved in the same solvent are added, and the resulting mixture is stirred for 5-10 minutes. At (-78) - (-68) ° C, 1.3 equivalents of the corresponding aldehyde () in the same solvent are added and the resulting reaction mixture is stirred for 30-60 mic. Then 1.3 equivalents of acetyl chloride are added, stirring at -78 ° C is continued for 10 minutes and then the product is isolated, the mixture is poured into ice water, extracted with ethyl acetate, the wire is dried and the solvent is evaporated in vacuo.
    Example 13. Benzyl-6-beta- (thiazol-2-yl) acetoxymethyl-1, 1-dioxopenicillanate.
    To a solution of 74.6 g (134 mmol) of benzyl-6-b rom-6- (thiazol-2-yl) acetoxy-methyl-1, 1-dioxopenicillanate in 850 ml of benzene was added 43.99 g (151.2 mmol a) tri-n-butyl tin hydride. The mixture was heated under reflux for 5.5 hours and allowed to stand overnight. The solvent is evaporated in vacuo, the residue is taken up in hexane and extracted with acetonitrile (2 x 250 ml). The acetonitrile layer is evaporated, the residue is slurried with ethyl ether, filtered and the filter cake is washed with ether to form 33.28 g of colorless crystals. Another 2.8 g is obtained by evaporation of the filtrate to dryness. The residue is taken up in benzene and 10 g of tri-n-butyl tin hydride is added. The mixture is heated with a freezing condenser for 1 h.
    eleven
    and treated the same way as the first batch. Overall increase of 56.3%.
    The first batch is subjected to chromatographic purification on a column with silica gel, using chloroform: ethyl acetate in a 9: 1 ratio as an eluant. The product fraction is concentrated, slurry with diethyl ether: ethyl acetate 4: 1, filtered, washed with ether and 22.6 white solids are obtained.
     H-NMR (CDCl1) S, ppm: 1.25 (s., 3N); 1.53 (s., ZI); 2.1 (s., NN); 4.58 (s, 1H); 4.80 (d, 1H); 5.2 (dd, 1H); 5.22 (q, - 2H); 6.75 (d, 1H); 7.35 (s, 5H); 7.4 (d, 1H); 7.8 (d, 1H).
     P-NMR (CDC1,) S, ppm: 17.7;
    H-NMR (), ppm: 1.38 (p. 3N); 1.55 (s., ZN); 4.25 (s, 1H); 4.44 (dd., 1H); 5.05 (d, 1H); 6.68 (d, 1H); 7.4 (t, 7H); 7.55 (t, UO; 7.58 (d, 1H); 7.7 (d, 1H); 7.95 (d, 1
    19.9; 20.5; 54.5; 63.06; 63.6; 63.8; 64.5; 68.1; 121.8; 128.8; 128.9; 134.3; 141.6; 164.6; 166.5; 169.2; 170.5.
    Similarly, by debromination of the remaining compounds obtained in Example 12, compounds are obtained, the characteristics and yields of which are given in table. 6
    Example 14. (6-Alpha, 8K) -6- - (thiazol-2-yl) propion 10 × methyl-1, 1-dioxogenenicillanic acid.
    A mixture consisting of 1.89 g (10%) of palladium on carbon (catalyst) in 20 ml of a mixture of tetrahydrofuran (THF) and water in a ratio of 9: 7 is saturated with hydrogen and a solution of 689 mg (1.4 mmol) of benzyl is added - (6-alpha, 8R) -6- - (thiazol-2-yl) propionoxymethyl-l, 1 dioxopenicillanate in 13 ml of THF and 7 ml of water. The resulting mixture is hydrogenated at a pressure of 3 bar for 20 minutes, the catalyst is filtered off, the filtrate is extracted with ethyl acetate (3x200 ml) and the extracts are dried (MgSO4). By evaporation of the NIN solvent in vacuo, 330 mg of a yellow solid are obtained.
    (6-Llf, 8K) -6- (thiazal-2-nl) benzosyuksimetil-1, 1-dioxoepicillanic acid.
    A but obtained procedure is obtained from the corresponding benzyl ether in 57% yield.
    - g
    ten
    15
    12
    IR spectrum, (KBG),: 3473, 1782, 1729, 1622.
    Example 15. The benzyl jiOBbie esters obtained are converted into the corresponding carboxylic acids by hydrogenation over a palladium-carbon catalyst in accordance with the procedure of Example 14, the characteristics and outputs of which are listed in Table. 7
    6-Beta- (thiazol-2-yl) acetoxymethyl-1,1-dioxope} shcyllanic acid is converted to the corresponding potassium salt by treating an aqueous suspension of acid with an appropriate amount of potassium bicarbonate in water and subsequent purification using liquid chromatography medium pressure
    20
    thirty
    f
    18
    cMeci:
    using yes: acetonitrile at 9: 1 to obtain the corresponding potassium salt in
    on the column, the eluent ratio is 60%.
     H-NMR () 5, ppm: 1.37 (s., ZN); 1.48 (s., NN); 2.07 (s., ZN); 3.80 (s, 1H); 4.92 (dd., 1H); 5.12 (d, 1H); 6.55 (d, 1H); 7.89 (m, 2H).
    IR spectrum (KBG), cm 1630.
    3454, 1788,
    five
    .
    0
    0
    five
    Example 16. 6-Bromo-6- (thiazol-2-yl) acetoxymethyl-potassium 1,1-dioxopenicillanate.
    By the reaction of 96 mg (0.2 mmol) of allyl-6-bromo-6- (thiazol-2-yl) -acetoxymethyl-1, 1-dioxopenicillanate (obtained in Example 12), carried out for 10 min according to the procedure of the example 10, after the product treatment described, 46 mg (48) of a yellow solid is obtained.
     C (g-octadecisilicate.
     H-NMR (DjO) i, ppm: 1.45 (s., 3N); 1.6 (s., NN); 4.4 (s, 1H); 5.55 (s, 1H); 6.85 (s, 1H); 7.72 (d, 1H); 7.86 (d, 1H).
    6-Bromo-6- (thiazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate potassium.
    Similarly, by the reaction of 220 ml of allyl-6-bromo-6- (thiazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate obtained in example 11, carried out for 20 minutes according to this method, is obtained with 52% the output named salt in the form of a pale yellow solid.
     H-NMR () S, ppm: 1.35 (s., ZN); 1.47 (s., NN); 3.75 (with ..
    0.4and); 3.83 (s., O. p.); 5.3 (d, 0.4H); 5.32 (d, 0.6H); 5.45 (s., 0.611); 5.5 (s, 0.4H); 7.6-8.0 (m., 2H).
    IR spectrum (KVg),: 3442, 1794, 1633.
    Example 17. (6-Beta, 85) -6- - (thiazol-2-yl) potassium hydroxymethylphenicillate.
    Allyl-6-bromo-6- (thiazol-2-yl) hydroxymethyl: 1 is glant.
    To a solution of 9.971 g (24.99 mmol) of allyl-6,6-dibromopenicillayate in 150m dry tetrahydrofuran, cooled to -78 ° C under a nitrogen atmosphere, was added 8.77 ml of a 2.85 M (24.99 mmol) solution of methylmagnesium bromide in THF and the resulting mixture is stirred for 15 minutes A solution of 2.824 g is added.
    (24.99 mmol) of thiazole-2-carboxaldehyde in 5 ml of THF and the resulting mixture is stirred again for 20 minutes at -78 C. The reaction is quenched by adding 1.43 ml (24.99 mmol) of glacial acetic acid , the mixture is stirred for 10 minutes and then allowed to warm to room temperature. Then the mixture was poured into water, extracted (2x250 ml) with ethyl acetate, the extracts were washed with water (2x250 ml), dried (HgSO4) and the solvent was evaporated in vacuo to give 10.36 g of an orange oil. This oil is purified by chromatography on a column of silica gel, wire is eluted with a mixture of chloroform: ethyl acetate in a ratio of 9: 1, with the formation of 4.54 g of a yellow solid (mixture of isomers) and 0.443 g of a yellow foam pny isomer (total yield 46%)
    For yellow foam, n-NMR (CDCl}), ppm: 1.56 (s., 3N); 1.76 (s., NN); 4.60 (s, 1H); 4.7 (m, 2H); 4.9-6.4 (m., 6H); 7.45 (m, 1H); 7.8 (m, 1H).
    Allyl-6-beta- (thiazol-2-yl) hydroxymethyl penicillanate.
    200 mg (0.462 mmol) of the more polar of the isomers obtained are dissolved in 1 ml of benzene and 0.183 m (0.693 mmol) of 1.5 equivalents of a solution of tri-n-butyl tin hydride in benzene is added. The resulting mixture was heated under reflux for 3 hours and left to stand overnight at room temperature. The solvent is evaporated in vacuo, the residue is transferred to
    14
    d
    five
    5 About Q
    five
    five
    with t in acetonitrile, evaporated with hexane and evaporated to a small volume, which is passed through a column of silica gel, eluted with chloroform, yielding 73 mg (45%) of the indicated product.
     n-NMR (SSCS) S, ppm: 1.6 :; (s., NN); 1.87 (s., NN); 3.8-4.4 (m, 1H); 4.05-4.3 (dd., 1H); 4.65 (s., 1I); 4.78 (m, 2H); 5.3-5.6 (m, 2H); 5.6-6.3 (m, 3N); 7.45 (m, W); 7.85 (m, 1H).
    73 mg (0.206 mmol) of the resulting product are converted to the potassium salt by the method of Example 10 to form 58 mg (80%) of the title compound as a yellow solid.
    4i-HMP (300 MHz, 1) 0) (, ppm: 1.36 (s., 3N); 1.55 (s., JH); 4.13 (d., 1H); 4, 18 (s., 1H); 5.32 (d., 1H); .5.41 (d, 1H); 7.56 (d., 1H); 7.60 (d, W).
    Example 18. Using the appropriate aldehyde, instead of thiazole-2-carboxaldehyde, according to the method of example 17, compounds are obtained, the characteristics and outputs of which are listed in Table. eight.
    The debromination of these compounds according to example 17 receive compounds whose characteristics are shown in Table. 9.
    From the obtained allyl ethers, according to the method of Example 10, potassium salts are synthesized, the characteristics of which are given in Table. ten.
    Example 19. Pivaloyloxymethyl-6- (3-methylbenzimidazol-2-yl) oxyethyl penicillanate.
    A solution of 600 mg (1.5 mmol) of 6-1 (3-methylbenzimidazol-2-yl) oxymethyl J potassium penicillanate in 2 ml of dimethylformamide is cooled to 0 ° C. Then 0.216 ml (1.5 mmol) chlorine is added. - methyl pivalate, the reaction mixture is heated to room temperature and stirred overnight. Then the reaction mixture was poured into water, extracted with diethyl ether (3 × x 20 ml) and dried over sodium sulfate. The solvent is evaporated, the mixture is triturated with a mixture of diethyl ether and hexane, the precipitate is collected by filtration, and 438 mg of pivaloyloxymethyl-6- (3-methylbenzimidazol-2-yl) oxymethyl penicillanate is obtained in the form of a reddish-brown solid.
     H-NMR (CDCl,) J, ppm: 1.22 (s, 9H); 1.44 U, 3N); 1.66 (s, ZN); 2.92 (d, - 1H / OH /); 3.86 (s, ZN); 4.52 (s, - 1H); 4.59 (dd, 1H); 5.46 (d, 1H); 5.61 (d, 1H); 5.82 (AB-apt., 2H); 7.12-7.38 (m, - ЗН); 7.6-7.76 (m, 1H).
    Example 20. Using the appropriate acid chlorides of the formula K C1 or acid anhydrides and the corresponding 6-R2 CHOH-substitutions of 1,1-dioxopenicillanate esters according to the method of Example 3, the compounds shown in Table 2 are obtained. eleven.
    Example 21. (6-Alpha, 8K) -6- - (thiazol-2-yl) propionyloxymethyl-1,1-dioxoxy-nitcillanic acid.
    A mixture of 1.89 g of catalyst (10%) palladium on carbon and 20 ml of a mixture of tetrahydrofuran (THF) and water (9: 7) is saturated with hydrogen and a solution of 689 mg (1.4 mmol) of benzyl L- (6-alpha) is added. , 8R) -6- (thiazol-2-yl) propioyloxymethyl-1,1-dioxopenicillayate in I3 ml of THF and 7 NOI of water. Collect (the uus mixture is hydrogenerated at a pressure of 3 bar for 20 minutes, then the catalyst is removed by filtration, the filtrate is extracted with ethyl acetate (3x200 ml) and the extracts are dried (N§804). Distillation of the solvent and vacuum gives 330 mg of a yellow solid.
    (, fa, 8K) -6- (thiazol-2-yl) benzoyl-yloxymethyl-1, 1-dioxo-11-yenistric acid.
    These compounds are prepared according to the described procedure, having the corresponding benzyl ether with a 57% yield.
    H-NMR (), ppm; 1.38 (s, 3N); 1.55 (with OA); 4.25 (s, 1H); 4.44 (dd, 1H); 5.05 (d, 1H); 6.68 (d, HI); 6.8 (d, 111): 7.4 (t, 7H); 7.55 (t, 1H); 7.58 (d, 1H); 7.7 (d, 1H); 7.95 (d, 1H).
    IR spectrum (KBG), cm i 3473, 1782, 1729, 1622.
    Example 22. (6-Alpha, 8S) -6- - (hyazol-2-sh) ethoxycarbonyloxymethyl-l, 1-dioxonenicillanic acid.
    To a solution of 557 ml (0.954 mmol) of diphenylmethyl- (6-alpha, 85) -6- (thiazol--2-yl) ethoxycarbon-10 xmethyl-1,1-dioxopenicillanate in 5 ml of methylene chloride was added 0.62 ml. (5.72 mmol) anisole. The mixture is cooled to -5 ° C and a mixture of 382 mg is added slowly over a 15 t-sin mixture.
    ten
    20
    25
    3683 6
    (2.86 mmol) of anhydrous aluminum chloride and 2 ml of nitromethane. The reaction mixture is diluted with 50 ml of EP-S-acetate, water is added and adjusted to pH 7.5. The aqueous layer was separated, acidified to pH 3 and extracted with ethyl acetate. Removal of the solvent gave a glassy product, which was stolen in ethyl ether, filtered, and hexane was added to the filtrate to form a precipitate. After filtration to separate the solid and dry, 211 mg (53%) of the product are obtained.
    H-NMR (300 MHz, CDC1,) 5, h / or: 1.40 (t, 3N); 1.53 (s, 3N); 1.67 (s, ZN); 4.28-4.42 (m, 3N); 4.50 (s, 1H); 4.92 (s, 1H); 6.58 (d, 1H); 7.63 (d, 1H); 7.93 (d, 1H).
    IR spectrum (KBG), 3443, 1797, 1754.
    When using the (6-alpha, 8K) -isomer of the starting diphenylmethyl ether described in Example 20, but the indicated procedure is obtained
    0
    five
    a (6-alpha, 8R) -isomer of 6- (thiazol-2- -yl) ethoxycarbonyloxymethyl-1,1-dioxopenicillanic acid. ,
    H-NMR (300 MHz, (CDCl1) (ppm: 1.34 (t, 3N); 1.53 (s, 3N); 1.65 (s, 3N); 4.2-4, 4 (m, 3N); 4.44 (s, 1H); -5.04 (s, 1H); 6.67 (d, 1H); 7.53 (d, 1H); 7.90 (d, W).
    IR Spectrum (KBG), 3418, 1803, 1750.
    Example 23. When the corresponding allyl ether described in Example 20 is used as the starting material, potassium salts are obtained according to the procedure of Example 10 in Table. 12.
    Example 24. Allyl-6-bromo-6- - (2-thiazolyl) oxymethyl-1,1-dioxopenylnilanate.
    5 A solution of 8.84 g (20 mmol) of allyl-6,6-dibromo-1,1-dioxopenicillanate in 100 ml of dry tetrahydrofuran is cooled to -78 ° C, 7.02 ml (20 mmol) of methyl magnesium bromide is added and the mixture
    Q stirred for 5 min. At a solution of 2.26 g (20 mmol) of thiazole-2-carboxaldehyde in 10 m), 1 of the same solvent is added and the resulting mixture is stirred for 20 minutes.
    5 Acetic acid (1.2 ml) was added, the mixture was poured into water and extracted with ethyl acetate and chloroform. The combined organic layers are dried () and the solvent is distilled off in
    I 15
    vacuum to obtain 8.5 g of a crude product in the form of glass. The crude glass product was purified by column chromatography on silica gel, eluted with chloroform: eth1, and 89:11 lacetate to give 6.2 g (72%) of pure product, which is one isomer.
     H-NMR (CDCl,), ppm: 1.4 (s, 3N); 1.6 (s, 3N); 4.0 (s, 1H); 4.42 (s, 1H); 4.6 (d, 2H); 5.3 (s, III); 5.55 (s, 1H); 5.1-6.3 (m, 3N); 7.35 (d, 1H); 7.75 (d, 1H).
    Benzyl-6-bromo-6- (2-thiazolip) hydroxymethyl-1,1-dioxopenicillanate.
    When using benzyl-6,6-dibromo-1,1-dioxopenicillanate instead of allnl ether, the indicated compound is obtained as an orange foam.
     H-NMR (SOSTS) S, ppm: 1.32 (s, 3N); 1.60 (s, 3N); 4.5 (s, 2H); 5.2-5.8 (m, 4H); 7.3 (d, 1H); 7.4 (s, 5H); 7.8 (d, 1H). . The compounds listed in Table 2 are prepared analogously. 13.
    Potassium salts having a 6-beta, 8S stereo-configuration, obtained similarly by the indicated methods, are listed in Table. 14.
    Example 25. (6-Beta, 85) 6 - (1-methipbenzimidazol-2-yl) oxymethyl potassium penicillanate „
    Allyl-6-bromo-6- (1-methylbenzimide-azol-2-yl) oxymethylpenicillanate.
     A solution of 18.88 g (0.0473 mmol) of al = 1-6,6-dibromopenyillanate in 400 ml of methylene chloride is cooled and 16.90 ml (0.073 mmol) of 2.8 M methylmagnesium bromide in ethyl ether are added. The mixture was stirred at -78 ° C for 30 minutes, a solution of 7.58 g (0.0473 mmol) of 1-methylbenz-imidazole-2-carboxaldehyde in 30 ml of methylene chloride was added and stirring was continued for another 30 minutes. Acetic acid (2.71 ml, 0.0473 mmol) is added, the mixture is poured into a saturated ammonium chloride solution, the layer is separated and the organic layer is dried (MgSO4). Distillation of the solvent gives an orange oil, which is used without purification, except that the last traces of the chlorinated solvent are removed by evaporation of its solution in benzene.
    Allyl-6- (1-methylbenzimidazol-2-yl oxymethylphenicillanate.
    i
    The resulting product was dissolved in 150 ml of tetrahydrofuran, 22.45 ml (0.0946 mol) of three n-6-utilovylohydride was added, the mixture was boiled for 6 hours and stirred overnight at room temperature. The solvent was distilled off in vacuo, The residue is transferred. A mixture of acetonitrile: hexane and acetonitrile is washed with hexane. The acetonitrile layer is evaporated in vacuo to a dry substance, yielding 16.8b g of brown oil, which is purified by flash column chromatography on
    600 g of silica gel, eluting with 30% ethyl acetate in chloroform, to give two fractions.
    The first fraction. 3.64 g (20.8%) of the more polar isomer, having a 6-beta, 83-stereoconfiguration, as determined by H-NMR at 300 MHz.
     H-NMR (CDC1,) S, ppm: 1.32 (s, 3N); 1.58 (s, 3N); 3.71 (s, 3N); 4.43 (s, 1H); 4.52 (dd, 1H); 4.58 (d,
    2H); 5.16-5.42 (m, 3N); 5.49 (d, 1H); 5.76-5.94 (m, 1H); 7.06-7.26 (m, 3N); 7.52-7.60 (m, 1H).
    The second fraction. 2.6 g (14.0%) less polar isomer.
    To 3.64 g (0.0098 mmol) of the indicated 6-beta, 85-isomer, 360 mg of tetrakis (triphenylphosphine palladium (O), 360 mg of triphenylphosphine and 19.6 ml of solution) were added to 20 ml of ethyl acetate. 2-ethyl35
    potassium hexanoate and the mixture is stirred at room temperature for 1 h (nitrogen atmosphere). An excess of ethyl ether is added to precipitate a solid product, which is separated by filtration and dried in vacuo to yield 1.38 g of product. When an additional amount of ether is added to the mother liquor, a second portion of 1.51 g is deposited. Both portions
    g are combined and chromagrafted, eluting with 15% acetonitrile in water to give 1.37 g (35%) of the product, freeze dried, as a pale yellow solid.
    50
     H-NMR (30 MHz, D, 0) (f, ppm:
    1.36 (s, 3N); 1.58 (s, 3N); 3.84 (s,
    ZN); 4.24 (s, 1H); 4.40 (hell, 1H);
    5.38-5.48 (m, 2H); 7.22-7.38 (m, 2H);
    55 7, -7.54 (m, 1H); 7.6-8.7 (m, 1H).
    IR spectrum (KBG), cm-: 1610, 1750, 3440.
    Calculated,%: C47,67; H 4.99; N 9.81.
    С, тН, К 1,6 HjO
    Found,%: C 47.74; And 5.12; N 9.73.
    Example 26. (5-Methyl-2-ox-co-1,3-dioxolen-4-yl) methyl, 8Sj-6- - (1-methylbenzimidazol-2-yl) oxymethylpenicillanate.
    A mixture of 200 mg (0.5 mmol) (6 beta, 8S) -6- (1-methylbenzimidazol-2-yl) potassium hydroxymethylpenicillanate, 96 mg (0.5 mmol) 4-bromomethyl-5-methyl-2- oxo-1,3-dioxolene and 4 ml of dimethylformamide are stirred at room temperature for 18 hours. The resulting mixture is drunk in water, extracted three times with ethyl ether, the extracts are dried (MgSO4) and the solvent is distilled off to obtain a golden oil, gradual -} but hardening in vacuum, 110 mg (46%).
     H-NMR (300 MHz.) S, ppm: 1.34 (s, 3N); 1.62 (s, ZN); 2.16 (s, 3N); 3.82 (s, 3N); 4.46 (s, 1H); 4.52 (YES, 1H); 4.88 (AB-q, 2H); 5.4 (d, 1H); 5.56 (d, 1H); 7.08-7.38 (m, 3N); 7.58-7.78 (m, 1H).
    Example 27. 1- (Ethoxycarbonyloxy) ethyl-6- (1-methylbeneimidazol-2-yl) -oxymethyl penicillanate.
    To a solution of 150 mg (0.374 mmol) of 6- (1-methylbenzimidazol-2-yl) hydroxymethyl potassium penicillanate in 20 ml of dimethylformamide was added 0.051 ml (0.374 mmol) of 1-chloroethyl ethyl carbonate and 56 mg (0.374 mmol) of iodine on three . The mixture is stirred overnight, poured into water, extracted with ethyl ether, the extracts are dried (MgSO4) and the solvent is distilled off in vacuo to give 60 mg of the product as a pale yellow oil, a mixture of two isomers.
    CMYR (300 MHz, CDC1,) 5, ppm 1.04-1.34 (m, 3N); 1.4 (s, 1.5H); 1.42 (s, 1.5H); 1.52 (d, 1.5H); 1.54 (d, 1.5H); 1.61 (s, 1.5H); 1.63 (s, 1.5H); 3.82 (s, 3N); 4.08 (q, W); 4.18 (q, 1H); 4.41 (s, 0.5H); 4.46 (s, 0.5H); 4.52 (dd, 1H); 5.39 (d, 1H); 5.52 (d, 0.5H); 5.54 (d, 0.5H); 6.66-6.82 (m, 1H); 7.06-7.40 (m, 3N) 7.50-7.80 (m, 1H).
    Example 28. 1- (Ethoxycarbonyloxy) ET1SH-6- (1-methylbenzimidazol--2-yl) -oxymethylpenicillanate.
    1- (Ethoxycarbonyloxy) ethyl-6-bromo-6- (1-methylbenzimidazol-2-yl) oxymethyl penicillanate.
    To a solution of 1- (ethoxycarbonyloxy) -ethyl-6,6-dibromopenicillanate (8.24 g, 0.0186 mol) in 150 ml of methylene chloride at -78 ° C was added 6.64 ml (0.0186 mol) of 2.8M methylmagnesium bromine - yes in ethyl ether and the mixture is stirred for 30 minutes A solution of 3.28 g (0.02 mmol) of 1-methyl-2-benzimidazolecarboxydehyde in 20 ml of methylene chloride is added and stirred at -78 C for 1 h. Then 1.06 ml of acetic acid is added, the mixture is poured into water and a saturated ammonium chloride aqueous solution is added to cause separation of the layers. The organic phase is washed with brine, dried (MgSO4) and the solvent is distilled off to obtain a golden oil. It is transferred to benzene and vacuum embedded in order to remove the last traces of the chlorinated solvent.
    The resulting product is dissolved in 125 ml of distilled tetrahydrofuran.
    and 10 ml (0.0372 mol) of tri-n-butyltin hydride was added. The mixture was boiled for 6 h and left under stirring overnight at room temperature. The solvent is distilled off in vacuo, the residue is dissolved in acetonitrile and washed three times with hexane. The acetonitrile layer is evaporated in vacuo, the remaining oil is triturated with hexane and petroleum ether to remove residual tin compounds. The crude product is purified by flash chromatography on a column of 150 g of silica gel, eluting with 30% ethyl acetate in chloroform to obtain 340 mg of LP isomer and 419 ml
    Mr isomer. The LP fraction was triturated with ethyl ether to give 303 mg of a yellow solid, which was determined by NMR as a (6 beta, 88) -isomer. Mr isomer when standing in vacuum
    forms a white solid
    (250 mg), identified as the (6-beta, 8S) -isomer. Both compounds have a (5) -stereoconfiguration in the 1- (ethoxycarbonyloxy) ethyl ester group.
    LP isomer. H-NMR (300 MHz, CDCl1) (ppm: 1.28 (t, 3N); 1.46-1.62 (m, 6H); 1.66 (s, 3N); 3.74 (s, 3N); 4,) 8 (q, 2H); 4.3-4.42 (m, 2H); 5.36 (d, 1H); 5.56 (d, 1H); 6.74 (q, W);
    7.10-7.30 (m, 3N); 7.58-7.72 (m, 1H); (6-beta, 8K-5-ether).
    Mr isomer, H-NMR (300 MHz, CDCl1) S, ppm: 1.30 (t, 3N); 1.46 (s, 3N); 1.54 (d, 3N); 1.64 (s, ZN); 3.88
    21
    (s, ZN); , 18 (KB, 211); 4.42 (s, 1H) 4.52 (dd, 1H); 5.46 (d, 1H); 5.58 (d, 1H); 6.74 (KB, 1I); 7.16-7.42 (m, 3N); 7.64-7.72 (m. III), (6-beta 88, -5-ether).
    Example 29. Compounds are mixed to obtain a powder with a uniform composition in the following ratio, May. 4 .:
    (6-Alpha, 8R) -6- (thiazol-2-yl) acetoxy-methyl-1,1-dioxopenicillanate potassium (a) 1.0 Ampicillin trihydrate (b) 1.0 Lactose (c). 0.5 Polyethylene glycol (average molecular weight 4000) (g) 3.0 A mixture of gelatin capsules (1375 mg) of suitable size is filled and capsules containing 250 mg of each active ingredient are obtained.
    redienta. Capsules with a greater or lesser than 25 internationally active ingredient content are obtained by a corresponding change in the size of the capsule and the mass of the contents of the capsule. The mass ratios of the active ingredients are changed and capsules are obtained in which the mass ratios of the active ingredients differ from I, for example, the ingredients are mixed in a mass ratio of 0.75; 1.5; 0.5 and 3.0, with a total mass of the capsule content of 1700 mg, and receive capsules containing 225 mg of active ingredient (a) and 450 mg of active ingredient (b).
    Formulations for oral administration from other proposed beta-lactamase inhibitors and known beta-lactamase antibiotics are prepared in a similar manner.
    Example 30 Recipe for injection.
    Equal mass parts of cefoperazone sodium and 1,1-dioxo-6 (E) - (2-pyrazinyl) methi-Lenpenencyllanate potassium, and also 20 wt.h. are mixed together. water. Using known techniques, the solution is sterile filtered, poured into ampoules, tightly fixed with rubber gaskets, and freeze dried in trays. The volume injected is such that each lyophilized vial, sealed under vacuum, contains 500 mg of each
    th
    0368-3 active1T) ingredient. Before umipK-tion each; Miiyjiy can be put together by injecting 10 ml of sterile water for injection through a rubber stopper into it and injecting sterile water for injection and shaking until dissolved. An injectable solution with a volume of 1-10 ml is taken through a rubber stopper using a hyiodermic needle.
    Tests for beta-lactamase activity in viLro.
    The beta-lactamase inhibitory activity is determined by comparing the results of in vitro minimal inhibitory concentrations (MIC) in vitro for the test compound to combine with the known beta-lactamase antibiotic ampicillin. Inhibition of beta-lactamase is determined by the degree of synergistic effect of combination compared with ampicillin alone.
    The MIC is determined by the method recommended by
    20
    five
    A typical study of the sensitivity of antibiotics when using extracts from the brain and heart on agar (BH1) and a device for replication of seeding.
    0 Tubes in which growth occurred overnight were diluted 100-fold for use as standard seeding. Approximately 20,000-10000 cells per 0.002 and 20 ml of BH1 agar per dish are placed on the surface of the agar. Twelve dilutions were used 2 times the test compound with an initial concentration of the test medication of 200 µg / ml. Single colons are not taken into account when reading cups after 18 hours at 37 ° C. Sensitivity (MIC) of the test organism is defined as the lowest concentration of test compound or
    5 combinations of compounds that can cause complete inhibition of growth when it is determined with the naked eye.
    The results of the experiments are given in table. 15-17, where the following notation is entered: I - connection only;
    II - ampicillin and compound (1: 1);
    III - ampicillin synergy; PS - clearly expressed synergy; S - synergies;
    g A - additive; N - nothing; AT - antagonism; N1 - no interpretation; NT - not tested.
    From the test results it follows that the proposed compounds have
    0
    23
    each high level of activity as beta-lactamase inhibitors, as they always show activity in experiments with one or more organisms.
    权利要求:
    Claims (1)
    [1]
    1.M, en ;; b, j-b, b (, m, 4H); b, J-b, b (.m,
    2H); 7.45 (m, 1H)
    A mixture of 6-alpha, 8R and 6-alpha, 8S isomept1
    ditch
    1.4 (s, 3N); 1.60 (s, 3N); 2.50 and 2.60 (s, 3N); 4.1-4.4 (m, 1H); 4.4 and 4.5 (s, 1H); 4.6-5.0 (m, 3N); 5.1-6.0 (m, 4H); 6.0-7.2 (m, 4H)
    1.4 (s, 3N); 1.6 (s, 3N); 3.0 (ws, IH); 3.7-4.0 (m, 1H); 4.4-4.8 (m, 4H); 5.0 N 6.3 (m, 6H)
    and D, J VM, OP
    1.36 (s, 1.5H); 1.40 (s, 1.5H); 1.60 (s, 1.5H); 1.65 (s, 1.5H); 3.7 (s, ZN); 4.0- 4.5 (m, 2H); 4.4 (s, 1H); 4.5-4.8 (m, 2H); 5.0-6.0 (m, 4H); 6.7 (s, 1H); 6.85 (s, 1H)
    R
    52
    CeHj-H-N 42
    U
    57 -A (less (syrup polar) isomer) 9 (LP). 9 (MP)
    26
    SNS
    And - chloroform: ethyl acetate (9: 1); B - ethyl acetate: chloroform (7: 3); C - chloroform: ethyl acetate (19: 1); D is chloroform: methanol (19: 1); E is chloroform; F - chloroform: ethyl acetate (1: 1); G - ethyl acetate, Original aldehyde: -diethoxymethylimidazole-2-carboxaldehyde.
    ALLYLT SCh lI and L 2 6- (substituted by acetoxy and metnp) 1H1N1; 1ty form.cho OCOCHIO / O
     he.
    -rrVcH:. „;
    СООСН2СН СН2
    N
    N Mixture 6-al-100 fa, 8S and 6-apf, 8R
    A mixture of 6-al fa, 8S and 6-alpha, 8R (60:40)
    - 69
    A mixture of 6-alpha, 8S and 6-alpha, 8R (60:40)
    66
    92
    Tabli ca 3
    Potassium salts of 6- (substituted acetoxymethyl) penicillanic acids
    formulas
    OOSNZ about 0
    but
    A mixture of 6-al- A mixture of iso- Purified: 1.45 (s, 3N); 1.58 fa, 8S and measures: 57 (s, 3N); 1.25 (s, 1.05H); 1.32 6-alpha, 8R (crude) (s, 1.95H); 4.25 (s, 0.65H); 4.28 (65:35) 21 (chromium- (s, 0.35H); 4.37 (dd, 0.65H);
    tografy is 4.45 (dd, 0.35H); 5.15 (d, 0.65H);
    Cheschi 5.2 (d, 0.35H); 6.25 (d, 0.65H);
    H:. „;
    СООСН2СН СН2
    I, 43 (s, 3N); 1.63 (s, ZN); 2.25 (s, 3N); 4.51 (m, 2H); 4.79 (m, 2H); 5.43 (m, 2H); 5.98 (m, 1H); 6.65 (d, 1H); 7.5 (m, 3N); 7.98 (s, 1H); 8.20 (m, 2H)
    1.4 (s, 1.8H); 1.43 (s, 1.2H); 1.56 (s, 1.2H); 1.62 (s, 1.8H); 2.2 (s, 1.2H); 2.3 (s, 1.8H); 4.35 (m, -IH); 4.4 (s, 0.6H); 4.43 (s, 0.4H); 4.78 (d, 0.6H); 4.8 (d, 0.4H); 5.3-5.5 (m, 2H); 5.8-6.05 (m, 1H); 6.3 (m, 1H); 7.45 (d, 1H); 8.82 (d, 1H); 9.25 (m, 1H)
    1.4 (s, 1.8K); 1.5 (s, 1.2H), 1.6 (c l, 81i); 1.65 (s, 1.2H); 2.2 (s, 1.2H, 2.26 (s, 1.8H); 4.23 (dts, 0.4H); 4.35 (dd, 0.6H); 4.4 (s, 0, 6H); 4.45 (s, 0.4H); 4.68 (m, 2H);
    4.74 (d, 0.6H); 5.0 (d, 0.6H); 5.0 (d, 0.4H); 5.35 (m, 2H); 5.9 (m, 1H); 6.45 (m, 1H); 8.6 (m, 2H);
    8.75 (m, 1H)
    Dark green liquid
    sn.
    A mixture of 6-alpha, 8S and 6-alpha, 8R in a ratio of 6: 1
    cleared Hbrfl)
    6A
    A mixture of 6-al-84 (sypha, 8S and 6-swarm) 43 alpha, 8R (30:70)
    (after chromatographic
    cleaning -...- ki)
    Using C (monooctadecylsilicate) column.
    Table A 6-Bram-6- (substituted oxymethyl) and propyl formula
    He vg o
    ,, tH O li- - -OOOO,
    6.35 (d, O.ZN); 7.73 (m, 1H); 8.85 (m, 1H); 9.15 (m, 1H)
    1.44 (s, 3N); 1.5 (s, 3N); 1.62 (s, ZN); 2.2 (s, 0.4H); 2.24 (s, 2.6H); 3.8 (s, ZN); 4.27 (s, 1H); 4.4 (dd, 1H); 4.96 (d, W); 6.45 (d, 0.15H); 6.5 (d, 0.8H); 7.07 (s, 0.15H); 7.1 (d, 0.85H); 7.16 (s, 0.15H); 7.2 (d, 0.85H), IR spectrum (KBG), cm-: 3409, 1786, 1740, 1620
    1.3 (s, 2.1H); 1.34 (s, 0.9H); 1.42 (s, 3N); 2.13 (s, 0.9H); 2.2 (s, 2.1H); 3.66 (s, 0.7H); 3.7 (s, 0, 3N); 4.1 (yes, 0, 3N); 4.95 (d, 0.7H); 5.07 (d, 0, 3N); 6.24 (d, 0, 3N); 6.36 (d, 0.7H); 8.7 (s, 2H); 8.8 (s, 0.7H); 8.83 (p. O, 3N); IK-sp (KVg), 3468, 1781, 1746, 1623
    6-Bromo 6- (substituted acetoxime (yl) penicides) and 1ate of formula
    Especially about I BP V SNG
    K2-CH,
    sn
    SNS
    tb l and c and
    Table 8 Allyl-6-bromo-6- (substituted hydroxymethyl) genicillanates of the formula
    HE
    I CH
    BG H.S
     %
    (0-,
    N
    J
    Sbnb
    (
    v
    20 (isomer Isomer A: 1.46 (s, 3N); 1.64 (s, 3N); 4.42 A, white (d, 1H); 4.50 (s, 1H); 4.64 ( m, 2H); 5.26-crystals), 5.50 (m, 3N); 5.84 (s, 1H); 5.8-6.0 (m, 13 (isomer 1H); 8.58 (d, 2H); 8.9 (s, 1H); s-NMR B, yellow (CDCl): 26.4; 32, 5; 64.4; 66.1; 69.8; oil) 170.9; 73.7; 74.9; 119.5; 131.0; 143.0;
    144.3; 144.6; 152.1; 166.8; 167.8
    Isomer B: 1.45 (s, 3N); 1.63 (s, ZN); 4.56
    (s, 1H); 4.65 (m, 2H); 5.1-5.5 (m, 4H);
    5.6-6.0 (m, 1H); 5.91 (s, 1H); 8.57 (m, 2H);
    8.78 (m, 1H), C-NMR (CBC1e): 26.27; 32.57;
    64.30; 66.19; 69.19; 69.94; 70.77; 72.38;
    74.73; 119.70; 130.98; 143.30; 144.57;
    144.70; 152.04; 166.99; 167.99
    25 (isomer 1.52 (s, 3N); 1.70 (s, 3N); 4.64 (s, 1H);
    A, 8S) 4.72 (m, 2H); 4.86 (d, 1H); 3.34-5.48 (m,
    ZN); 5.91 (s, 1H); 5.92-6.05 (m, 1H); 7.39
    (t, 1H); 8.87 (d, 2H); 52 (s, ZN); 1.71. (S, 3N);
    40 4.61; (s, 1H), 4.72 (m, 2H); 4.98 (d, 1H);
    (isomer 5.30-5.52 (m, 3N); 5.90-6.04 (m, 1H); 6.10
    B, 8R) (s, 1H); 7.40 (t, 1H); 8.85 (d, 2K)
    83 (foam) 1.49 (s, 3N); 1.69 (s, ZN); 3.56 (d, 0.7H); 3.89 (d, 0, 3N); 4.7 (m, 3N); 5.5 (m, 3N); 5.9 (m, 3N); 8.14 (m, ЗН)
    SNS SNZ
    СООСН2СН СН2
    Continuation of table.8
    5.2-6.2 (m, 5H); 8.67 (sh. S, 2H); 9.00 (sh. S, 1H)
    R
    ABOUT
    N
    TO
    {8B)
    35 (oil from isomer A, 8S)
    65 (of isomer B, 8S)
    100
    81 (without cleaning)
    36 (after cleaning)
    7.5 (6p, 8r)
    CH2CH2CHN
    14 (6, 8S)
    ABOUT
    30 (yellow oil, 6., 8S)
    1.51 (s, 3N); 1.47 (s, 3N); 4.01 (dd, 1H); 4.44 (d, 1H); 4.60 (s, 1H); 4.70 (d, 2H); 5.40 (m, 3N); 5.60 (d, 1H); 5.96 (m, 1H); 7.34 (t.Hi); 8.80 (d, 2H)
    1.52 (s, AH); 1.78 (s, 3N); 4.23 (m, 2H); 4.64 (s, 1H); 4.71 (d, 2H); 5.30-5.46 (m, 3N); 5.53 (d, 1H); 5.90-6.04 (m, 1H); 7.34 (t, 1H); 8.85 (d, 2H)
    1.47 (s, NN); 1.67 (s, ZN); 4.16 (m, 2H);
    4.64 (m, ЗН); 5.47 (m, 4H); 5.94 (m, 1H);
    7.43 (m, 3N); 8.02 (m, ЗН)
    1.42 (s, 3N); 1.7 (s, 3N); 4.4 (dd, J 4 Hz, 8.1 N); 4.5 (s, 1H); 4.65 (m, 2H); 5.2-6.3 (m, 3N); 5.6 (d, J 4 Hz, 1H);
    5.6 (d, J 8 Hz, 1H); 7.2-7.6 (m, 2H); 7.8-8.1 (m, 2H)
    1.45 (s, ZN); 1.55 (s, 3N); 4.15 (d, 1H);
    4.5 (s, 1H); 4.65 (m, 2H); 5.2-6.5 (m, 5H); 7.2-7.6 (m, 2H); 7.8-8.2 (m, 2H)
    1.3 (s, 3N); 1.54 (s, ZN); 3.68 (s, 3N); - 4.42 (s, IH); 4.56 (m, 2H); 5.1-5.4 (m, 3N);
    5.48 (d, IH); 5.76-5.94 (m, 1H); 7-7.3 (m, 3N); 7.54 (d, 1H)
    -8R isomer: 1.40-1.55 (m, 6H); 1.75 (s, NN); 4.1-4.4 (m, 2H); 4.52 (m, 2H); 4.6 (dd, 1H); .
    4.7 (d, 2H); 5.2-5.3 (m, 3N); 5.8-5.1 (m, 1H); 7.2-7.5 (m, 3N); 7.7-7.9 (m, 1H), 8S isomer: 1.4-1.55 (m, 6H); 1.64 (s, ZN); 4.14 (q, 1H); 4.42 (q, 1H); 4.5 (s, 1H); 4.64 (m, 2H); 5.2-5.5 (m, 2H); 5.9 (d, 1H); 5.8-6.0 (m, 1H); 7.1-7.4 (m, 3N); 7.65 (m, 1H)
    0.98 (t, 3N); 1.5 (s, 3N); 1.7 (s, 3N); 1.87 (m, 2H); 4.0-4.4 (m, 2H); 4.4-4.6 (m, 2H); 4.68 (d, 2H); 5.2-5.5 (m, 3N); 5.7 (m, 1H); 5.84-6.00 (m, IH); 7.2-7.3 (m, 3N); 7.667 .8 (m, 1H)
    1.0 (t, 3N); 1.40 (s, 3N); 1.64 (s, ZN); 1.9 (m, 2H); 4.05 (m, 1H); 4.3 (m, 1H); 4.5 (s, 1H); 4.6-4.7 (m, 3N); 5.2-5.4 (m, 4F); 5.6 (d, 1H); 5.84-6.00 (m, 1H); 7, -7.3 (m, 3N);
    7.6 (m, 1H)
    1.44 (s, 3N); 1.64 (s, ZN); 4.3 (dd, 1H);
    4.65 (s, P1); 4.66 (d, 2H); 5.2-5.6 (m, 31); 5.62 (d, 1H); 5.8-6.1 (m, 1H); 7.32-7.42 (m, 2H); 7.52-7.64 (m, 1H); 7.7-8.2 (m, 1I)
    I
    SNS
    13 (6 | 3,8R)
    sn
     18 (6p, 8R)
    16 (6p, 8R)
    7.5-7.7 (m, 2H)
    1.5 (s, 3N); 1.68 (s, ZN); 3.28 (s, 3N); 4.36 (dd, 1H); 4.44 (s, 1H); 4.66 (m, 2H); 5.14 (d, W); 5.24-5.5 (m, 2H); 5.7 (d, 1H); 3.8-6.0 (m, 1H); 6.9 (s, 1H); 7.2-7.5 (m, 3N); 7.6-7.8 (m, 2H)
    1.3 (s, 3N); 1.58 (. S, AH); 2.25 (s, 3N); 2.3 (s, 3N); 3.65 (s, 3N); 4.45 (s, 1H); 4.54
    ; 4.6 (m, 2H); 5.2-5.4 (m, 3N); 5.48 5.8-6.0 (m, 1H); 6.77 (s, 1H); 7.26
    (dd, 1H) (d, 1H); 1H)
    (d, 1.44 (s.
    ZN);
    1.62 (s, ZN); 2.18 (s, 3N); 2.26 (s, 3N); 3.62 (s, 3N); 4.34 (s, 1H); 4.4 (ds, 1H); 4.6 (d, 2H); 5.2-5.4 (m, 3N);
    1H); 5.8-6.0 (m, 1H); 6.88 (s, 1H);
    5.44 (d, 7.24 (m
    1H)
    9.6 (two isomers 6 (3, 8S) 14 (two isomers 6p, 8R)
    (a mixture of 3,5-dimethyl- and 3,6-dimethyl- compounds-)
    SNZ Oh
    13 (6p, 8s)
    10 (6p, 8r)
    SNZO
    (85) -isomer: 1.42 (s, 3N); 1.68 (s, ZN); 2.46 (s, 1.5H); 2.5 (s, 1.5H); 3.82 (s, 3N); 4.52 (s, 3N); 4.6 (2dd, 1H); 4.7 (m, 2H); 5.2-5.7 (m, 4H); 5.8-6.05 (m, 1H); 7.0-7.3 (m, 2H); 7.4-7.7 (m, 1H), 8R-H30Mep: 1.44 (s, 3N); 1.64 (s, ZN); 2.32 (s, 1.5H); 2.4 (s, 1.5H); 3.6 (s, 1.5H); 3.64 (s, 1.5H); 4.36 (s, 1H); 4.4 (dd, 1H); 4.6 (m, 2H); 5.2-5.5 (m, 2.4H); 5.8-6.0 (m, 1H); 6.8-7.2 (m, 2H); 7.2-7.6 (m, 1H)
    1.32 (s, 3N); 1.58 (s, 3N); 3.66 (s, 3N); 3.78 (s, ZN); 4.46 (s, 1H); 4.52 (dd, 1H); 4.6 (d, W); 5.2-5.4 (m, 3N); 5.5 (d, 1H); 5.8-6.0 (m, 1H); 6.48 (d, 1H); 6.86 (dd, 1H); 7.43 (d, 1H) 1, 46 (s, 3N); 1.66 (s, ZN); 3.66 (s, 3H) v 3.8 (s, 3N); 4.4 (m, 2H); 4.64 (d, 2H) ;. 5.2-5.4 (m, 3N); 5.62 (d, 1H); 5.82-6.0 (m, 1H); 6.58 (d, 1H); 6.8 (d, 1H); 7.5 (d, W)
    1.28 (s, 3N); 1.54 (s, ZN); 3.68 (s, 3N); 3.72 (s, 3N); 4.4 (s, 1H); 4.52 (dd, W); 4.56 (m, 2H); 5.1-5.4 (m, 3N); 5.48 (d, W); 5.76-5.9 (m, 1H); 6.8 (dd, 1H); 6.96-7.1 (m, 1H); 7.28 (s, 1H)
    ZN);
    ZN); 4.6
    1H)
    16 (6p, 8R)
    75
    82
    94
    95
    8R (isomer A)
    8S (isomer B)
    8S (isomer A)
    8R
    97
    8R
    85
    65
    91
    8R
    87 (crude) 34 (cleaned)
    59 (solid)
     /
    COOK
    1.46 (s, ZN); 1.56 (s, ZN); 3.76 (s, .1H); 4.13 (dd, 1H), 5.05 (d, 1H) ;. 5.4 (d, 1H); 8.58 (d, 2H); 8.72 (s, 1H), IR spectrum, (KBG), 3478, 1761, 1607
    1, A2 (s, 3N); 1.65 (s, ZN); 4.25
    (s, ZN); 4.27 (dd, 1H); 5.3 (d,
    1H); 5.35 (d, 1H); 8.6-8.7 (m, 2H); 8.8 (m, 1H)
    (Da): 1.32 (s, 3N); 1.54 (s, ZN);
    4.18 (s, 1H); 4.14-4.19 (m, 1H);
    5.19 (d, IH); 5.25 (d, 1H); 7.45 (t, 1H); 8.75 (d, 2H)
    (DjO): 1.44 (s, 3N); 1.58 (s, 3N); 4.12 (s, 1H); 4.18 (m, 1H); 5.22 (d, 1H); 5.49 (d, 1H); 7.46 (t, 1H); 8.75 (d, 2H)
    1.47 (s, 3N); 1.58 (s, 3N); 3.79
    (s, 1H); 4.13 (dd, 1H); 5.2 (d, 1H); 5.4 (d, 1H); 5.95 (sh. S, 1H); 7.45 (t, 1H); 7.60 (t, 2H); 8.03 (d, 2H) 8.26 (s, 1H)
    1.48 (s, ZN); 1.67 (s, ZN); 4.27 (dd, J 4 Hz, 1H); 4.73 (s, 1H);
    5.45 (d, J 4 Hz, 1H); 5.57 (d,
    J 10 Hz, 1H); 7.45-7.65 (m, 2H);
    8.04 (t, J - 8 Hz, 2H), IR spectrum (KBr); 3424, 1765, 1746, 1592
    1.42 (s, 3N); 1.56 (s, ZN); 4.16
    Cc, 1H); 4.25 (dd, j 4 and 8 Hz, 1H);
    5.46 (d, J 4 Hz, 1H); 5.5 (d, J 10 Hz, IH); 7.4-7.6 (m, 2H); 7.88 .05 (m, 2H)
    (B; o): 1.26 (s, 3N); 1.48 (s, 3N); 3.76 (s, 3N); 4.16 (s, 1H); 4.36 (dd 1H); 5.3-5.45 (m, 2H); 7.2-7.3 (m, 2H); 7.3-7.6 (m, 2H)
    53 1503683
    Table
    Esters of 6- (substituted 11yi acyloxnmethyl) | 1e111111il.ch. and (oic acid
    formulas
    WITH
    2-Tiaeolil
    9
    ((less polar, yield 22%)
     2-thiazolyl
    About With, N, CI I
    + (R)
    (S)
    (more than half of p 11, exit 4IZ)
    (S) (less. Polar)
    (R) (more polar)
    1.6 (s, 2.1H); 1.65 (s, 0.9H); 4.4 (s, 0.7H); 4.5 (s, 0, 3N);
    4.5-5.0 (m, 4H); 5.1-6.2
    (m, 3N); 6.9 (d, 1H); 7.4 (m,
    1H); 7.8 (d, 1H)
    1.37 (m, 3N); I, 50 (m, 3N); 1.65 (s, ZN); 1.82 (s, 3N); 2.70 (m, 1H); 4.61 (s, 1H);
    4.7 (m, IH); 4.9 (m, 2H); 5.12 (d, 1K); 5.41 (m, 1H); 5, -6 (m, W); 5.8-6.5 (m, 1H); 6.75 (d, 1H); 7.7 (d, 1H); 7.97 (d,
    1H)
    1.18 (m, 3N); 1.48 (m, 3N); 1.33 (s, 3N); 1.52 (s, 1H); 2.6 (m, 1H); 4.3-4.7 (n, 5H); 5.0-5.4 (m, 2H); 5.45-6.2 (m, 1H); 6.47 (d, 1H); 7.23 (d, 1H); 7.63 (d, 1H)
    1.4 (s, 3N); 1.6 (s, 3N);
    4.5 (s, 1H); 4.4-4.6 (m, 1H); 5.1 (d, 1H); 5.2 (s, 2H); 6.7 (d, 1H); 7.2-8.2 (m, I2H),
    1.3 (s, 3N); 1.6 (s, 3N); 4.5 (s, 1H); 4.6 (ds, 1H); 4.86 (d, 1H); 5.2 (s, 2H); 5.83 (d, 1H); 7.3-7.7 (m, 9H);
    7.8 (d, 1H); 8.15 (dd, 2H)
    150368356
    Table 12 Salts of b- (substituted acyloxymetesh) penidyl lanates of the formula
    OR,
    R (yield 27%)
    Table 13
    6- (substituted hydroxymethyl) penicillanic acid esters
    formulas
    OH SH about. about
    B, 4n.
    CHj
    soy
    Benzyl
    c: x
    100
    All il
    38
    3.73 (s, 1H); A, 23 (dd. 1H); A, 93 (d, lH) j 6.50 (d, 1I); 7.85 (m, 2H), IR spectrum (KBG), 3777, 3472, 3447, 3402, 3270, 1783, 1746,) 621
    1.17 (d, 3N); 1.20 (d, 3N); 1.6 (s, 3N); 2.69 (m, 1H); 3.68 (s, 1H); 4.12 (dd, 1H); 4.93 (d, 1H); 6.59 (d, 1H); 7.84 (m, 2H); IR spectrum (KBG), cm-: 3543, 3498, 3437, 3415, 3348, 3270, 3119, 1917, 1783, 1745, 1718, I S. I 9
    CHj
    soy
    1.25 (s, 3M); 1.52 (s, 3N); 4.45 (s, 0.75H); 4.52 (s, 0.2511); 5.1-5.4 (m, 4P); 7.3 (s, 5I); 8.6 (m, 2H); 9.0 (m, 1H)
    1.38 (s, ZI); 1.60 (s, 3N); 4.38-4.73 (m, 3N); 5.0-6.0 (m, 5H); 7.10 (s, 1H); 8.51 (p. 111)
    Nssb
    U
     n-NMR () 5, ppm: 1.45 (s, 3N); 1.65 (s, ZN); 4.3 (s, 1M); 4.4 (dd, j 10 and 4 Hz, 1H); 5.43 (d, J 4 Hz, 1H); 5.55 (d, J - 10 Hz, 1H); 7.85-7.9 (m, 2H); 8.0-8.3 (m, 2H); IR spectrum (KVg), cm: 3413, 1763, 1591
     n-NMR () S, h, ppm: 1.42 (s, 3N); 1.62 (s, ZN); 4.16 (dd, 1H); 4.24 (s, 1H); 5.46 (d, J - 5 Hz, 1H); 5.5 (J 8 Hz, 1H); 7.4-7.6 (m, 2H); 7.75-7.95 (m, 2H); IR spectrum (KVg), cm: 3489, 1765, 1597
    591503683
    Imgmbironin beta-lzhtaia1i l compounds of the formula
     ABOUT,
    60
    Table 16
    Ingnirovakep Oet-lactampey for compounds of the formula
    OR,
    I "OH
    B, CH
    CH5
    About COOK
    Table 17
    CH5
    About COOK
    (Ri - Na or K)
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    同族专利:
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    CS248749B2|1987-02-12|
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    YU119687A|1988-04-30|
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    ES548427A0|1987-05-01|
    PL256015A1|1986-11-18|
    ES8604972A1|1986-02-16|
    ES548426A0|1986-11-16|
    NO850350L|1985-07-31|
    ES539890A0|1986-02-16|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US57535484A| true| 1984-01-30|1984-01-30|
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