• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Cephalosporin derivatives of formula (I): wherein R Is an acyl group of the formula: wherein R' is a 5- or 6-membered heterocyclic ring and ⊕R1 is an optionally substituted thieno- or furo-pyridinium system are particularly effective antibacterial agents; or (R is hydrogen) useful intermediates. Also disclosed is the useful and novel intermediate 2-carboxy-thieno(3,2-c)pyridine".
    公开号:SU1169542A3
    申请号:SU823485553
    申请日:1982-09-06
    公开日:1985-07-23
    发明作者:Генри Уолкер Ланн Вильям；Теодор Васильефф Роберт
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    3
    1000 mg of the proposed antibiotic in 50 and 100 ml of O, 9% saline. An intravenous solution can be obtained, for example, by forming a single dose of an antibiotic in a plastic capsule, to which a diluent is added before infusion.
    The pharmaceutical compositions of the subject compound also include unit doses. Such doses include from 200 mg to 10 g of an antibiotic or a pharmaceutically acceptable non-toxic salt thereof in solid form in a sterile vial, vial or plastic container such as a capsule for intravenous use. The antibiotic may be in an amorphous or crystalline state. Such moldings may also contain a buffering agent, an agent for dissolving, an agent for producing a clear solution, a stabilizing agent, and other excipients.
    An example of a pharmaceutical composition of the inventive compound for intravenous use comprises 500 mg of a dry powder antibiotic or its pharmaceutically acceptable salt in a 10 ml sterile rubber-sealed ampoule. Another composition includes 4 g of a dry antibiotic powder in a 100 ml sterile ampoule. The further composition comprises 10 g of the antibiotic as a dry powder in a closed sterile plastic bag. Suppositories can also be used to treat bacterial infections in mammals (humans and animals) using an effective amount of from 100 mg to 2 g of the compound of formula (1) or a pharmaceutically acceptable salt of this compound to mammals.
    The antibiotic can be administered in a single dose or repeatedly, for example, one to four times a day. Intravenous dosage can be administered over an extended time interval, for example, for hospitalized patients within one to two hours. This method can practically also be used to administer a dose simultaneously with an intravenous fluid such as plasma, plasma filler, 5% dextro or glucose using the dropper method. Typically, for intravenous infusion, the unit dose composition of the antibiotic in the plastic intravenous bag 5 is dissolved in the desired volume of diluent and the solution is infused.
    The invention is illustrated by examples where the following abbreviations are used: TMSI - trimethylsilyl 10 iodide, THF - tetrahydrofuran, HPLC high performance liquid chromatography, NMR - nuclear resonance spectrum, DMSO D - deuterated dimethyl sulphoxide; and symbols, which characterize the signals of the NMR spectrum; s - singlet, d doublet, k - quartet, m - multiplet, o - very, w - wide.
    NMR spectra were obtained on a YEOLFX-90 instrument,
    Preparative examples describe the preparation of the starting compounds: thienopyridines and furopyridines. Examples describe the preparation of target compounds of formula (1),
    Preparative example 1, 2-Carboxithieno (3,2-e) pyridine. Freshly distilled diisopropylamine (18.5 g, 180 b) was dissolved in dried molecular
    sieve tetrahydrofuran (200 ml). The solution was cooled to and stirred under nitrogen. Then n-butyl lithium (176 mM) was added, keeping the temperature not higher. Then the temperature of the reaction mixture was lowered to using dry ice-acetone. A solution of thieno (3.2-s) pyridine (150 mM) in tetrahydrofuran was added dropwise, maintaining the temperature not higher. The addition was completed after 20 minutes, during which stirring was continued. - Then to the reaction mixture
    carbon dioxide gas was bubbled in such a way that the temperature remained lower for 30 minutes, below -40 ° C for 1 hour and below -15 ° C for 30 minutes. The solvent was evaporated in vacuo and the residue was dissolved in water. The aqueous solution of the diisopropylammonium salt of this compound was washed (X3) with methylene chloride and 120 ml of 5% sodium hydroxide. Cooling in ice water with stirring resulted in precipitation of sodium salt (24.8 g after filtration under vacuum and drying)
    The sodium salt was dissolved in a 10% aqueous solution of methanol and the solution was acidified to pH 6.0 with concentrated hydrochloric acid. After filtration and drying under vacuum, 19.0 g of the indicated target product was obtained.
    NMR (DMSODb): signals at 8.1 (d, 1 proton), 8.2 (s, 1 proton) I 8.5 (d, 1 proton), 9.1 (s, 1 proton).
    Preparative example 2. Furo- {3, 2:) pyridine. To a neat solution of 117.3 g (0.85 mol) of furan-2-acrylic acid. One liter of acetone dried with molecular sieves was added with stirring under nitrogen atmosphere triethylamine (101 g) and the solution was cooled in a bath with an alcohol-ice mixture . 119.35 g (1.1 mol) of ethyl chloroformate was added to the cooled solution over 20 minutes. The rate of addition was such as to keep the solution temperature below 30 ° C. Thereafter, the solution was stirred for 15 minutes, and a solution of 74.5 g (1.3 mol) of sodium azide in 300 ml of water was added at such a rate as to keep the temperature of the reaction mixture below. The reaction mixture was stirred for one hour without external cooling and poured crushed ice into 4 hours and the mixture was stirred gently. The product was filtered, washed with ice water and dried under vacuum to obtain 131 g of furan-2-acrylic acid azide.
    A mixture of 150 ml of diphenylmethane and 27 g (145 mmol) of tributylamine was heated under nitrogen at reflux at 230 ° C using a Wood alloy bath. To the hot mixture was carefully added and in portions 25 g of azide prepared by the above procedure. The temperature of the reaction mixture was maintained at 225-235 seconds during the addition and thereafter at 30 minutes. Diphenylmethane was distilled off from the reaction mixture under vacuum, the residue was cooled and diluted with diethyl ether. The solid was filtered and recrystallized from hot water. After drying, furopyridone (3.14 g) of formula (15) was obtained.
    (one)
    3.14 g of Uropiridone was heated at reflux temperature under nitrogen with 10 ml of phosphorus oxychloride under stirring. Reflux was continued for 1.5 h and then the reaction mixture was poured into: ice. After the ice melted, the product was extracted with 4-chlorofuro (3,2-c) pyrvdine. The extract was dried over sodium sulfate, filtered to remove the drying agent, and quenched to dryness to give 3 g of product.
    A portion of chlorofuropyridine 3 g was added to 35 ml of glacial acetic acid, and 7.5 g of metallic zinc was added to the solution. The reaction mixture was heated under reflux for 4 hours. After completion of the reaction, the mixture was filtered and the filtrate containing furo (3,2-s) pyridine was added to dryness to obtain 5.1 g of crude product. The product was purified by chromatography on a column of silica gel in methylene chloride. The column was eluted successively with 500 ml of methylene chloride, 500 ml of 25% acetone in methylene chloride, 500 ml of 4% acetone in methylene chloride with one liter of 8% acetone in methylene chloride, 500 ml of 12% - acetone in methylene chloride and acetone. The fractions containing the product as shown by thin layer chromatography were combined and evaporated. The semi-solid product was dissolved in 30 ml of methylene chloride and 30 ml of water was added, the pH of the mixture was adjusted to 8.4 with 1N. sodium hydroxide solution and the organic layer was separated. The orsanic layer was dried over sodium sulfate, expelled and blown dry to obtain 1.43 g of furo (3,2-s) pyridine.
    Preparative example 3. Furo (2,3-c) pyridine. Furan-3-methanol (60 g) was dissolved in 3 liters of molecular sieve-dried methanol. 240 g of barium manganate was added to this strongly stirred solution under nitrogen at room temperature. After stirring for 24 hours, thin layer chromatography showed (3: 1 petroleum ether / ether) availability of the starting material, so that 60 g of barium manganate was further added and stirring was continued for 48 hours. so about half of the methylene chloride was removed on the steam bath, and the crude reaction mixture was filtered through a pad of celite. Distillation of this solution at 33 Torr resulted in the recovery of 47.3 g of furan-3-aldehyde, at 67–64 ° C. The prepared furan-3-aldehyde (9.6 g) was dissolved in 200 ml of chloroform. To this solution, stirring at room temperature in a nitrogen atmosphere, a solution of 36.56 g (10 mM) of carbetoxy methylene triphenylphosphorane in 400 ml of chloroform was added dropwise. After the addition was complete, the reaction mixture was heated to reflux for 1 h, cooled to room temperature and evaporated in vacuo. Chromatography on silica gel using methylene chloride as the eluate yielded 4.6 g of furan-3-acrylic acid ethyl ester. The prepared ester was combined with the same ester prepared by the same procedure in the amount of 6.8 g. This substance was dissolved in 60 ml of absolute ethanol, l of magnetic stirring under a nitrogen atmosphere, and at the same time, 16.5 were added dropwise ml 5n. an aqueous solution of sodium hydroxide. The white precipitate formed was stirred at room temperature for 3 hours and evaporated to dryness under vacuum. The obtained solid was dissolved in di-ionized water, a layer was formed with methylene chloride and acidified to pH 1.0 with 6N. hydrochloric acid. The methylene chloride was separated and the aqueous acid solution was washed twice with methylene chloride and the organic extracts were combined, dried over sodium sulfate and evaporated to give 5.3 g of furan-3-acrylic acid. To a solution of 10.2 g obtained by. This furan-3-acrylic acid method in 100 ml of acetone, dried by molecular sieves, and stirred vigorously under nitrogen at a temperature of methanol / ice mixture was added 9.7 g (97 mM) of triethylamine in one portion. 9.33 g (87 mm) of isobutyl chloroformate was added to the cooled solution over a period of 20 minutes so that the temperature did not exceed. After stirring the solution for 15 minutes, a solution of 7.2 g of sodium azide in 30 ml of water was added at a rate to keep the temperature of the reaction mixture lower. Then the reaction mixture was stirred for 3 hours without external cooling and poured into 500 ml of powdered stirred ice. The product was filtered, washed with ice water and dried in vacuo to give 9.1 g of furan-3-acrylic acid azide. A mixture of 36 g of diphenylmethane and 9.72 g of tri-butylamine was vigorously stirred and heated to nitrogen under a Wood alloy bath. 9 g of acid azide was added in portions to the hot reaction mixture and the reaction mixture was stirred for 30 min after the addition and distilled under vacuum; the residue was cooled and diluted with diethyl ether. The solid was separated by filtration and used without further purification in the next reaction. A mass of 6, .1 g of 4.56 g of furopyridone obtained in the preliminary reaction was dissolved in 20 ml of phosphorus oxychloride in a nitrogen atmosphere. After heating for 30 minutes at 110 ° C, a solid began to separate from the solution in the oil bath. Thin layer chromatography of small portions of the reaction mixture neutralized with bicarbonate in 5% acetone / methylene chloride showed no starting material and a new spot. The reaction mixture was cooled to ice temperature and poured into a highly stirred mixture of 300 ml of ice / / 100 ml of ether. This mixture was basified to pH 10 with 50% sodium hydroxide, the organic layers were separated and the aqueous base was extracted with 3X diethyl ether. The organic extracts were combined, dried over sodium sulfate, and evaporated to give 6-chlorofuro solid (2, pyridine, 5.33 g, melting point. 5 g of chlorofuro-C2,3-e) pyridine was dissolved in 50 ml of strongly stirred glacial acetic acid in atmosphere of nitrogen, 11 g of zinc powder was added to this clear solution and the reaction mixture was heated under reflux at 115 ° C in an oil bath for 1.5 hours. Thin layer chromatography with 5% acetone / methylene chloride showed no starting material and the new spot. The zinc powder was filtered using celite and the acetic acid was removed under vacuum. The resulting resin was dissolved in methylene chloride / water and the pH of this mixture was adjusted to 10 with sodium hydroxide. After stirring with a magnetic stirrer for 30 minutes to a stable pH value of 10, the mixture was filtered through celite, the organic phase was separated, dried over sodium sulfate and the solvent was removed under vacuum. Distillation of this liquid in a molecular distillation device at 1 Torr resulted in 2.15 g furo (2,3-e) pyridine. Example 1. syn-7- / 2- (2-amino thiazol-A-yl) -2-methoxyiminoacetamido-3- (thieno / 2,3-b / pyrvidinium-7-shmethyl-3-cephem-4-carboxylate I To a suspension of 910 mg of syn-7- / 2- (2-aminothiazol-4-shl) -2-methoxyimine-cell-amide / -3-acetoximethyl-3-cepheme-4-cannabis acid in 4 ml of chloroform were added 1.25 ml of N -methyl-K-three methypsilyl trifluoroacetamide and the suspension was stirred for one hour after preparing a solution of the silylium derivative. 800 microliters of TMJ was added to the solution with a pipette and the reaction mixture was stirred for 15 minutes and then evaporated. The residue of silylated 3-iodomethyl was The derivative was dissolved in 4 ml of acetonitrile and 175 microliters of THF were added to the solution using a syringe. The solution was stirred for 5 min, after which a solution of 324 mg of thieno (2,3-v) pyrvdin in 1 ml of acetonitrile was added to the solution. for 3 hours at room temperature And then treated with 135 microliters of water. Product., 850 mg, separated by filtration and purified in reversible phase silica gel with HPLC using acetonitrile – acetic acid – water mixture, 5: 2: 93% by volume. After purification, 125 mg of product was obtained. NMR (DMSOD): signals at 9.6 (m, 2H) -, 9.05 (m, 1H) i 8.31 (d. 1H), ca 8.2 (m, 1H) i 7.89 (bs,) ; 6.72 (s, 1H); sa 5.7 (shm, 3N); 5.08 (d, 1H), 3.79 (s. 3N) and ca 3.5 (M, 2H + protons of water) delta. Example 2. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3- (thieno / 3,2-b / pyridinium-4-yl methyl) -3-cephem-4- carboxes1at The specified compound was obtained by the reaction of syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3-iodomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester with thieno (3,2-in a) pyridine according to the procedure described in Example 1. WR (DMSOD): signals at 3.2 (q, 2H, Cj-H) 3.8 (s, 3N, OCHj); 5.0 (d, 1H, Cg-H); 5.6 (q, 1H,) -, 5.8 (q, 2H, Cz-H); 6.65 (s, 1H, H thiazole) 7.2 (s / 2H, H); 7.2-9.6 (multisignals for thienopyridine) and 9.6 / d, 1H, N / delta. Example 3. syn-7- / 2- (2-aminothiazol-4-Sh1) -2-methoxyiminoacet-. amvdo / -3- (thieno / 2, 3-c / pyridinium-6-ylmethyl) -3-cephem-4-carboxylate was obtained by the reaction of trimethylsilylated syn-7- / 2- {2-aminothiazol-4-yl) - 2-methoxyiminoacetamido / -3-iodometsh1-3-cephem-4-carboxylic acid and thieno (2,3-e) pyridine according to the method of example 1. NMR (DMSOD): signals at ca 3,2 (k, 2H, Cj- Hj, masked BUT) -; 3.8 (s, 3N, OCHj)} 5.05 (d, 1H, Ci-H) -, 5.2 (s) i 5.6 (k, 1H, CI-H) J 5.9 (s); 6.7 (s. 1H, H thiazole) J 7.2 (s, 2H, Hj) and 7.95 d 8.55 d, 9.45 m, 10.45 s (H thienopyridinium) delta. Example 4. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3- (thieno / 3,2-c / pyrvdinium-5-shshetil) -3-cephem-4-carboxy-1 prepared by the reaction of trimethylsilylated syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3giodomethyl-3-cephem-4-kvrbonovoy acid with thieno (3,2-e) pyridine according to the method of example 1 .
    NMR (DMSODb): signals at 3.3 (k, 2H, Cj-H); 3.8 (s, 3N, OCH); 5.1 (d. 1H. Ct-H) i 5.7 (m. 2H. Cz-H); 6.7 (s, 1H, thiazole-H); 7.2 (s, 2H, Hj) and 8.0-10.0 (thienopyridinium H). delta.
    255 nm, 8: 19,557.
    UV: L
    tossh
    According to the procedure described and in example 1, the following compounds were prepared.
    Example 5. syn-7- / 2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-yl) -oxyiminoacetamido / -3- (thieno / 3,2-s / pyridine-5- ylmethyl) -3-cephem-4-carbox sipat.
    NMR (DMSOD): signals at 9.98
    (s. 1H) i 9.45 (d, 1H) i 9.25 (d 1H); 8.8 (d, 1H); 8.35 (d, 1H): 7.95 (d, 1H) -, 7.25 (s, 1H), 6.7 (s, 1H); 5.7 (q, 1H); 5.5 (q, 2H), 5.1 (d. 1H);
    3.4 (q, 2H); 1.4 (s, 6H) delta. UV: nm, E: 25,726. Example 6. syn-7- / 2- (2 aminothiazol-4-yl) -2-methoxyimino acetates. Up to / -3- (2-methylthieno / 3,2-s / pyridinium-5-ylmetsh1) -3-cephem- 4-carboxylate.
    NMR (DMSOD): signals at 9.8 (s, 1H) -, 9.5 (d, 1H) j 9.2 (d, 1H) i 8.65 (d, W); 7.6 (s, 1H) i 7.15 (s, 2H); 6.7 (s, 1H); 5.45 (m, 3N); 5.05 (d, 1H), 3.8 s, 3N); 3.3 (q, 2H); 2.7 (s, dd) delta.
    UV: 71t “242 nm,: 31,614.
    Example 7. syn-7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamidO / -3- (2-carboxitieno / 3, 2-c / pyridinium-5-ylmethyl) -3-cephem-4 carboxypate
    NMR (DMSOD: signals at 9.7 (s, 1H); 9.5 (d, 1H) 9.0 (d, 1H) -, 8.7 (d, 1H); 8.1 (s, 1H) ; 7.1 Kc, 2H) i 6.7 (s, IH); 5.7 (q, 1H); 5.3 (d, 2H) and 5.1 (d, 1H); 3.8 (s, 1H); 3.4 (q, 2H) delta,
     nm: 46,000.
    Example 8. syn-7- [2- (2-amino thiazol-4-yl) -2-methoxyiminoacetamido / -3- (3 6-thromieno / 3,2-c / pyridinium-5-ylmetnl) -3-cephem-4 -carboxstat.
    NMR (DMSO / 1 (,): signals at 10.04 (s, 1H); 9.45 (m, 2H) i 8.8 (d, fH);
    8.5 (s, 1H); 7.15 (s, 2H) j 6.65 (s, 1H); 5.6 (q, 1H); 5.5 (q, 2H); 5.05
    (d. 1H); 3.75 / s, 3H) i 3.3 (q, 2H) delta.
     nm, e: 33,500.
    Example 9. syn-7- [2- (2-aminothiazol-4-yl) 2-methoxyiminoacetamido] -3- (2-methoxycarbonylthieno / 3,2-c / pyridinium-5-ylmethyl) -3-cephem-4- carboxylate.
    NMR (DMSOD): signals at 10.1 (with 1H); 9.45 (m, 2H) i 8.8 (d. 1H); 8.55 (s, 1H) i 7.15 (s, 2H) j 6.65 (s, 1H) -, 5.6 (q, 1H); 5.45 (q, 2H), 5.05 (d. 1H); 3.95 (s, ZN); 3.8 (s, 3N), 3, 3 (k, 2H) delta.
    UV nic.3 nm, Y: 52,500. .
    Example 10. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetam-to / -3- (furo / 3,2-s / pyridinium-5-S1methyl) -3-cephem-4 carboxylate
    A suspension of 910 mg (2 mmol) of syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3-acetoxymethyl-3-cephem-4-carboxylic acid in 5 ml of methylene chloride was treated with 1.24 ml (7 mmol) N-methyl-N-trimethyl silyl trifluoroacetamide. (MSTFA). and the mixture was heated to 40 ° C to achieve silylation. After the solution was formed, it was cooled to room temperature and 0.77 ml: (5.4 mmol) TMSI was added using a syringe. The reaction mixture was stirred: dried at room temperature under a nitrogen atmosphere for 3/4 h and then blended to form a brown oil. The oil was dissolved in 5 ml of acetonitrile and 0.73 ml (9 mmol) of THF was added. The solution was stirred for 10 minutes. 286 mg (2.4 mmol) of furo (3,2-e) pyridine in 5 ml of acetonitrile was added to the solution, to which 0.43 ml (2.4 mmol) of MSTFA was added. The combined solutions were stirred at room temperature under nitrogen atmosphere in for 2 hours. The reaction mixture was diluted with diethyl ether and three drops of water were added to precipitate the product as a tan solid. The mixture was allowed to settle, filtered, washed with diethyl ether and dried at 40 ° C for 1 h under vacuum to obtain 1.28 g of crude cefelosporin product. The product was purified by preparative HPLC using 5% acetonitrile, 2% acetic acid, and 93% water. Received 14 mg 2-ce
    The product themes and 580 mg of 3-cephem are in the form of a white powder.
    PRI me R 11. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide / -3- (2.-methylfuro / 3,2-s / pyridinium-4-ylmetsh1) -3-cephem-4-carboxylate.
    syn-7- [2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxime. methyl-3-cephem-4-carboxylic acid, 910 mg (2 mmol) was suspended in 5 ml of methylene chloride and the suspension treated with 1.24 ml (7 mmol) of MSTFA under nitrogen. The suspension was heated at 40 ° C until a solution of the silylated derivative was formed (3 minutes). The solution was cooled to room temperature and 0.77 ml (5.4 mmol) TMSI was added using a syringe. The solution was stirred for 45 minutes at room temperature under a nitrogen atmosphere to form a silylated 3-iodomethyl derivative. Thereafter, a solution of 319 mg (2.4 mmol) of 2-methylfuro (3,2-b) pyridine in 10 ml of acetonitrile was added to the reaction solution and the mixture was stirred for 3 hours. Then the reaction mixture was diluted with diethyl ether and two drops of water were added . A thick yellowish-brown precipitate was formed and was subjected to ultrasound, filtered, washed with diethyl ether and dried under vacuum at 40 ° C to obtain 1.03 g of the product. The product was purified by reversible chromatography on silica gel using 5% adetonitrile, 2% acetic acid, 93% water (by volume) to give 348 g of purified product.
    NMR (90 MHz, DMSOD): 9.45 (d, 1 9.3 (d, 1H) i 8.7 (d, 1H) i 7.9 (m, 1H 7.15 (s, 2H); 6 , 65 (s, 1H), - 5.6 (m, ZN) - 5.0 (d, 1H); 3.8 (s, ZN); 3.4 (q, 2H); 2.7 ( s, ZN) delta.
    UV: 1n, ah256 nm, t: 17,924.
    EXAMPLE 12 syn-7- / 2- (2-amia thiazol-4-yl) -2-methoxyiminoacetamido / -3- (2-metsh1furo / 2,3-c / pyridinium-6-sh1methyl) -Z-cephem-4-carboxylate.
    Following the procedure and conditions of the previous example, 11, 910 g (2 mmol) of the same starting material was converted to an I-silipated 3-iodomethyl derivative and the reaction was performed after 2-methyl-furo (2,3-c) pyridine. The product was precipitated, recovered and purified using the procedures described in Example 18 to obtain 526 mg of the purified title compound.
    NMR (90 MHz, JJMCOflg): 10.03 (s, 1H 9.45 (d, 1H) J 9.15 (d, 1H) i 8.15 (d, 1H); 7.1 (s, 3N); 6.65 (s, 1H); 5.6 (m, 2H) i 5.05 (m, 2H) i 3.75 (s, 3N) 3, 3 (k, 2H), 2.65 (s, ZN) Delta.
    UV:; | „268 nm,: 22,278.
    Similarly, examples were obtained. Example 13. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3- (furo / 2,3-v / pyridinium-7-ylmetnp) -Z- cephem-4-carboxylate.
    NMR (DMSOD): signals at 9.4 (m, 2H) i 8.1 (m, 2H); 7.2 (s, 2H); - 6.7 (s, 1H); 5.65 (m, 3N) {5.05 (d, 1H), 3, 8 (s, 3N); 3.2 (s, 2H) delta.
    UV Lo, x232 nm, e: 19,100j
    252 nm, e: 18,000.
    So
    Example 14. syn-7- [2- (2-amine thiazol-4-yl) -2-methoxyiminoacetamido-3- (furo (3,2-in / pyridinium-4-ylmethyl) -3-cephem-4-carboxylate .
    NMR (DMSOD): signals at 9.4 (m, 2H); 8.85 (m, 2H); 8.0 Cm, 2H); 7.15 (s, 2H); 6.65 (s, 1H); 5.6 (m, 3N) 4.95 (d, 1H); 3.7 (s, ZN); 3.15 (q, 2H), delta.
     nm, B: 22,844.
    Example 15. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyimino acetates to -3- (furo / 2,3-c / pyridinium-6-ylmethyl) -3-cephem-4- carboxylate.
    NMR (DMSOD): signals at 10.2 (s, 1H); 9.5 (d, 1H) i 9.3 (d, 1H); 8.8 (s, wildebeest, 8.35 (d, 1H) -, 7.45 (s, W) -, 7.15 (s, 2H) i 6.65 (s, 1H) i 5.65 ( k, 1H); 5.4 / k, 2H) j 5.05 (d, 1H); 3.75 (s, 3N); 3.3 (q, 2H) delta.
     nm, E: 20,642.
    Example 16. syn-7- / 2-C2-ami.notia-4-yl) -2-methoxyiminoacetamido / -3- (thieno / 3,2-s / pyridinium-5-ylmeTSH1) -3-cephem-4- Carboxylate.
    7-aminocephalosporic acid (2.7 g, 10 mmol) and thieno (3,2-c) pyridine (3.0 g, 10 mmol) in the form of its tolylsulfonyl salt were suspended in a mixture of water (25 ml) and acetonitrile (25 ml), the pH was adjusted to .7.3 with sodium hydroxide. Then the reaction mixture was heated in an oil bath for 2 and 3/4 h and then cooled to 0 ° C and the pH at that time was 6.8 °. Next, the pH of the reaction mixture was adjusted to 7.5 with 2N. sodium hydroxide. The product of this procedure was a compound of the formula (16) yy, kk s However, this product was not isolated, but was used on site in the next reaction stage. In other words, the 7-amino nucleus represented by the formula (16) was immediately acylated by adding the active ester CIN-1 - / (2-amino-4-thiazolyl) (methoxyimino) acet.yl / 3-hydroxy-1H-ben zotriazolium hydroxide, intramolecular salt (3.0 g) as a solid, to the reaction mixture. After 30 minutes, the pH was adjusted to 7.3 with sodium hydroxide and the reaction mixture was allowed to settle for 16 hours. After standard treatment, 900 mg of the indicated compound was obtained. NMR (DMSOD): signals at 3.3 (2H); 3.8 (s, 3H) i 5.1 (d, 1H) 5.7 (m, 2H) j 6.7 (s, 1H) i 7.2 (s, 2H) and 8-10 (H thienopyridinium a) delta. (x255 nm,: 19,557. Likewise prepared. Example 17. syn-7- / 2- (2-am notiazol-4-yl) -2-methoxyimino-acvtamido / -3- (thieno / 2,3-b / pyridin-7-ylmethyl) -3-cephem-4-carboxylate. NMR (daSOD): signals at 9.6 (m, 2H), 9.05 (m, 1H) -, 8.31 (d, 1H ca 8 , 2 (m, 1H)} 7.89 (Ws, 2H); 6.7 (s, 1H); ca 5.7 (bm, GN); 5.08 (d, 1H), 3.79 (s , 3H) j and Ca 3.5 (m, 2H protons of water) delta. Example 18. syn-7- / 2- (2-am notiazol-4-yl) -2-methoxyiminocetate to / -3- (thieno / 3.2-in / pyridinium-4-ylmethyl) -8-cephem-4-carboxylate. NMR (DMSODb): signals at 3.2 (q, 2H,) - 3.8 (s, 3N, OCHj); 5 ; 0 (d, 1H, Cb-H); 5.6 (c, 1H,; 8 (c, 2H, C -H) -, 6.65 (s, 1H, H thiazole); 7.2 (c , 2H, Hj; 7.29 .6 (multisignals d dienopyridine) and 9.6 (d, 1H, I) delta. Example 19. syn-7- / 2- (2-aminothiazol-4-sh1) -2-methoxyiminoacetamido / -3-Stieno / 2, 3-s / pyridinium-6-ylmethyl) -3-cephem-4-carboxylate. NMR (DMSOD): signals at ca 3.2 (k, 2H, Cj-Hji disguised HOD); 3.8 (s, 3N, OCHj) 5, 05 (d, 1H,) 5.2 (s), 5.6 (q, 1H, C, -H)} 6.7 (s, 1H, thiazole H) 7.2 (s, 2H, H); and 7.95 d 8.55 d 9.45 m, 10.45, s (H thienopyridinium) delta. I. . Example 20. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacet-. amido / -3- (thieno / 3,2-c / pyridinium-5-ylmethyl) -Z-cephem-4-carboxylate. NMR (DMSODb): signals at 3.3 (k, 2H, C, H); 3.8 (s, 3N, OCH) -, 5.1; (d, 1H, Ct-H); 5.7 (m, 2H,); ; 6.7 (s, 1H, thiazole H); 7.2 (s, 2H, Hg) and 8.0-10.0 (H, thienopyridinium) delta. UV: P1 ".255 nm, C: 19,557. PRI me R. 21. syn-7- [2- (2-aminothiazol-4-yl) -2- (2-carb, oxyprop-2-. -sh1) -oxyiminoacetamido [3- (thieno] / 3,2-c / pyridine-5 -methyl) -3-cephem-4-carboxylate. NMR (DMSOD): signals at 9.98 (c, .1HJJ 9.45 (d, 1H) i 9.26 (d, 1H)} 8.8 (d, 1H) i 8.35 (d, 1H); 7 ., 95 (d, 1H) j 7.25 (s, 1H); 6.7 (s, 1H) -, 5.7 (q, 1H), 5.5 (q, 2H); 5.1 ( d, 1H); 3.4 (q, 2H); 1.4 (s, 6H) delta. UV: nm, t: 25.726. Example 22. syn-7- / 2- (2-aminothiazole-4- (yl) -2-methyriminoacetamido / -3- (2-methylthieno / 3,2-s / pyridinium-5-ylmethyl) -3-cephem-4-carboxylate. NMR (DMSOD): signals at 9.8 (s, 1H ); 9.5 (d, 1H)} 9.2 (d, 1H); 8.65 (1d, 1H) j 7.6 (s, 1H); 7.15 (s, 2H) -, 6, 7 (s, 1H) i 5.45 (m, 3N) -, 5.05 (d, 1H) i 3.8 (s, 3N), - 3.3 (q, 2H) 2.7 (s, ZN) delta. UVL, 242 nm,: 31,614. PRI me R 23. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3- (2-carboxythieno / 3 , 2-c / pyri di-5-ylmethyl) -3-cephem-4-carboxy Lat., NMR (DMSOD): signals at 9.7 (s, t 9.5 (d, 1H) i 9.0 (d, 1H) j 8.7 (l, 1H); 8.1 (s, 1H) j 7.1 (s, 2H) j 6.7 (s, 1H) V 5.7 (k, 1H) j 5.3 (d, 2H, 5.1 (d, W); 3.8 (s, 3H) i 3.4 (c, 2H) delta. UV:; | 245 nm,: 46,000. Example 24. syn-7- / 2- (2-notiazol-4-yl) -2-methoxyimino acetamido (-3- (3-bromothieno / 3,2-c / pyridinium-5-ylmethyl) -3-cephem-4-carboxyl) NMR (DMSOD); signals at 10.04 (s, 1H) - 9.45 (m, 2H) -, 8.8 (d. 1H); 8.5 (s, 1H) i 7.15 (s, 2H) -, 6.65 (s, 5.6 (q, 1H); 5.3 (k, 2H) G5.05 (d, 1H); 3.75 (s, 3N), 3.3 (q, 2H) delta nm, e: 33,500. Example 25. syn-7- / 2- (2-aminothiazol-4-Sh1) -2-methoxyimino acetates to -3- (2-methoxycarbonylthieno / 3,2-c pyridinium-5-ylmethyl) -3-cephem-4-carboxylate. NMR (DMSOD): signals at 10.1 (s, 1HH 9.45 (m, 2H) / 8 , 8 (d, 1H); 8.55 (s, 1H); 7.15 (s, 2H) 6.65 (s 1H) i 5.6 (k, 1H); 5.45 (k, 2H) 5.05 (d, 1H); 3.95 (s, 3N) 3.8 (s, 3H) i 3.3 (q, 2H) delta nm, e: 52,500. Example 26. syn-7- / 2- (2-aminothiazol-4-Sh1) -2-methoxyiminoacetamido / -3- (furo / 3,2-c / pyridinium-5-ylmethyl) -3-cephem-4-carboxylate. Example 27. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamino / -3- (2-methylfuro / 3,2-c / pi Yidinium-4-ylmetsh1) -3-tsvfem-4-carboxylate. NMR (90 MHz, DMSOD): 9.45 (d, 1H); 9.3 (d, 1H); 3.7 (d, W), 7 , 9 (m, 1H) -, 7.75 (s, 1H) i 7.15 (s, 2H) j 6.62 (s, 2H) i 6.65 (s, 1HN 5.6 (m, 1H ); 3.8 (s, 3N); 3.4 (q, 2H), 2.7 (s, 3N) delta. UV: D | 256 nm,: 17.924, Example 28, syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3- (2-methylfuro / 2,3-c / pyridinium-6-ylmetsh1) -E-cephem-4-carboxyYMR (90 MHz, DMSOD): 10 , 03 (s, 1H); 9.45 (d, 1H); 9.15 (d, 1H), 8.15 (d, 1H); 7.1 (s, 9.65 (s, 1H)} 5.6 (m, 2H); 5.05 (m, 2H); 3.75 (s, 3H) 3.3 (q, 2H); 2.65 (s, 3N) delta. UV: a „d 68 nm, b: 22.278. Example 29. syn-7- / 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / -3- ( furo / 2,3-b / pyridinium-7-ylmethyl) -3-cephem-4-carboxylate NMR (DMSOD) signals at 9.4 (m, 2H) i 8.1 (m, 2H) - 7.2 ( s, 2H) 6.7 (s, 1H); 5.65 (m, 3H) i 5.05 (d, 1H) i 3.8 (s, ZN); 3.2 (s, 2H) delta, UV: Lr, nm, f: 19,100. I „d 252 nm,: 18,000. Example 30. syn-7- / 2- (2-amnothiazol-4-yl) -2-methoxyiminoacetamido / -3- (furo / 3,2 -v / pyridinium-4-ylmethyl) -3-cephem-4-carboxylate, NMR (DMSOD4) g signals at 9.4 (m, 2H) i 8.85 (m, 2H); 8.0 (m, 2H ), 7.15 (s, 2H), 6.65 (s, 1H); 5.6 (m, 3H) i 4.96 (d, ZN) 3.7 (s, ZN); 3.15 ( k, 2H) delta., 260 nm, 22.844. Example 31 syn-7- / 2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido / -3- (Furo / 2 C-pyrvdinium-6-yl-methyl) -3-cephem -4-carboxylate. NMR (DMOSD4): signals at 10.2 (s, 1H); 9.5 (d, 1H) - 9.3 (d, 1H) i 8.8 (s, 1H), 8.35 ( d, 1H) -, 7.45 (s, 1H), 7.15 (s, 2H) i 6.65 (s, 1H) i 5.65 (k, 1H) j 5.4 (k, -2H ); 5.05 (d, 1H) i 3.75 (s, 3N); 3.3 (q, 2H) delta. Example 32. In analogy to Example 1, syn-7- / 2- (2-amino-thiazolyl-4) -2-methoxy-imino-JETO / -3- (2-aminothieno / 3,2-c / pyridinium-5-yl-methyl) -3-cefem -4-carboxylate. NMR (DM80, 9.5 (doublet, 1H); 9.2 (s, 1H); 8.7 (d, 1H) i 8.3 (d, 2H) i 7.3 (, s, 2H); 7.2 (s, 2H), 6.7 (s, 1H)} 5.6 (m, 1H); 5.1 d, 1H)
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING THYNOPYRIDININE- OR FUROPYRIDININE - SUBSTITUTED DERIVATIVES OF CEPHALOSPORIN methyl, f
    methoxycarbonyl, a carboxy-general formula group or amino group;
    R 4 is a hydrogen or telogen atom, at least one of the substituents R 3 and R 4 is a hydrogen atom;
    R 5 and R t - a hydrogen atom or methyl, characterized in that,
    6 as syn-isomers where R, is C ^ C ^ -alkyl, free or · f substituted by a carboxy group; R 2 is a bicyclic thienopyrzdinium or furopyridinium radical selected from the group of one of the above general formulas of the silyl acid derivative as a syn isomer.
    where R 1 has the indicated meanings, is reacted with the corresponding SU 1169542 with appropriate thienopyridine or furopyridine in an inert organic solvent in the presence of a base.
    Priority by signs:
    09/08/81 a method for producing thienopyridinium - substituted derivatives of cephalosporin;
    01/18/82 a method for producing furopyridine-substituted derivatives of cephalosporin.
    1 1169542 2
    类似技术:
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    同族专利:
    公开号 | 公开日
    EP0074268A3|1984-05-23|
    PL238158A1|1984-11-19|
    PT75518B|1985-11-12|
    DK399282A|1983-03-09|
    NZ201833A|1985-09-13|
    ES8505374A1|1985-05-16|
    ES8404361A1|1984-04-16|
    EP0074268A2|1983-03-16|
    RO84456B|1984-08-30|
    PT75518A|1982-10-01|
    KR840001585A|1984-05-07|
    GB2105719A|1983-03-30|
    CS232735B2|1985-02-14|
    ES515548A0|1984-04-16|
    CS650582A2|1984-06-18|
    HU187575B|1986-01-28|
    RO84456A|1984-06-21|
    PH19756A|1986-06-26|
    DD209633A5|1984-05-16|
    GR76701B|1984-08-29|
    FI823088L|1983-03-09|
    FI823088A0|1982-09-07|
    ES527763A0|1985-05-16|
    IL66726D0|1982-12-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1399086A|1971-05-14|1975-06-25|Glaxo Lab Ltd|Cephalosporin compounds|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|
    DE2714880A1|1977-04-02|1978-10-26|Hoechst Ag|CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION|
    FR2440738B1|1978-11-13|1981-11-27|Parcor|
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    DE3207840A1|1982-03-04|1983-09-15|Hoechst Ag, 6230 Frankfurt|"CEPHALOSPORINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF"|DE3374410D1|1982-06-28|1987-12-17|Bristol Myers Co|Cephalosporin derivatives, a process for the manufacture thereof and pharmaceutical compositions containing said derivatives|
    US4480098A|1982-11-12|1984-10-30|Eli Lilly And Company|Preparation of alkali metal thienopyridines|
    US4525473A|1983-03-30|1985-06-25|Bristol-Myers Company|Cephalosporins|
    EP0137442A3|1983-10-08|1986-01-15|Hoechst Aktiengesellschaft|Cephalosporin derivatives and process for their preparation|
    NZ209833A|1983-10-17|1988-04-29|Lilly Co Eli|3-bicyclicpyridiniummethyl-cephalosporins and pharmaceutical compositions|
    AT89826T|1985-03-01|1993-06-15|Takeda Chemical Industries Ltd|ANTIBACTERIAL CONNECTIONS, THEIR PRODUCTION AND USE.|
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    US4868294A|1986-07-11|1989-09-19|Bristol-Myers Company|Process for preparing cephalosporin intermediates|
    US4714760A|1985-08-20|1987-12-22|Bristol-Myers Company|Cephalosporin intermediates|
    GB8626245D0|1985-11-27|1986-12-03|Ici Pharma|Cephalosporin compounds|
    US4918067A|1986-07-24|1990-04-17|Beecham Group P.L.C.|Heterocyclic substituted penicillin antibiotics|
    TW526202B|1998-11-27|2003-04-01|Shionogi & Amp Co|Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity|
    US6642238B2|2000-02-10|2003-11-04|Pharmacia And Upjohn Company|Oxazolidinone thioamides with piperazine amide substituents|
    EP1263742B1|2000-02-10|2005-08-24|Pharmacia & Upjohn Company LLC|Oxazolidinone thioamides with piperazine amide substituents|
    US7847093B2|2003-04-16|2010-12-07|Sandoz Ag|Processes for the preparations of cefepime|
    ES2348299T3|2003-04-16|2010-12-02|Sandoz Ag|PROCEDURES FOR THE PREPARATION OF CEFEPIME.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US30035781A| true| 1981-09-08|1981-09-08|
    US34062882A| true| 1982-01-19|1982-01-19|
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