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    • 专利摘要:
    Antibacterial activity is exhibited by compounds having the formula <CHEM> and salts thereof, wherein R1, R2, R3, R4, R5 and R6 represent various organic groups.
    公开号:SU1391496A3
    申请号:SU833543246
    申请日:1983-01-03
    公开日:1988-04-23
    发明作者:Бройер Герман；Денцель Теодор
    申请人:Е.Р.Сквибб Энд Санз,Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new azetidinone derivatives, namely, azetidinones of the general formula
    R.NHR
    I
    3lNn-, 1 |,
    n N-C-NHSO, N-C-Ro and „II i
    Oh oh
    (I)
    de RI is hydrogen or lower alkyl; RJ - lower alkyl, chloromethyl,
    methoxymethyl, phenyl, amino, methylamino, dimethylamino, 4-methyl-2,3-dioxopiperazinyl 1,2-oxopyrrolidinyl-1, 2-oxo-oxazolidinyl-1, 2-oxoimidazolidine-1, unsubstituted or substituted in position 3 by lower alkyl, 2-hydroxyethyl, 2-aminoethyl, amino, 1-methylethylene-amino, or mesyl; RJ - group
    .0
    CeHg-CH-c-.
    NH-CO- N {N-C2H5
    n
    oh oh
    or
    , 0
    -C-C II N-0-4 where
    N- D
    H2 M S
    - lower alkyl or 1-carboxyisopropyl,
    which possess antibacterial activity and can be used in medicine.
    The aim of the invention is to develop, on the basis of known methods, a method for producing new azetidinone derivatives, which possess valuable pharmacological properties.
    Example 1. Dikaliev salt / 3S / Z // - N- / 1 / (acetylamino / sulfonyl / - amino / carbonyl / -2-oxo-3-azetidinyl) - 2-amino-a- / methoxyimino / -4thiazole-amide .
    45 but) -4-thiazole acetic acid (450 mg of 1 g of dicyclichexylcarbodiimide and 150 mg of N-hydroxybenzotriazole. The resulting solution was stirred overnight, the urea was filtered off and the solvent was removed in vacuo. The remaining solid was chromatographed on KR-20. water as eluent and as a result 400 mg is obtained
    A. Kaliev Phenylmethyl salt of ether / S / - / l - (/ acetylamino / sulfonyl) amino / carbonyl / -2-oxo-3-acetidinyl / - carboxylic acid.
    (S) -3- C (Phenylmethoxy) carboxide amino -2-aletidinone (4.4 g) suspension of the product, m.p. 255-2 ° C (decomp.).
    Example: 3S / Z / -2 - /// 2 - // 1- // Acetylamino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amino / -1- / 2-amino-4-thiazolyl / -2-oxoethylene /
    Dirut in dry ethyl acetate. The mixture is cooled to and 3.1 g of chlorosulfonyl isocyanate are added dropwise with stirring at such a rate that the temperature does not exceed. Stirring with continued 20 min. After that, A g of hexamethyldisilazane is added and the resulting solution of IL-11 is heated at ambient temperature for 12 hours. Acetyl chloride (3.2 g) is added and the resulting solution is stirred again for 48 hours. Then the ethyl acetate is rinsed with water and extracted twice (50 ml) in bulk This aqueous bicarbonate solution. The organic layer is removed and the aqueous phase is treated with a solution of hydrochloric acid to a pH of 1.0. Extraction with ethyl acetate, drying and adding the solvent gives 4 g of the title compound as a raw material. This product is dissolved in the acetone /
    / water (1: 1), the pH is adjusted to 6.5, the solvents are removed in vacuo and the crystalline compound mentioned is filtered off with the aid of ether. As a result of additional purification, carried out by high pressure chromatography (HP-20), water / acetone (4: 1) in the separation, m.p. 130-135 ° C (decomp.) N. / 33/77 / -K- / 1 - // // Acetylanine / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / -2-amino-a- / methoxyimino / - 4-thiazole-acetamide, dipotassium salt,
    (s) Calcium salt of phenylmethyl ether / S / - / 1 - // // acetylaminosulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (940 mg) is dissolved in 50 ml of dry dimethylformamide and hydrogenated in the presence of 500 mg of 10% palladium on carbon for 30 minutes, after which the catalyst is filtered off. (Z) -2-Amino-a- (metroxyimino) -4-thiazoleacetic acid (450 mg} 1 g of dicyclobhexylcarbodiimide and 150 mg of N-hydroxybenzotriazole) are added to the filtrate. The resulting solution is stirred overnight, the precipitated urea is filtered. under vacuum.The remaining solid is chromatographed on a CR-20 using water as eluent, and 400 mg are obtained.
    product, so pl. 255-2 ° C (decomp.).
    amino / -oxy / -2-methylpropanoic acid.
    A. Monox li diphenylmethyl ester 2 - /// 2 - /// 2 - // 1 - // // acetylamino / sulfonyl / amine / clononyl / -2-oxo-3-azetidinyl / amino / 1- / 2-amino-4-thiazolyl / -2-hydroxyethylidene (amino) o-hydroxy / -2-methylpropanoic acid
    The potassium salt of feilmethyl ester of ra / 3 / - / 1 - // // acetylamino / sulfone1 / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (1.38 g, example IA) is hydrogenated in dry dimethylformamide in the presence of 700 mg of 10% palladium on carbon for 30 minutes, after which the catalyst is filtered off. (G) -2-amino-a-2- (diphenylmethoxy) -, 1-dimethyl-2-oxo-ethoxy-imino-4-t "azole-acetic acid (1.32 g), 1.2 g of dicydohexyl - carbodiimide and 150 g of N-hydroxybenzotriazole and the resulting solution is stirred for 12 hours. The precipitated urea is filtered off and the solvent is removed in -vacuum. The precipitate obtained is dissolved in 50 ml of acetone, filtered and poured into 100 ml of ether. The precipitated compound is filtered and dried to form 2.5 g of a substance.
    B. / 38 /% / - 2 - /// 2 - // 1 - //// Acetyl-amino / sulfonyl / amino / carbonyl / 2-ox-3-azetidinyl / amino / -1- / 2 -amino-4-thiazolyl-2-oxo-ethylideneamino / -oxy / 2-methylpropanoic acid.
    Mono potassium diphenylmethyl ester 2 - /// 2 - // 1 - // // acetylamino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amino / -1- / 2-amino- 4-thia zolsh1 / -2-oxostilidene / amino7oxy / -2-methylpropanoic acid (2.5 g) is suspended in 5 ml of anisole and cooled to 0 ° C. Trifluoroacetic acid (12 ml) was added dropwise with stirring, while maintaining the temperature at 0 ° C. After 3.5 hours, the solution is poured into 100 ml of ether, while precipitating the desired product. The crude product is filtered off and purified by HP-20 chromatography using water / acetone (9: 1) as eluent to give 620 mg of product, mp. 225-230 C (decomp.).
    Example 3. Phenylmethyl ester / 1 - ///// chloroacetyl / amino / sulfonyl / amino / -carbonyl / -2-oxo-3-azetidinyl / carbamic acid.
    (S) -3- (Phenylmethoxy) carbonyl J amino 1 | -2-azetidinone (4 G) suspended
    j 0 5 o

    five
    0
    0
    diat in 150 ml of dry ethyl acetate. The mixture is cooled to -50 ° C, 3.3 g of chlorosulfonyl isocyanate is added with stirring; stirring is continued without heating until the temperature reaches 0 ° C. K- (trimethylsilyl) chloroacetamide (6.0 g) is added and the solution is stirred overnight. The insoluble material is filtered off and the filtrate is washed with water. The organic layer was extracted twice with a saturated sodium bicarbonate aqueous solution. The alkaline aqueous layer is acidified to pH 1 with 20% hydrochloric acid and extracted twice with 150 ml portions of ethyl acetate. The organic layers are combined, dried and evaporated to dryness. The oily residue is dissolved in 50 ml of acetone and the pH is adjusted to 6.5 by the addition of a 1 N potassium hydroxide solution. The solvent is removed in vacuo and the crystalline residue is filtered off in the presence of ether to form 3.9 g of the desired compound.
    Potassium salt / 3S / R / -N- / 2 - // 1 - // // acetylamino / sulfonyl / -amino / carbonyl / -2-oxo-3-azetidinyl / amino / -2-oxo- 1-phenyl-ethyl / -4-ethyl-2,3-dioxo-I-piperazinecarboxamide.
    Following the procedure of Example 1B, but replacing (R) -2-amino-a- (methoxyamino) -4-thiazoleacetic acid with (R) -a (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl amino benzoacetic acid , get the named connection, so pl. 160-165 C (decomp.).
    PRI me R 4. Kaliev salt / 3S / Z // 2-aMHHo-1 - ///// chloroacetate / amino / - sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / -a- (methoxyimino) -4-thiazolacetamide.
    Phenylmethyl ether / 1 - //// chloroacetyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (1.0 g, example 3) is slowly added to 20 ml of 40% a solution of HBr in acetic acid at 10 s, the resulting solution is stirred for 5 minutes Dry diethyl ether (100 ml) was added and the precipitate was filtered, washed with ether and dried thoroughly. This compound was dissolved in 50 ml of water, the pH was adjusted to 6.5 with 1 N KOH solution and the resulting solution was freeze dried. The compound obtained is dissolved in 50 ml of dry dimethylformamide and (7) -2-amino-a- (methoxyimino) -4-thiazoleacetic acid, 0.04 g of H-hydroxybenzotriazole and 0.76 g of dicyclohexylcarbodiimide, obtained the solution is stirred over night at ambient temperature. The precipitated urea is filtered off and the solvent is removed in vacuo. The residue is chromatographed using HP-20 resin (eluent is water) to give 0.19 g of product, mp 2 5 22G ° C.
    PRI me R 5, Dikaliev salt / ZB / g /// - 2 - /// 1- / 2-amino-4 thiazolyl / - 2 - // 1 - //// chlorine til / amine / sulfo-n1sh / amino / carbonyl-1-2-oxo-3-aetidinyl / amino / -2-oxoethylidea / amino / oxy / -2-methylpropanoic acid,
    Phenylmethother / 1 - ///// chloroethyl / amino / sulfonyl / aminocarbonyl / -2-oxo-3-azetidinyl / carbamic acid (2.0 g, example 3) is added with stirring to 40 ml of a 40% aqueous solution of hydrogen bromide in acetic acid, after 5 minutes a clear solution is obtained. Dry ether (200 ml) was slowly added dropwise and the precipitate was filtered, washed with ether and dried. The white powder is then dissolved in 50 ml of water and the pH is adjusted to 6.5, the resulting solution is freeze-dried. The compound obtained is dissolved in 100 ml of dry dimethylformamide and 2.72 g added.
    ten
    20
    25
    thirty
    (x) -2-amino-a- 2- (diphenylmethoxy) - 35.
    2.23 g of the crude title product are obtained. Purification is carried out by the method of HP-20 chromatography (eluent.-water) with the formation of 0.5 g of product, t, mp, 220-225 ° C (decomp.,).
    Approx 6, Dikaliev salt / 35/77 / -2 - //// 1- / 2-amino-4-thiazolyl / 2 - // 1 - ///// methoxy acetyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azeti dinyl / amino- / 2-oxoethylidene / amino / oxo / -2-methylpropanoic acid.
    A, Monopotassium salt of phenylmethyl esters / 8 / -1 - //// methoxyacetyl / amno / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid,
    (I) -3-1 G (Phenylmethoxy) carbonyl amino -2-azetidinone (4.4 g) is suspended in 100 ml of dry ethyl acetate. The resulting mixture is cooled before and while stirring, 3, J2 g of chlorosulfonyl isocyanate are added, the cooling is stopped and when the temperature reaches, a clear solution is obtained, i.e., 30 min with 13.9 g of K-trimethylsilylmethoxyacetate amide added and stirring is continued for 24 hours at ambient temperature . Thereafter, the ethyl acetate solution is washed with water, dried, and the solvent is removed. The residue was dissolved in acetone / water (9: 1) and the pH was adjusted to 6.5 with 1 N KOH. The acetone is removed in vacuo and the aqueous solution is dried with freeze-drying, 1-dmethyl-2-oxoethoxy-imino-4-thiazoleacetic acid, 0.08 g of N-hydroxybenzotriazole and 1.52 g of dicyclohexylcarbodiimide and the resulting ratb, dical salt / 3S / Z // - 2 - /// 1/2-amino-4-thiazolyl / -2 - // 1 - //// meth-oxyacetyl / amino / sulfonyl / amino / carbonyl / -2-oxo -3-azetidinyl / amino / -2vor is stirred for 12 h. The precipitate is filtered oxoethylidene / amino / oxy / -2-methylpro.
    0
    five
    0
    2.23 g of the crude title product are obtained. Purification is carried out by the method of HP-20 chromatography (eluent.-water) with the formation of 0.5 g of product, t, mp, 220-225 ° C (decomp.,).
    Primer 6, Dikaliev salt / 35/77 / -2 - //// 1- / 2-amino-4-thiazolyl / - 2 - // 1 - //// methoxy acetyl / amino / sulfonyl / amino (carbonyl) -2-oxo-3-azetidinyl / amino- (2-oxoethylidene) amino / oxides / -2-methylpropanoic acid.
    A, Monokaliev's salt of phenylmethyl ester / 8 / -1 - //// methoxyacetyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid,
    (I) -3-1 G (Phenylmethoxy) carbonyl amino -2-azetidinone (4.4 g) is suspended in 100 ml of dry ethyl acetate. The resulting mixture is cooled before and while stirring, 3, J2 g of chlorosulfonyl isocyanate are added, the cooling is stopped and, when the temperature reaches, a clear solution is obtained, i.e., 30 min with 13.9 g of K-trimethylsilylmethoxyacetamide being added and the stirring is continued for 24 hours at ambient temperature environment. Thereafter, the ethyl acetate solution is washed with water, dried, and the solvent is removed. The residue was dissolved in acetone / water (9: 1) and the pH was adjusted to 6.5 with 1 N KOH. The acetone was removed in vacuo and the aqueous solution was dried by freezing, Dicalium salt (3S / Z) - 2 - /// 1- / 2-amino-4-thiazolyl / -2 - // 1 - /////met- hydroxyacetyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amino / -2
    Stir and remove the solvent in vacuo. The half residue is stirred with 100 ml of dry ether and filtered. Then this compound is suspended in 6 ml of anisole and cooled to -15 ° C. At this point, 12 ml of trifluoroacetic acid are added dropwise with stirring at such a rate that the temperature does not exceed, after which stirring is continued at 2 hours. Cold ether (200 mp) is added and the precipitated substance is filtered, washed with water, dried and dissolved in 50 ml ace45 mixtures
    50
    Panovoy acid.
    Phenylmethyl ester monopotassium (S / -1 - ///// methoxyacetyl / amino / sulfonyl / carbonyl) -2 -alko-3-azetidinyl / carbamic acid (0.43 g) is dissolved in 50 ml of dry dimethylformamide. Palladium on carbon (100%, 0.25 g) is added and hydrogen is bubbled through the system for 30 minutes with stirring. The catalyst is filtered off and 0.42 g of (Z) -2-amino-a-2- (diphenylmethoxy) -1,1-dimethyl-2-oxo-ethyl-amino-4-thiazole acetic acid, 0.01 g of N- hydroxy niton / water (i: l), pH is rav-55benzotriazole and 0.24 g of dicyclohexyl 6.5 with 1 N KOH solution, carbodiimide, the resulting peacetone solution is removed in vacuo and the remaining is stirred at room temperature
    the aqueous solution is freeze-dried, 12 hours. The precipitate is filtered off and grown.
    0
    Panovoy acid.
    Phenylmethyl ester monopotassium (S / -1 - ///// methoxyacetyl / amino / sulfonyl / carbonyl) -2 -alko-3-azetidinyl / carbamic acid (0.43 g) is dissolved in 50 ml of dry dimethylformamide. Palladium on carbon (100%, 0.25 g) is added and hydrogen is bubbled through the system for 30 minutes with stirring. The catalyst is filtered off and 0.42 g of (Z) -2-amino-a-2- (diphenylmethoxy) -1,1-dimethyl-2-oxo-ethyl-amino-4-thiazole acetic acid, 0.01 g of N- the hydroxy solvent is removed in vacuo. The residue is suspended in diethyl ether and the precipitate is filtered off (0.76 g). This compound is suspended in 3 ml of anisole and cooled until 6 ml of trifluoroacetic acid are added dropwise with stirring and the stirring is continued so that the temperature does not exceed. After that, the temperature is maintained for 2 hours. Cold diethyl ether (100 ml) is added and the precipitate is filtered, dried and dissolved in water, the pH is adjusted to 6.5 by adding 1 N KOH solution and the resulting solution is chromatographed on HP-20 resin using water as eluent to form 200 mg of product, mp. 245-250 C (decomp.).
    Example. Kaliyev salt / 3S / g // - 2-amio-K- / - ///// methoxyacetyl / amino / sulfonyl / amino / carbonyl / -2- occo-3-azethidinyl / a- / methoxyimino / - 4- thiazole-acetamide.
    (S / - / 1 - ///// methoxyacetyl / amino / sulfonyl / amino / carbonyl-2-oxo-3-azetidinyl / carbamic acid, phenyl methyl ether, monopotassium salt (0.5 g) is hydrogenated in 30 ml dry dimethylfornamide in the presence of 0.25 g of 10% palladium on carbon for 30 minutes. The catalyst is filtered off and 0.22 g (g) -2-amino-a- (methoxyimino) -4-thiazoleacetic acid, 0.01 g of N-hydroxybenzotriazole and 0.21 g of dicyclohexylcarbodiimide are added. The resulting solution was stirred overnight, filtered and evaporated to dryness. The residue is chromatographed (HP-20, water as eluent) to give 0.12 g of product, mp, 170-175 ° C (dec,).
    In the example, Dikaliev salt / 3 / ZB / g / -2 - /// 1- / 2-amino-4-thiazolyl / -2 // 1 - ///// benzoylamino / sulfonyl / amino / carbonyl / - 2-oxo-3-azetidinyl (amino) -2-oxoethylene / amino / oxo / -2-methyl propanoic acid.
    A, Kaliev salt of phenylmethyl ester (s) - / 1 - // aminosulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamate acid.
    Method 1. () - (2-oxo-3-azetidinyl) carbamic acid, fenusmethyl ester (11 g) is dissolved in a mixture of 200 ml of apetoyl and 50 ml of dichloromethane. The resulting mixture is cooled
    to -50 ° C and a solution of chlorosulfonyl isocyanate (9 g) and 25 ml of dichloromethane are added with stirring. After the mixture is heated, a solution of 6 g of ammonia in 60 ml of acetopitrile is slowly added. The reaction temperature rises to -10 ° C, then up to. Reaction time 3 hours. Deposits
    ammonium salt of the named compound, it is filtered by suction (20 g). The crude product is purified by HP-20 chromatography (100-200 mesh), eluting with 2000 ml of a mixture of water and water / acetone system (8: 2), fractions are taken by volume 20 ml. The course of the elution was followed by thin layer chromatography. From fraction 142-154, 9.3 g of product is obtained by evaporation.
    20
    thirty
    The ammonium salt of the title product is dissolved in 100 ml of water, layered with 200 ml of ethyl acetate and acidified. After separating and washing the aqueous layer with two portions of ethyl acetate, the organic layer is washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, and evaporated to give 8.1 g of the title product as free acid.
    Method 2. A mixture consisting of (s) - (2-oxo-3-azetidinyl) carboxylic acid phenylmethyl ester (11 g) in 175 ml of dichloromethane is cooled to. When mixing dropwise
    35 7.7 g of chlorosulfonyl isocyanate in 75 ml of dichloromethane are added over 15 minutes. The temperature of the solution is raised to within 30 minutes. Thereafter, the clear solution is cooled again to give -30 ° C and 8.8 g of bis (trimethylsilyl) amine dissolved in 30 ml of dichloromethane are added, while passing dry nitrogen through the flask. After 1 hour, increase the reaction temperature to 45 ° C to -15 ° C for 30 minutes. The solvent is distilled off in vacuo and the residue is treated with 400 ml of ether to form a solid (16.6 g), which is washed with another 20 ml of ether. Of
    50 etheric mother liquor receive a second batch of product (4.2 g).
    The raw material (18.0 g) with 20 g of resin HP-20 is suspended in 30 ml of water and the mixture is purified by chromatography55 on a column of HP-20, the elution wire is 3 liters of water; 2.5 L of a water / acetone mixture (4 L of a water / acetone mixture (7: 3) or 6 L of a mixture of 91
    yes / acetone (6: 4). From the last fraction, 6.2 g of the title product are obtained, b.p. 50-152 s,
    B. Kaliyev salt of phenylmethyl ester / S / - / 1 - ///// benoylamino / sulfonyl / amino / carbonyl-2-oxo-3-azet 11 dinyl / carbamic acid.
    (5) -1 - // Aminosulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbaic acid, phenyl methyl ether, potassium salt (2.3 g) and 2.2 g of potassium carbonate are mixed in 50 ml of dry dimethylformamide with 5 g of benzoyl chloride and 0.6 g of dimethylaminopiridine overnight. The solvent is removed in vacuo and the residue is extracted with ethyl acetate, the organic layer is dried and evaporated to dryness. The residue is dissolved in a water / acetone mixture (1: 9) and the pH is adjusted to 6.5 with 1 N KOH solution. The acetone is removed in vacuo and the remaining aqueous solution is freeze dried to life. Purification of the resulting white powder was carried out using HP-20 chromatography using a water / acetone (9: 1) system as eluent, to obtain 1.1 g of product, m.p. 96-99 C (decomp.) .
    V. / 33 / g // - 2 - /// 1- / 2-Amino-4-tia- ZOLIL / -2 - // 1 - // benzoylamino / sulfonyl / amino / carbonyl-2- oxo-3-azetidinyl / amino / -2-oxo-ethylendenamino / oxy / 2-methylpropanoic acid, dicalum salt.
    The potassium salt of phenylmethyl ester of ra / S / -1 - //// benzoylamino / sulfonyl amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (0.5 g) is hydrogenated in 100 ml of dry dimethylformamide in the presence of 0.25 g of 10% palladium on charcoal for 1 h. The catalyst is filtered off and 0.46 g of (8) -2-amino-a- (2-diphenylmethyl hydroxy-1,1-dimethyl-2-oxoethoxy) imino is added. 4-thiazoleacetic acid, 0.0 g of N-hydroxybenzotriazole and 0.24 g of dicyc lexylcarbodiimide and the resulting solution is stirred for 12 hours. The solvent is distilled off in vacuo and the residue is filtered in the presence of 100 ml of ether and dried T (0.92 g). The resulting compound is suspended in 2 ml of anisole, cooled to -10 ° C and 4 ml of trifluoroacetic acid are added with stirring. This temperature is maintained for 5 hours. Then add
    ABOUT
    five
    20
    100 ml of dry ether are added and the precipitated compound is filtered off, dissolved in 5 ml of water and the pI is set to 6.5 with 1 N KOH solution. The resulting aqueous solution is chromatographed on HP-20 resin (using water as eluate), to give 0.24 g of product,, 0 mp. 225-230 C (decomp.).
    PRI me R 9. Kaliev salt / 3S / / R // - N- / 2 - //// // benzoyllamino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amino -2-oxo-1-phenylethyl / -4-ethyl-2,3-dioxo-1-piperazine carboxamide.
    The potassium salt of the phenylmethyl ester / 5 / -1 - ///// benzoylamino / sulfonyl amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (0.25 g) (Example 8B) is hydrogenated according to Example 8B. (N) -a - {(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl amino is added to the resulting solution with stirring overnight
      benzeneacetic acid (0.17 g), 0.01 g of N-hydroxybenzotriazole, and 0.13 g of dicyclohexylcarbodiimide. The solvent is distilled off in vacuo and the residue is chromatographed using HP-20 resin and water / acetone mixture (I9: 1) as eluent to give 0.14 g of product, m.p. 180-185 ° C (decomp.).
    Example 10. Kaliev salt
    35 / Zo / 7 // - 2-amino- / - ///// Benzoylamino / sulfonyl / amino / carbonyl / - 2-oxo-3-azetidinyl / a- (methoxyimino) -4-thiazole acetate.
    The potassium salt of phenylmethyl ester 40 ra / B / - / 1 - //// benzoylamino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (0.25 g, example 8B) is hydrogenated according to example 8B . To the resulting
    45% of the solution was added with 0.01 g of N-hydroxybenzotriazole, 0.11 g (g) -2-amino-a- (methoxyimino) -4-thiazoleacetic acid and 0.13 g of dicyclohexylcarbodiimide. After stirring for
    .JQ overnight at room temperature the solvent is removed in vacuo and the residue is chromatographed using HP-20 resin and water / acetone mixture (l9: l) as eluent to form 0.05 g of product, m.p. 205-210 C.
    Example 11. Phenylmethyl ether / 3 / -1 - //// // acetylmethylamino /
    eleven
    sulfo1 il / ami ocarbonyl / -2-oxo-3-azetidnsh1 / carbamic acid.
    (D) -3- (Feiylmethoxy) carboyl amio -2 -2-azetidione (2.2 g) is suspended in 100 ml of anhydrous furan tetrahydride and cooled to with stirring. Chlorosulfonyl isopyanate (1.56 g) is added and the temperature is maintained for 30 minutes. After that, 3.51 g of heptamethyldisilazane is added and stirred at room temperature for


    ; s, 1A
    h
    P
     20
    thirty
    nights Acetyl chloride is added and the solution is stirred for an additional 48 h., G The solvent is removed in vacuo, the residue is dissolved in ethyl acetate and extracted with 2 x 50 ml of water. The aqueous layer was separated and the ethyl acetate solution was dried with and evaporated to dryness. The residue was dissolved in acetone / water (9: 1), the pH was adjusted to 6.5 with 1 AND the KOI solution and the acetone was removed in vacuo. Ostapis vodnsh rast-25 is supported by a thief dried by freezing. The resulting crude substance (1.9 g) was purified by HP-20 chromatography to form 1.03 g of product.
    Kaliev salt /35/7.//-2- amino- G1- / 1 - ///// 2-methylpropaniol / aminosulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / -a- / methoxyimino / -4-thiazole-amide.
    (s) -3- (Phenylmethoxy) carbonyl amino -2-azetidinone (2.2 g) is suspended in 100 ml of dry ethyl acetate, cooled to -50 ° C and 1.56 g of chlorosulfonyl isocyanate is added. After 30 minutes, a clear solution is obtained at 0 ° C. and 4.78 g of N-trimethylsilyl-2-methylpropionamide are added and the mixture is stirred at room temperature for 12 hours. The resulting solution is washed with 100 ml of water, dried and evaporated to dryness. The residue was dissolved in a water / acetone mixture (1: 9) and the pH was adjusted to 6.5 with an I N KOH solution. The acetone was removed in vacuo and the remaining aqueous solution was freeze dried 0.28 g of the compound. This compound is dissolved in 50 to 20 ml of dry dimethylformamide and hydrogenated in the presence of 0.1 g of 10% palladium on carbon for 30 minutes. The catalyst is filtered off and add 40
    45
    A. Kaliev salt
    ether / S / - / 1 - ///// a but / sulfonyl / amino /
    3-azetidinyl / karyam
    (S) -3-5 (Phenylme amino) -2-azetidinone is dipped in 300 ml dry wound at. Chlorine (11.1 g) in 80 ml dry and added dropwise to the obtained
    cooling it for 30 minutes. Lilmurea is added (10.5 g of sulphide is continued at night for removal overnight in vacuum and methanol. The resulting stitching is carried out for 30 minutes, dissolved and the residue is taken up in ethyl acetate, and the 100 ml cc layer is separated, removed. After removal of the slurry solution of acetone and 10 ml of water is equal to 6.5 in bromide of a 1 N solution guide. After evaporation, work up the target compound, mp 120-125 ° C (
    B. Kaliev salt of N - /} - ///// aminocarbonyl / amino / carbonyl / dinyl / - - / amide methoxy.
    The potassium salt of fenra / S / - / I - ///// amino sulphonyl / amino / carbididinyl / carbamine is hydrogenated in 100 ml of amide in the presence of
    The potassium salt of the phenylmethyl ester of ra / S / - / I - ///// aminocarbonyl / amino / sulfonyl / amino / carbonyl / -2-oxO-aza tidinyl / carbamic acid (1.4 g) is hydrogenated in 100 ml of dry dimethylformer amide in the presence of 0.7 g of 10%
    0.1 g of (S) -2-amino-a- (methoxyim-55 palladium on carbon as catalino) -4-thiazoleacetic acid, 0.01 g H-hydroxyb} zotriazole and 0.13 g dicyclohexylcarbodiimide and received
    congestion. After 30 minutes, the hydrogenation is completed, the catalyst is filtered off and 0.66 g of (Z) -2-aMHHo-a- is added.
    ten
     20
    thirty
    r 25 support

    35 50
    40
    45
    the mixture is stirred overnight at room temperature. The solvent is removed in vacuo and the residue is chromatographed on HP-20 resin, eluted with a water / acetone system (19: 1) to give 50 mg of product, m.p. 185-190 ° C (decomp.).
    Example 12. Potassium salt / 3S / Z // 2-amino-N- / 1 - //// aminocarbonyl / amino / sulfonyl / amino / carbonyl / - 2-oxo-3-azetidinyl / -a / methoxyimino / -4-thiazole-acetamide.
    A. Kaliyev phenylmethyl salt
    ether / S / - / 1 - ///// aminocarbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo3-azetidinyl / karyamic acid.
    (S) -3-5 (Phenylmethoxy) carbonyl J amino) -2-azetidinone (13.2 g) is suspended in 300 ml of dry tetrahydrofuran at. Chlorosulfonyl isocyanate (11.1 g) in 80 ml of dry dichloromethane and added dropwise to the mixture while transferring. Tempes using external cooling at a level for 30 min. Trimethylsilyl urea (10.5 g) is added and stirring is continued at room temperature overnight. The solvent is removed in vacuo and 200 ml of methanol are added. The resulting solution is stirred for 30 minutes, the solvent is evaporated and the residue is treated with 200 ml of ethyl acetate and 100 ml of water. The organic layer is separated, dried and filtered. After removing the solvent, the oily residue is dissolved in 100 ml of acetone and 10 ml of water and the pH is adjusted to 6.5 by the addition of a 1 N potassium hydroxide solution. After evaporation of the solvent, the desired compound is obtained. Yield 11.0g 120-125 C (decomp.).
    B. Kaliev salt / 35 /, // - 2-amino-N - /} - ///// aminocarbonyl / aminosulfonyl / amino / carbonyl / 2-oxo-3-azetidinyl / a- / methoxyimino (4-thiazole-amide).
    The potassium salt of the phenylmethyl ester (S / - / I - ///// aminocarbonyl / amino / sulfonyl / amino / carbonyl) -2-oxO-azetidinyl / carbamic acid (1.4 g) is hydrogenated in 100 ml of dry dimethylformamide in the presence of 0.7 g of 10%
    55 palladium carbon as a catalyst. After 30 minutes, the hydrogenation is completed, the catalyst is filtered off and 0.66 g of (Z) -2-aMHHo-a is added.
    131
    (methoxyimino) -4-thiazoleacetic acid and 0.2 g of Kg-odroxybenzotriazole. Dicyclohexylcarbodiimide (20 mg) dissolved in 100 ml of dry dimethyl formamide, slowly added dropwise to the system with stirring for 10 hours. Stirring is continued for another 12 hours. The mixture is cooled to 0 ° C, the precipitated urea is filtered, the solvent is removed in vacuo and the residue is chromatographed n-resin HP-20 using water as eluent. Output 900 mg, so pl. 205-210 ° C (decomp.).
    Example 13. Dikaliev salt / ZB / g / -2 - /// 2 - // 1 - //// aminocarbonyl amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amino / -1- (2-amino-4-thiazolyl) -2-oxoethylidene (amino) oxide / -2-methylpropanoic acid.
    The potassium salt of phenylmethyl ester / 5 / -1 - ///// aminocarbonylamino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carboamyric acid (1.98 g, example 12A) is hydrogenated in the presence of 1 g of 10% Palladium on carbon in 200 ml of dry dimethylformamide for 30 minutes. The catalyst is filtered off and 300 mg of N-hydroxybenzotriazole and 2.5 g (g) of -2-amino-a-K 2- (diphenylmethoxy) -1,1-dimethyl 2-oxoethoxy-imino-A-thiazole acetic acid are added. Dicyclohexylcarbodiimide (1.1 g), dissolved in 100 ml of dimethylformamide, is slowly added dropwise to the system for 10 hours. Then stirring is continued for 10 hours. The solvent is removed in vacuum and the solid residue is suspended in 10 ml of anisole and cooled to 0 ° C. At this temperature, 20 ml of trifluoroacetic acid are added dropwise with stirring. The temperature is maintained at 0 ° C with cooling. After 3.5 h, the reaction is completed and the solution is poured into 200 ml of ether. The precipitate is filtered, dried and dissolved in 10 ml of a water / acetone mixture (1: 1) and the pH is adjusted to 6.5 by the addition of a 1 N potassium hydroxide solution. The acetone is removed in vacuo and the aqueous phase is chromatographed on HP-20 resin using water as eluent. Output 1.5 g, t, pcs. (different)
    Example 14. Potassium salt / 3S / R / - / 2 - // 1 - ///// aminocarbonyl / amylo / sulfonyl / amino / carbonyl U-2-oxo-3-azetidiyl / amino / -2-oxo-1 -phenyl






    0
    five
    1496
    n
    5 5 0
    five
    14
    Ethyl / -4-Ethyl-2,3-dioxo-1-piperazine carboxamide.
    The phenylmethyl ester potassium salt / S / -1 - ///// aminocarbonyl / amino / sulfonyl / amino / carbonyl-2-oxo-3-azetidinnl / carbamic acid (1.34 g, example 12A) is hydrogenated in the presence of 0.6 g of 10% palladium on carbon as a catalyst in 100ml of dry dimethylformamide for 30 minutes. The catalyst is filtered off and 1.23 g of (E) ta- {G (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl1 amino benzeneacetic acid and 100 mg of hydroxybenzotriazole, Dicyclohexylcarbodiimide (0.8 g) in 100 ml are added. dimethylformamide is added dropwise with stirring for 10 hours. The solvent is removed in vacuo and the residue is chromatographed on a pH-20 resin using water as the solvent. The output of 590 mg, so pl. 198 C (decomp.).
    PRI me R 15. Kaliev salt / ZB / 2 // - 2-amino-a- / methoxyimino / -N- / 1 - /////// methylamino / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / -4-thiazole-acetamide.
    A. Kaliyev salt of phenylmethyl ester / 3 / -1 - ////// methylamino / carbonyl / amino / sulfonyl / amino / carbonyl / 2oxo-3-azetidinyl / carbamic acid.
    The potassium salt of phenylmethyl ester (S / -1 - /// aminosulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamate acid (1 g, Example 8A) is dissolved in 20 ml of dry dimethylformamide. Methyl isocyanate (500 mg) was added and the solution was stirred overnight at ambient temperature. The solvent was removed in vacuo and the residue was treated with acetone / ether (1: 1) and filtered. Output 0.9 g, so pl. 153-160 C (decomp.).
    B. Kaliev salt / 33/2 // - 2-amino-a / methoxyimino / -K- / 1 - // // methylamino / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo- 3-azetidinyl / -4-thiazole-acetamide.
    The potassium salt of phenylmethyl ester / H / -1 - /////// methylamino / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (437 mg) is hydrogenated in 50 ml of dry dimethylformamide in the presence of 200 mg of 10% palladium on carbon. After 45 minutes the reaction is complete and catalysis5
    0
    the torus is filtered out. At ambient temperature and at the time of stirrup, (G) -2-a-gino-a- (methoxyimino) -A-thiazoleacetic acid (220 mg), 30 mg of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimim are added. Stirring is continued for 12 hours, the solution is cooled to 0 ° C and the precipitated urea is filtered off. The mother liquor solvent was removed in vacuo and the residue was chromatographed on HP-20 resin using water. The output of 305 mg, so pl. 220-225 C (decomp.).
    Example 16. Kaliev salt / ZS / N // - 4-ethyl-G1- 2 - // 1 - // // methyl / methyl amipo / carbonyl / asio / sulfonyl / amio / carbonyl / -2-oxo-3- azetidinyl / amino / -2-OXO-1-phenylstil / -2,3-diox-1-piperazinecarboxamide.
    A. Kaliyev salt of phenylmethyl ester / K / - / 1 - // // methyl / carbonyl / amino / sulfonyl / amino / carbonyl-2-oxo-3-azetidinyl / carbamic acid.
    4.4 g of (o) -3-G (phenylmethoxy) carbonyl amino -2-azetidinone are suspended in 100 ml of dry tetrahydrofuran and the mixture is cooled to -10 s. At this temperature, 1.6 g of chlorosulfonyl isocyanate is added and the reaction mixture is allowed to reach room temperature. 5.2 g of trimethylsilyl-K, K-dimethylurea are added and stirring is continued at room temperature.
    was removed in vacuo, and the residue was dissolved in 100 ml of ethyl acetate. The organic solution is washed twice with 50 ml portions of water, 50 ml of 2N. phos
    15
    20
    Tylamino / carbonyl / amino / sulfonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (900 mg) is hydrogenated in 50 ml of dry dimethylformamide in the presence of 400 mg of 10% palladium on carbon. After 30 minutes, the absorption of hydrogen ceases. The catalyst is filtered off and 700 mg of (H) -c - {4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl-amino-benzene-acetic acid, 100 mg of N-hydroxybenzotriazole and 600 mg of dicyclohexylcarbonate are added with stirring. body imide After 12 hours at room temperature, the precipitated urea is filtered off and the solvent is removed in vacuo. The residue obtained is chromatographed on HP-20 resin, using water / acetone (| 9: 1) as eluent. Exit 700 mg, m.p. 1 (different).
    PRI me R 17. Dikaliev salt / 38 / g // - 2 - /// 1- / 2-amino-4-thiazolyl / - 2 - // 1 - // methyl / methyl / carbonyl / amino / sulfonyl / amino / car6onyl-2-oxo-3-azet-schinnil / amino / -2-oxoethenyl / amino / oxy / -2-methylpropanoic acid.
    Phenylmethyl ester potassium salt / S / - / l - // // methyl / methylamino / carboxyl / amino / cyphenyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (900 mg, example 16A) hydrated in 50 ml of dry di
    2 h. Solvent 35 methylformamide in the presence of 450 mg
    10% palladium on charcoal for 30 min. The catalyst is filtered off and with stirring at room temperature 1 g of (Z) -2-aMH25 is added.
    thirty
    fororic acid and brine. The organic-c / - (G2- (diphenylmethyloxy) -1), the 1-dimetic layer is evaporated to dryness, the residue is dissolved 100 mg of N-hydroxybenzo-1 (1: 1), the pH is adjusted to 6.5 triazole and 600 mg of dicyclohexylcarbo-1N potassium hydroxide. Acetone is evaporated in vacuo and the aqueous solution of cyuiaT is frozen to obtain
    45
    diimide After 12 hours, the solution is cooled to 0 ° C and the precipitated urea is filtered off. The solution is evaporated to dryness and the residue is filtered off with 50 ml of ethyl acetate. The crude compound is suspended in 2 ml of anisole, cooled to -5 ° C and 6 ml of trifluoroacetic acid are added dropwise at such a rate as to maintain the temperature at 0 ° C. After 2 hours, 100 ml of dry zfir were added and the precipitate was filtered, washed with ether and dried. The crude compound is dissolved in 20 ml of WATER and the pH is adjusted to 6.5 with 1N. potassium hydroxide. After freezing the crude potassium salt
    the crude target compound is sufficiently pure for further 8 g
    neither
    subsequent use
    reactions.
    B. Kaliyev salt / Zo / K / -4-ethyl- K- / 2 - // 1 - // // methyl (methylamino) carbonyl / amino / sulfonyl / amino / carbonyl 2-oxo-3-azetidinyl / amino 2-oxo-1-phenylethyl / -2,3-dioxo-1-piperazinecarboxamide.
    Kalievur salt of the phenylmethyl ester / G / - / 1 - // // methyl // meno-C / - (G2- (diphenylmethyloxy) -1, 1-dimethyl-2-oxoethoxy-imino} -4-thiacolus) acids, 100 mg of N-hydroxybenzotriazole and 600 mg of dicyclohexylcarboxylate
    diimide After 12 hours, the solution is cooled to 0 ° C and the precipitated urea is filtered off. The solution is evaporated to dryness and the residue is filtered off with 50 ml of ethyl acetate. The crude compound is suspended in 2 ml of anisole, cooled to -5 ° C and 6 ml of trifluoroacetic acid are added dropwise at such a rate as to maintain the temperature at 0 ° C. After 2 hours, 100 ml of dry zfir were added and the precipitate was filtered, washed with ether and dried. The crude compound is dissolved in 20 ml of WATER and the pH is adjusted to 6.5 with 1N. potassium hydroxide. After freezing the crude potassium salt
    chromatographed on HP-20 resin, eluted with water and then freeze dried. The output of 400 mg, so pl. 220 C (decomp.).
    Example 18. Kaliev salt / 5 / g // - 2-amino-c (- (methoxyimino) -N- / 1 - // // methyl / methylamino / carboyl / amino / sulfonyl / amino / carbonyl / -2 -oxo-3-azetidinyl / -4-thiazole-acetamide.
    Phenylmethyl ester potassium salt / S / - / 1 // methyl // methylamino / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (440 mg, example ISA) Hydrogenated according to Example 5. 220 mg (s) -2-amino- (methoxyimino) -4-thiazoleacetic acid, 50 ml of K-oxibenzotriazole and 250 ml of dicyclohexylcarbodiimide are added after removal of the catalyst. Stirring at room temperature is continued for 12 hours. The solvent is removed in vacuo and the residue is chromatographed on HP-20 resin, using water / acetone (9: 1) as eluent. Exit 350 mg (freeze dried), so pl. 192 C (decomp.).
    PRI me R 19. Kaliev salt / 35 / g // - 2 - /// 1- (2-amino-4-thiazolyl) - 2 - // 1 - ///// (dimethylamino; carbonyl / amino / sulfonyl / amino / carbon / 1--2-ca-3-azetidinyl / amino / -2-oxo-ethylene / amino / -2-methylpropanoic acid
    A. Kaliev Phenylmethyl Salt Ester / S / - / 1 - ///// (dimethyl amino) carbonyl / amino / sulfonyl / amino carbonyl / -2-oxo-3-azetidinyl / carbamate acid.
    4.4 g of (c) -3- (phenylmethoxy) arbonyl amino -2-azetidinone are suspended in 150 MP of ethyl acetate and cooled to -15 ° C. Chlorosulfonyl isocyanate (3.0 g) is added and the resulting mixture is stirred until a clear solution is obtained. 2 g of N, I-dimethyl urea and 2 g of triethyla are added and stirring is continued overnight. The precipitate is filtered off and the mother liquor is washed with two portions of water, 50 ml each, 50 ml of 2N. phosphoric acid and brine. The solvent is removed in vacuo, and the residue is dissolved in 50 ml of a water / acetone mixture (1: 1). pH set 6.5 1N. potassium hydroxide. The acetone is removed in vacuo, and the aqueous solution is freeze dried. 7 g of the crude target compound are obtained, which
    0
    five
    clean enough for further work.
    B. Kaliev salt / 3S / 7V / -2 - /// 1- / 2-amino-4-thiazolyl / -2 - // - ///// (dimethylamino) carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amino / -2-oxoethylidene / amino / hydroxy / -2-methylpropanoic acid.
    451 mg of the potassium salt of the phenylmethyl ester (S / - / 1 - ///// (dimethylamino) carbonyl / amino / sulfonyl / amino / carbonyl) -2-oxo-3-azetidinyl / carbamic acid is dissolved in 50 ml anhydrous dimethylformamide, 200 ml of 10% palladium on carbon are added and hydrogen is bubbled through the solution for 45 minutes. The catalyst is filtered off and 450 mg of (g) -2-amino-o-2- (diphenylmethoxy) -1,1-dimethyl-2-oxo-ethomino-imino-4-thiazole acetic acid, 100 mg of N-OK-sibenzotriazole and 300 mg of dicyclohexoacetic acid are added. silcarbodiimide, the resulting solution is stirred at room temperature for 12 hours. The precipitated urea is filtered off and the solvent is removed in vacuo. The residue is chromatographed using HP-20 resin and a water / acetone mixture (7: 3) as
    0 eluent. The benzhydryl ester of the title compound (600 mg) is isolated by freeze drying. This compound is suspended in 2 ml of anisole, the mixture is cooled to -10 ° C
    5 and 4 ml of trifluoroacetic acid are slowly added dropwise so that the temperature does not exceed. After that, stirring with continued 2-5 hours. The target compound
    0 is precipitated by adding 100 ml of ether, filtered, dissolved in 5 ml of water and the pH adjusted to 6.5 with 2N. potassium hydroxide. The resulting solution is chromatographed on resin.
    5 HP-20, using water as eluent. Exit 280 mg, so pl. 191 C (decomp.) T
    PRI me R 20. Dikaliev salt / 3S / Z // - 2 - /// l- (2-amino-4-thiazolyl) Q 2-111 - ///// (3-ethyl-2- oxo-1-imidazolidinyl) carbonyl / -amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / amchO / -2-oxoethylidene / amino / oxy / -2-methylpropanoic acid.
    A.Kaliyev Phenylmethyl ester salt / S / - / - ///// (3-ethyl-2-oxo-1-imidazolidinyl) carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3- azetidinyl / carboxylic acids.
    five
    1913
    (S) -3-5 (Phenylmethoxy) Carboiyl amino-2-2-aethypion (6.6 g) is suspended in 200 ml of anhydrous ethyl acetate and half finished) the mixture is cooled to -IS c. At this temperature, 5 g of chlorosulfonic isonium ionate are added and, with stirring at 0 s, the resulting solution (rastpore (Yu)) is added. 4 g of triethylamine and 5.2 g of 1-amino-carbonyl-3-ethylimidazolidine 2-one are added and stirring is continued another 12 h. The reaction mixture is made up with two 50 ml portions of water, 50 ml of 2N, phosphoric acid and brine. The organic phase is evaporated to dryness, the residue is dissolved in I50 ml of water / acetone (1:) and pM is set at 6.5 of 1N hydroxide} Sodium potassium. Acetone is distilled off in vacuo and the remaining solution is taken up by the exgestion, liter 1. A crude crude compound of 2.2 g is pure enough to allow for further reactions,
    B. Dikaliepa salt / 3S / 7, // - 2 - /// 1- (2-amino-4-thiazolyl / -2 - // 1 - ////// 3- ETHYL-2-OXO-1 -imidazolidinle / carbonyl / amino / sulfoyl / amine / carbox; pl./- 2-oxo 3-azethidinyl / amio IIo-2-oxy-ethylenide / amino / oxy-2-methylpropanoic acid.
    520 mg of the potassium salt of fe) ylmethyl-ester ester / S / -1 - //// // 3-ethyl-2-oxy-1-imidazo: idynyl / yrg) onyl / amino / sulfonic / amino / carbonyl-2- oxo-3-azetindinyl / carbamic acid is hydrogenated in 50 ml of anhydrous dimethylformamide in the presence of 200 mg of 10% palladium carbon for iO min. The catalyst is filtered off, 460 mg (Z, 1-2-amino-, - G2- (diphenylmethoxy) -1,1-dimethyl-2-o-x-ethoxy-jimo j-4-thiazoleacetic acid-Tbi, 100 ml of H-hydroxybenzotriazole) are added. and 300 mg of dicyclohexy, pcbodiimide and
    the solution is stirred overnight
    The solvent is distilled off in vacuo and the residue is filtered with ethyl acetate, suspended in 2 ml of anisole and cooled to. 4 ml of trifluoroacetic acid are piped up at such a rate that the temperature does not exceed -5 ° C. Stirring at this temperature is continued for 2 hours. After adding 100 ml of ether, the precipitated precipitate is filtered off, dissolved in 10 ml of water, the pH is adjusted to 6.5 n. potassium hydroxide and an aqueous chromatographic solution of flP-20, used in ca5
    1/4
    Q n
    five
    five
    five
    0 5
    9620
    water, and freeze drying, the desired compound iHie is isolated. Yield 250 mg, m.p. 245 p.
    PRI me R 21. Kaliyev salt / ZNYA / 7.//-2- amino- /- / ethoxyimino/-1- ////// 3-ethyl-2-axo-1-imidazolidinyl / carbonyl (amino) sulfonyl (amino) carbonyl (-2-oxo-3-azetidinyl) -4-thiazole-acetamide.
    Potassium salt of phenylmethyl ester / 5 / -1 - //// // 3-ethyl- 2 - OXO-1-imidazolidinyl / carbonyl / amy-1u / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinc / carbamic acid (520 mg, example 20A) is hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on carbon for 40 minutes. The catalyst is filtered and 230 kg of (Z) -2-amino-o (- (ethoxyimino) -4-thiao-acetic acid, 100 mg of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodimide are added. The solution is stirred at room temperature. 12 hours. After that, the solvent is distilled off in vacuo, and the residue is filtered off with ethyl acetate. The resulting compound is purified by chromatography on HP-20 using water / acetone (9: 1) as an eluant, and the target compound is isolated by freezing. 420 mg, mp 125 C.
    PRI me R 22. Kalieva salt / WN /% // - 2-amino-M- / 1 - //// // 3-ethyl-2- oxo- - and 1-1 Adazolidinyl / carbonyl / amino (sulfonyl) amino (carbonyl) -2-oxo-3-azstidylinyl-o; - (methoxyimino) -4-thiazole-acetamide. In example 21, however, replacing (Z) -2-amino-in - (ethoxyimino) -4-thiazoleacetic acid by (l.) - 2-aMHHo-N- (MeTOKCHHMHHG) -4-THa-eoluxacetic acid, 400 mg of the title compound. M.p. (different).
    Example 23. Kaliyev salt (35/R.//-4-4-ethyl-M-/2-//1-//////3- ethyl- 2-oxo-1-imidazolidinyl / amino / sulfonyl / amino / carbonyl (-2-oxo-3-azetidinyl) / amino (-2-oxo-1-phenylstil) - 2,3-dioxo-1-piperazinecarboxamide.
    Potassium salt of phenylmethyl ester / S / - / 1 - //// // 3-ethyl-2-ca with o-imidaz olidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo- J -azetidinyl / carbamic acid (520 mg, example 20A) is hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on carbon in
    for up to min. After filtering, 330 mg of (K) G (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl amino 6-benzeneacetic acid 1L, 300 mg of dicyclohexylcarbodiimide and 100 mg of N-hydroxybenzotriazole are added and the resulting solution is stirred at room temperature for 12 hours The solution is then evaporated to dryness in vacuo and the residue is filtered with ethyl matter. Purification of the obtained compound was carried out chromatographically on HP-20 oylu, using a mixture of water / acetone (9 :) as a Bptoent. B1COD AZO mz, tpl, lerc (decomp.),
    PRI me R 2D. Kaliev salt / 3S / Z // - 2-amino-c - /. Chetoxyimino / -1 - // // A-ethyl-2,3 dioxo 1-piperazinyl / carbonyl / 1o / sulfonyl / amino (carbonyl) -2-oxo-3-azetidinyl / 4-thia zolacetamide.
    A.Kaliyev salt of phenylmethyl pseud ether / 5 / -1 - ////// 4 et1SH-2,3
    Sh
    IS
    20
    R; 210 mg (m) of 2-amino-c / - (methoxyimine D-thiazoleacetic acid, 50 mg of hydroxybenzotriazole N and 300 mg of dicyc 1 exilcarbodiimide are added to the hydrogenated solution and the solution is stirred at 20 ° C for 16 hours. The solvent is removed in vacuo, the residue filter with ethyl acetate; and the resulting compound is chromatographed on resin H using water / acetone (9: 1) as eluent, yield 280 mg.
    Example 25, f potassium Sol / ZS / g // - 2 - /// 2 - // 1 ///// 4-ethyl-2, dioxo-1-piperazins / carbonyl / am sulfonyl / amino / carb yl / -2-oxo 3 e tyd inyl / -1 - / 2 - e mino - 4 - ty a 3 ol and l oxoetheylH1iden / amnno / oxy / - 2-methylpanoic acid,
    Calcium. Phenylmethyl ester salt / E / - / 1 - //// 4-ethyl 2 f 3-DIOXO - 1-piperaznyl / carbonyl am1pyu / cyphenyl / anno / carboxyl / -2-occo-4 -; zetidinyl / carbamic CI
    Dioxo-1-piperazinyl / carbonyl / amino / g ™ (mg, example 24L) is hydrogenated
     - yy
    thirty
    35
    40
    sulfonyl / amino / carbonyl-2-oxo-3 aetidinyl / carbamic acid,
    (S) -3- {(Phenylmethoxy) carbonyl amino-J-2-azetidinone (4.4 g) is suspended in 200 ml of ethyl acetate at -15 ° C and then 3 g of chlorosulfonyl isocyanate are added with stirring. Through
    15 min at 0 s get clear solution. 5 g of triethylamine and 4 g of 1-amino-bononyl-4-ethyl 2,3-dinoxoliperazine are added and mixed
    16h The resulting mixture is pro-duced in two portions of water, 50 ml each, 50 ml.
    2n, phosphoric acid and brine. After evaporation of the solvent, the residue was dissolved in 100 ml of a mixture of acetone / water (1: 1) and the pH was adjusted to 6.5, the acetone was distilled off and freeze dried to obtain 8 g of crude compound,
    B, Kaliev salt / SZ /% // - 2-amino ID / - / labels CHHMHHo / -N- / 1 - // // // 4-ethyl-2,3-dioxo 1-piperazinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / 4-thiazole-acetamide, 50
    548 mg of the potassium salt of the phenylmethyl ester / S / - / 1 - ////// 4-ethyl-2,3-dioxo-1-piperaeinyl / carbonyl / amino / sulfonal / amino / carbonyl / - 2-oxo -3-azetidinyl / carbamic acid is hydrogenated in 50 ml of dimethylformamide in the presence of 270 mg -10% palladium on carbon for 45 minutes.
    in 50 ml of dimethylformamide in the presence of 270 mg of 10% palladium per g for 45 minutes. After removal of the catalyst, 450 mg (g) -2, mino-2- (difenshmethomethoxy) -1, 1-d 1 -ethyl -2-oxoethoxy J-imis 4-thiase acetic acid, 100 mg N are added. -oxibe. -k) 1 riazole and 300 mg dicyclohexyl .., arbodiimide. This solution was stirred for 16 hours. The solvent was removed in a vacuum, and the residue was filtered with ethyl acetate. Crude benzhydryl ester of Kbszhevogo compound is suspended in 2 ml of anisole, cooled before and with stirring, dripped with 4 ml of trifluoroacetic acid, the temperature is maintained at for 2 hours. Ether is added (100 ml) and the precipitated precipitate is filtered, dried and dissolved The pH is adjusted to 6.5 in 5% water of 1.1 ° C, and the resulting solution is chromatographed on HP-20 cm using water as the eluent, 180 mg of the title compound is isolated by freeze drying.
    Example 26, Kaliev salt / 3S / R // - 4-3THn N- / 2 - // I - // // methy amino / carbonyl / amino / sulfonyl / amy no / carboxyl / -2-occo- 3-azethidinyl / amino / -2-oxo-1-phenylethyl-2,3-dio
    co-piperazincarboxamnd.
    Potassium salt of feiylmethyl ester / G / - / 1 - //// methyl, / k arbonyl / amino / sulfonyl / amino
    0
    R; 210 mg (m) of 2-amino-c / - (methoxyimino) -D-thiazoleacetic acid, 50 mg of N-hydroxybenzotriazole and 300 mg of dicyclo-1 exilcarbodiimide are added to the hydrogenated solution and the solution is stirred at 20 ° C for 16 hours. The solvent is removed under vacuum, the residue is filtered with ethyl acetate and the resulting compound is chromatographed on a resin using water / acetone (9: 1) as eluant. The yield is 280 mg.
    Example 25, f potassium salt / CS / g // - 2 - /// 2 - // 1 ///// 4-ethyl-2,3-dioxo-1-piperazins / carbonyl / amino / sulfonyl / amino / carbyl / -2-oxo3- a 3 e tyd inyl / -1 - / 2 - e mino - 4 - ty a 3 ol and l / 2 - oxoetheyl G1idene / amnno / oxy / - 2 methylpropanoic acid,
    Calcium. Phenylmethyl ester salt / E / - / 1 - //// 4-ethyl-2 f 3-DIOXO-1-piperaznyl / carbonyl / am1pyu / cyphenyl / anno / carbonyl / -2- occo -four-; zetidinyl / carbamic acid
     ™ (mg, example 24L) hydrogenate
    yy

    in 50 ml of dimethylformamide in the presence of 270 mg of 10% palladium on carbon for 45 minutes. After removal of the catalyst, 450 mg (g) -2-, mino -.- 2- (difensh1methoxy) -1, 1-di-1-ethyl-2-oxoethoxy J-imisis 4-thiazole-acetic acid are added, 100 mg of N-hydroxy-b-1) riazole and 300 mg of dicyclohexyl-, arbodiimide. This solution is stirred for 16 hours. The solvent is removed in a vacuum and the residue is filtered with ethyl acetate. Crude benzhydryl ester of Kbshevogo compound is suspended in 2 ml of anisole, cooled before and 4 ml of trifluoroacetic acid are added dropwise with stirring, the temperature is maintained at for 2 hours. Ether is added (100 ml) and the precipitated precipitate is filtered, dried and dissolved The pH was adjusted to 6.5 ml with 5 ml of water and the resulting solution was chromatographed on an HP-20 using water as the eluent, 180 mg of the target compound was isolated by freeze drying.
    Example 26, Kaliev salt / 3S / R // - 4-3THn N- / 2 - // I - // // methyl-amino / carbonyl / amino / sulfonyl / amine-on / carbonyl / -2- oco-3-azethidinyl / amino / -2-oxo-1-phenylethyl-2,3-dioxo-piperazinecarboxamnda.
    Potassium salt of feiylmethyl ester / G / - / 1 - // // methylamino / k arbonyl / amino / sulfonyl / amino /
    231391
    carbonyl / -2-oxo-3-azeti, cynil / -carbamic acid (DZ mg, example 15A) is hydrogenated in 50 ml of dry dimethylformamide in the presence of 200 mg of 10% palladium on carbon for 5 45 min The catalyst is filtered off. 350 mg of (R) -c (-t (4-ethyl-2, 3-dioxo-1-piperazinyl) carbonyl-1-benzene-acetic acid, 50 mg of K-oxybenzotriazole and 300 mg of d-cyclohexylcarbodiimide) are added, the resulting solution is mixed 12 hours. After removal of the solvent in vacuo, the residue is chromatographed on HP-20 resin, using water / acetone (9: 1) as eluent, Yield 380 mg, mp 178-183 ° C (decomp.).
    Example 27, Dikaliev salt / 3S / Z // 2 - /// 1 - 2-amino-4-thiazolyl / 10
    15
    9624
    amino / carbonyl / amino / sulfoiyl / amino / carbonyl / -2-Oxo-3-azetidinyl / carbamic acid (451 mg, example 13A) was hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on coal for 45 min. The catalyst is filtered off and 201 mg of (g) -2-amino-o (- (methoxyimino) -4-thiazoleacetic acid, 50 mg of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimide are added, the resulting solution is stirred for 12 hours at room temperature. The solvent is removed under vacuum, the crystalline residue is chromatographed on HP-20 resin, using water / acetone (9.5: 0.5) as eluent. Yield 285 mg, t, mp, 201 C (decomp.)
    Example 29. Kaliev salt
    25
    thirty
    35
    -2 - // 1 - //// methylamino / carbonyl / ami-20 / WE / g // - 2-amino-c / - (methoxyimino) -K- but / sulfonyl / amino / carbonyl / -2 -OXo-3-azetidinyl / amino / -2-hydroxyethylidene / amino / hydroxy / -2-methylpropanoic acid.
    Phenylmethyl ester potassium salt / S / - / 1 - // // Methyl-amino / carbonyl / amino / sulfonyl / amino / carbonyl / -2-OXO-3-azetidinyl / arbamic acid (437 mg, Example 15A) is hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on carbon for 45 minutes. The catalyst is filtered off and 450 mg of (5) -2-amino-o / - 2- (diphenylmethoxy) -, 1-dimethyl-2-oxo-ethoxy-imino-4-thiazole acetic acid, 50 mg of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimide. The resulting solution is stirred overnight, evaporated to dryness, the residue is suspended in 2 ml of anisole, cooled to -10 ° C and 4 ml of trifluoro-acetic acid are added dropwise. Stirring is continued for 2 hours at -5 ° C. After adding 100 ml of ether, the precipitate is filtered, dissolved, dissolved in 5 ml of water, the pH is adjusted to 6.5 1N. potassium hydroxide and the aqueous solution is chromatographed on HP-20 resin using water as eluent. By freezing, the desired compound (280 mg) is isolated. M.p. 215-220 ° C (dec,).
    Example 28. Potassium salt / 38 / g // - 2-amino-N- / 1 - ///// dimethylamino / carbonyl / amino / sulfonyl / amino / to arbonyl / -2-ok-3-azetidinyl (-c-meth- oxyimino) -4-thiazole-acetamide,
    Potassium salt of phenylmethyl ester / S // 1 - // // dimethyl50
    55
    / 2-oxo-1 - //// // 2-oxo-1-pyrrolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl-3-azetidinyl / -4-thiazole-acetamide.
    A. Kaliev salt of phenylmethyl ester / 5 / - / 2-oxo-1 - /////// 2-oxo-1-pyrrolidinyl / carbonyl / amino sulfonyl / amino / carbonyl / -3-azetidinyl / carbamic acid.
    3 g of (s) -3- {(phenylmethoxy) carbonyl amino} -2-azetidinone is suspended in 100 ml of dry tetrahydrofuran at. Under stirring, 2.1 g of chlorosulfonylisosinate is slowly added dropwise with stirring, maintaining the temperature at 0 ° C, after 30 minutes a clear solution is obtained. At (J C, 1.7 g of triethylamine and 2.05 g of L-carbamoylpyrrolidone are added. Stirring is continued at room temperature for 15 hours. After that, the residue is filtered off into the mother liquor and evaporated to dryness. The resulting residue is dissolved in 50 ml of water / acetone (j: l), the pH is adjusted to 6.5 with 1N potassium hydroxide, the acetone is removed in vacuo and the remaining aqueous solution is freeze dried to obtain 6 g of the desired compound.
    B, Kaliev salt / ЗВ/7.//-2- amino- "- / methoxyimino / - - / 2-oxo-1 - ////// 2 oxo-1-pyrrolidinyl / carbonyl / amino / sulfonyl / amino (carbonyl) -3-azethyl-4-thiazole-acetamide.
    1 g of potassium salt of phenylmethyl ester / 5 / - / 2-oxo-1 - ////// 2-oxo-1-pyrrolidinyl / carbonyl / amino / sulphonyl / amino / carbonyl-3-azetidinyl / carbamine hydri acid
    624
    amino / carbonyl / amino / sulfoiyl / amino / carbonyl / -2-Oxo-3-azetidinyl / carbamic acid (451 mg, example 13A) is hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on coal for 45 min. The catalyst is filtered off and 201 mg of (g) -2-amino-o (- (methoxyimino) -4-thiazoleacetic acid, 50 mg of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimide are added, the resulting solution is stirred for 12 hours at room temperature. The solvent is removed under vacuum, the crystalline residue is chromatographed on HP-20 resin, using water / acetone (9.5: 0.5) as eluent. Yield 285 mg, t, mp, 201 C (decomp.)
    Example 29. Kaliev salt
    / WE / g // - 2-amino-c / - (methoxyimino) -K-
    five
    0
    five
    0 / WE / g // - 2-amino-c / - (methoxyimino) -K-
    0 З
    0
    five
    / 2-oxo-1 - //// // 2-oxo-1-pyrrolidinyl / carbonyl / amino / sulfonyl / amino /, carbonyl-3-azetidinyl / -4-thiazole-amide.
    A. Kaliyev salt of phenylmethyl ester / 5 / - / 2-oxo-1 - /////// 2-oxo-1-pyrrolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azetidinyl / carbamic acid .
    3 g of (s) -3- {(phenylmethoxy) carbonyl amino} -2-azetidinone is suspended in 100 ml of dry tetrahydrofuran at. Under stirring, 2.1 g of chlorosulfonyl isosuccinate is slowly added dropwise with stirring, maintaining the temperature at 0 ° C, after 30 minutes a clear solution is obtained. At (J C, 1.7 g of triethylamine and 2.05 g of L-carbamoyl pyrrolidone are added. Stirring is continued at room temperature for 15 hours. The residue is then filtered into the mother liquor and evaporated to dryness. The resulting residue is dissolved in 50 ml of water / acetone (j: l), the pH is adjusted to 6.5 with 1N potassium hydroxide, the acetone is removed in vacuo and the remaining aqueous solution is freeze dried to obtain 6 g of the desired compound.
    B, Kaliev salt / ЗВ/7.//-2- amino- "- / methoxyimino / - - / 2-oxo-1 - ////// 2- oxo-1-pyrrolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azethynyl / -4-thiazole-acetamide.
    1 g of potassium salt of phenylmethyl ester / 5 / - / 2-oxo-1 - ////// 2-oxo-1-pyrrolidinyl / carbonyl / amino / sulphonyl / amino / carbonyl-3-azetidinyl / carbamine hydri25 acids
    Dimethylformamide using 10% palladium on carbon as catalyst. The catalyst is filtered off, 0.44 g of (Z) -2-amino-dt- (methoxyimino) -4-thiazoluccyclic acid, 30 mg of N-hydroxybenzotriazole and 0.82 g of dicyclohexylcarbodiimide are added to the mother liquor. The resulting solution was stirred overnight, the solvent was removed in vacuo, and the residue was chromatographed on HP-20 resin (eluted with water), giving 300 mg of the title compound.
    Example 30, Dikaliev salt / 38 / g // - 2 - /// 1/2-amino D-thiazolyl / - 2-OXO-2 - // 2-OXO-1 / - ////// 2- OXO-1-pyrrolidine / carVonyl / amino / sulfonyl / amio / carbonyl / -3-azetidinyl / am10
    15
    20
    25
    thirty
    but / ethylidea / amino / hydroxy-2-methylpropanoic acid.
    Potassium salt of phenylmethyl ester / 5 / - / 2-oxo-1 - ////// 2-oxo-1-pyrrolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azetidinyl / carbamium Acids (1.5 g, Example 29A) are hydrogenated in dimethylformamide using 10% palladium on carbon as a catalyst. The catalyst is filtered off, 1.47 g of (Z) -2-amino-c / -2- (diphenylmethoxy) -1, 1-dimethylp-2-oxoethoxy-imino) -4-thiazolinacetic acid, 40 mg is added to the mother solution. N-hydroxybenzotriazole and 1.26 g of dicyclohexylcarbodiimide. The solution is stirred overnight, the solvent is distilled off in vacuo, and the residue is filtered with ether. The resulting residue is suspended in 5 ml of anisole and cooled to -5 ° C. While stirring, 13 ml of trifluoroacetic acid are slowly added dropwise and after 30 minutes the crude product is precipitated by adding 100 mp of ether and filtered off. The resulting product was dissolved in 5 ml of water and the pH was adjusted to 6.5 by adding 1N. potassium hydroxide. As a result of chromatography on HP-20 resin (eluting with water), 500 g of final compound were obtained, m.p. (different).
    PRI me R 31. Potassium salt / ZB / K // - 4-ethyl-2,3-dioxo-K- / 2-oxo-2 - // 2-ok co-1 - ///// (2-oxo-1-pyrrolidinyl) carbonyl (amino) sulfonyl (amino) carbonyl-3-azetidinyl (amino) -1-phenyl-ethyl) -1 piperazinecarboxamide.
    Potassium salt of phenylmethyl ester / B / - / 2-1 - //// 2-oxo139149626
    1-Pyrrolidinyl / carbomyl / amino / sulfonyl / amino / carboxy / 3-azetidinyl / r-bamic acid (1 g, Example 29A) was hydrogenated in Dimethylformamide using 10% palladium on carbon as a catalyst. The catalyst is filtered off, and 0.7 g (c) - (/ - (4-ethyl-2, 3-dioxo-I-piperazinyl) carbonyl amino benzeneacetic acid, 30 mg of N-OKCH-benzotriazole and 0.82 is added to the mother liquor. g of dicyclohexylcarbodiimide and the resulting mixture is stirred overnight at room temperature, the solvent is distilled off in vacuo, and the residue is chromatographed on HP-20 resin, eluting with water to obtain 300 mg of the desired compound, m.p.
    PRI me R 32. Kaliev salt / ZB / 7 // - 2-amino - (- / methoxyimino / -M- / 2-oxo-1 - // //// 2-oxo-3-oxazolidi- nyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azetidinyl / -4-thiazole-acetamide.
    A. Kaliev Phenylmethyl Salt Ester / 3 / - / 2-oxo-1 - ///// 2-oxo-Z-oxazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl-3-acetidinyl / carbamic acid.
    3.0 g of (S) -3- t (phenylmethoxy) carbonyl amino J-2-azetidinone are suspended in 300 ml of dry tetrahydrofuran and cooled to, 2.3 g of chlorosulfonyl isocyanate are dissolved in. 10 ml of dry tetrahydrofuran and added dropwise with stirring. The temperature is allowed to rise up to and maintained for 10 minutes. After that, it is lowered to -40 s. 1.65 g of triethylamine and 1, 95 g of T 1-carbamoyl-2-oxoxoxazolidine are added. The resulting mixture was stirred at room temperature for 14 hours and the solvent was distilled off in vacuo. After dissolving in ethyl acetate, 100 ml of 1N are added. phosphoric acid and extracted three times with ethyl acetate. The combined organic layers are evaporated in vacuo, the residue is dissolved in 100 ml of a mixture of acetone / water (1: 1) and the pH is adjusted to 6.5 1N. Kagti hydroxide. After the acetone was removed in vacuo, the aqueous solution was freeze-dried to obtain 5.2 g of the crude product.
    35
    40
    45
    50
    B. / 3 / Z // - 2-AMHiio-c - / labels siimi- BUT / -K- / 2-oxo-1 - ////// 2-oxo-3-oxazolididinyl / carbamoyl / amino / sulfonyl /
    B. / 3 / Z // - 2-AMHiio-c - / labels siimi- BUT / -K- / 2-oxo-1 - ////// 2-oxo-3-oxazolididinyl / carbamoyl / amino / sulfonyl /
    20
    25
    271391
    amino / carbonyl / -3-azetidinyl / -4-thiaolacetamide, potassium salt.
    1 g of potassium salt of phenylmethyl pseudary ether / B / - / 2-oxo-1 - //// // -oxo-Z-oxazolidinyl / carbonyl / ami- o / sulfonyl / amino / carbonyl / -3-azididyl / carbamic acid hydrated in 80 ml of dry dimethylforma- a using 0.5 g of 10% pallium. n on coal as a catalyst. After 20 minutes, the hydrogenation is complete, the catalyst is filtered off. To the mother liquor, 0.44 g of (Z) -2-amino- - (methoxyimino) -4-thiazolucanoic acid, 30 mg of N-OK-sibenzotriazole and 0.91 g of dicyclohexylcarbodiimide are added. The solution is stirred for 1 to 2 hours at room temperature, the solvent is removed in vacuo and 1.7 g of the residue is chromatographed using HP-20 resin and water as eluent to give 0.3 g of the title compound, m.p. 208 C (decomp.).
    Calculated,%: C 30.99; H 2.79; N 20.65; S 11.82; K 7.21
    With E iKNGOgS,
    Found,%: C 30.08; H 3.13; N 19.52; S 10.34; K 7.41
    PRI me R 33. Kaliev salt / ZB / N // - 4-ethyl-2,3-dioxo-I- / 2-oxo-2 - // 2-OXO-1 - ///// 2 -oxo-3-oxa-olefinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azetidinyl / amino / -1 - phenylethyl / -1-piperazinecarboxamide. 35
    The potassium salt of the phenylmethyl ester of (s) - (2-oxocarbonyl-3-azetidinyl) carbamic acid (1 g, Example 32A) is hydrogenated in 80 ml of dry dimethylformamide, using 0.5 g of 40 10% palladium on carbon as a catalyst .
    The catalyst is filtered off, to the mother liquor, 0.7 g of (R) -O (- {G (4-ethyl-2,3-dioxo-1-pipera-45-sinyl) carbonyl amino benzenexpuy acid, 30 mg of N-hydroxybenzotriazole I) is added. ; 0.91 g of dicyclohexylcarbodiimide, the mixture was stirred for 14 hours at room temperature. The solvent was distilled off in vacuo, the residue was chromatographed on HP-20 resin, washed with water to obtain 0.36 g of the title compound, m.p. 187 s (decomp.).
    Calculated,%: C, 41.81; H 3.81; N 16.96; S 4.85; K 5.92
    СГвН „} a;, о„ к
    Found,%: C 40.04; H 3.93; N 16.33; S 4.45; K 5.59
    496
    28
    0
    five

    five
    0
    50
    Note 34. Dikaliev salt / 3/2/2 / OXO-2 - /// 1- / 2-amino-4-thiazolyl / 2-OXO-2 - // 2-OXO-1 - // /// oxo-3-oxazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azetidinyl / amino / ethylidene / amino / oxy / -2-methylpropanoic acid.
    Potassium salt of phenylmethyl ester / B / - / 2-oxo-1 - ////// 2-oxo-3-oxazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -3-azetidinyl / carbamine acids (1 g, example 34A) are hydrogenated in 80 ml of dimethylformamide using 0.5 g of 10% palladium and 0.97 g of (Z) -2-amine-o / - {g- (diphenylmethyl) are added to the mother liquor ) -l, 1-dimethyl-2-oxo-ethoxy / imino} -4-thiazoleacetic acid, 30 mg of N-hydroxybenzotriazole and 0.91 g of dicyclohexylcarbodiimide. The solution is stirred for 14 hours and the solvent is removed in vacuo. The residue is suspended in 4 ml of anisole and cooled to -5 ° C. While stirring, 12 ml of trifluoroacetic acid are slowly added dropwise, after 20 minutes the crude product is precipitated, added with 100 ml of ether, and filtered. The resulting product is dissolved in 20 ml of a water / acetone mixture (1: 1) and the pH is adjusted to 6.5 with 1N. potassium hydroxide. The acetone is evaporated, the residue is freeze-dried, and the crude product is chromatographed on HP-20 resin to give P, 28 g of the desired compound. M.p.
    Calculated,%: C, 31.28; H 2.78; N 17.17; S 9.83; K 11.98
    C ,, H, eK, N80,, 3
    Found,%: C 29.54; H 3.23; K 16.93; S 8.97; K 11.86
    PRI me R 35. Kaliev salt / 3B //: // - 2-amino-Gb / 1 - //// // 3- / 2-amino-ethyl / -2-oxo-1- imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / - 2-oxo-3-azetidinsh1 / -e / - / methoxyimino / - 4-thiazole-acetamide.
    2 g of (S) -3- (phenylmethoxy) carbonyl amino -2-azetidinone are suspended in 200 ml of dry tetrahydrofuran and cooled to -70 ° C. 1.4 g of chlorosulfonyl isocyanate are dissolved in 7 ml of dry tetrahydrofuran and added with stirring. The temperature is allowed to rise to 0 ° C and maintained for 10 minutes. After that, the mixture is cooled to -40 ° C, 1.2 g of triethylamine are added dropwise and 2.9 g of 1-f2-f (tert-butoxycarbonyl) amino7 ethyl is added -Z-carboxyl-2-oxoimidazolidine. The resulting mixture was stirred at room temperature for 14 hours. According to Example 29A, 5 g of A of the potassium salt of the phenylmethyl ester (B / - / 1 - ////// 3- / 2-three butoxycarbonylamino / ethyl / -2-oxo- 1-imide-3-alkyl / carbon-1 / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinylcarbamic acid.
    The previously obtained compound (2.7 g is hydrogenated in 250 MP of dry dimethylformamide using 1, D g of 10% palladium on coal as catalyst catalyst. After 30 minutes, the hydrogenation is completed, the catalyst is filtered off, l) -2-amino - (- (methoxyimino) -A-thiazoleacetic acid, 54 mg of N-hydroxy benzotriazole and 1.75 g of dicyclohexylcarbodiimide. The resulting solution is stirred for 12 hours at room temperature, the solvent is removed in vacuo, and the residue dissolved in 6 ml of anisole and cooled to -5 ° C. While stirring, carefully add 15 ml of trifluoroacetic acid. The temperature is maintained for another 3 hours, the desired compound precipitates,
    add 150 ml of dry ether. The resulting product is filtered and dissolved in 30 ml of a mixture of water / acetone (1: 1) and the pH is adjusted to 6.5, by adding 1N potassium hydroxide. The acetone is evaporated, the residue is freeze-dried and 2.7 g of crude product by chromatography on HP-20 resin, eluting with water, to give 0.25 g of the title compound. M.p. 193 ° C (decomp.).
    PRI me R 36, Dikaliev salt / 3S / Z // - 2 - /// 2 - // l - ///// 3- / 2-aMH-ethyl / -2-OXO-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / 2-oxo-3-azetidinyl / amino / -1- / 2-amino-4-thiesolyl / -2-oxoethenyl / amino / oxy / -2-methylpropanoBo acid.
    Potassium salt of phenylmethyl ester / B / - / - 1 - //// // 3- / 4- / tert-butoxycarbonylamino / ethyl / -2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (2.7 g, example 35) is hydrogenated in dry dimethylformamide using 10% palladium on carbon as catalyst. This catalyst is filtered off and (7,) -2-amino-B1-2-(diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy-imino is added to the mother liquor.
    Q
    five
    0
    five
    0
    five
    0
    five
    4 acetic acids (2.1 g), 54 mg of N-hydroxybenzotriazole and 1.75 g of dicyclohexylcarbodiimide. In Example 37 and after chromatography on HP-20 resin, eluting with water, 0.3 g of the title compound is obtained, mp. 221 C (decomp.).
    Example37, Potassium salt / ЗS / Z // - 2 // - 2-amino-N- / l - ////// 3- / 2- OXYTHYL / -2-OXO-I-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / - / methoximino / -4-thiazole-acetamide.
    1.5 g of (S) -3- (phenylmethoxy) carbonyl amino -2-azetidine is suspended in 100 ml of dry tetrahydrofuran and cooled to -70 ° C. 1.1 g of chlorosulfonyl isocyanate are dissolved in 10 ml of dry tetrahydrofuran and added dropwise with stirring. The temperature is allowed to rise to and maintained for 20 minutes, then lowered to. Then, 0.9 g of triethylamine and 2.8 g of 1-carbomoyl-2-oxo-3-2-f (triphenylmethyl) oxy are added. ethyl imidazolidine, the mixture was stirred at room temperature for 14 hours. The solvent was removed in vacuo and after treatment in Example 32A, 4.3 g of the potassium salt of the phenylmethyl ester (G) / - / 1 - ///// 3- / 2 were obtained. -oxyethyl / -2-oxo-1-imidazolidinyl / carbonyl / amino / sugophyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid.
    The compound obtained is hydrogenated in 80 ml of dry dimethylformamide using 0.3 g of 10% palladium on carbon as a catalyst. After 30 minutes, the hydrogenation is completed and the catalyst is filtered off. 195 mg of (Z) -2-amino - (- (methoxyimino) -4-thiazoleacetic acid, 13 mg of N-hydroxybenzotriazole and 360 mg of dicyclohexylcarbodiimide are added to the mother liquor. The solution is stirred for 12 hours at room temperature, the solvent is removed in vacuum, and the residue is precipitated with ether. The crude product (0.5 g) is purified on HP-20 resin, eluting with water / acetone (9.5: 0.5). The yield of the target compound is 30 mg, mp. 193 ° C (different).
    Calculated,%: C 32.87; H 3.28; N 21, 56; S 10.97; K 6,69
    С ,, Н „Ю% С, 5,
    ; t 19
    Found,%: C 31.26; H 3.44; N 18.56; S 8.86; K 6.56.
    PRI me R 38. Dikapieva salt / 35 / g // - 2 - /// 1- / 2-amino-4-thiazolyl / - 2 - // - ///// 3- / 2-oxig thyl / -2-OXO-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidyl / amino / 2-oxo-ethylidene / amino / hydroxy / 2-methylpropanoic acid.
    Potassium salt of the phenylmethyl ester / 5 / -1 - //// // 3-hydroxyethyl / -2-oxo-l-imidazolidinyl / carbyl-nyl / amino / cypho- nyl / amino / carbonyl / - -2-oxo-3- azetidinyl / carbamic acid (470 mg, example 37) is hydrogenated in 80 ml of dry dimethylformamide, using 0.3 g of palladium on carbon as a catalyst. After 30 minutes, the catalyst is filtered off, (Z) 2-amino-o / - 2- (diphenylmethoxane) -1.1-dimethyl-2 oxoethoxy-imino-4-thiazole acetic acid, 13 mg K-oxo is added to the mother liquor sibenzotriazole and 360 ml of dicyclohexylcarbodiimide. In example 36 receive the target compound, so pl. 219 C (decomp.).
    Example 39. Dicapium salt / 38 / g // - 2 - /// 2 - // 1 - ///// 3-amino-2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / 2-oxo-3-azethidinyl / amine / -l- / 2-amio-4-β-thiazolyl / -2-oxoethylidene / amine / oxy / 2-methylpropanoic acid.
    A. Kaliev Phenylmethyl ester salt / S / - / 1 - ///// 3 - // tert-butoxycarbonyl / amino / -Z OKCO-1-imidazolidinyl / carbonyl / amino / sulfonyl amino / carbonyl / 2 -oxo-3-azetidinyl / carbamic acid.
    {s) -3- {(Phenylmethoxy) carbonyl amino J-2-azetidinone (1.5 g) is suspended in 150 mg of dry tetrahydrofuran and cooled to -60 ° C. 1.1 g of chloro-sulfonyl isocyanate is dissolved in 20 ml of dry tetrahydrofuran. and when dripping with stirring. The temperature is allowed to rise to 0 ° C and maintained for 15 minutes, then lowered to -60 ° C, 0.9 g of triethylamine and 1.7 g of 1-carbamoyl-3- - (tert-butoxycarbonyl) are added α-amino -2-oxoimidazolidine. The resulting mixture was stirred at room temperature for 14 hours, then treated as in Example 34A, whereby 1.5 g of the title compound were obtained.
    B. Dikaliev salt / 3S / Z // - 2 - /// 2- - // 1 - ///// 3-amino-2-skso-1-imidazolidinyl / carbopyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidin1-1L / amino / -1- / 2-amino-4-thiazolyl / 2-oxoethylidene / amino / hydroxy / -2-methylpropanoic acid.
    I 0.79 g of potassium salt of phenylmethyl ester / S / 1 - ///// 3- - // tert-butokeicarbonyl / amino / -2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-α-azethidinyl / carbamic acid is hydrogenated in 60 ml of dry dimethylformamide using 0.4 g of 10% pal-
    Ladies on coal as a catalyst. After 20 minutes, the hydrogenation is completed and the catalyst is filtered off. 0.63 g of (Z) -2-aMHHO-d - {2- (diphenylmethoxy) -, 1-dimethyl-2-hydroxyethoxy-imino-4-thiazole acetic acid, 19 mg of N-hydroxybenzotriazole and 540 are added to the mother liquor. mg dicyclohexylcarbodiimide. In Example 34B, 48 mg of the title compound is obtained.
    m.p. 208 ° C (decomp.).
    Example 40. Kaliev salt / 3S / Z // - 2-amino- (methoxyimino) -N- - / 1 - //// // 3- / 1-methylethylidene / amino / - -2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / -4-thiazole-acetamide.
    Potassium salt of phenylmethyl ester / 3 / -1 - ///// 3- / tert-butoxycarbonyl / amino / -2-oxo-1 -imidazolidinyl / carbonyl / amino / sulphonyl / amino / carbonyl / -2 -oxo-3-azetidinyl / carbamic acid (0.7 g, example 41 A) is hydrogenated and then reacted with 0.26 g of (z) -2 -2 amino-t-(methoxyimine) -4-thiazole - acetic acid according to example 37B, resulting in a gain of 65 mg of the target compound, so pl. different
    Calculated,%: C 34.22; H 3.55; N 23.47; S 10.75; To 6.55.
    Cf ttt-f, (p
    nil, rJ. , 0 8
    Found,%: C 32.56; H 3.88; N 21.37; S 9,10; K 7.03
    Example 41. Kaliev salt / ЗS / Z // - 2-amino-N- / l - //// 3-methyl-2-oxo-1-imidoazolidinyl / carboxyl / amine / sulfonyl / amino / carbonyl / 2-oxo-3-azetidinyl / - (- / methoxyimino / -4- -thiazole acetamide.
    A. Kaliev salt of phenylmethyl ester / S / - / l - //// 3-methyl--2-oxo-1-imidazolidinyl / carbonyl /
    0
    five
    0
    five
    0
    five
    amino / sulfonyl / a "1-n / carbonyl / -2-oxo-3-azetidinyl / carbamic acid,
    3.0 g (Sl-3- (phenylmethoxy) carbonyl amio-2-azetidinone is suspended in 300 ml of dry tetrahydrofuran and cooled to -70 ° C, 2.1 g of chlorosulfonyl isocyanate is dissolved in 10 ml of dry tetrahydrofuran and The temperature is allowed to rise until and maintained for 10 minutes and then reduced to 1. Add 1.7 g of triethylmine and 2.3 g of 1-carbamoyl-3-methyl-2-oxoimidazolidine. In Example 34A, 4.3 g of the title compound are obtained.
    B. Kaliyev salt / 35 / g / -2-amino- -N- / 1 - ///// 3-methyl-2-oxo-1-imidazo-lidinyl / carbonyl / amine / cyphosphonyl / amio noo / carbox / -2-oco-3-azethidinyl / -ol - - / methoxyimino / -4-thiazole-acetamide.
    Potassium salt of phenylmethyl ester / B / - / 1 - //// // 3-methyl--2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-- -oxo-3- azetidinyl / carbamic acid (1.2 g) was hydrogenated to 80 ml of dry dimethylformamide, using 0.6 g of 10% palladium on carbon as a catalyst. After 30 minutes, the catalyst is filtered off, and 0.52 g (g) -2-amino-in (- (methoxyimino) -4-thiazoleacetic acid, 32 mg of N-hydroxybenzotriazole and 1.0 g of dicyclohexylcarbodiimide are added to the mother liquor. The resulting solution was stirred for 13 hours at room temperature, then the solvent was distilled off in vacuo.The residue was chromatographed on HP-20 resin, eluting with water to obtain 0.120 g of the title compound, mp 205 ° C (decomp.).
    Calculated,%: C 32.43; H 3.27; N 22.69; K 1 1.54; K 7.04.
    with „to ,, :: цс, 5а
    Found,%: C 30.83; H 3.44; N 21.34; S 10.20; To 7.30.
    Example 42. Dikaliev salt / 38 / g // - 2 - /// 2 - // 1 - //// 3-ethyl-2-oxo-I-imidazolidinyl / carbonyl / amnno / sulfonyl / amino / carbonyl / -2-oxo-3 nitrogen; inyl / amino / l- / 2-amino-4-thiazolyl / -2-oxo-ethylidene / amino / hydroxy / -2-methylpropanoic acid.
    Potassium salt of phenylmethyl ester / B / - / 1 - ///// 3-methyl
    five
    0
    five
    0
    five
    0
    five
    0
    five
    -2-oxo-I-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-azetidinyl / carbamic acid (1.5 g, example 41 A) was hydrogenated in 80 ml of dry dimethylformamide using 0 , 8 g of 10% palladium on carbon as a catalyst. After 30 minutes, the catalyst is filtered off and 1.4 g (70-2-amino-c) -2- (diphenylmethoxy) -, 1-dimethyl-2-oxoethoxy-imino} -4-thiazo-acetic acid is added to the mother liquor. acids, 40 mg of N-hydroxybenzotriazole and 1.3 g of dicyclohexylcarbodiimide. In Example 36, 0.5 g of the title compound is obtained, m.p.
    Calculated,%: C, 32.47; H 3.18; N 18.94; S 9.63; K 1 1.75.
    C ,, nj, K, N, 0, o S,
    Found,%: C 30.55; H 3.58; N 18.12; S 8.65; By 10.97.
    Example 43. Dikaliev salt / 38/7 // - 2 - /// 2 - //// // 2-oxo-1-imidazolidinedinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo- 3-azetidinl / amino / - - / 2-amino-4-thiazolyl / -2-oxoethylidene / amino / hydroxy / -2-methylpropanoic acid.
    A. Kaliyev salt of phenylmethyl ester / 3 / - / 1 - //// // 2-oxo-3- / triphenylmethyl / -1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2- oxo-3-azetidinyl / carbamic acid.
    1.3 g of (S) -3- (phenylmethoxy) carbonyl amine -2-azethidine is suspended in 130 ml of dry tetrahydrofuran and cooled to -70 ° C. 0.9 g of chlorosulfonyl isocyanate is dissolved in 5 ml of dry tetrahydrofuran and added dropwise to the solution with stirring. The temperature is allowed to rise to 0 ° C and is maintained at this for 10 minJ, after which it is lowered to -40 ° C. 0.8 g of triethylamine and 0.65 g of 1-carbamoyl-2-oxo-3- (triphenylmethyl) imidazolidine are added, and the mixture is then treated as described in 34A, to give 3.2 g of the title compound.
    B. Dikaliev salt / 3S / Z, /// 2- - /// 2 - // 1 - //// // 2-OXO-1-imidazolidinyl / carbonyl / amylo / sulfonyl / amino / arbonyl / - 2-oxo-3-azetidinyl (amine) - l - / 2-amino-4-thiazolyl / -2-oxo-ethylidene / amino / hydroxy / -2-methyl 11-propanoic acid.
    Phenylmethyl ester potassium salt / S / -1 ///// 2-oxo-3 - / triphenylmethyl / -1 imidaaolidinyl / carbonyl / amino / sulfone 1 / amino / carbonyl / -2-oxo-Z-azetidinyl / carbs - New acid (.1.5 g) is hydrogenated in 80 ml of dry dimethylformamide, using 0.9 g of 10% palladium on carbon as a catalyst. After 30 minutes, the catalyst is filtered off and 0.98 g of (Z) -2-aMHHO-d - {2- (diphenylmethoxy) -, 1-dimethyl-2-OKCosTOKCHjHMH-Ho J-4-thiazo-acetic acid is added to the mother liquor. , 27 mg N-hydroxybenzotriazole and 0.84 g dicyclohexylcarbodiimide. In Example 36, 0.28 g of the title compound is obtained, mp. 228 C (decomp.).
    Example 44. Kaliev salt / 3S / Z // - 2-aMHHO-N- / l - ///// 2-OKCo-l-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo -3-azeti dinyl / -c / - / methoxyimino / -4-thiazole acetate amide.
    A. Kaliev salt of phenylmethyl ester / 3 / - / 1 - ///// 2-oxo 1- -imidazolidinyl / carbonyl / amine / sulfur-phenyl / amino / carboxyl / 2-oco-3-azethynyl / carbamine acid.
    Potassium salt of phenylmethyl ester / S / - / 1 - ///// 2-oxo-3- - / triphenylmethyl / -1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3- oxo 3-azetidinyl / carbamic acid (1.7 g, example 43A is treated with 2 n phosphoric acid and 1 n potassium hydroxide as in example 32A, resulting in 1.78 g of the title compound.
    B. Kaliev salt / 3S / Z // - 2-amino- -N- / 1 - //// // 2-OXO-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2- oxo-3-azetidinyl / -of- / methoxyimino / -4-thiazole-acetamide.
    0.8 g of the potassium salt of the phenylmethyl ester (S / 1-//.////2- oxy-co-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3- -azetidinyl / carbamic acid is hydrogenated to 70 ml of dry dimethylformamide using 0.5 g of 10% palladium on carbon as a catalyst. After 20 minutes, the catalyst was filtered off, and 0.38 g (g) -2-amino-o (- - (methoxyimino) -4-thiazole acetic acid, 27 mg of N-hydroxybenzotriazole and 0.78 g of dicyclogl xylcarbodiimide were added to the mother liquor.
    five
    The resulting solution was stirred for 14 hours at room temperature and then the solvent was removed in vacuo. The residue is chromatographed on resin RP-20 to obtain 200 mg of the title compound, m.p. (different).
    Example 45. Kaliev salt
    0 / ZB / 7, // - 2-amino-K- / 1 - ///// 3- / methyl-sulfonyl / 2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2-oxo-3-a-zetidinyl / -o / - / labels siimino / -4-thiazole-acetamide.
    A. Kaliyev salt of phenylmethyl ester / 8 / - / 1 - //// // 3- / methyl-sulfonyl / -2-oxo-1-imidazolidinyl / carboNYL / amino / sulfonyl / amino / carbonyl / 2- oxo-3-azetidinyl / carbamic acid.
    3.0 g of (s) -3 f (phenylmethoxy) carbonyl amino -2-azetidinone is suspended in 300 ml of dry tetrahydrofuran and cooled to -70 ° C. 2.1 g of chlorosulfur
    5 phonyl acylate is dissolved in 10 ml of dry tetrahydrofuran and added dropwise to the mixture with stirring. The temperature is allowed to rise to 0 ° C and maintained for 10 minutes, then
    0 reduced to -40 ° C. 1.7 g of triethylamine and 2.3 g of 1-carbamoyl-3 - - (methylsulfonyl) -2-oxoimidazolidine are added. In Example 32A, 2.8 g of the title compound is obtained.
    B. Kaliev salt / 3S / Z // - 2-aMHHO- -N- / 1 - ///// 3- / methylsulfonyl / -2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl-2-oxo-3- - azetidinyl (-o-) meroxyimino / tia-acetamide.
    1.8 g of potassium salt of phenylmethyl ester / S / - / 1 - ////// 3- - / methylsulfonyl / -2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino /
    5 carbonyl / -2-oxo-3-azetidinyl / carbamic acid is hydrogenated in 300 ml of dry dimethylformamide using 2.0 g of 10% palladium on carbon as a catalyst. After 30 minutes, the catalyst was filtered off and 1.1 g of (Z) -2 -2 amino-o / - (methoxyimino) -4-thiazole acetic acid, 70 mg of N-hydroxybenzotriazole and 2.0 were added to the mother liquor. g dicyclohexylcarbodiimide. The resulting solution was stirred for 12 hours at room temperature and then the solvent was removed in vacuo. The residue is chromatographed on resin IG-20, eluting with water / acetone
    five
    0
    0
    five
    371
    (9: 1) to obtain 200 mg of the title compound, m.p. 204 C (decomp.).
    Example 46. Dikaliev salt / 35 / g // - 2 - /// 2 - // 1 - //// // 3- / methylsulfonyl / 2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2 oxo-3 azetidinyl / amine // - 1 - / 2-amino 4-thiazolyl / -2-oxyethyl den / amino / oxy / -2-methiLpropanoic acid.
    Potassium salt of phenylmethyl ester / 8 / - / 1 //// // 3- / methylsulfonyl / -2-oxo-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2 oxo-azetidinyl The carbamic acid (1.5 g, Example 45A) was hydrogenated to 15 ml of dry dimethyl form of the amide using 0.9 g of 10% palladium on carbon as a catalyst. After 20 minutes, the catalyst is filtered off and 1.23 g of (g) -2-amino-) (diphenylmethoxy) -, 1-dimethyl-2-oxo-toxy-imino} -4-thiazo-acetic acid, 40 mg is added to the mother liquor. N-hydroxybenzotriazole and 1.1 g of dicyclohexylcarbodiimide. In Example 36, 180 mg of the title compound is obtained, mp. 296 ° C (decomp.).
    Example 47, Kaliev salt / 33 / g // - 2-amino-H- / 1 - //// // 3-nzpropyl-2-OXO-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / - -2-oxo-3-azetidinyl / - / methoxyimino-4-thiazole-acetamide.
    A. Kaliyev salt of phenylmethyl ester / 5 / - / 1 - //// // 3-isopropyl-2-oxo-1-imidazolidinyl / carboiyl amino / sulfonyl / amino / carbonyl / -2-oxo-3- azetidinyl / carbamic acid.
    3.0 g of (S.) -3-C (phenylmethoxy) carbonylMaminoJ-2-azetidinone is suspended in 300 ml of dry tetrahydrofuran and cooled to 2.1 g of chlorosulfonyl isocyanate is dissolved in 10 ml of dry tetrahydrofuran and added dropwise with stirring to slurry. The temperature is allowed to rise up to and maintained for 10 minutes and then lowered to -40 ° C. 1.7 g of triethylamine and 2.74 g of 1-carbamoosh-3-isopr011-2-α-oxoimidazolidine are added. In Example 32A, 5.9 g of the title compound are obtained.
    B. Kaliev salt / 35/2 // 2-amino- -N- / 1 - //// // W-isoproxy-2-OKCO-l-imidazolidinyl / carbonyl / amino / sul





    0
    five
    0
    five
    96
    38
    fonyl / amino / carbonyl / -2-oxo-3-azetidinyl / - (/ - / methoxyimino / -4-thiazole-acetamide.
    1.5 g of potassium salt of phenylmethyl ester / 5/1 - ////// 3-isopropyl-2-OXO-1-imidazolidinyl / carbonyl / amino / sulfonyl / amine / carbonyl / 2- oxo-3-azetidinyl / carbamic acid is hydrogenated in 150 ml of dry dimethylformamide, using 0.8 g of 10% palladium on carbon as a catalyst. After 20 minutes, the catalyst is filtered off and 0.6 g of (Z) - -o (-2-amino- (methoxyimino) -4-thiazole-acetic acid, 40 mg of N-hydroxybenzotriazole and 1.2 g of dicyclohexylcarboxylic acid are added to the mother liquor The resulting solution was stirred for 14 hours at room temperature and then the solvent was evaporated in vacuo.The residue was chromatographed on HP-20 resin, eluting with water / acetone (9.25: 0.75) to give 300 mg of the desired compound. (different).
    Example 48. Dikaliev salt / ZB / g // - 2 - /// 2-1 - //// 3-isoproxy 1 -2 -2-OXO-1-imidazolidinyl / carbonyl / amino / sulfonyl / amino / carbonyl / -2- -oxo-3-azethidinyl (amine) -l-amino-4-thiazolyl / -2-hydroxyethylidene (amino) oxy / -2 methylpropanoic acid.
    Potassium salt of phenylmethyl ester / 3 / - / 1 - ////// - 3-methyl-2-OXO-1-imidazolidinyl / carboxyl / amino / sulfonyl / amino / carbonyl / - -2-oxo -3-azetidinyl / carbamic acid (1.5 g, Example 41A) was hydrogenated to 150 ml of dry dimethylformamide using 0.8 g of 10% palladium on carbon as catalyst. After 20 minutes, the catalyst was filtered off, and 1.3 g (g) -2-amino-o / 2- (diphenylmethoxy) -, 1-dimethyl-2-oxoethoxy-imino |) - was added to the mother liquor. 4-tia ev acetic acid, 40 mg of N-hydroxybenzotriazole and 1.2 g of dicyclohexylcarbodiimide. In Example 36, 0.4 g of the title compound is obtained, mp. 234 ° C (decomp.).
    The antibacterial activity of the compounds (l) was studied. The minimum inhibitory concentration (MIC) is determined by the dilution method on
    0
    five
    0
    0
    five
    an agar in which an aqueous solution of the test compound after a series of consecutive dilutions is poured
    In the test Petri dishes, to which trypticose soy agar is added, everything is mixed. Then the agar plates are seeded with the bacterial suspension of the test organism. After incubation, the lowest concentration of the test compound, which leads to the complete inhibition of the growth of the testovog of the organism, is taken as the MIC.
    Test data are presented in the table (.Af dilution CFU - colony-forming units).
    Compounds (1) show no signs of toxicity at active doses.
    Thus, azetidinones of general formula (l) exhibit high antibacterial activity and are non-toxic.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining azetidinone general formula
     QJ - N-c - mso2N-0-1 2 о о
    where R is hydrogen or lower alkyl;
    R - lower alkyl, chloromethyl, methoxymethyl, phenyl, amino, methylamino, dimethylamino, 4-methyl -2,3-dioxopiperazinyl-1,2-oxopyrrolidinyl-1,2-oxo-oxazolidin-1, 2-oxoimidazolidinyl- 1, unsubstituted or substituted in position 3 to a lower alkyl, 2-hydroxyethyl, 2-aminoethyl, amino group, 1-methylethylidene-amino, or mesyl; R. - group
    ABOUT
    SbH5-CH-S
    NH-CO-Nr N-CjHs
     W
    Oh oh
    TM H-S
    g
    j- b
    N-0-R / t
    where R4 is lower alkyl or 1-carboxyisopropyl,
    characterized in that 3-benzyloxycarbonylaminoazetidinone--2 of formula
    C HsCHjOCONH-j-I
    1SH
    is reacted with chlorosulfonyl isocyanate to form α-chloro 1-chlorosulfonylaminocarbonyl-3-benzyloxycarbonylaminoazetidinone-2 of the formula Q
    CeHgCH oco JH-r-i {i- -c HS02C1
    s
    0
    0 5 o
    five
    five
    0
    five
    subjected to interaction with the compound of the General formula
    , -C-R, 2 II 2
    ABOUT
    where R - amino, methylamino, dimethylamino, 4-methyl -2,3-dioksipiperazinil-1, 2-oxooxazolidin-1, 2-oxopyrrolidin-1, 2-oxooxazolidin-1, 2-oksoimida- zolidinil-1 unsubstituted or substituted in position 3 to a lower alkyl, 2-aminoethyl, amino group, 1-methyl-ethylidene-amino group or mesyl or with a compound of the general formula
    (CHjUSi-N-C-R.,
     I II p.
    RI O
    with R, is indicated above;
    R is lower alkyl, chloromethyl or
    methoxymethyl,
    or with hexamethyldisilazane, followed by acylation of the resulting product with acetyl chloride or benzoyl chloride and the resulting azetidinone of the general formula
    ССН5СН, ОС-Ь1Н-г-111
    Ltd
    wherein R and RQ are as described above, are reduced in the presence of palladium on carbon in dimethylformamide or hydrogen bromide in acetic acid and the azetidinone of the general formula
    About RI o
    , II I II
    Q N-C-NH-S02-N-C-R.,
    where R, and R yKa3aHbi are higher,
    exposed to acid
    general formula
    RH - Soon
    where R is above
    in dimethylformamide in the presence of
    di1C1clohexylcarbodiimide and} -hydr
    hydroxybenzotriazole.
    H2 -41
    Priority signs: 04,01.82 with RJ - lower alkyl, chloromethyl, methoxymethyl, phenyl, 4-methyl-2, 3-dioxopiperazinyl-1,2-oxo139
    Pret.vulgirli I “t. cloeol r. orceieent P.Mru (PI. Mrueinota .SCH)
    / 0,050,20,1 0,05 0,, 050 ,,, 05 0,051,6
    0.10.40,, 05 0.2 0.0.050,, 05 0.053.1
    0.40, 0.40, 0.4, 0.4, 0.80, 20.2, 0.10, 5
    3.16.33.10.4 3.1 3.11.61.6 1.61.6t7, i
    12.5 12.5 1.6 0.4 50I2, J 2.5 3.1
    kgshtuu concrete BTtHM m | sroorgan ma
    0.8
    6.3
    100
    e
    139149642
    pyrrolidine-1, 2-oxooxazolidi-nyl-1.
    15.02.82 with R / g - amino group, methylamino group or dimethylamino group.
    0.8
    6.3
    100
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    同族专利:
    公开号 | 公开日
    IE54388B1|1989-09-13|
    EP0085291A1|1983-08-10|
    CA1272726C|1990-08-14|
    DE3377712D1|1988-09-22|
    JPS58121269A|1983-07-19|
    FI830017L|1983-07-05|
    HU188986B|1986-05-28|
    PH21695A|1988-01-13|
    EP0085291B1|1988-08-17|
    DD207907A5|1984-03-21|
    DK583D0|1983-01-03|
    DK583A|1983-07-05|
    ES518758A0|1984-03-01|
    AU9161782A|1983-07-14|
    KR840002808A|1984-07-21|
    NZ202891A|1986-02-21|
    AU570912B2|1988-03-31|
    CA1260472A1|1989-09-26|
    KR890000418B1|1989-03-17|
    IL67528A|1986-04-29|
    NO830003L|1983-07-05|
    GR77135B|1984-09-07|
    IE823087L|1983-07-04|
    PT76064A|1983-02-01|
    ES8403108A1|1984-03-01|
    FI830017A0|1983-01-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NZ199981A|1981-04-09|1985-08-16|Squibb & Sons Inc|2-oxo-1-amino)carbonyl)azetidines|EP0117053A1|1983-02-10|1984-08-29|Ajinomoto Co., Inc.|Azetidinone derivatives|
    US4534896A|1983-06-13|1985-08-13|E. R. Squibb & Sons, Inc.|3-Acylamino-2-oxoazetidine-1-|
    US4576749A|1983-10-03|1986-03-18|E. R. Squibb & Sons, Inc.|3-Acylamino-1-carboxymethylaminocarbonyl-2-azetidinones|
    EG18314A|1985-09-26|1993-02-28|Squibb & Sons Inc|Process for preparing of 2-oxo-1amino)carbonyl)-azitidines|
    WO1987007273A2|1986-05-23|1987-12-03|The Upjohn Company|N-1 substituted sulfonylaminocarbonyl, c-4 substituted monobactams|
    US4801705A|1986-06-23|1989-01-31|E. R. Squibb & Sons, Inc.|2-oxo-1-amino)-carbonyl)azetidines|
    US5006650A|1987-02-11|1991-04-09|The Upjohn Company|Novel N-1 substituted beta-lactams as antibiotics|
    WO1988006587A1|1987-02-27|1988-09-07|The Upjohn Company|ANTIBIOTIC beta-LACTAMS CONTAINING A PYRIDONE CARBOXYLIC ACID OR ACID DERIVATIVE|
    CA1317298C|1987-03-03|1993-05-04|Upjohn Company |Antibiotic sulfonylaminocarbonyl activated .beta.-lactams|
    US5015737A|1987-07-22|1991-05-14|The Upjohn Company|Therapeutically useful beta-lactams|
    EP0344707A3|1988-06-02|1990-04-18|E.R. Squibb & Sons, Inc.|2-Oxo-1-[[-amino]carbonyl]-azetidine derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US33653782A| true| 1982-01-04|1982-01-04|
    US36860982A| true| 1982-04-15|1982-04-15|
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