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    • 专利摘要:
    The method of obtaining cephalosporin derivatives of the general formula C C ONH-pY y Ke N CT l V R, O COORz-SNGSOS | O where RJ is a hydrogen atom or a protecting group forming an ester; R. a. Of hydrogen or a protective group forming an ester; R, a hydrogen atom or methyl; R ,, hydrogen or chlorine atom, methyl, vinyl, methoxy group, methoxymethyl, methylthiomethide or acetoxymethyl, and one of RI and R4 means a hydrogen atom or their salts with alkali metals, when R (and / or Rj is a hydrogen atom, in the form of syn -isomers, about tl and h aJtpsc and also with the fact that the compound of the general formula H, Nr-rV, COOE R and E.L have the indicated values of R. cha VIA, or its reactive derivative in the amino group, or its salt is subjected to interaction with compound of general formula
    公开号:SU1155159A3
    申请号:SU823475519
    申请日:1982-08-02
    公开日:1985-05-07
    发明作者:Такая Такао；Такасуги Хисаси；Яманака Хидеаки
    申请人:Фудзисава Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for the preparation of new antibiotics of the cephalosporin series, namely, the derivatives of the cephalosporin of the formula s-gC-esh-, -, .b-cn, juice. where R, is a hydrogen atom or a protective group forming an ester; Rj is a hydrogen atom or a protecting group forming an ester; R is hydrogen or methyl; RA - atom in d | genus a or chlorine, methyl, vinyl, methoxy, methoxymethyl, methylthiomethyl or acetoxymethyl, with one of R and RA signifying a hydrogen atom ,. or their salts with alkali metals, when R. and / or Rj is a hydrogen atom in the form of syn-esters. These compounds have an antimicrobial effect and can be used in medical practice for the treatment of infectious diseases in humans and animals. The known method of obtaining biologically active derivatives with 7-oxides, acetamidocephalosporins, acylation of the corresponding 7-aminocephalosporus or its reactive production by the amino group, or its salt, with the corresponding oxyiminoacetic acid or with the reactive production, or by means of the carboxy group, I will be a part of the carboxy group. g50- + 50 C, s, after graduation, if necessary, removing the protective groups and exposing the desired product in free form or as a salt lj. The purpose of the invention is to obtain new antibiotics of the cephalosporin series with a low minimum inhibitory concentration. This goal is achieved by the method of obtaining cephalus sporin formula (1) or their salts with alkali metals, the compound, the formulas based on the acyliroacanc 7-aminocephalosporin reaction based on the reaction.
    Cs
    -gu
    (111
    .NV
    CZK
    about cool. Where. R ,, R., and R. have the indicated meanings, or its reactive derivative in the amino group, or its salt is reacted with a compound of the general formula K. -tr-Cc soon n JT I H N O-CHrCOOR where R has the indicated values , or with its reactive derivative at the carboxy group, or with its salt and, if necessary, in the resulting compound, where R is a protecting group forming an ester, removing the protective group to give a compound, where Rj is a hydrogen atom, and / or the resulting compound. The scientific research institutes, where R is a protective group forming an ester, remove the protective group to form a compound, where R2 is a hydrogen atom, and the target product is isolated in free form or as a salt with an alkali metal, when R and / or R are hydrogen atoms , in the form of sich-isomer. A suitable reactive derivative at the amino group of the compound (P) may include an imino group of the Schiff's base type or its tautomeric enamine isomer of the type obtained by reacting the compound (P) with a carbonyl compound such as aldegtsz or ketone; silyl derivative, obtained by reacting compound (P) with a silyl compound, such as Sac (trimethylsilyl) acetamide or trimethylsilylacetamide, a derivative obtained by reacting compound (P) with phosphorus trichloride or phosgene. Suitable salts of the compound (P) Moryt include alkali metal salts — sodium or potassium salts, alkali metal salts, for example, calcium or magnesium salts. ammonium salts, salts of organic bases, for example, trimethylamine triethylamine, pyridine, picol new, dicyclohexylamine or N, N-dibenzylethylenediamine salt of organic acids, for example, acetate, maleate, tartrate, methanesulfonate, sodium formate, formate, or formati, formati, i, formati, i, i, i, xe, io, oleo, omethylamine bromohydrate, sulphate or phosphate, or salts obtained as a result of reactions with an amino acid, for example, arginene, aspartic acid or glutamic acid. As suitable salts of the compound (III), the same salts as for compound (P) can be mentioned. The reactive T1O derivative of the carboxy group of the compound (III) may include halide anhydride, anhydride acid, an activated amide, or an activated ester. Examples include acid acid acid azide, the reaction product of a mixed acid anhydride with an acid, such as substituted cetars, such as dialkylpolyic acids, dialkylphosphoric acids, phenylphosphate, diphenylphosphoric acid, dibeneylphosphoric acid, or halo-substituted phosphoric acid, sulfuric acid, thioacetic acid, glycosulfuric acid or acid halide phosphoric acid; , for example, Tr, Methyluxusma, Peitanova, Isopenta Novova, 2-ethnacaCl3 or trichloroacetic acid or aromatic carboxylic acid, for example, benzoic acid , symmetric anhydride, you can use an amndz product with imidazole , 4-dinitrophenyl ,. trichloride, pentachloride pyridone, N-oxysuccinde is 1, 59 - 4 N-hydroxyphthalimide or 1-hydroxy-6-chloro 1H-benzotriazyl. These reactive derivatives can be chosen according to the type of compound (III). Typically, the reaction is reacted in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformavd, pyridine, or any other organic solvents that do not adversely affect the reaction. These solvents can also be used in a mixture with water. When the compound (III) is used in the form of the free acid or its salt, the reaction is carried out in the presence of a conventional condensing agent, such as N, N-dicyclohexylcarbodiimide, K-cyclohexyl-M -morpholinoethylcarbodiimide, N-tsiklogeksiln- (4-dietilaminotsiklogeksnl) karbodiimnts, -dietilkarbodiimvd M N, N, N -diizoprotsilkarbodiimid, N-etylN - (Z-dimetilaminoprotsh) -karbodiim ut, N, N-2-kapbonil- ic- metilimidazol) pentametilenketen- N-cycloheximine, diphenyl ketene-N-cyclohexylimine, ethoxyace Tylen, 1-alkoxy-1 chloroethylene, trialkylphosphite, ethylplyphocanecane, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzoxoxhydrode salt, Icro, Icro, isoxazole, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, the so-called Vilsmeier reagent, obtained by the reaction of M, J-dimethylformamide with thionyl chloride; phosgene or phosphorus oxychloride. The reaction can also be carried out in the presence of an inorganic or organic base, such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, M- (high) alkyl morpholine, M, H-di (lower) alkyl benzylamine or the like. The reaction temperature is not critical, and the reaction is usually carried out during cooling or at ambient temperature. The target compounds (1) and their pharmaceutically acceptable salts according to the invention are
    iUM.bie stsddinenn, which exhibit phKdKjTo antibacterial act and ma: 5 from proliferation, a large number of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and are used as antimicrobial agents, especially ly, oral npJMTMM. For therapeutic
    For the purposes of the proposed compounds,
    used in the form of a pharmaceutical preparation, which contains these compounds as an active ingredient in a mixture with a pharmaceutically acceptable carrier, such as an organic or inorganic solid or liquid drug medium, suitable for oral, perentral or external use. Pharmaceutical drugs can be in the form of tablets, capsules, pills, ointments, suppositories, solutions, suspensions or emulsions. If necessary, the preparations may include additional substances, stabilizing agents, wetting or emulsifying agents, buffer mixtures and other additives.
    Since the dosage of the compounds varies with age. and the patient’s condition, the average unit doses of 10, 50, 100, 250, 300, and 1000 mg are effective for treating infectious diseases caused by pathogenic bacteria. Typically, these preparations can be used in an amount of from 1 to 6,000 mg / kg body weight per day.
    To illustrate the usefulness of the target compounds, the antimicrobial activity of urine excretion and biliary excretion, representative proposed compounds are shown below.
    Test compound 7- 2-carboxymethoxyimino-2- (4-thiazolyl) acetaminzo-3-cephem-4-carboxylic acid (syn-isomer) (compound A). about
    A. Minimum inhibitory concentrations.
    In vitro antibacterial activity is determined by the method of diluting an agar plate folded in half. One loop with a culture of each test strain overnight in trypticaea-soy Lulone (10 viable cells: 1 ml) was applied to a heart pentone containing differentiated
    Concentrations of the tested compound. After incubation of P for 20 hours at 37 ° C, the minimum inhibitory concentrations of MICs are given in Table. 1, T a b l and c a 1
    . 0.05
    0.05
    V. Urea excretion about.
    Rat urine is collected using a shed through 0-6 and 6-24 h after peroxide; 100 mg / kg of the test antibiotic is tested and applied to the level of antibiotic in Wetter samples using a standard solution obtained by M / 15 phosphate buffer solution (pH J, 0). Urine excretion in 24 hours (Compound Az) is 43.5%.
    WITH;. Bile excretion.
    The rats were anesthetized with petibarbital and fixed in a supine position and a polyethylene tube was inserted into the bile duct. Obrazdz bile: Surrounded 0-3; 3-6 and 6-24 and after oral administration of 100 mg / kg of the antibiotic to be tested. A bioassay was carried out for the antibiotic content in samples of bile using a standard solution prepared using M / 15 phosphate buffer solution (pH 7.0). Bile flow in 24 hours (compound A) was 7.9%.
    Comparative testing of target compounds 1-4 of formula (1) and one of the known cephalosporins (compound B)
    Test compounds:
    1.7-2-carboxymethoxyimino 2 (4-thiazolyl) acetamido-cephalosoranic acid (syn-isomer);
    2.7 - 2-carboxymethoxyimino-2 (4-thiazolyl) acetamido -2-methyl-Zepham-4-carboxylic acid (syn-isomer);
    7t1
    3.7-2-carboxymethoxyimino-2 (A-thiazolne) acetamido} -3-chloro-Zeph-4-carboxylic acid (syn-ISO8);
    4.7-2-carboxymetoxymino-2 (4-thiaolyl) acetamide-3-cephem-4-carboxylic acid KHcnoia (syn-isomer);
    B. 7- 2-methoxyimino-2- (2-thienyl) aueraMMfloj-cephalosporanic acid {syn-isomer).
    Test Method In vitro aHTH bacterial activity is determined by the double plate method, unless 511598
    , deni on agar. One loop of a culture grown overnight of each test strain in triptycase-JOBOM broth (10 viable cells per ml) was applied to heart-loosening agar (H1-agar) containing specific concentrations of the test compound and after incubation at 37 ° C for 20 hours, 10 MICs were determined.
    The results of the test MIC (µg / ml) are given in Table. 2
    Table 2
    As can be seen from the above data, new cephalosporins have lower MIC values and, thus, are more effective. EXAMPLE 1 A solution of Vilsmeier is obtained from a solution of phosphorus oxychloride (0.76 g) and N, K-dimesh1 formamide (0.36 g) in etipacetate (1.44 ml). Into a stirred suspension of Vilsmeier reagent in ethyl acetate (20 ml), 2-trwt-butoxycarboylmethylimoimino-2- (4-thiazolyl) acetic acid (syn-isomer) (t, 2 g) is added under ice-cooling, the mixture is stirred at At the same temperature, 20 minutes, an activated acid solution is obtained. In the mix; a suspension of 7-amino-3 cephem-4-carboxylic acid (0.76 g) in tetragvdrofuran (15 ml) was added trimethylsilyl acetamide (3.5 g) and the mixture was stirred for 20 minutes at 3A-C, To this solution was added Under a mixture of activated acid at -10 ° C and at the same temperature the mixture is stirred for 30 minutes. Water is added to the reaction mixture, the separated organic layer is added to water and the pH of the mixture is adjusted to 7j, 5 using an aqueous solution of potassium carbonate. The pH of the separated aqueous layer was adjusted to 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extracted layer is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, evaporated and 7- 2-tertbutoxycarboshmethoxy No. kno-2 (4-thiazolyl) acetym-J-3-cep-4carboxylic acid (syn-isomer) (racidol) is obtained. . IR (reg.Nuch): 3240; t775} 1715; 1670; t63Q see NMR (daOd, 8): 1.44 (9H, s); 3.60 (2H, m); 4.61 (2H, s); 5.10 (1H, d, 1-5.0 Hz); 5.86 (1H, double line, 5.00 and 8.0 Hz); 6.43 (1H, t,, 0 Gp; 7.88 (1H, d,, 0 Hz); 9.10 (tH, ri,, 0 Hz) ;, 9.49 (1H, d, .0 Hz ), where d is a doublet, a c-singlet, m is a multiplet, t is a triplet, c is a quadruplet Example 2. From a solution of phosphorus oxychloride (t, 3 g) and H, N-dimethylformamide (0.6 g) in ethyl acetate (2.4 ml) was used to obtain a Vilsmey-pa reagent. To a metered slurry of Vilsmeier's reagent in ethyl acetate (20 ml) was added 2-fpeT-butoxycarbonylmethoxyimino-2- (4-thiazolyl) acetic acid (sip-isomer) (2.0 d). With ice cooling, stir the mixture at the same temperature for 20 minutes and obtain an activated acid solution. Enzyme 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.4 g) in. tetrahydrofuran (28 ml) was added trimethylsilylacetamide (5.8 g) and the mixture was stirred for 20 minutes at 38-42 ° C, The aforementioned activated acid solution is added to this solution at -10 ° C and the mixture is stirred for 30 minutes at the same temperature, water is added to the reaction mixture, and a separated organic layer is added to the water with the aid of a saturated aqueous solution. potassium carbonate, the pI of the mixture is adjusted to 7.5. The pH of the separated aqueous layer was adjusted to 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, evaporated and 7-2-tert-butoxycarbonylmethoxyiminoimino-2- (4-thiaoolyl) acetamyl-1 -3-methyl 3-cephem-4-carboxylic acid (2) (2, 25g) IR (p-Neuzh); : 1750 (wide); 1710; 1680. NMR (DMSO-Y4,, 5): 1.46 (9H, s); 2.02 (2H, s); 3.45 (2H, k, 0 Hz); 4.61 (2H, s); 5, tO (1H, d, OHz) 5.73 (1H, double line,, 0 Hz and 8.0 Hz); 7.89 (1H, d, 1-2.0 Hz); 9.10 (1H, d, 0 Hz); 9.47 (1H, d, 0 Hz). . EXAMPLE 3 A solution of Vilsmeier B reagent, a stirred suspension of the Vilsmeier reagent in ethyl acetate, is obtained from a solution of phosphorus oxychloride (2.2 g) and N, N-dimethyl formacpa (1.0 g) in ethyl acetate (4 ml). 40 ml) 2- (ben3-hydryloxycarbonyl methoxyimino) -2- (4-thiazolyl) acetic acid (syn-isomer) (4.8 g) is added with fresh cooling, the mixture is stirred at the same temperature for 30 minutes and a solution is obtained activated sour. In a stirred suspension of 7ami o-3-cephem-4-carboxylic acid (2.2 g) in tetrahydrofuran. (30 ml) was added trimethylsilane acetamne 1 910 (10.1 g) and the mixture was stirred for 30 minutes at 35-40 ° C. This solution was added with the above-mentioned activated acid solution at -10 ° C and the mixture was stirred at the same temperature 30 min. Water is added to the reaction mixture, the separated organic layer is added to water, and the mixture is adjusted to pH 7.5 with 20% potassium carbonate aqueous solution. The pH of the separated aqueous layer was adjusted to 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with an all-saturated aqueous solution of sodium chloride, dried over magnesium sulfate, evaporated, and 7-2-bende1Edryloxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido-Z-cephem-4-carboxylic acid (syn-isomer) (6.2 g ). IR (rn Neuzh): 1775; 1720; 1675; 1630 .. NMR (DMSO-a; B): 3.56 (2H, m); 4.93 (2H, s) ;. 5.13 (1H, d, .0. Hz); 5.92 (1H, double line,,, 0, and 8.0 Hz); 6.48 (1H, m); 6.90 (1H, s); 7.11-7.65; (YUN, s); 7.90 (1H, d, 0 Hz); 9.16 (1H, d, 0 Hz); 9.68 (1H, d, GTO. EXAMPLE 4. The following compounds are prepared analogously to Examples 1-3. 7-2-kaoboxymethoxyimino-2 (4-thiazolyl) acetamido-3-methyl-3-cephem-4- carboxylic acid (syn-isomeo). IR (p-nuzhol): 1765; 1715; 1670 cmH - 7-2 tert-Butyroxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido -2 metsh-3-cephem-4-carboxylic acid (syn-isomer). IR (p-nuzhol): 1780; 1720; 1670; 1630. NMR (daso-ab, 8): 1.28-1.67 (12I, m); 3.76 (1H , m); 4.62. (2H, s); 5.13 (N, D, 1-5.0 Hz); 5.92 (1H, double line, 1 5.0 and 8.0 Hz); 6, 53 (1H, d, 0 Hz); 7.90 (GN, d, 0 Hz); 9.14 (1H, d, 0 Hz); 9.53 (1H, d, 0 Hz). 7-C2-Carboxymethoxyimino-2 (4-thia 3 ol yl) ace tamide about | -2-м т yl-3 cefem-4-carboxylic acid (syn-isomer). IR (p-r Nuchol): 1770; 1720; 1670; 1630. 4-Nitrobenzyl-7-12-tr "t -butoxycarbonylmethoxyimino-2- (4-thiazolyl acetamvdoi-3-methoxy-3-cefem-4-carboxol (syn-isomer). IR (p Ijujol): 3230; 1770; 1710; 1675; 1600 cm-, NMR (dasO-a, 8): 1.43 (9II, c): 3.69 (2H, s); 3.80 (3N, s); 4.62 (2H, s); 5.19 (1H, d, 0 Hz); 5.32 (2H, s) 5.65 (1H, double line,, 0 Hz and 8.0 Hz); 7.60 (2H, d, 0 Hz); 7.94 (1H, d, 0 Hz); 8.18 (2H. D, 0 Hz); 9.11 (1H, d, 0 Hz); 9.49 (1H, d, 0 Hz). 7- 2-Carboxymethoxyimino- (4-thiaoolyl) acetamido-3-methoxy-3-cephem 4-carboxylic acid (syn-isomer). IR (rn Neuzh): 3180; 1760; 1665 cm 7- 2-tert-Butoxycarbonylmethoxy, Y4INO-2- (4-thiazol) -acetamido T-3methoxy-3-cephem-carboxylic (syn-isomer). IR (rn Neuzh): 1770, 1690 (wide). 7- 2-tert-Butoxycarbonylmethoxy. Ymino-2- (4-thiazolyl) -acetamyso3 cephalosporanic acid (syn-isomer). IR (reg.Nuzh): 3200; 1780; 1720; 1670. NMR (DMSO-a ,, 8): 1.42 (9H, s); 2.01 (ЗН, s); 3.54 (2H, m); 4.62 (2H, s); 4.83 (2H, r, 0 Hz); 5.16 (1H, d ,, O Hz); 5.83 (1H, double line,,, 0, and 8.0 Hz); 7.89 (1H, d, and 2.0 Hz); 9.11 (1H, D, o; Hz); 9.53 (1H, d, 0 Hz, 7-2-Carboxymethoxyimino-2 (4-thiazolyl) acetamide-cephalosporic acid (syn-isomer). IR (p-n Nuchol): 3200; t780; 1723; 1675. BenzhydrSh1-7 - 2-7eet-butoxycarbonylmethoxymino-2- (4-thiazolnl) acamido-3-methylthiometh-1-3-cephem-4carboxylate (syn-isomer). IR (p-p Nuchol): 3270; 1770; 1720; TbbO cm-. YMZ (DMSO-a, S): 1.42 (9H, s); 1.78 (ZN, s); 3.42-3.73 (4H, m); 4.61 (2H. S); 5.26 (1H d, 0 Hz) .5, 87: (1H. double line .0 and 8.0 Hz); 6.88 (1H. s); 7.13-7.60 (10H. m); 7.91 (1H , d, 0 Hz); 9.11 (W, d, 0 Hz); 9.56 (1H. d 1-8.0 Hz). 7-2-Carbox1 1-methoxyimino-2 (4-tnazolyl) acetamocyto3 -3 -metnylthiome tyl-3-cephem-4-carboxylic KHcnot-a (ein isomer). IR (p- P Nuzhol): 3.180; 1775; 1720; 1675. Benzhydryl-7-2-treg-butoxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido-3-methoxymethyl-3-cephem-4carboxylate (syn-isomer). IR (p- p Nuzol): 3250; 1780; 1720; 1655 cm-. NMR (flMCO-d, S): 1.43 (9H. s); 3.06 (3N, s); 3.56 (2H. m); 4.08 (2H, c); 4.63 (2H, s); 5.23 (1H, d, 1 "5.6 Hz); 5.91 (1H, double line, and 8.0 Hz); 6.92 (1H, s); 7, l7-7.62 (UN, m); 7.91 (1H, d, 0 Hz); 9.12 (1H, d, 0 Hz); 9.58 (1H, d, 0 Hz). 7-p-Carboxymethoxyimino-2 (4-thiazolyl) acetamido-3-methoxymethyl-3-cephem-4-carboxylic acid (syn-isomer), IR (p-p Nuchol): 3200; 1775; 1720; 1675 cm 7- 2-Tert-Butoxycarbonylmethyl, 1ino-2- (4-thiazolyl) acetamido-3 chloro-3-cephem-4-carboxylic acid (syn-isomer). IR (rn Neuzh): 1780; 1720; 1680 cm. . 4-Nitrobenzyl-7-2 tert-butoxcarbonylmethoxyimino-2- (4-thiazolip) acetamido-3: -chloro-3-cephem-4 carboxylate (screen isomer). IR (rn, n Zhol): .1780; 1720; f670; 1600 NMR (DMSO-a, 8): 1.43 (9H, s); 3.88 (2H. C, 0 Hz); 4.63 (2, d) -, 5.33 (1H, d, Hz); 5.45 (2H, s); 5.94 (| N. double line, 0 and 8.0 Hz); 7.67 2K, d, 0 Hz); 7.91 (1H, d, 0 Hz); 8.23 (2H, d, 0 Hz); 9.14 (1H, d. 1 2.0 Hz) 9.67 (1H, d, 0 Hz). 7- 2-Carboxymethoxyimino-2- (4thiazolyl) acetamido-3-hlrr-3-cephem 4carboxylic acid (syn-isomer). IR (rr Pujol): 3200; 1775; 172O; 1670. Benzhydrin-7- 2-Tert-butoxycirbonylmethoxymino-2- (4-thiazole1) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer). K (rn Neuzh): 3250; 1770-1720; 1710; 1655 cm MP (flMCO-dj, S): 1.44 (9H, s); 3.75 (2H, m); 4.64 (2H, s) .; 5.28 (1H, d, 0 Hz); 5.29 (1H, D,, 0 Hz); 5.62 (1H, d, 1-17.0 Hz); 5.93 (1H, double line, 1-5.0
    311551
    8.0 Hz); 6.77 (1H, double line, 11.0 and 17.0 Hz); 6.93 (1H, s); , 35 (YUN, s); 7.93 (1H, d, 0 Hz); , 14 (1H, d,, 0 Hz); 9.62 (1H, d, 0 Hz) .5
    7- 2-Carboxymethoxyimino-2 (4-thia olyl) acetamvdo-3-vinyl-Zeceph-4-carboxylic acid (syi-iso es). CI (rn Neuzh): 1765 | 1710; 1665 cm-. "About
    7- 2-Carboxymethoxy-2 (4-thiazolyl) acetamido-3-cephem-4-carboxylic acid (syn-isomer). IR (rn Neuzh): 3280; 1750; 1725; 1655; 1620
    1-11 propionyloxyethyl-7-2-benzhydryloxycarbonylmethoxyimino-2- (A-thiazolyl) acetamido-3-cephem 4-carboxylate (syn-isomer). CI (rn Neuzh): 1775 | t735; 1680 cm. 20
    1-Ethoxycarbonyloxyeth-1-7-2benzgndryloxycarbonylmethoxy-shadino2- (4-thiazolyl) acetammy-3-ceFem-4carboxylate (syn-isomer). IR (rn Neuzh): 1780; 1750; 1680 cm. 5
    Pivaloyloxymethyl-7-, 2-benzhydryoxycarbonylmethoxyimino-2- (4-tras5 lil) acetamido-3-cephem-4-carboxylate C-synomer). IR (rn Neuzh): 1780; 1740; 1680.30
    (5-Methyl-2-oxo-1,3-dioxol-4-i) fetiyl-7 - -benz hydryloxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido-3-cephem-4-carboxylate (snn-isomer). IR (rn Neuzh): 1810} 1770; 1730; 5 1670 cm. 1-Propionyloxyethyl-7- 2-carboxymethoxyimino-2- (4-thiao-EH1) acetamide-3-cephem-4-carboxylate (si-isomer). F r-r Neuhol): 3250; 1780; 1730; 40 t6SO.
    1-Ethoxycarbonyloxyethyl-7-2-carboxmethoxynmino-2- (4-thiazolyl) acetamido-3-cephem-4-carboxylate (syne isomer). IR (rn Neuzh): 1750 5 (wide); 1770 cm
    PNVALOYLOXYETHYL-7-2-carboxymethoxyimino-2- (4-thiazolyl) acetamines AoJ-3-cephem-4-carboxylate (syn-isomer 50). IR (r. Nyuzh) 1740 (wideM); 1680 cm
    (5-Metsht-2-oxo-1, 3-dioxol-4-yl) methyl-7-2-carboxymethoxy-amino-2 (4-thiazolyl) acetamido T-3-cephem-4- 55 carboxyl (syn-isomer). IR (rn Neuzh): 1810; 1770; 1730; 1670.
    59
    Example5. In a suspension of 7-2 tert-butoxycarbonylmethoxyimino, 2 (4-thiazolyl) acetamido-3-cephem-4carboxylic acid (syn-isomer) (1.3 g) in a mixture of methylene chloride (2 ml) and anisole (1.3 ml) is added trifluoroacetic acid (5.2 ml) at ambient temperature and at the same temperature transfer the mixture for 1.5 hours. Diisopropyl ether (40 ml) and N-hexane (30 ml) are added to the resulting solution with stirring. The precipitate is collected by filtration, washed with a solution of diisopropyl ether and N-hexane (1: 1). The precipitate is added to a mixture of ethyl acetate and water and the pH of the mixture is adjusted to 7.5 with a saturated solution of (aqueous) potassium carbonate. The pH of the separated aqueous layer was adjusted to 4.0 with 10% hydrochloric acid and the solution was washed with ethyl acetate. With ice cooling, the pH of the resulting solution is adjusted to 1.8 with 10% hydrochloric acid. The precipitate is collected by filtration, washed with cold water, dried over phosphorus pentoxide in vacuo, and 7- 2-carboxymethoxyimines-2- (4thiazolyl) adopamo3-3-cephem-4-carboxy acid (syn-isomer) is obtained (1.0 g ). IR (rn Neuzh): 3280; 1750j J725; 1655; 1620. NMR (DMSO-a, 8): 3.58 (2H, m); 4.67 (2H, s); 5.12 {1H d, Hz); 5.88 (1H, d, 0 and 8.0 Hz); 6.45 (1H, m); 7.93 (W, d, 0 Hz); 9.02 (1H, d, 0 Hz); 9.52 (W, d 1-8,0 Hz).
    Take p6. In susnu.iyu 7- 2- .trat -butoxycarbonylmethoxy mino-2- (4-tIazolyl) aietamndo-3methyl-3-cephem-4-carboxylic acid (syn-isomer) (2.1 g) in a mixture of methylene chloride ( 4.2 ml) with anisole (2, t ml) was added trifluoroacetic acid (8.4 ml) at ambient temperature and the mixture was stirred for 1.5 hours at the same temperature. To the resulting solution was added diisopropyl ether (50%). ml) and i-hexane (30 ml) and the mixture is stirred. The precipitate is collected by filtration, washed with a solution of simple diisopropyl ether in and - hexa e (1: 1). The precipitate is added to a mixture of ethyl acetate and water and a saturated aqueous solution of the PLTP1TN carbonate solution, the pll of the mixture is adjusted to 7.0. With the help of hydrochloric acids. The pI of the separated aqueous layer is adjusted to 4, and the solution of ethn seed solution is washed; Using 10% hydrochloric acid, the pH of the aqueous layer was adjusted to 1.8 and filled with sodium chloride. The acidic solution {is extracted with a mixture of ethyl acetate and tetrahydrofuran (t: l). The extract is washed with a saturated aqueous solution of sodium chloride, dried over sulfate, evaporated and 7- 2-carboxy-methoxy-mino-2- (4-thiazolyl) acetamido-3-methyl-3-cephem-4-carboxylic acid (syn-isomer) is obtained ( 1.0 g). IR (rn Neuzh): 1765; 1715; 1670cm NMR (flMCO-dg, S): 2.03 (3N, s); 3.47 (2H, m); 4.67 (2H, s); 5.13 (1H, d, 0 Hz); 5.78 (1H, single line,,, 0, and 8.0 Hz); 7.96 (1H, d, 1 2.0 Hz); 9.15 (1H, d, 0 Hz); 9.52 (1H, d, 0 Hz). EXAMPLE 7: To a suspension of 1-pro pionexthoxyethyl-7-2-benzgi, Cyryloxycarbonylmethoxyimino-2- (4-thiazolyl) a7 Detamndo-3-cephem-4-carbox1shat (syn-eomer) (1.2 g) in a mixture of chlorine methylene (10 ml) and anisole (0.8 ml) is added) iforoacetic acid (1.4 ml) at ambient temperature and the mixture is stirred at the same temperature for 2 hours. To the resulting solution is added simple diisopropyl ether (50 ml) and the mixture is stirred. The precipitate is collected by precipitation and washed with diisopropyl ether. The precipitate is added to a mixture of ethyl acetate c. water and the pH of the mixture was adjusted to 7.5 with 20% potassium carbonate aqueous solution. The pH of the separated aqueous layer was adjusted to 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue is washed with diisopropyl ether and filtered to give 1-propionyloxethyl-7-2-carboxymethoxyimino-2 (4-thiazolyl) acetam1CHO-3-cephem-4carboxylate (syn-isomer) (0.47 g). IR (rn Neuzh): 3250; 1780; 1750; 1680, NMR (daso-a, 5): i, 05 (zp, t, i 7.0 Hz); 1.49 (.И, д,, 0 Ги): 2.36 С2Н..К, П Hz); 3.63 (2H, m), bh (: H, s); Z.Ty.SI, l, .C GO ;, (1H, dssyil line, 1--4, () and 8.0 | -c); 6.59 (111, t, 0 Hz); 6.89 (1H, к,, 0 Hz); 7.93 (1H, d, 1-2.0 Hz); 9.13 (1I, d, 7 Hz); 9.54 (1H, d, 0 Hz), (. Example 8. Mix the suspension with benzhydryl-7-2-tert-butoxycarbonylmethoxyimino-2- (4-thiazolyl) azotamido-3-vinyl-3-cephem-4carboxylate (syn-isomer) (2.8 g) in a mixture of methylene chloride (5.6 ml) and anisole (2.8 ml), trifluoroacetic acid (11.2 ml) was added at ambient temperature and the mixture was stirred at the same temperature 1.5 hours. To the resulting solution are added diisopropyl ether (40 ml) and H-hexane (30 ml), and the mixture is stirred. The precipitate is collected by filtration, scaled with a solution of diisopropyl ether in y-hex. Ane (1: 1). The precipitate is added to a mixture of ethyl acetate and water and the pH of the mixture is adjusted to 7.0 with a saturated aqueous solution of potassium carbonate. The pH of the separated aqueous layer is adjusted to 4.0 with 10% hydrochloric acid and the solution is washed with ethyl acetate. The pH of the aqueous layer is adjusted to 1.8 with 10% hydrochloric acid and saturated with sodium chloride; reagent. The acidic solution is extracted with a mixture of ethyl acetate and tetrahydrofuran (1: 1). i The extract is washed with a saturated aqueous solution of sodium chloride. , dried over MarHiiH sulphate, evaporated and 7-2 carboxymethoxy are obtained. ino-2- (4-thiazolyl) -3-vynil acetamido-3-cephem-4-carboxylic acid (syn isomer) (1.22 g). IR (rn Neuzh); 1765; 1710.1665 cm-NMR (LMSO-dg,): 3.71 (2H, m); , 72 (2H, s); 5.26 (tH, d,, 0 Hz); 5.37 (1H, d, 0 Hz); 5.61 (1H, d, 0 Hz); 5.91 (1H, double line,,, 0, and 8.0 Hz); 6.98 (1H, double line,, 0 and 17.0 Hz); 8.02 (1H, d, 0 Hz); 9.21 (W, d, 1 2.0 Hz); 9.64 (1H, d, 0 Hz). Further, by reacting 7- 2-carboxylicsimethoxymtto2- (4-thiazol-11l) acetamido3-3-vinyl-3cepheme-4-carboxylic acid (syn-isomer) with sodium bicarbonate, 7-2-carboxylatemethoxy1 sodium-2- (4- thiazo-acetamido3-3-vi17-nyl-3-cephem-4-carboxylate (syn-iso-mer). EXAMPLE 9 The following compounds are prepared analogously to Examples 5-8. 7- 2-Kapboxymethoxyimino-2 (4-thiazolyl) acetamido -2-methyl-3-p-fem-4-carboxylic acid (sei-from measures). IR (rn Neuzh): 1770; 1720; 1670; 1630. NMR (nMCO-Oj, S): 1.43 (3N, n, 1,1.0 Hz); 3.72 (1H, l); 4.67 (2H, s) 5.13 (1H. D, 0 Hz); 5.93 (1H, double line,, 0, and 8.0 Hz); 6.55 (GN, d, 0 Hz); 7.92 (1H, 0 Hz); 9.12 (1H, d, 0 Hz) 9.53 (1H, d, 0 Hz). 7- 2-Carboxymethoxyimino-2 (4-thiaoolyl) acetamido3-3-methoxy-3 cephem-4-carboxylic acid (syn-mer). IR (rn Neuzh): 3180; 1760; 1665. NMR (flMCO-d (,. S): 3.60 (2H, broad s); 3.75 (ZN, s); 4.68 (2H, s 5.18 (1H, d, 0 Hz); 5.62 (1H, double line,, 0 and 8.0 Hz); 8 (1H, d, ... 0 Hz); 9P5 (1H, d, 1 ..2.0 Hz); 9.52 (1H, d, 0 Hz.) 7- 2-Carboxymethoxyimino-2 (4-thiazolyl) acetamcene cephalosporic acid (syn-isomer). IR (p-n Nuzhol): 3200; 1780; 1723 1675. NMR (flMCO-d ( ,, S): 2.01 (3N, s); 3.56 (2H, m); 4.67 (2H, s); 4.83; 2y, r, 0 Hz; 5.17 (1H, d, 1 4.0 Hz); (1H, double line, 1 "4.0 and 8.0 Hz); 7.92 (1H, d, 1 2.0 Hz); 9.12 1H, d,, 0 Hz); 9.54 (1H, d, ..., 0 Hz)., 7-2-Carboxymethoxyimino-2 (4-thiazoyl) acetamido-3-methyl methyl 3-a; efem-4-carboxylic acids {syn isomer). IR (reg.joujol): 3180; 1775; 1720 1675 cm. RA, S): 1.96 (ЗН, s); 3.47-3.76 (LN, m); 4.67 (2H, s); 5.20 (fH. D, 0 Hz); 5.79 (1H, dtoAna line,, 0, and 8.0 Hz); 7.93 (tfl, d, 1 2.0 Hz); 9.12 (TH, Hz); 9.54 (1H, d, 0 Hz) 7-2-Car-ox-methoxy-imino-2 (4-thiazrilyl) acetamchlo3-3-methoxymethyl-n-3-cephem-4-ca-1-bonic acid (rin-isomeo). 98 IR (rn Neuzh): 3200; 1775; 1720; 1675 cm. NMR (nMCO-d.S): 3.27 (3N, s); 3.52 (2H, m); 4.16 (2H, s); 4.66 (2H, s); 5.16 (1H, p,, 0 Hz); 5.81 (1H, double line,,, 0, and 8.0 Hz); 7.91 (1H, d, 0 Hz): 9.11 (1H, d, 0 Hz); 9.52 (1H, d, 0 Hz). 7-2-Car-oxymetoxyimino-2 (4-thiazolyl) acetamido-3-xpor-Zce) em-4-carboxylic acid (syn-isomer). IR (reg.Nuzh): 3200; 1775; 1720; 1670. NMR (DMSO-dj, 8): 3.81 (2H, k, 1 18.0 Hz); 4.66 (2H, s); 5.25 (1H, d, 1-5.0 Hz); 5.87 (tH, double lines,, 0 and 8.0 Hz); 7.72 (1H, d, 1 2.0 Hz); 9, to (1H, d, 0 Hz); 9.63 (1H, d, 0 Hz). 1-Ethoxycarbonyloxyethyl-7- | 2-carboxymethoxyimino-2- (4-thiazolyl) acetamdo-3-cephem-4-carboxylate (syn-isomer). IR (rn Neuzh): 1750 (wide); 1770. NMR (DMSO-a, 5): 1.09 and 1.22 (total EF, each t, 0 Hz); 1.50 (3N, d, 0 Hz); 3.63 (2H, m); 4.16 (2H, r, 0 Hz); 4.66 (2H, s); 5.16 (1H, d, 0 Hz); 5.93 (1H, m); 6.62 (W, t, 0 Hz); 6.77 (1H, q, 0 Hz); 7.94 (1H, d, 0 Hz); 9.14 (1H, d, 0 Hz); 9.56 (1H, d, 0 Hz). Pivaloylok (gimetsh1-7- 2-carboxymethoxyimino-2- (4-thiazolyl) acetamido-3-cephem-4-carboxylate (syn-iso-, mer), IR (p-p Nuzhol): 1740 (wide); 1680 cm NMR (daCO-d, S): 1.14 (9H, s); 3.60 (2H, q,, 0 Hz); 4.63 (2H, s); 5.13 (1H, d, 0 Hz; 5.62-6.03 (ZN, m); 6.55 (1H, t, 1 4.0 Hz); 7.87 (1H, d, O Hz); 9.06 (1H , d, 0 Hz); 9.48 (1H, d, 0 Hz). (5-Metsh1-2-oxo-1i 3-dioxol-4-yl) methyl-7-2-carboxy-methoxy-amino-2 (4 -thiazolyl) acetamido-3-cephem-L-carboxylate (syn-isomer). IR (p-p Nuchol): 1810; 1770; 1730; 1670 cm-.i NMR (flMCO-d, B): 2.18 ( ZN, s); 3.62 (2H, m); 4.67 (2H, s); 5.15 (2H, s); 5.16 (TH, d, 0 Hz); 5.93 (1H , double line,, 0 and 8.0 Hz); 6.60 (1H, t, ..., 0 Hz); 7.95 (1H, d, Hz); 9.15 (1I, d, ..., 0 Hz); 9.5 6 (1H, d, 0 Hz). Example 10. 4-Nitrobenzyl-7 2-tert-butoxycarbonylmethoxyimino2- (4-thiazolyl) acetamido-3-methoxyZ-cephem-4-carboxylate (syn-isomer) (2.9 d) dissolved in a mixed solution of methanol (50 ml), tetrahydrofuran (30 ml) and glacial acetic acid (0.3 ml). After adding 10% palladium on a carbon substrate (1.5 g) to the solution, the mixture is catalytic. reduction at ambient temperature and atmospheric pressure. The catalyst is filtered off and the filter is concentrated under reduced pressure. Water and ethyl acetate are added to the residue and the pH of the mixture is adjusted to 7.5 with an aqueous solution of potassium carbonate. The pH of the separated aqueous layer was adjusted to 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is added with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, evaporated and 7-2-tert-butoxycarboylnylmethoxy imino-2- (4 thiazolyl) acetamido-3-methoxy-3-cephem-4-carboxylic acid (ein isomer ) (1.71 g). JC (Neuhol reg.): 1770; 1690 (wide) see NMR (DMSO-d.S): 1.44 (9H, s); 3.60 (2H, s); 3.75 (ЗН, s); 4.63 (2H, s); (1Hpd, 0 Hz); 5.61 (W, double on line, 0 and 8.0 Hz); 7.96 (1H, d, 0 Gd); 9.13 1H, d, 1 2.0 Hz); 9.50 1H, d ,, 0 Hz). EXAMPLE 11 The following compound was prepared as described in Example 10. 7- 2-tert-Butoxycarbonylmethoxy-imino-2- (4-thiazolyl) acetamnc} -3methyl-3-1 | efem-4-carboxylic acid (sine-isomer ). IR (rn Neuzh): 1750 (wide); 1710; 1680. t-Karbszheime Tokimo-2- (4thiazolkl) acetamidoT-3-methyl-3-cephem 4-carboxylic acid (syn-isomer). IR p-p Nuchol): 1765; 1715; 1670cm 7- 2-tr "t -Butbicarbonshshetoksi No. eno-2 - {4-thiazolsh1) ace tamido -2meti - 3-cephem-4-carbono-acid (si-isomer) 4 IR (rt Nuhol): 1780, 1720 ; 1670; 1630. 920 7- 2-Carboxymethoxy-Migmo-2- (4thiazolyl) acetamide-2-methyl-3-cephem-carboxylic acid (syn-isomer). IR (r.Ruguzhol): 1770; 1720; 1670; 1630. 7- 2-Carboxymethoxyimino-2 (4-thiazolyl) acetamido1 3-methoxy-.3 cefem-4-carboxylic acid (si isomer). IR (rn Neuzh): 3180; 1760; 1665 cm 7- 2-tert-Butoxycarbonylmethoxyimino-2- (4-thiazole1) acetamidoZcephalosporanic acid (syn isomer). IR (reg.Nuzh): 3200; 1780; 1720; 1670. 7- 2-Carboxymethoxyimino-2- (4-. Thiazolyl) acetamido cephalosporanic acid (syn-izvmer) ... IR (solution Nujol): 3200; 1780; 1723; 1675. 7- 2-Carboxymethoxyimino-2 (4-thiazolyl) acetamndo-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn-isomer). IR (rn Neuzh): 3180; 1775; 1720; 1675 CM-. 7- 2-Carboxymethoxyimino-2 (4-thiazole-1) acetaminzo3-3-methoxy-ethyl-3-cephem-4-carboxylic acid (syn-isomer). IR (reg.Nuzh): 3200; 1775; 1720; “7- 2-tert-Butoxycarbonylmethoxy imino-2- (4-thiazolyl) acetamido-3 chloro-3-cephem-4-carboxylic acid (syn-isomer). IR (rn Neuzh): 1780; 1720; 1680cm NMR (DMSO-a, 8): 1.43 (9H, s); 3.81 (2H, k ,, a Hz); 4.61 (2H, s); (1H, d, 0 Hz); 5.86 (1Y, double lines,, 0 and 8.0 Hz); 7.99 (1H, d, 0 Hz); 9.12 (1H, d, 0 Hz); 9.64 (1H, d, 0 Hz). 7- 2-Carboxymethoxyimino-2 (4-tyazolyl) acetamnc} -3-chloro-3-tseyom-4-carboxylic acid (syn-iso- -, er). K (p-n Nuzhol): 3200; 1775; 1720; 1670. 7- 2-Carboxymethoxyimino-2 (4-thiazolyl) atsetamtstso} -3-vinyl-Zefem-4-carboxylic acid (syn-isoer) .. K (solution Nujol): 1765; 1710; 1665 cm 7- 2-tert-Butoxycarbonylmethoxymino-2- (4-thiazole1) acetamidoZ-3211 tsfem 4-carboxylic acid (c; in and omer). IR (reg.Nuch): 3240; 1775; 1715; 1670; 1630 cm 7- 2-Carboxymethoxychimino-2 (4-thiaoolyl) atstamido-3-cephem-4-carboxylic acid (syn-isomer). IR (rn Neuzh): 3280; 1750; 1725; 1655; 1620 cm 7- 2-Benzhydroloxycarbonnemethoxyimino-2- (4-thiazolyl) acetam) -3 cefem-4-carboxylic acid (syn-isomer). IR (rn Neuzh): 1775; 1720; 1675; 1630. Example 12, 1-Chloroethylpropionate (0.6 g) was added to a mixture of 7-2 benzhydryloxycarbonylmethoxyimino2- (4-thiazole1) acetamido-3-cephem-4carboxylic acid (syn-isomer) (2.0 g), dimethyl sulfoxide (13 ml) and potassium carbonate (0.3 g) and stirred the mixture at 40 ° C for 2. h. The reaction mixture was added to an ice-water-ethyl acetate mixture and the pH of the mixture was adjusted to 7.5 with a 20% aqueous solution potassium carbonate. The separated organic layer is washed with water, evaporated over magnesium sulfate, evaporated, and 1-propioncloxyethyl-7 2-7 benzhydryloxycarbonylmethox imino-2- (4-thiazolyl) acetamido 3 cemem 4-carboxylate (syn-isomer) (1.3 g) is obtained. IR (rn Neuzh): 1775; 1735; 1680 cm NMR (DMSO-a, 5): 1.04 (3N, t, 1,7.0 Hz); 1.51 (3N, d, 0 Hz); 2.38 (2H, q, 0 Hz); 3.60 (2H, m) 4.94 (2H, s); 5.18 (1H, d, OHz) 5.96 (1H, double line,, 0, and 8.0 Hz); 6.63 (1H, t, O, Hz); 6.91 (1H, s); 6.93 (1H, k, Oz) 7.20-7.59 (UN, m); 7.92 (1H, d, 0 Hz); 9.18 (1H, d, 0 Hz); 9.68 (| N, d, 1-8.0 Hz). Example 13. 4-Bromomethyl-5methyl-1, 3-dioxol-2-one (0.5 g) was added to a solution of 7-2-benegryl-hydroxycarbonylmethoxyimino-2- (4-thiazo-l1x) acetamido-1-3-cephem-4 -caroic acid (syn-isomer) (1.0 g) in a mixture of dimethyl sulfoxide (7 ml) and potassium carbonate (0.17 g) and all stirred for 2 hours at ambient temperature. The reaction mixture is added to an ice-water-mixture. ethyl acetate and the pH of the mixture was adjusted to 7.5 with a 20% 9 aqueous solution of potassium carbonate. The separated organic layer is washed with water, dried over magnesium sulfate. The crude product obtained after concentration is purified by silica gel column chromatography using a mixture of ethyl acetate and n hexane (3: 2) as eluant. Eluted fractionation was carried out, and (5-methyl-2-oxo-1,3 dioxol-4-yl) methyl-7-2-benzhydyr-1-hydroxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido-3-cephem-4-carboxylate (syn-isomer ) (0.37 g). IR (rn Neuzh): 1810; 1770; 1730; 1670 cm NMR (ZlMCO-dg.S): 2.14 (3N, s); 3.53 (2H, m); 4.86 (2H, s); 5.09 (2H, s); 5.10 (1H, d, 0 Hz); 5.88 (1H, double line,,, 0, and 8.0 Hz); 6.51 (1H, t, 0 Hz); 6.81 (1H, s); 7.09-7.50 (UN, c); 7.80 (1H, d, 0 Hz); 9.06 (1H, d, 0 Hz) .; 9.57 (1H, d, 1-8.0 Hz). Example 14. The following compounds are prepared according to the pre-heterograms 12 and 13. 4-Nitrobenzyl-7-2-tert-butoxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido-3-m8toxy-3-cephem-4carboxylate (syn-isomer), IR (reg.Nuzh): 3230; 1770; 1710; 1675; 1600 cm Benzhydryl-7- 2-tert-butoxycarbonylmethoxyimino-2- (4-triazolylUcetamide0-3-methylthiomethyl-3cephamis-4-carboxylate (syn isomer). IR (Neutol solution): 3270; 1770; 1720 1660 cm Benzhydryl-7- G2-tert-butoxycarbonylmethoxyimino-2- (4-thiazolyl) acetamido-3-methoxymetl-3-cephem4-carboxylate (syn-isomer). IR (p-p 11cule): 3250; 1780; 1720; 1655 cm. 4- Nitrobenzyl-7- 2-tert-butoxycarbonylmethoxyimino-2- (4-thiazole1) acetamido-3-chloro-3-cephem-4-carboxylate (syn-isomer). IR (Neuhol solution): 1780; 1720; 1670; 1600 cm-. Benzhydryl-7- 2-Tert-butoxycarbonylmethoxyimino-2- (4-, thiazoleŠ1) acetamch3-3-vinyl-3-cephem-4 carboxylate (syn-isomer). IR (p-nuzhol): 3250; 1770; 1720; 1710; 1655 cm. 1-Ethoxycarbonyloxyethyl-7-2benzhydryloxycarbonstmoxyimino-231. -C thiaolol acetamido T-3-cephem-acarboxylate-syn ). IR (rn Neuzh): 1780; 1750; 1680 cm NMR (DMSO-a, 8): 1.09 (3N, t, 1 7.0 Hz); 1.52 (3N, d, 0 Hz); 3.63 (2HjM); 4.17 (2H, к,, О, Hz) 4.93 (2H, s); 5.17 (1H, d, OHz) 5.97 (1H, double line,, 0 and 8.0 Hz); 6.65 (1H, t, 0 Hz); 6.81 (1H, к,, 0 Hz); 6.92 (1H, s) 7.20-7.60 (YUN, m); 7.92 (1H, d, 0 Hz); 9.68 (1H, d, 0 Hz); 9.19 (1H, d, 0 Hz). Pivaloyloxymethyl-7- 2-benegcryl oxycarbonylethoxyimino-2- (4-thiazolyl) acetamido-3-cephem-4-carboxylate (syn-isomer). IR (rn Neuzh): 1780; 17-40; 1680 cm NMR (flMCO-d (,, g): 1I6 (9H, s); 3.61 (2H, m); 4.91 (2H, s); 5.16 (1R, d, 0 Hz) ; 5.69-6.04 OZ, m); 6.59 (1H. M); 6.89 (1H, s); 7.16-7.60 (UN, m); 7.89 (1H, d, 0 Hz); 9.16 (1H, d, 0 Hz); 9.68 (1H, d, 0 Hz). 924 1-Propionyloxyethyl 7- 2-car-oxymetoxyimino-2- (4-thiazolyl) acetamido-3-cephem-4-carboxylate (sinisomer), IR (p-p Nuchol): 3250; 1780; 1750; 1680. 1-Ethoxycarbonyloxyethyl-7-2carboxymethoxyimino-2- (4-thiazo-lyl) acetamio-3-cephem-4-carboxylate (syn-isomer). IR (rn Neuzh): 1750 (wide); 1770 cm-Pivaloyl-oximegly-7-C2-carbo 1CC; Methoxyimino-2- (4-thiazolyl) acetaMWoJ-3-cephem-4-carboxylate (sinisomer). IR (r-uzhol): 1740 (shi1yuki); 1680 cm. (5-Methyl-2-oxo-1,3-dioxol-4-. Yl) methyl 7-2-carboxymethyl-methoxy-2- (4-thiazolyl) acetamntz-3 is cephem-carboxylate (syn-isomer). IR (rn Neuzh): 1810; 1770; 1730; 1670 cm
    权利要求:
    Claims (1)
    [1]
    A method for the preparation of cephalosporin derivatives of the general formula k c — CONH-r— or; „Κςς, O-CH 2 COOHt COOR Z where Rj is a hydrogen atom or a protective group forming an ester;
    R ,, is a hydrogen atom or a protective group forming an ester;
    R $ is a hydrogen atom or methyl;
    R 4 is a hydrogen or chlorine atom, methyl, vinyl, methoxy, methoxymethyl, methylthiomethide or acetoxymethyl, wherein one of Rj and R 4 is a hydrogen atom or their salts with alkali metals, when R (and / or R 2 is a hydrogen atom, in the form of syn-isomers, with a loin and the fact that the compound of the general formula where R and R 4 have the indicated meanings, or its reactive derivative with respect to the amino group, or its salt is reacted with the compound of the general formula
    N p ~ s - C UN
    N at I
    N
    S in
    0-CHf-COORi where Rj has the indicated meanings, either with its reactive derivative with respect to the carboxy group, or with its salt and, if necessary, in the obtained compound, where Rj the ester forming protective group, the protecting group is removed to obtain the compound where R; - hydrogen atom, and / nli in the resulting compound, where R - a protective ester-forming group, the protective group is removed to obtain a compound where Rg is a hydrogen atom, and the target product is isolated in free form or in a vice salt with an alkali metal when R <and / or Rg is a hydrogen atom, in the form of syn - ioner.
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    US4179502A|1979-12-18|7[2-Hydroxyiminoacetamido]cephalosporins
    CH634327A5|1983-01-31|7- | -CEPHEMCARBONIC ACIDS, THEIR PRODUCTION AND MEDICINAL PREPARATIONS.
    EP0113242B1|1989-11-08|Cephalosporin derivatives
    US3948905A|1976-04-06|Substituted sulfonylacetamido cephalosporins
    EP0075450B1|1986-04-23|Cephalosporin derivatives
    US4681877A|1987-07-21|Pivaloyloxymethyl 7-β-[2-|-2-methoxyiminoacetamido]-3-|-3-cepheme-4-carboxylate and pharmaceutical composition containing the same
    EP0113245B1|1989-03-15|Cephalosporin derivatives
    EP0075452B1|1986-07-02|Cephalosporin derivatives
    EP0155103B1|1989-10-25|Cephalosporin derivatives
    同族专利:
    公开号 | 公开日
    US4649136A|1987-03-10|
    DE3274548D1|1987-01-15|
    IE821772L|1983-02-03|
    DK335882A|1983-02-04|
    FI73688C|1987-11-09|
    HU188586B|1986-04-28|
    EP0071891B1|1986-12-03|
    CA1209125A|1986-08-05|
    US4515788A|1985-05-07|
    AU8642382A|1983-02-24|
    US4736039A|1988-04-05|
    PT75349B|1984-07-31|
    NO160079B|1988-11-28|
    ES8504817A1|1985-05-01|
    GR76166B|1984-08-03|
    AU556624B2|1986-11-13|
    ES514652A0|1983-08-16|
    FI822632L|1983-02-04|
    NO822634L|1983-02-04|
    EP0071891A2|1983-02-16|
    KR880001411B1|1988-08-01|
    FI73688B|1987-07-31|
    NO160079C|1989-03-08|
    EP0071891A3|1984-05-16|
    FI822632A0|1982-07-28|
    PT75349A|1982-08-01|
    ES521047A0|1985-05-01|
    IE53429B1|1988-11-09|
    KR840000565A|1984-02-25|
    ES8308569A1|1983-08-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3971778A|1972-05-12|1976-07-27|Glaxo Laboratories Limited|Cephalosporins having acylamido groups at the 7-position|
    US4364943A|1976-04-12|1982-12-21|Fujisawa Pharmaceutical Co., Ltd.|Syn-isomer of 7-[2-alkoxyimino-2- acetamids]-3-[hexanoyl-, or phenylalkanoyl-oxymethyl or benzothiazolylthiomethyl]-3-cephem-4-carboxylic acid|
    JPH0158193B2|1979-04-03|1989-12-11|Fujisawa Pharmaceutical Co|
    GB1592149A|1976-10-08|1981-07-01|Fujisawa Pharmaceutical Co|3 7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof|
    SE439312B|1977-03-25|1985-06-10|Roussel Uclaf|SET TO MAKE NEW OXIME DERIVATIVES OF 3-ACETOXIMETHYL-7-AMINOTIAZOLYLACETAMIDO CEPHALOSPORANIC ACID|
    FR2421907B1|1978-04-07|1981-07-24|Roussel Uclaf|
    DE2822860A1|1978-05-26|1979-11-29|Hoechst Ag|CEPHEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION|
    FR2445830B1|1979-01-05|1982-09-17|Roussel Uclaf|
    DE2914327A1|1979-04-09|1980-10-30|Hoechst Ag|CEPHEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION|
    US4409215A|1979-11-19|1983-10-11|Fujisawa Pharmaceutical Co., Ltd.|7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof|
    US4409214A|1979-11-19|1983-10-11|Fujisawa Pharmaceutical, Co., Ltd.|7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof|
    US4572801A|1981-04-30|1986-02-25|Takeda Chemical Industries, Ltd.|4-Carbamoyloxymethyl-1-sulfo-2-oxoazetidine derivatives and their production|
    IE53429B1|1981-08-03|1988-11-09|Fujisawa Pharmaceutical Co|New cephem compounds and processes for preparation thereof|
    US4499088A|1983-01-04|1985-02-12|Fujisawa Pharmaceutical Co., Ltd.|Cephem compounds|IE53429B1|1981-08-03|1988-11-09|Fujisawa Pharmaceutical Co|New cephem compounds and processes for preparation thereof|
    US4874856A|1985-06-24|1989-10-17|Bristol-Myers Company|3-propenyl-7- ceph-3-em-4-carboxylic acids and esters thereof|
    US4708955A|1985-06-24|1987-11-24|Bristol-Myers Company|3-propenyl-7-aminothiazol-ylcephalosporanic acids and esters thereof|
    US4731362A|1985-08-05|1988-03-15|Shionogi & Co., Ltd.|Alkylcarbamoyloxymethylcephem compounds|
    EA028342B1|2011-09-09|2017-11-30|Мерк Шарп И Доум Корп.|Methods for treating pneumonia|
    US8809314B1|2012-09-07|2014-08-19|Cubist Pharmacueticals, Inc.|Cephalosporin compound|
    US8476425B1|2012-09-27|2013-07-02|Cubist Pharmaceuticals, Inc.|Tazobactam arginine compositions|
    US9872906B2|2013-03-15|2018-01-23|Merck Sharp & Dohme Corp.|Ceftolozane antibiotic compositions|
    KR102226197B1|2013-03-15|2021-03-11|머크 샤프 앤드 돔 코포레이션|Ceftolozane antibiotic compositions|
    US20140275000A1|2013-03-15|2014-09-18|Cubist Pharmaceuticals, Inc.|Ceftolozane pharmaceutical compositions|
    ES2800603T3|2013-09-09|2021-01-04|Merck Sharp & Dohme|Treatment of infections with ceftolozane / tazobactam in patients with renal impairment|
    US8906898B1|2013-09-27|2014-12-09|Calixa Therapeutics, Inc.|Solid forms of ceftolozane|
    KR102192524B1|2019-06-28|2020-12-17|에스케이씨 주식회사|Preperation method of polyvinyl acetal resin composition, the polyvinyl acetal resin composition and film for laminating comprising the same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8123683|1981-08-03|
    GB8131261|1981-10-16|
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