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    • 专利摘要:
    Novel 3-vinyl-cephalosporin derivates of the general formula <IMAGE> (I) in the bicyclooct-2-ene or bicyclooct-3-ene form, in which R1 is a protective radical or is a radical of the general formula <IMAGE> (II) in which R5 is hydrogen, alkyl, vinyl or cyanomethyl, or a protective radical, and R6 is hydrogen or a protective radical, and R2 is a protective radical or an enzymatically removable radical, or R1 is an acyl radical, which may carry various substituents, and R2 represents a protective radical, and R3 and R4, which are identical or different, represent alkyl (optionally substituted by hydroxyl, alkoxy, amino, alkylamino or dialkylamino) or phenyl, or form, together with the nitrogen atom, a saturated 5-membered or 6-membered heterocyclic ring optionally containing another hetero-atom, their E- and Z-forms and their mixtures, are useful as intermediates for the preparation of 3-thiovinyl cephalosporins useful as antibacterial agents.
    公开号:SU1031409A3
    申请号:SU802926697
    申请日:1980-05-21
    公开日:1983-07-23
    发明作者:Фарж Даниель；Ле Руа Пьер；Мутоннье Клод；Пейронель Жан-Франсуа
    申请人:Рон-Пуленк Эндюстри (Фирма)；
    IPC主号:
    专利说明:

    j The invention relates to methods for producing new compounds, derivatives of 3-aminovinyl cephalosporin, which are intermediates in the synthesis of 3-thiovinyl cephalosporin derivatives with biologically active properties.  A known method for the preparation of 3-thiomethyl cephalospopyr derivatives possessing biologically active properties is obtained by the interaction of 3-acetoxymethyl cephalosporin with the corresponding thiol Cl.  The aim of the invention is to obtain new intermediates in the synthesis of cephalosporin antibiotics containing in the 3-position of the thiovinyl radical.  .  This goal is achieved by the npewiaraem method for the production of 3-amino-vinyl cephalosporins of general formula I: CODE, 5 where the dotted line indicates that the double bond can be in the position of a 2,3- or 3,4-cephalosporin core; R, together with the nitrogen atom, form a phthalimide radical or R - into a donor and Rj - trityl or radical of the general formula.  Rfe- CO -.  where R is a tert-butoxy, 4-nitrobenzyloxy group or phenyl, or Rj is p a dialyl of the general formula RJ CH - Sat where R is a phenyl or phenoxy group and RU is hydrogen or a tert-butoxycar bonylaminogroup / or R-, is a radical of formula 1Т - WM - HSBNZ zS-imv as a syn-isomer.  where Rg is methyl or viyl; R and Rji are both methyl or, together with the nitrogen atom, form the morfol new or piperidine radical; methyl, pivaloyloxymethyl, 4-methoxybeneyl, 4 nitrobenzyl or benzhydryl,.  by reacting a compound of general formula TI or III: K-iR-z -N V COORg where the dotted lines R, Rj and Rg have the indicated meanings, with a compound of the general formula TV: From RIO-CH-NC; I RI where one of the groups R, is a dimethylamino group, and the other is an ethoxy or tert-butoxy group, or R, each means methoxy, neopentyl-OXY, piperidino or morpholino, R, and R have the indicated meanings in dimethylformamide in the temperature range from to the boiling point of the reaction mixture.  All proposed compounds are  Stereochemistry presented on a fragment of the following formula o3l3pl.  DG, -HN-inExample.  one.  to a solution of 0.45 g trit-butylate to. 0.85 tons of N, H, N, H tetramethylformamidemethyl sulfate is added dropwise to a mixture of 20 ml of anhydrous tetrahydrofuran in a dry nitrogen atmosphere over 1 minute.  The reaction mixture is stirred at 25 ° C for 35 minutes, then heated to reflux.  A solution of 0.96 g of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1 azabicyclo (4.2.2) octene-2 in 20 MP anhydrous N, N-dimethylformamide, then maintain the reaction mixture at boiling under reflux for 5 minutes  The reaction mixture is poured into 250 ml of ethyl acetate, the organic layer is washed with two portions of 100 ml of distilled water and two portions of 100 ml of half-saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate and filtered.  After distilling off the solvent under reduced pressure (20 mm Hg. Art. ) and 30 ° C obtain 1.05 g of an orange substance.  Rf 0,29 (chromatography on silica gel; eluent - a mixture of cyclohexane: ethyl acetate 50:50 by volume).  The study of NMR and IR spectra allows us to conclude that mainly 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3- (2-dimethylaminovinovyl) -8-oxo-5-thia-1-azabicyclo (4,2,0) is produced mainly. octene-2 (E form).  Characteristic absorption bands in the IR spectrum (SNBr), 3430, 3350, 2820, 17b5 1b9a, 1615, 1540, 1505, 1495, 1465, 1370, 1240, 940, 745, 600.  UV-visible spectrum (ethanol):;. g. (390 nm, e 29,000 (with 2-10 M). . -.  The spectrum of the proton magnetic resonance (350 MHz, APSC, “G in n. P. m , I in Hz): 1.48 (singlet, / CH / C-O-CO9H); 2.89 (singlet, - 6H); 3.17.  (AB, I 14, -SCHj- cephem, 2n) 5.02 (doublet, I 4, H by 6, 1n); 5.27 (dv  doublet, and 9, N by 7 (1H); 5, SO. (doublet, -I 9, -OSONN-, 1H), 6.71 (doublet, I 14, -CH CH-N lH) j 6.49 (doublet ,. I. .  14, -CH Cfl-N IH); 6.95 (singlet, -CH / C Hj / 2, lH) j from 7.2 to 7.5 (numerous ,. , aromatic Yun). : Mass spectrum: molecular peak 535 characteristic fragments: m / e 378 and 3. 7 9 (fragments of | b-lactam).  2-Benzhydryloxycarbonyl-7-tert-bu toxicity arbonyl amino 3 -methyl-8-oxo-5-thia-1-azabicyclo (4; 2.0) approx. ten-2 can be obtained according to the following method.  To a solution of 188.6 g of 7-tert-butoxycarbrylamino-2-carboxy-3-methyl-8-oxb-5-thia-1-azabicyclo (4.2.2) oct is added in 2100 ml of acetonitrile dropwise over 45 minutes at 25-30.  a solution of 116.5 g of diphenyldiazo methane in 800 ml of acetonitrile.  Stir the reaction mixture. The mixture is evaporated to dryness under reduced pressure (20 mm Hg). st,) and 40 ° C.  The residue is again dissolved in 2 L of ethyl acetate and the resulting solution is washed.  700 md 2n. hydrochloric acid, 700 ml of a saturated aqueous solution of sodium bicarbonate and 700 ml of a saturated aqueous solution of sodium chloride.  The solution is dried over sodium sulfate, treated with vegetable soot, filtered and concentrated under reduced pressure (20 mm Hg. Art. ) dry at.  The residue is dissolved in 600 ml of ethyl acetate at the boil.  1 L of cyclohexane is added to the solution, heated to reflux and allowed to cool.  The crystals thus formed are separated by filtration, washed three times with 250 ml of diethyl ether and dried.  In this way, 191 g of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.2) octene-2 are obtained in the form of white crystals (t. square  179c).  By concentrating the mother liquors to 500 ml, a second fraction of the product is obtained (32.6 g, t. square  178 ° C).  7-tert-Butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.0) octene-2 can be obtained according to the following method.  371 g of 7-amino-2-carboxy-. 3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) octene-2 is dissolved in a solution of 307 g of sodium bicarbonate in a mixture of 2 liters of distilled water and 2 liters of dioxane.  A solution of 421 g of di (tert-butyl) carbonate in 2 liters of dioxane is added to the resulting solution over a 10-min solution.  The reaction mixture is stirred for 48 hours at 25 ° C; the suspension obtained is concentrated under reduced pressure (20 mm). Hg Art. ) and 50 ° C to a residual volume of approximately 2 liters, after which it is diluted with 1 liter of ethyl acetate and 2 liters of di. Stilled water.  The aqueous phase is decanted, washed with 500 ml of ethyl acetate and acidified to pH 2 with 6N. hydrochloric acid in the presence of 1500 ml of ethyl acetate.  The aqueous phase is extracted twice twice with 1 liter of ethyl acetate.  rganic; ki The phases are combined and washed with two 250 ml portions each time with a saturated solution of an aqueous solution of sodium chloride and sodium acetate over sodium sulfate.  After filtration, the solvent is distilled off under reduced pressure (20 mm Hg.  Art. ) and.  In this way, 486 g of 7-tert-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.2) octene-2-in the form of yellow crystals (t. square  190 ° C with decomposition).  .  Example 2  90.5 g of 2-benzdryloxycarbonyl-7-tert-butoxycaronyl-amino-3-methyl-8-oxo-5-thia-1-az5-cyclo 4, 2.0) octene-2 is dissolved in 400 ml of anhydrous N, B. . - dimethyl feeds A: The resulting solution was heated to nitrogen under nitrogen, and then 36.1 g of bis-dimethylamino-tert-butoxyethane in 60 ml of anhydrous H, H-dimethylormamide, preheated, were quickly added. The reaction mixture was incubated for 5 minutes, then poured into 3 liters of ethyl acetate.   Add 1 liter of distilled water to decant the organic phase, pour it over the head once with 1 liter of distilled water, dry it over sodium sulfate and filter in the presence of vegetable black.  The solution is concentrated to dryness under reduced pressure {20 mmHg. Art. ) and 30 ° C.  101 g of product, identical to that obtained according to example 1, are obtained in the form of an orange substance.  Ef 0,29, chromatography on silica gel (cyclohexane ethyl acetate 50:50 by volume).  Example 3  To a solution of 0.48 g of 2-benehydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1-azabicyclo (4.2.0) octane in 25 ml of anhydrous H, H-dimethylformamide D9 -0.38 g of bis-dimethylamino-tert-butoxymethane, keeping the reaction mixture at 25 ° C and under reduced pressure (400 mm Hg. Art. ) within 15 min.  The reaction mixture was made with 200 ml of ethyl acetate and washed three times with 300 ml of a saturated aqueous solution of sodium chloride.  The organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.  C20 mmHg Art. ). and -30 ° C.  In this way, 0.41 g of product is obtained, which is identical to that obtained in Example 1, in the form of an orange substance.  2-Benzhydryloxycarbranyl-7-tert-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1-azabicyclo (4.2.2) octane can be obtained according to the following method. .  .  21.3 g of 2-carboxy-7-tert-butyloxycarbonylamino-3-methy-1-8-oxo-5-thia-1-azabicyclo (4.2.2) octane; fter 11.2 g of diphenyldiazomethane according to the method described in example 1.  18j35 g of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1 are obtained. - azabicyclo (4,2,0) octane in the form of white crystals (t. square  135-137 0 after recrystallization from ethyl acetate).  7-tert Butoxycar6-aminyla-2-car-hydroxy-3-methylene-8-oco-5-thia-1-azabicyclo (. 4, 2, 0) octane can be obtained by electrochemical reduction of 10 g of 3-acetoxymethyl-7-tert-butoxycarbonylamino-2-carboxy-8-oxo-5-thia-1-azabicyclo (4,2.0 octene-2 .  6 g of 7-tert-butoxycarbonylamino-2-carboxy-3-methylene-8-oxo-5-thia-1-aabioicly (4.2.2) octane are obtained in the form of a light brown fiber with m. square  180 ° C (with effect after recrystallization.  from Acionitrile). , (3-Acetoxymethyl-7-tert-butoxycarbonylamino-2-carbroxy-8-oxo-5-thia-1-azabicyclo (4,2,0) octen-2 can be made from 13.1 g of 3-acetoxymethyl 7-aMino-2-carboxy-8-oxo-4-thia-1-azabicyclo (4,2,0) octeca-2 according to the method described in 1.  In this way, 11.8-g 3-acetoxymethyl-7-tert-butoxycarbonylamino-2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.2) octene-2 is obtained in the form of a light brown fibrous substance. .  Rf 0.54 (chromatography on silica gel, eluent: ethyl acetate: acetone: water: acetic acid 60 J 20: 2: 2 by volume. ).  Approximately 4.  A solution of 1.0 g of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-7-methyl-8-oxo-5-thia-1-azabicyclo (4.2.2) octene-3 in 100 ml of anhydrous N, N. -dimethylformamide is heated to 80 ° C. under a nitrogen atmosphere.  Then 0.86 ml of bis-dimethylamino-tert-butoxymethane is quickly added to the reaction mixture.  The reaction mixture was kept at 80 ° C for 5 minutes, after which it was poured into 50 ml of ethyl acetate.  After being added to the reaction mixture.  25 ml of distilled water decanted the organic phase, washed with 4 portions of 25 ml of distilled water, dried over magnesium sulfate and filtered.  The solvent is distilled off to dryness under reduced pressure (20 mm Hg). Art. ) and 30; ° C, while receiving. 1.1. g of an orange fiber residue, whose NMR and IR spectra confirm that it is mainly 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo 5-thia-1-azabicyclo (4.2, 0) octene 2 (E form).   2-Benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) octen-3 can be obtained by esterification of 3.2 g 7-tert-butoxycarbonylamino -2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) -octene-3 and 2.1 g of diphenyldiazomethane according to the method described in example 1.  after recrystallization from. mixtures of cyclohexane with ethyl acetate 90:10 (by volume) give 2.3 g of 2-benzhydryoxy-carbonyl-7-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2; 0) octene- 3 in the form of white crystals (t. square  ). 7 t-Butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) octene-3 can be obtained by conversion.  8.28 g of 7-tert-butoc Sicarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-: ri-1-azabicyclo (4.2.2) octene-2.  In this way, 5.4 g of 7-tert-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-TIa-1-azabicyclo {4, 2.0) octene-3 are obtained with t. square   200 ° C (with decomposition after recrystallization from ethyl acetate).  Rf 0.59. (chromatography on silica gel, eluent - a mixture of ethyl acetate: acetone: water: formic acid 60:: 20: 1: 1 by volume).  - 7-tert-Butoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-azabicyclo {4, 2,0) octene-2 can be obtained by etherization 16.7 g 7- tert-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2,0) octene-2 ether solution of diazomethane.  13.6 g of 7-tert-butoxycarbonylamino-2-methoxycarb-nyl-3-methyl-8-oxo-5-thia-1-azabicyclo (4 ,. 2.0) ovTeHa-2 in the form of white crystals (t. .  square   148 ° CK Rf 0.45 (chromatography on silica gel, zyuNe - ottsigeloheksan: ethyl acetate 60:40 by volume).  Example 5  A solution of 4.8 g of 2-benzhydryloxycaronyl-7-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabiiiklo (4.2.2) -octene-2.  in a mixture of 25 ml of tetrahydrofuran and 25 ml. N, N-dimethylformamide (anhydrous) is heated to 80 ° C under nitrogen atmosphere.  Quickly added to the solution.  3.1 MP of bis-dimethylamino-tret-butox of methane.  The reaction mixture was kept at 80 ° C for 10 minutes, then poured into 400 ml of ethyl acetate. After adding 100 ml of distilled water, the organic phase was decanted, washed with three portions of 100 ml of distilled water and 100 MP of saturated sodium chloride solution, and then dried over sulfate magni.  Ethyl acetate is distilled off under reduced pressure. (20 mmHg Art. ) and 30 ° C to obtain 5.35 g of product identical to that obtained in Example 1 as an orange fibrous substance. .  P m and me r b.  4.8 g of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azog bicyclo [4.2.2) octene-2 is dissolved in 50 MP of anodeless H, H- dimethylformamide and heat the resulting solution in a dry nitrogen atmosphere up to 80 ° C.  2.92 g of bis-dimethylaminoethoxymethane in 10 ml of anhydrous K, N-dimethylformamide was added to the solution, maintaining the temperature of the reaction mixture at 80 ° C for 40 minutes. The reaction mixture was diluted with 200 ml of ethyl acetate and washed with three 100 ml portions distilled water and 100 m saturated sodium chloride solution.  The organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg. Art.  Y  5.15 g of the product, identical to that obtained in Example 1, is obtained in the form of an orange fibrous web. Example 7  To a solution of 2.4 g of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.2) octen-2 in 12 ml of anhydrous N, N-dimethyl form amide was added in a dry nitrogen atmosphere at 25 ° C a solution of dimethoxymethylaminomethane in 12 ml of anhydrous H, H-dimethylformamide.  The reaction mixture is heated to 80 ° C for 3 h 20 min, then poured into a mixture of 150 ml of ethyl acetate and 150 ml of distilled water.  The organic phases are combined and washed with two portions, 100 ml of distilled water, then dried over magnesium sulfate and filtered.  After distilling off the solvent under reduced pressure (20 mm Hg. Art. ) and get 2.7 g of a light brown residue.  Data from thin-layer chromatography (silica gel, eluent cyclohexane: ethyl acetate 60:40 by volume) and IR-spectroscopy indicate that 2-benzhydryloxycarbonyl-7-tert-butoxycar6-nylamino-3- (2-dimethylaminovinyl) was obtained mainly) -8-oxo-5- thia-1-azabicyclo (4,2,0) octene-2 (E-form).  Example 8  1.7 g 7-tert-butoxycarbo-ylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-azabicyclo (4.2.2) octene-2 (described in example 4) is treated with 1.74 d bis-dimethylamino-tert-butoxymethane in 15 ml of anhydrous H, H-dimethylformamide according to the method described in Example 2, obtaining 1.7 g of an orange fibrous substance.  The NMR and IR spectra confirm that 7-tert-butoxycarbonylamino-3- (2gdimethylaminovinyl) -2-methoxycarbonyl-8-oxy-5-thia-l-azabicyclo (4.2.2) octene-2 (E- the form).  IR spectrum (CHCIg); characteristic absorption bands, 2800, 1760, 1710, 1690, 1610.  Proton Nuclear Resonance Spectrum: Signals characteristic for E-isomer of bicyclo-octen-2.  (350 MHz, CDCIj, cG in p. P. m , 1 to Hz): 1.49 (singlet, 9H,): 1.96 Csinglet, 6H, / CHE / 2H-CHCH-); 3.76 (singlet, 3H, -CO3CH3); 6.57 (Yaublet, I 14, 1n, -CH CH-nS); b, 8b doublet, I 14, 1H, -CH CH-HC.  Example 9  The procedure of Example 2 is followed, but it comes from a solution of 1 g of 7-tert-butoxycarbonyl1 ino-3-methyl-8-OXO-2-PI valoylloxymethoxycarbonyl-5-thia-1-aza-bicyclo (4,2,0) octane -2 in 10 cm anhydrous H, N-dimethylformamide and O, 8 g of bis-dimethylamino-tert-butoxymethane.  75 g of crude product in brown meringue form (meringue) are obtained, the IR and NMR spectra of which indicate that this product represents 7-tert-butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxyb in ocHoBHoM 2-pivaloyloxymethyroxycarbonyl-5-thia-1-aza-bicyclo (4,2,0) -oken-2 (mixture | forms Z and E).  Rf 0.36 (chromatography plate of silica gel; cyclohexane eluting agent: ethyl acetate: 50: 5 by volume).  IR spectrum (CHCIg); characteristic bands. , cm-: 2810, 1770, 176 1720, 1705, 1615.  NMR spectrum: (350 MHz, CBC1, cG in m. d. , f 5 in Hz); / characteristic signals: 3.0 (singlet, broad, / CH, /, / N-CH CH- /, isomers Z and. 3.14 and 3.35 / AB, j 14, -3-CHa-cephem, isomer E /; 5.06 / oak / year, J 4, H in b, isomer E /; 5.13 / doublet, J 4, H in 6, isomer Z /; 5.25-5.4 massif, H in 7 and -SOYN-, isomers Z and E /, 5.7-6.0 / 2 AB, -CO3 H3CO2-, isomers Z and E /; 6.52 / doublet, J 14, —CH, isomer E /; 6.92 / doublet,,, measure E /; 6, 24 / doublet, 5,, isomer Z /; 6.72 / doublet, J 6/5, isomer. Z /.   7-tert-Butoxycarbonylamino-3-me.  Tyl-8-OXO-2-PI Valoylloxymethoxycar 1bonyl-5-thia-1-aza-bicyclo (4,2,0) octyl-2 can be obtained according to. the method of example 1.  From 6.9 g tosyldt: 7-amino-3-methyl-8-oxo-2-pivaloyloxymethoxycarbonyl-5-thia-1-azabicyclo (4.2.2) -octene-2, 4.6 g of 7-tert- butoxycarbonylamino-3-methyl-8-oxo-2-pivaloyloxymethoxycarbonyl-5-thia-1-aza-bicyclo- (4,2,0) -oct-2 in the form of an oil that slowly crystallizes (t. square  97 ° C). .  Example 10  1.5 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7. -phthalimido-5-thia-1-aza-bitsi. Clo {.  4,2,0-Octane-2-treated in a stream of nitrogen O, 71 g of di-methoxymethylaminomethane.  in 13 cm anhydrous And, N-dimethylformamide according to example 7.  1.6 g of crude product are obtained, containing mainly 2-benzhydryloxycarbonyl-3- (2-dimethyl-danovinyl) -8-oxy-7 phthalimido-5-thia-1-aza-bicyclos (4.2 octen-2 ( Form E) in the form of orange meringue color (meringi), Rf 0.42.  The starting product has an Rf of about 70.  Silica gel plate;. cyclohexane ethyl acetate 50: 5 eluting agent (by volume). .  IR spectrum (CHCIz) t characteristic, bands, cmM: 2820, 1785, 1775 1730, 1615, 1390, 695, 620, 605.  V PMR spectrum (60 MHz, CBC1, 5. in m. D. , J in Hz): 2.9 (singlet, 6H, / CH3 / 2-I-) Zr52, (AB, J 14, 2H, -Z-CH-cefem); 5.26 (doublet, J 5, 1H, H in 6); 6.8 (doublet, J 8, IH, -CH CH-NC); b; 98 (singlet, 1H, / C H5 2CH-d-); 7.2-7.8 (array, 11H SI- + -CH CH-NC); 7,8-8 massif, 4H, aromatic: phthalimido.  P . RIMER 11.  1.5 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-phthalimido-5-thia-1-aza-. bicyclo (4,2,0) -octene-2 is treated with 1.2 g of bis-dimethylamino-tert-butoxymethane in 13 cm anhydrous N, N-dimethylformamide, acting as in example 2.  Get 1.6 g of the product, the characteristics of which are identical to the product obtained in example 10, in the form of meringue orange.  Example 12  A solution of 6.14 g of 2-benzhydryloxycarbonyl-7- (D-oi-tert-butoxycarbonylaminophenylacetamido) -3-methyl-8-oxo-5-thia-1-aza-bicyclo- (4,2,0) -actin-2 in 90 cm of anhydrous M, M-dimethylformamide at 80 ° C are treated in a nitrogen atmosphere 3.49 g of bis-dimethylamino-tert-butoxymethane in 30 cm of N, I-dimethyl, cetamide.  By proceeding as in Example 2, 6.27 g brown meringue is obtained, which is mainly 2-benzhydryloxycarbonyl-7- (D-c-tert-butoxycarbonylaminophenylacetamido) -3- (2-dimethylaminovinyl) -8-occo-5- thia-l-aza-bicyclo (4,2,0) -octen-2 (form E).  Rf 0.33 (chromatographic silica gel plate, eluent cyclohexane: ethyl acetate 50:50 by volume).  .  IR spectrum (CHBrj), characteristic bands, cm-: 3420, 3310, 2800, 1760, 1710, 1690, 1610.  Example 13  A solution of 6.13 g of 2-benzhydryloxycarbonyl-7- (D-oC-tert-butoxycarbonylaminovyl acetates-j to) -3-methyl-8-oxo-5-thia-1-aza-bicycl-4,2,0} - octene-2 in 50 cm of anhydrous N, and dimethylformamide is heated under a dry nitrogen atmosphere.  A solution of 2.92 g of bis-dimethylaminoethoxymethane in 5 cm of anhydrous H, I-dimethylforma 1 &quot; ida is quickly added.  The reaction mixture was kept at 80 ° C for 38 minutes, diluted with 200 cm of ethyl acetate. And 100 cm of distilled water.  The organic phase is decanted, washed twice with 100 cm of distilled water, then with 150 cm / saturated sodium chloride solution, and dried over sulfate. magnesium and filtered.  Ethyl acetate is evaporated under vacuum (20 mm Hg. Art. ) at 30 ° C.  Get g 2-benzhydryloxy-carbonyl-7- (D-ct-tert-butoxycarbonylaminophenylacetamido) g-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-aza-bicyclo (4,2,0) -oocten-2 (Form E) characteristics: which are identical to the product obtained in example 12.  PRI m e. p 14.  Following the procedure of Example 3, from 1.83 g of 2-benzhydryloxycarbonyl-7- (D-ottert-byproxycarbonylamine-phenyl-acetamido) -3-methyl-8-oxy-5-thia-1-aza-bicyclo (4.2.2), octane, 1.84 g of 2-benzhydryl icarbonyl-3- (2-dimethylaminovinyl) (- 7- (P-cb-t-butoxycarbonylaminophenylacetamido) -8-oxo-5-thia-1-aza-bicyclo (4,2,0 ) -octene-2 (Form E) in the form of orange meringue, the characteristics of which are ideal for the product obtained in Example 12.   .  Example 15  A solution of 17 g of 3-methyl-2- (4-nitrobenzyloxycarbonyl-8-oxo-7-phenoxyacetate-5-thia-1-aza-bsh cyclo 4,2,0) -octene-2 in 100 cm anhydrous N, N-dimethylformamide heated at atmospheric conditions with dry nitrogen, then treated with 10.8 cm of bis-dimethylamino-tert-buto simethane for 1 minute at 80 ° C.  The reaction mixture is then. . diluted with 400 cm of ethyl acetate and 250 cm of distilled water.  The organic phase is decanted, 250 cm of distilled water is passed twice, then 250. see aqueous sodium chloride solution, dried and filtered. Obtained after evaporation of the solvent under reduced pressure (20 mm Hg. Art. ) at 30 ° С the residue is again. dissolved in 50 cm.  methylene chloride and solution: dropwise pour into 1600 cm of diisopropyl ether.  The precipitate formed is filtered off with suction, washed 4 times with 100 cm of diisopropyl ether and dried under reduced pressure. (10 mm Hg. Art. ) at 25 C.  6 g of ocher powder are obtained, the IR and NMR spectra of which indicate that it is essentially 3- (2-dimethylaminovinyl) -2- (4-nitrobenzyloxycarbonyl) -8-ok-7-phenbxyacetamido-5- thia-1-aza-biiyklo (4,2,0). -okten-2 (form E).  Rf 0.3 (silica gel chromatography plate: eluent hexohexane: ethyl acetate 40:60 by volume PMR spectrum (350 MHz,. . CDCIv, G M. D. , J in Hz): 2.97 (singlet, bN, -n / sns / g); h, 23 (AB, j.  is, 2H,); 4.62 (singlet, 2H, C6HJOCH2CO-) ;. 5.15 (doublet, J 4.5 1H, H at 6); 5.31 (AB, J 14, 2H, —COjCHACgH NOj); 5.46 (double doublet, J 4.5 and 10, 1H, H to 7); 6.55 and 6.9 (2 doublets, J 14, -CH CH-NC 6.97 (doublet, 2H, ortho-C (, H50-)): 7.0 (triplet, 1Y, napa-CgHjO-); . 7.3 (trilet, 2H, meta-C-HdO-); 7.6 and 8.2 (2 doublets, 2x2H,. -); Example 16  A solution of 5.8 g of 3 --- methyl-2- (4-nitrobenzyloxycarbonyl) -8-oxo-7-fecoxy-acetamido-5-thia-1-aza-bicyclo (4,2,0) -octene-2 in 50 cm anhydrous K, N-dimethylformamide is heated at 80 ° C in a dry nitrogen atmosphere.  A solution of 2.8 dimethoxymethylaminomethane in 20 cm of anhydrous N and dimethylformamide is added and the temperature is maintained for 2 hours; after addition of 5 cm of triethylamine, the mixture is stirred in the same. 30 NWH at, then the reaction mixture is poured into 300 cm of ethyl acetate.  The organic solution is washed 4 times with 300 cm of an aqueous half-saturated sodium chloride solution, dried over magnesium sulfate in the presence of vegetable black, then filtered.  Evaporation of the solvent under reduced pressure (20 mmr. stL gives 6.05 g of resinous product.  A solution of 5 g of the previous product in 25 cm3 of methylene chloride is added dropwise to 800 cm of diisopropyl ether.  The precipitated product is filtered off with suction, washed 2 times with 100 cm of diisopropyl ether and dried in a desiccator under reduced pressure (10 mm Hg). Art. ) at 25 ° C.  3.7 g of product are obtained in the form of an ocher powder; Its IR and NMR spectra show that it is a mixture of isomers.  This product is chromatographed on. 400 g of silica gel (grain size 0.040, 063 mm; column 6 cm in diameter and 30 cm high, under nitrogen pressure of 40 kPa) to obtain a purified sample of 3- (2-dimethylaminovine) -2- (4-nit. robenzyloxycarbonyl) -8-oxo-7-phenoxy-edetamido-5-thia-1-aza-bicyclo (4,2,0) -octene-2 (. form E) „Rf 0.26 (chromatography on a silica gel plate; eluting agent cyclohexane ethyl acetate 50:50 by volume. ).   IR Spectrum (SNR), characteristic bands, 2820, 1770, 1690, 1610, 1520, 1345, 1240. .  PMR spectrum (350 MHz, CDCIj / cT in m. d. , J in Hz): 2.96 (singlet; -N / GH- / 2, 6H); 3.23 (AB, J 15, -3-CH2-cephem, 2H); 4.62 (singlet, C H50-CH2-CO-, 2H); 5.15 (doublet, J 4, 5H to 6, 1H); 5.31 (AB, J 14, n-NOjC H -CH-OCO-. , 2H); 5.46 (double doublet, J 4.5 and 10, H to 7, 1H); 6.55 and 6.9 (2 doublets, J 14, 2H trans-ethylene, 2H); C6.97 / doublet, ortho, 2H /; 7.03 / triplet, pair, 1H /; 7.30 / dzblet, meta, 2H / 7.5-7.7 multiplet, 3N, -CONH- and aromatic in meta position (N0); 8.2 (doublet, 2H, aromatic. Ortho N02).  Mass spectrum (main peaks): molecular peak M 538; t / e 348 and 347 (fragmentation / 5-lactam); t / e 493 (loss -H / CH3 / 2b t / e 403 (loss C (, HsO-CH2-CO-)) t /. e 359 (loss -N / CH, / 2l.  Note -r vl7.  Following the procedure of Example 15, but from 2.44 g of 3-methyl-2- (4-nitrobenzyloxycarbonyl) -8-oxy-7-phenoxycetatetamide-5 thia-1-aa-bicyclo- (4,2, p) -octyene- 2 and 2.31 g dimethylam no di neopa. ntilo xyme a na get 1.05 g of solid,
    ocher colors, the characteristics of which are identical to the product obtained in example 15.
    Example 18, Solution of 9.2 g of 3-methyl-8-oxo-7-phenoxy-acetamido-2-pivaloxyloxy-methoxycarbonyl-5-, -thia-1-aza-bIcyclo (4,2,0) -octene-2 per 100 cm of dry N, N-dimethylformamide is placed in a nitrogen atmosphere and heated at. 6.2 cm of bis-dimethylamino-tert-butoxymethane are quickly added and the reaction mixture is kept at 80 ° C for 5 minutes before diluting with 400 cm of ethyl acetate and 100 cm of distilled water. The organic phase is decanted and washed successively 3 times with 100 cm of distilled water and 150 cm of an aqueous saturated solution of sodium chloride, then dried over magnesium sulfate and filtered. Evaporation of the solvent under reduced pressure (20 mm Hg) while yielding 5.5 g of brown meringue. This product is dissolved in 75 dcm of cyclohexane mixture. with ethyl acetate 45:55 (by volume) and chromatographic 4 liters of this eluting agent on silica gel (0.04-0.63 mm, a layer height of silica gel 30 cm, column diameter 5 cm) under a nitrogen pressure of 40 kPa.
    Collect fractions of 125 cm. Fractions 15 and 16 are concentrated to dryness under reduced pressure (20 mm Hg) at 30 ° C. Get 0.45 g of 3- (2-dimethylamino. Nyl) -8-oxo-7-phenoxyacetamido-2-pivaloyloxymethoxycarbonyl-5-thia-1-aza-bicocyclo (4,2,0) -octene-2, (form E).
     Rf O, 23 Chromatographic Silica Gel Plate j-eluting agent cyclohexane: ethyl acetate 50: 5 by volume).
    IR spectrum (CHBrg), characteristic bands, cm: 2820, 1760, 1740, 1696, 1610.
    PMR spectrum (350 MHz, CDCI, “f in MD, J in Hz): 1.21 (singlet, / CH3 / sC-CO-, 9H); 3.00 (singlet, / CHgAN-, 6H); 3.22 and 3.30 (AB,; J. a4, -3-CH2-cephem, 2H.); 4.55 (AB, J 14, CgHs-O-CHo-CO-, 2H); ; 5.09 doublet, J 4, H in 6, 1H); 5.36 (double doublet, J 9, and 4, .N to 7, 1H); 5.71 and 6.00 (AB, J 6, —COi —CHgOCO-, 2H); 6.92 (doublet, J 9, aromatic.orto, 2H); . 7.01. (Triplet, J 9, aromatic steam, 1I); 7.29 (doublet, J 9, aromatic meta, ° 2H); 7.77 (doublet, У 9, СОНН-, 1Н) ;. And p. 19. Following the procedure of Example 7, but from 10 g of 2-benzhydryloxycarbonyl-3-methyl-7- (4-nitrobene "eyloxycarbonylamino) -8-oxo-5-thia-1-aaa-bicyclo (4.2.2) octene -2 to 100 cmо of anhydrous K, N-dimethylformamide, treated with 4.8 cm-dimethoxymethylaminomethane, 10 g of crude product formed mainly of 2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -7- (4-nitrobenzylrxylcarbonylamino) -8 -oxo-5-thia-1-aza-bicyclo (4,2,0) -octylene-2 (form E).
    Rf 0.27 (silica gel plate; cyclohexane eluting agent: ethyl acetate 50:50 by volume).
    IR spectrum (СНС1з), characteristic bands, cm-: 2800, 1770, 1730, 1615, 1525, 1850.
    2-Benzhydryloxycarbonyl-Z-methyl-7- (4-nitrobenzyloxycarbonylamino) -8-oxo-5-thia-1-aza-bicyclo (4,2,0) -octene-2- can be obtained as follows
    50 T 7-ADCA is acylated with 50 g of para-nitrobenzyl chloromate to obtain 62.2 g of crude 2-carboxy-3-methyl-7- (4-nitrobenzyloxycarbonylamino) -8-oxo-5-thia-1-aza-bicyclo (4, 2.0) -octene-2 (yellow crystals). 38.5 g of this acid are esterified according to example 1. To obtain 36 2-benzhydroloxycarbonyl-3-methyl-7- (4-nitrobenzyloxycarbonylamino) -8-oxo-5-thia-1-aza-bicyclo (4.2.2) -Oktena-2.
    Rf 0.72 (silica gel chromatography plate, cyclohexane eluting agent: ethyl acetate 50: 50 by volume).
    Example 20. To a solution of 24 g of 2-benzihydryloxycarbonyl-7-benzoylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo (4.2.2) -octen in 100 cm anhydrous N, M-dimethylformamide added under a dry nitrogen atmosphere. Southern bis-dimethylamino-tert-butoxymethane. The reaction mixture is stirred at 23 hours; then it is drunk into a mixture of 300 cm of ethyl acetate with 700 cm of an aqueous saturated solution of sodium chloride. The aqueous phase is decanted and extracted with 250 cm-ethyl acetate. The organic phases are combined, washed with 250 cm of a 1N aqueous solution of hydrochloric acid, 500 cm of distilled water and 300 cm of an aqueous saturated solution of sodium chloride, then dried over magnesium sulfate in the presence of vegetable black and filterworm.
    The solvent is evaporated under reduced pressure (20 mm Hg) at. The residue is dissolved in 200 cm of methylene chloride and fixed on 50 g of silica. The resulting powder was introduced into a column 60 cm in height, 5 cm in diameter, containing 415 g of silica gel in a mixture of cyclorexane and ethyl acetate (by volume). Elute with 5 L of cyclohexane / ethyl acetate 95: 5 (by volume) J, then 5 L of cyclohexane / ethyl acetate, volume 90:10 (by volume), then 5 l of a mixture of cyclohexane with ethyl acetate 80:20 (by volume), then 7 , 5 liters of a mixture of cyclohexane and ethyl acetate 70:30 (by volume) to elute impurities, then 8 liters of a mixture of cyclohexane and ethyl acetate 60:40 (by volume), which are combined and triturated to dryness. 2.-benzgndryloxycarbonyl-7-benzoylamino-3- (2-dimethylaminovinil) -8-ox-5-thia-1-aza-bicyclo- (4,2,0) -octene -2 (form E) in the form, solid substances yellow color. Rf 0,24 ( silica gel chromatographic plate eluting agent cyclohexane: ethyl acetate 50: by volume). IR spectrum (CHCIj), characteristic bands, 2800, -1760, 1740, 1660, 1605. PMR spectrum (60 MHz, CDCl.cTB m. J in Hz), main signals: 2.85 (singlet, 6H, / CHi / Jr-CH CH-); 5.1 (doublet, J 4 Hz; T.N, H in b); 5.65 (double doublet, J 9, and 4 Hz, 1H H 7); 6.8 (singlet, 1H, -CH / CgH / 7.05-8.2 (solid, aromatic, and -CONH-). V UV spectrum (C2H50H, from 1.9 Yu 1 1 cm): L d: 392 nm, 16000. Example 21. Following the procedure of example 1, but replacing methyl sulfate No., I, l, N-tetramethylformamidini with 1 g of methyl sulfate N, K-dimethylmorpholinomethylenimog1, is obtained from 0.96 g of 2-benzhydryl-6-xycarbonyl-7-tert-by-current syc Zaron bonil amyio-3-methy-8-oxo-5-thia-1-az-bicyclo (4.2.0 ) octene-2 1.1 g meringues orange. This product contains mainly 2-benzhydryloxycaronyl-7-tert-butoxycarbonylamino-3- (2-morpholinyl-8-oxo-5-thia-1-aza-bicyclo (4,2,0) -octen-2. (Form E) Rf 0.43 (chromatographic plate of silica gel eluting agent cyclohexane: ethyl acetate 50:50 by volume). Example 22. Solution 8.06 G of 2-benzhydryloxycarbonyl-7- (2-methoxyimino-2) 2-triphenyl-amino-amino -4-thiazolyl- (acetamido) -3-methyl-8-oxo-5-thiath1-aza-bicyclo (4,2,0) -octene-2 (syn-isomer) in 160 cm of waterless noggr K, N-dimethylformamide heated to. Adding 2.26 g of bis-dimethyl agonette-butoxymethane The reaction mixture is diluted with 645 cm O} of the precipitated ethyl acetate and washed 4 times with 250 cm of distilled water, then with 100 cm of an aqueous saturated solution of sodium chloride. The organic solution is dried over magnesium sulfate and filtered. Evaporation to dryness under reduced pressure (20 mm Hg) gives 8.1 g of meringue brown color, the IR and NMR spectra of which show that it consists mainly of the isomer E, syn, 2-benzhydryl, oxycarbonyl-7- (2 -methoxyimino-2) 2-tritylamino-4-thiazolyl- (acetamido) -3- (2-dimethylaminobinyl) -8-oxo-5-thia-1-az a-bicyclo (4,2,0) -octene-2. Rf 0.18 (chromatographic silica gel plate; cyclohexane eluting agent: ethyl acetate 50: 50 by volume). , IR spectrum (solution in CHBrg), characteristic bands: 1765 cm carbonyl jb-lactam; 1610 enamine double bond. NMR spectrum (350 MHz, - CDCIj, / - B ppm, J in Hz): 2.87 (singlet, 6H, / CHjVfj-N-); 2.98 and 3.15. (AB, J 14, 2H, -8-CH2-cephem); 4.08 (singlet, 3N, NO-CH); 5.12 (doublet, J 4, 1H, Nvb); 5.51 (double doublet, J 4 and 8, 1H, H at 7); 6., 42 and (AB, J 14, 2H, -H trans-vinyl); 6.38 (singlet, 1H, H thiazole cycle); 6.94 (singlet, 1H, -COOCH / CiHj / ah 7.01 (singlet, broad, 1H, CNH -); 7.107, 50 (15H, aromatic) 5 7.63 (doublet, J 8, 1H, -CONH -). 2-Benzhydryloxycarbonyl-3-methyl-8-oxo-7- (2-methoxyimino-2) 2-trithylamino-4-thiazolyl (ace amido) -5-thia-1-aza-bicyclo (4,2 , O) -octene-2, isomer, syn, can be obtained as follows: To a solution of 3.15 g of 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclr ( 4,2,0) -octene-2, in 31.5 cm of methylene chloride, a solution of 7.2 g of 2- (2-tritylimino-4-thiazolyl) -2-methoxyiminoacetic acid anhydride (form syn) in 22 is added immediately; 5 cm - methylene chloride. rises from 8 to 14 ° G. Stir for 15 minutes, the temperature rises to 20 ° C, then washed with 10 cm 2 of 0.5 N hydrochloric acid, 10 cm of distilled water, then 20 cm of saturated sodium bicarbonate solution. The mixture is filtered, the organic phase is again washed twice with 20 cm of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm Hg) at 40 ° C. The residue is chromatographed on a column (diameter 3 cm, height 33 cm) containing 125 g of silica gel, eluting with mixtures of ethyl acetate and cyclohexane 20:80, then 40:60 (by volume), respectively 1, 2 and 1 l, collecting fractions of the eluate by 50 cm- Fractions; 31-44 are evaporated and get 2.8 g of 12-benzhydryloxycarbonyl-7- (2-meth
    imino-2-) 2-tritidino-4-thiazolyl acetamido) -3-methyl-8-oxo-5-thia-1az-bicyclo (4,2,0) -octene-2 (syn isomer) as a solid c. of the company. pale yellow color.
    Example 2 3. To a solution of 2.5 g of 2-benzgi, rryloxycarbonyl-3-methyl-8-oxo-7- 2- (2-tritylamino-4-thiazolyl) -2-vinyloximine-potassium-tamido} -5-thia-l -aza-bicyclo-C4, 2.0) - octene-2 syn-isomer, 0.7 cm of tert-butoxy-bis-dimethylaminomethane was added under nitrogen atmosphere in 80 cm of dimethylformamide and stirred at 80 ° for 10 minutes C and the mixture is taken up in 250 cm of ethyl acetate and 15 250 cm ice water. Decanted, washed 3 times with 150 and, 150, saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness. 20 Under a pressure of 20 mm Hg. (kPa1; at 30 ° C. 2.5 g brown meringue is obtained, consisting mainly of 2-benzohydryloxica; rbo 1yl-3- (2-dimethylaminovinyl) -8-oxo-, 25 (2-tritylamino-4- thiazolyl) -2-vinyloxyminoacet.amido-B-thia-1-aza-bicyclo (4,2,0) -octena-2, (syn-isomer, form E),
    IR spectra (KBr), characteristic bands, CM-I: 1770, 1670, 1635, 1610, 1530, 1495, 1450, 1000, 945, 755, 700.
    PMR spectrum (350 MHz, CDCLj, sGw ppm, J in Hz): 2.90 (singlet, bN, -N / CH /.jJ 4/25 (double doublet,
    J 2 and b, 1H, -x); J4.73 (double. Fg ,.
    Noah doublet, and 14, 1H,); 140
    5.18 (doublet, J 4, 1H, H in 6); 5, BO (double doublet, J 4 and 9, 1H, H to 7); 6.53 and 6.75 (2 doublets, J 16, 2H,); 6.88 (singlet, 1H, -soosen -) ;, 7.10 (double doublet, J 45 6 and 14, 1H, IOSN).
    2-Benzhydryloxycarbonyl-3-methyl-8-oxo-7-C2- (2-tritylaminr-4-thiazolyl) -2-vinyloximino-acetamido.1-, -Q-5-a2iaa-1-aza-bicyclo (4, 2.0) -octene-2, a syn-isomer, is obtained by condensation of 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyminoacetic acid, syn-isomer, (4.6 g) with 7-ADCA benhydryl ester ( 3.8 g) in the presence of H, 1} -dicyclohexylcarbodiimide (2.3 g) and 0.05 g of 4-methylmethylaminopyridine in 40CM methylene chloride at 520 ° C for 4 hours. After chromatography on silica gel (200 g) with 60 using methylene chloride get 5 g of the desired product in the form of meringue yellow eta,
    IR spectrum (KBG), characteristic features, cm-: 3400, 1785, 1725 ,. 65
    1690, 1640, 1525, 1495, 1450, 1040, 1000, 940, 755, 700.
    PMR spectrum (350 MHz, .tf in ppm, J in Hz): 2.12 (singlet, 3N, -CHj); 3.22 and 3.49 (2 doublets, J 18, 2H, -CH2-); 4.25 (double oak - H. years, J. 2 and 6, 1H, J ;.
    4.76 (double doublet, J 2 and 14, 1) i5.08 (doublet, J 4 / 1H,
    H in b); 5.92 (double doublet, j 4 and 9, 1H, H at 7); 6.83 (SiNglet, 1H, H thiazole) .; 6.93 (singlet, 1H, -COOCH); 7.0 (singlet, 1H,
    -WH-C / Cj Hj / s) Example 24. To a solution of 21.8 g of a mixture of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-tritylamino-5, -thia-1-aza-bicyclo (4.2 , 0) octene-2 (40%) with its isomer - octene-3 (60%) in 120 cm of anhydrous m, N-dimethylf. Formulamide heated to, under nitrogen atmosphere, 10.8 cm of tert-butoxy-bis is added -dimethylaminomethane. After keeping for 5 minutes, the reaction mixture is poured onto 500 cm of ethyl acetate. 250CM distilled water is added, stirred, the organic phase is decanted, which is washed with 3 times 250 cm of distilled water, then dried over MgSO4 and concentrated under reduced pressure (40 mm Hg) at. A study using thin-layer chromatography of the residue shows the presence of the original unchanged product. It is again dissolved in 100 cm anhydrous and c-dimethylformamide to 80.degree. C. under nitrogen atmosphere and kept for 5 minutes at this temperature after adding 6 cm. butoxy bis-3-dimethylaminomethane. The reaction mixture is then diluted with 500 cm of ethyl acetate and worked up in the manner described above to obtain 24 g of orange meringue formed mainly by 2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-o. 7-tritylamino-5-thia-1-aza β-bicyclo (4,2,0) -octenone-2 (Form E).
    IR spectrum. (SNVg-e) characteristic bands, 3320, 2800, 1760, 1680, 1610, 1445, 760, 705.
    PMR spectrum (CDCI-j, 350 MHz, d in MD, J in Hz): 2.84 (singlet, 6H, -N / CH / a); 2,95 and 3,12Т2 doublet, j - 16V 2H, -zSNe-); 3.36 (doublet, J 10, 1H, -NH-T; 3.98 (double Year, J. 4, -1H, H at 6); 4.41 (double doublet, J 4 and 10.1H, H 7); 6.4 and 6.72 (2 doublets, j 14,) 6.82 (singlet, 1H, sn) g 7.2-7.6 (massif, 25H, aromatic
    A mixture of 2-benzhydryloxycarbol-3, -methyl-8-oxo-7-tritylamino-5-a-1-aza-bicyclo {4,2,0-oktena-2 (10%; and th isomer - octene-3 | 60%) can be obtained as follows. Within 15 minutes, a solution of 12.3 g of diphenyl diazomethane in 200 cm of acetonitrile is added to a suspension of 28.8 of the previous mixture in 500 cm of acetonitrile, then the reaction mixture is stirred for 2 hours at. The solvent is boiled under reduced pressure (40 mmHg) at 30 ° C and the spray residue is again dissolved in 500 cm of ethyl acetate. The solution is washed successively with 1 and hydrochloric acid (up to discoloration), then 3 times 100 cm of fine sodium bicarbonate solution, 100 cm of water and 100 cm of a saturated solution of sodium chloride, then dried and concentrated to dryness to obtain 35.4 g of a mixture of 2- benzhydryloxycarbyl-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo (4,2,0) -octene-2 (40%) and its isomer is octene-3 (60% as cream-colored meringues. IR spectrum (CHBr), characteristic bands, 3340, 1765.173 k 1620, 1590, 1490, 1445, 745, 700. PMR spectrum (CDCIji 350 MHz, dTT in ppm, J in Hz): 1.73 (singlet, octene-3); 2.0.0 (single t, -CH octene-2); 3.05 and 3.30 (2 doublets AB, J 18, -SCH27. octene-2); 4.20 (2 doublets, J 4, H to 6 octene-2 and octene-3); 4.60 (2 double doublets, J 4 and 10, H in 7 octene-2 and octene-3); 4.80 (singlet,. H in 2 octene-3); 5.75 ( singlet, broad, H in 4 octene-2); 6.78 (singlet, sktene-3); 6.89 (singlet, -CO CH / CgHe: octene-2); 7.2-7.50 (aromatic ) A mixture of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo (4,2,0) -octene-2 (4Q%) and its isomer - octene-3 ( 60%) can be obtained as follows. To a suspension of 42.8 g of 7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza. -Bicyclo (4,2,0) -octene-2 in 250 cm anhydrous NN noted the formamide to 55.6 cm of triethylamine was added, and then after cooling to -20 ° C, a solution of 55.8 g of chlorotryne phenylmethane in 250 cm of chloroform was added over 2 hours. The reaction mixture is stirred for 24 hours at, then poured into 400 cm 1 and. hydrochloric acid. After filtration, the organic phase is separated, which is concentrated to half under reduced pressure (40 mm Hg) and 400 cm of ethyl acetate is treated. The aqueous phase is extracted with 400 cm of ethyl acetate and the combined organic phases are washed twice with 250 cm 1 and hydrochloric acid, then extracted 4 times with 500 cm of a half-saturated solution of sodium bicarbonate and. These combined aqueous phases are washed with 300 ethyl acetate, then acidified to pH 3 12 and with hydrochloric KIS and extracted with 2 times 500 see ethyl acetate. Combined organic races thieves, after washing with 250 cm of a saturated solution of sodium chloride, are dried over sodium sulfate and concentrated to dryness under reduced pressure (40 NM Hg) with the residue treated (thick) with 250 cm of diisopropyl ether. The substances are filtered off with suction, washed with 100 cm of GDI isopropyl and dried. 22.2 g of a mixture of 2-carboxy-3-methyl-8-oxr-7-tritylamino-5-thia-1-aa-bicyclo (4.2.0) gOKtene-2 (40%) are obtained from its isomer - octene-3 (60%). in the form of a cream-colored solid. IR spectrum (HIW) characteristics of the bands, 3320, 3300, 2400, 1765, 1730, 1625, 1595, 1490, 1450, 750, 710. PMC-spectrum (CDCIj, 350 MHz fi in ppm, J in Hz) : singlet, -CH, octene-3 1,2,16 (singlet, -CHj, octene-2); 3.10 3.40 (2 doublets, J 10, -SCH-octen-2); 4.2 (2 doublets, J .4, H in 6 OKtena-2 and octene-3); 4.6 (2 double doublets, J 4 and 10, H in 7 octene-2 and octene-3); 4.73 (singlet, H in 2 octene-3); 5.77 (broad singlet, H in 4 octene-3 j 7.2-7.5 aromatic), Example 25. 4.6 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-fensh1acetamido- .5- tya-1-aza-bicyclo (4,2,0) -octene-2 is dissolved in 44 cm of dimethylformamide at. A solution of 2.68 g of ethoxy-bis- (dimethylamino) methane in 2..67 cm dimethylformamide is added over 30 minutes. The solution was poured into a mixture of 100 cm of hot water and 100 cm of ice and 300 cm of ethyl acetate. The organic phase is decanted, washed twice with 200 cm, 100 cm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (40 ° C, 20 mm Hg, 2.7 kPa). 5.0 g of 2-b enzhydryloxycarbonyl-3- (2-dimethylainowins1) -8-oxo-7-phenylacetamido-5-thia-1-aza-bicycl6 (4,2,0) -octene-2 (isomer E) in the form of brown oil. IR spectrum (SNGV), characteristic bands, cm1: 3320, 1680, 1755, 1620 and 1540. PMR spectrum (350 MHz, CDCIj, “G in MD, J in Hz): 2.72 (singlet, 6H, N / CHa / j); 2.30 and 3.15 (2 doublets, J 18, 2H, -SCH2-); 3.65 (singlet, 2H, -CH; i-CO-): 4.93 (doublet, J 4, 1H, Hj); 5.34 (double doublet, J 4.1 8, 1H, H,); 6.01 (doublet, J 12, j IH, -CH CH-N ::;); 6.11 (doublet, J 12, IH, C h 6.66 (singlet, IH, -CH C / benzhydryl)); 7.2-7.5 (multiplet, 15H, aromatic) 7.56 (doublet, J 8, IH, NH) .P p and, M ep 26-. To a solution of 21 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-phenoxy-acetamido-5-thia-1-aza-bicyclo (4.2, 0) -octene-2 in 400 cm of dimethylformamide, brought to 80 ° C., 7.8 g of bis-dimethylaminobutoxymethane are added over 30 seconds. The solution turns greenish brown. After 5 minutes at 80 ° C, the solution is poured into a mixture of 500 cm of water, 500 g of ice and 1500 cm of ethyl acetate. The organic phase is washed twice with 1000 cm of BOfsja, then 500 cm of a saturated solution of chlorine. dry sodium / magnesium sulphate and concentrate to dryness under reduced pressure (20 mm Hg. kPa). The residue is dissolved in 75, cm.T. Acetate, the solution is drunk in 250 cm of di ethyl ether, filtered; the filtrate is concentrated dry. under reduced pressure (20 mm Hg 2.7 kPa), the residue is dissolved in 50 cm of ethylodetate and the solution is drunk in 250 isopropyl ether. The precipitate formed is filtered off and then dried. Thus, 11 g of 2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-oxo-7-phenoxy acetamido-5-thiag1-aza-bicyclo (4,2,0-octen-2 (isomer E) are obtained solid yellow color. IR spectrum (KVg), a characteristic band, CMV3320, 1765, 1690, 1615, 1540, 1500, 1460, 1240, 760, 705, PMR spectrum (350 MHz, CDCIg, f in m, d., J in Hz): 2.90 (singlet, Nb., N- (CH3) 2; 2.93 and 3.18 (2 doublets, J 14, 2H, -S-CH2-); 4.62 . (broad singlet, 2H, -OCH-C-O-)) 5.11 (oak year, J 4, 1H, H at 6); 5.43. (double-doublet, J 4, and 8, 1H, n ); 6.42 (doublet, J 14, 1H., - CH CH - NC); 6.5 (doublet, J 14, IH, -CH CH-NC); 6.85 (singlet, IH, -СООСН C); 7.92 (doublet, J 8, IH, -COIC-). Example 27. Add t O, 88 cm of bis-dimethylamino-tert-bucket of simetan in a solution at 80 ° C from 2.34 C-methyl-2- (4-nitrobenzyloxycarbonyl) -7-phenylacetamido-8-oxo-5-thia-1-aza- bicyclo (4,2,0) -2-octa in 20 cm N, c-dimethylformamide and stir the reaction mixture for 1 min at 80 ° C, then dilute it with 100 cm of ethyl acetate and 100 cm of distilled water. The organic phase is washed with 100 cm of distilled water. The combined aqueous phases are different. An equal volume of saturated sodium chloride solution and extracting with 50 cm-ethyl acetate is added. The organic phases are combined and washed 2 times with 100 cm of a semi-oxidized solution of sodium chloride and 100 cm of distilled water, then dried over magnesium sulfate. After concentration to dryness under reduced pressure (30 mt Hg) at 30 ° C, the resulting residue is purified by column chromatography (height 28 cm, diameter 2.2 cm) with silica gel (0.040, 06 mm) by elution at a pressure of 0.5 bar with cyclohexane mixture. and ethyl acetate (45-55 volumes) and by selecting fractions of 25 cm. Fractions 15-28 are combined and concentrated at low pressures (30 mm Hg) at. About, 21 g of an orange solid is obtained, which is formed in the primary 3- (2-dimethylaminovinyl) -2- (4-nitrobenzyloxycarbonyl) -7-ffinylphenyl-8-oxy-5-thia-1-aza-bicyclo (4, 2 , 0) -2-octene Tisomer E). IR cijeKTp (СНВг j), characteristic bands, cm-h: 3400, 3320, 2800, 1760., 1680, 1610, 1495, 1450, 1345, 1230, 855, 7.30. . Proton Nuclear Magnetic Resonance Spectrum (MHz, CDCIj, d in PPM, I in Hz.): 2.97 (S, 6H, -H (CH3) 2) HrO And 3.23 (2d- I 15, G: 2n, -SCH-); 3.70: (S, 2H,; 5.08 d-, I 3.5, 1H, H in 6); 57l5 And a, 42 (2d, I - 14, 2H,.-COOCH = -); 5.45 (dd, 1 3.5 - and 8.5, 1H, H .7); 6.40 (d, I 8.5, 1H, -CONH-); 6.50: and 6.84 (2d, I 14, -CH CH-NC); .7.287, 40 (mt, 5H, C HfCO-); 7.56 (d ,, I 8, 2H, aromatic in meta NOj); 8.20 (d, I 8, 2H aromatic to ortho NOj). Example 28. In a solution of 9, 78 g of 2-benzgiDryloxycarbonyl-7-tert-butoxycarbonylamino-3-methyl8-oxo-5-thia-1-aza-bicyclo (4.2.0) -2-octene, containing 17% of the isomer 3-octene, in 85 cm of dry N, N-dimethylformamide at 80 ° C, a solution of 6.42 g of tripiperidinemethane in 50 cm of dry N, N-dimethylformamide is added dropwise over 30 minutes, then the reaction mixture is stirred for 45 minutes at 80 ° C and diluted with 300 cm of ethyl acetate. The organic solution is washed 6 times with 100 cm of distilled water and 6 times with 100 cm of a half-saturated sodium chloride solution. The combined aqueous phases are extracted with 2 times 200 cm of ethyl acetate, then washed with distilled water to Neutrality. The organic phases are combined, washed with 100 distilled water and dried over sodium sulfate. 450 g of a solution of 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-j-3- (2-piperidinovinyl) -5-thia-1-aza-bicyclo (4,2,0) -2-octene (isomer B); Evaporation to dryness of 10 g of this solution makes it possible to obtain 0.27 g of an orange substance, the chromatographic analysis of which shows that it is mainly 2-benzhydryl-6-hydroxycarbonyl-7-tert-6-oxycarbonylamino-8-oxo-3- {2-piperidinvil) -5-tia -1-aza-Oicyclo (4,2,0) 2-octene (isomer B) with the following characteristics. , Hk-cneKTp (qg), characteristic bands, cuf: 1770, 1720, 1690 1600, 1530. Spectrum of nuclear Magiite reso. Nant's proton (350 NHI, CDCI, rf in in.n.M. I in HZ): 1.42 (, (CH.) - C-) 1,, 50 fmt, 6H, SND in 3 and 4 yIperydin cycle); 3.1z (mt, 4H, -GHjj-S-CHh piperidine); 3.06 and 3.25 (2d, I 18, 2H, -ZSNd-); 5.01 (d, I 9, 1H, H in 6); 5.23 (ad, I 4 and 9, 1H, H at 7); 5.44 (d, I 9, ", -NH--); 6.62 and 6.68 (2d, I 14, en, O; 6.79 (S DN, -C02CH); 7.2-7; 5 (mt, Yun aromatic); -,. - Note e p 29, Work according to the principle described in example 28, but with 4.5 g of tripiperidine methane replaced by three .Morfinolinmethan, starting with 5; 33 g of 2-benzhydryl Oxycarbonyl-7 T-butoxycarbotyl-amino-3-methyl-8-oxo-5 -Tia-1-aza-bicyclo (4.2.0) -2-octvia, 6.2 g of a brown substance; Physical Chromatopically; 4 analysis of which shows the presence of 2-benzhydryloxycarbynyl-7-three-ay oxycarbonylamino-3- (2 -mor4 olinvinyl) -8-oxo-5-thia-1-aza-bicyclo-4,2,0-2-octene (isomer B). Rf 0.2 (xcf with silica gel; eluteite - cyclohexane: ethyl acetate T 70:30 by volume). EXAMPLE 30: Add 0.55 cm of bis-dimethylamino-three, a simethane stream, to a solution of 1g 7-three-butoxycarbonylamino-2 - (4-methoxybenzyl oxy Arbonyl) - 3-methyl-3-ox) -51-thia-1-aza-bicyclo (4.2.0) -2-octene in 12 cm dry N, N-dimethylformamide, preheated maintain and maintain at this temperature for 8 minutes, then dilute the reaction mixture with 100 cm of ethyl acetate. The mixture is washed with 2 times 100 cm of distilled water and 100 cm of a half-dollar of valuable sodium chloride solution and dried over magnesium sulfate. The residue obtained after evaporation of the solvent at; 1 low pressure (30 mm Hg) at is subjected to chromatography on a column (height 30 cm, diameter 1.4 cm) with silica gel (0.04-0.06JMM) by elution at a pressure of 0, 5 bar with a mixture of cyclohexane and ethyl acetate (65-35 volumes) and selection of fractions of 25 cm. The fractions 16-20 are combined and concentrated to dryness under reduced pressure (3t) mm Hg) at 0.12 g of 7-tert.-butbxycarbonylaminO-: -3- (2-dimethylaminovinil) -2- (4- methoxybenzyloxycarbonyl) -8-oxo-5-thia-1-aza-bicyclo (4.2.0) -2-octeHa (isomer E) as an orange, solid. , Proton Nuclear Magnetic Resonance Spectrum I (350 MHz, CD6I ,, f in PPM, I in Hz): 1.47 (S, 9J,: (CH3) ds-C); 2.91 (&amp; 6H, -N (CH, i)); 3.14 and 3.33 (2d, 1 15, 2H, 3.81 (S, 3N,); 5.05 (a, I 4, 1H, Hb); 5.15 (AB, I 12, 2H, , -SOLSNA-) 5.27 (dd, I 4 and 9, 1H, Hjj); 5.44 (d, I. 9, IH, -COIfH-); 6.48 and 6.80 (2d, I - 14, 2H, -CH-CH-HC); 6.87 and 7.32 (2a, I 7, 2 X 2H, aromatic). 7-tert.-Butoxycarbonylamino-2-4-methoxybenzyloxycarbonyl-e-3g-methyl -I-oxa-5-thia-1-az a-bicyclo (4,2,0) -2-octene can be obtained by esterification of 7-three-butoxycarbonylamino-2-carbox-3-methyl-8-oxo-5-thia -1-aza-bicycloG, 2.0) -2-octene with p-methoxybenzyl bromide.
    权利要求:
    Claims (3)
    [1]
    METHOD FOR PRODUCING DERIVATIVES
    [2]
    3-AMINOVINYLCEPHALOSPORIN of the general formula I
    R1K N · S where the dashed line is the double bond at the position of the 2,3- or 3,4-cephalospori new nucleus;
    . r. and Ro together with the nitrogen atom * form a phthalimide radical or R ^ - hydrogen and r 2 - trityl or a radical of the general formula R 6 -C0-, rfle Rg- trit-butoxy-y
    [3]
    4-nitrobenzyloxy or phenyl,. or Rj is a radical of the general formula
    R_ - SI - CO - ' 7 I. ··· R 8 where R -.- phenyl or phenoxy group and
    Rg is hydrogen or a tert-butoxycarbonylamino group, or R 2 is a radical of the general formula (c 6 and 5 ) 3 c-nk 'in the form of a syn-isomer.
    'k * where R g is methyl or vinyl;
    r ^ h R ^ - both methyl or together with the nitrogen atom form a morpholine or piperidine radical;
    R-. - methyl, pivaloyloxymethyl,
    4-methoxybenzyl < 4-nitrobenzyl or benzhydryl, distinguished by the fact that the compound of the general formula c or u (I)
    He) where the dotted line .R. and R have the indicated values, 2 5 .
    ! are reacted with a compound of general formula IV:
    R w is CH-N <.
    V R <
    <de one of the groups R ^ h R ^^ is a dimethyl ·.! amino group, and the other is an ethoxy or tert-butoxy group or R 1o h R ^ Kax. Smoke means methoxy, neopentyliloc. si, piperidino or morpholino group; 'Bj and R ^ have the indicated meanings in the medium of dimethylformamide in the range of temperatures from 20 ° C to the boiling point of the reaction mixture.
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    同族专利:
    公开号 | 公开日
    IL60139D0|1980-07-31|
    CS244405B2|1986-07-17|
    AT369375B|1982-12-27|
    FR2457296A1|1980-12-19|
    SE8003821L|1980-11-24|
    ATA270980A|1982-05-15|
    LU82477A1|1980-12-16|
    JPS55154981A|1980-12-02|
    IE801062L|1980-11-23|
    IE49814B1|1985-12-25|
    ES8102136A1|1980-12-16|
    JPH0246595B2|1990-10-16|
    BE883416A|1980-11-21|
    CH645379A5|1984-09-28|
    FI801641A|1980-11-24|
    GB2051062A|1981-01-14|
    DD150899A5|1981-09-23|
    ZA803038B|1981-05-27|
    NO801502L|1980-11-24|
    AU5859580A|1980-11-27|
    PL126481B1|1983-08-31|
    AU534806B2|1984-02-16|
    GB2051062B|1983-10-12|
    CA1144919A|1983-04-19|
    DE3019462A1|1980-12-04|
    ES491687A0|1980-12-16|
    FR2457296B1|1982-02-05|
    IT8022243D0|1980-05-21|
    PL224391A1|1981-02-13|
    SE451072B|1987-08-31|
    IT1140974B|1986-10-10|
    IL60139A|1984-04-30|
    DK222080A|1980-11-24|
    HU185890B|1985-04-28|
    GR68426B|1981-12-30|
    US4307233A|1981-12-22|
    PH15946A|1983-04-29|
    CS354380A2|1985-09-17|
    PT71276A|1980-06-01|
    NZ193799A|1983-03-15|
    YU136880A|1983-04-30|
    NL8003023A|1980-11-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4065620A|1971-06-14|1977-12-27|Eli Lilly And Company|3- vinyl cephalosporins|
    GB1463077A|1973-04-19|1977-02-02|Glaxo Lab Ltd|7-substituted-ethyl-cephalosporin derivatives|
    DK674674A|1973-12-21|1975-09-08|Glaxo Lab Ltd|
    US4095021A|1973-12-21|1978-06-13|Glaxo Laboratories Limited|3-Carbamoyloxymethyl or N-methyl-carbamoyloxymethyl-7-[2-carboxymethoxyimino-2-acetamido]ceph-3-em-4-carboxylic acids and derivatives thereof|
    JPS5129492A|1974-09-04|1976-03-12|Sankyo Co| Sefuarosuhorinjudotai no seiho |
    DK154939C|1974-12-19|1989-06-12|Takeda Chemical Industries Ltd|METHOD OF ANALOGUE FOR THE PREPARATION OF THIAZOLYLACETAMIDO-CEPHEM COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS OR ESTERS THEREOF|
    JPS5253890A|1975-10-14|1977-04-30|Syntex Inc|Production of cephalosporin type compound|
    PT71652B|1979-08-15|1982-01-21|Merck & Co Inc|Process for preparing allysulfoxide enzyme inhibitor|ES485938A1|1978-11-15|1980-07-01|Glaxo Group Ltd|Cephalosporin antibiotics|
    FR2494275B2|1980-11-20|1983-04-15|Rhone Poulenc Sante|
    FR2494279B1|1980-11-20|1983-02-04|Rhone Poulenc Sante|
    FR2494280B1|1980-11-20|1983-08-26|Rhone Poulenc Sante|
    FR2505334B1|1981-05-11|1984-01-20|Rhone Poulenc Sante|
    FR2511372B1|1981-08-17|1983-11-10|Rhone Poulenc Sante|
    US4486586A|1983-02-10|1984-12-04|Bristol-Myers Company|Cephalosporin derivatives|
    US4560749A|1983-11-18|1985-12-24|Eli Lilly And Company|Cephem-3-imidates and 3-amidines|
    US4708955A|1985-06-24|1987-11-24|Bristol-Myers Company|3-propenyl-7-aminothiazol-ylcephalosporanic acids and esters thereof|
    US4874856A|1985-06-24|1989-10-17|Bristol-Myers Company|3-propenyl-7- ceph-3-em-4-carboxylic acids and esters thereof|
    WO1987006232A1|1986-04-14|1987-10-22|Banyu Pharmaceutical Co., Ltd.|1-carboxy-1-vyniloxyiminoaminothiazole cephalosporing derivatives and process for their preparation|
    AT354577T|1996-11-06|2007-03-15|Basilea Pharmaceutica Ag|Vinyl-pyrrolidinone cephalosporin derivatives|
    CA2935651A1|2007-10-09|2009-04-16|Gladius Pharmaceuticals Corporation|Broad spectrum beta-lactamase inhibitors|
    EP3441071A1|2013-03-12|2019-02-13|Gladius Pharmaceuticals Corporation|Derivatized cephalosporins|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7913096A|FR2457296B1|1979-05-23|1979-05-23|
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