Method of producing 3-vinylcephalosporins or their pharmaceutically acceptable salts

专利摘要:
7-acylamino-3-vinylcephalosporanic acid derivatives of the formula: <CHEM> in which R<1> is amino-substituted-heterocyclic group which may have halogen, protected amino-substituted-heterocyclic groug which may have halogen, or a group of the formula: <CHEM> wherein R<3> is lower alkyl, R<2> is carboxy or a protected carboxy group, A is lower alkylene which may have certain substituents and pharmaceutically acceptable salt thereof and processes for their preparation and also a pharmaceutically composition comprising, as an effective ingredient, the above compound in association with pharmaceutically acceptable carriers. The invention also relates to the starting compounds <CHEM> and other starting compounds and their preparation. h
公开号:SU1186087A3
申请号:SU803009474
申请日:1980-11-18
公开日:1985-10-15
发明作者:Такая Такао；Такасуги Хисаси；Масуги Такаси；Яманака Хидеаки；Кавабата Кодзи
申请人:Фудзисава Фармасьютикал Ко.,Лтд (Фирма)；
IPC主号:

专利说明:

the fact that the compound of General formula 11
R2
where R ,, has the indicated meanings, or its reactive derivative of the amino group or its salt, is introduced into reaction with a compound of the general formula III
R - A - COOH
where R and A have the indicated meanings, either with its reactive derivative at the carboxy group, or with its salt in an inert solvent under the reaction conditions, such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate , M, N-dimethylformamide, pyridine, hexamethylphosphoramide, or a mixture thereof and optionally in the compound of formula I, wherein K - atsilaminotiazolil possibly substituted by chloro, di (C -C alkyl) aminometilenaminotiadiazolil, di (alkyl) aminometilenaminooksadiazolil , but cylaminopyridyl, tritylaminothiadiazolyl or tritylaminotetrazolyl, cleave the amino group by a compound to form a compound of formula R. , tert-butyl alcohol, tetrahydrofuran, N, N-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or their mixtures, and / or in the compound of the formula I, in which Rj is an esterified carbox the group cleaves the ester part to obtain a compound of formula I, in which Rj is a carboxy group, in an inert solvent under the reaction conditions, such as water, methanol, -ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, H, L-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, rsi mixtures thereof, and / or a compound of formula I, in which Rj is a carboxy group, is esterified with a compound of formula I, in which Rj is an esterified carboxy group, in a solvent which is inert under the reaction conditions, as H, M-dimethyl mamide, tetrahydrofuran, dioxane, methanol, ethanol, or mixtures thereof, and / or in a compound of formula I, in which A is methylene substituted by a group of formula N-OR, as a syn-isomer, where R is —C —Cj-alkyl, substituted an esterified carboxy group or 0,0-di (C-C-alkyl) phosphono group, or C -C-alkenyl substituted by an esterified carboxy group, cleaves the ester part to obtain a compound of formula I, in which A is methylene, the substituted group of formula N is OR , in the form of syn-isomer, where R is C -C-alkyl, for / substituted by a carboxy group or a phosphonogroup, or C -C-al kenyl, substituted with a carbox group, in an inert solvent under conditions of reaction, such as water, methanol, ethanol, propanol, t-butyl alcohol, tetrahydrofuran, S, H-dimethylformamide, dioxane, methylene chloride, V chloroform, diethyl ether, or mixtures and / or in a compound of formula I, in which the esterified carboxy group 1 is C, -C / alkoxycarbonyl, substituted by acylamino and esterified carboxy group, are cleaved off to form the compound of formula 1 in which the esterified carboxy group R. is C, -Cr-alkoxykyrbonyl, substituted by amino and carboxy groups, in an inert solvent under the reaction conditions, such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, N, H-dimethylformamide, dioxane , methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or in a compound of formula I, in which A is methylene, substituted by a group of formula -N - OR, as a syn-isomer, where R is C-C-alkoxycarbonyl -C-Cj-alkyl ,. the substituted acylamino and esterified carboxy group or C-C alkyl, substituted by the acylamino and esterified carboxy groups, split the acyl and ester parts to give a compound of formula I, in which A is methylene, substituted by a group of the formula sN - OR 4, as a synomer, R ,, - C, -Cg - alkoxyarbonyl -C, -C 4 alkyl, substituted with a minogroup and carboxy group, or -CJ-alkyl, substituted by an amino group and carboxy group, in an inert solvent under the reaction conditions, such as water, methanol, ethanol , propanol, tert-butyl alcohol, tetrahydrofuran, H, H-dimeshmormamid, dioxane, methylene chloride, chloroform, diethyl ether, or their mixtures, and / or in the compound of the formula I, in which A is methylene, substituted by a group of the formula N-OR4, as a syn-isomer, where R 4. C-C-alkyl substituted by a carboxy group or a phosphono group, or C, -C4-alkenyl substituted by a carboxy group, is esterified to give a compound of formula I in which A is methylene, substituted by the group of the formula N-OR4, as syn isomers, where R C is -C-alkyl substituted by an esterified carboxy group or 0,0-di (C-C4-alksh1) phosphonogroup, or -alkenyl substituted by an esterified carboxy group, in an inert under the reaction conditions solvent, such as N, N-dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, or mixtures thereof, and / or in a compound of formula I, in which A is methylene, the substituted acylamino group cleaves the acyl moiety to obtain a compound of formula I, in which A is methylene, substituted by an amino group, in a solvent inert under the reaction conditions, such as water, methanol, ethanol, propanol, t-butyl alcohol, tetrahydrofuran, K, K-dimethylformamide, dioxane, methylene Oridi, chloroform, diethyl ether, or mixtures thereof, and the desired product vschel dissolved in free form or in pharmaceutically acceptable salt thereof.
Priority featured:
11.19.79 with R - aminothiazolyl, acylaminothiazolyl or a group of the formula
RaSOzNR
C-64 alkyl;
Ri tvj
a carboxy group or ethe R, a fixed carboxy group;
And - methylene, which can
have a substituent selected from the group comprising amino, acylamino, hydroxy, oxo, and a group of the formula rN - OR, in the form of syn-isomer, where R4 is a hydrogen atom, CyC-alkyl, Cj-C alkenele or Cr -With alkinnl. 08.02.80 with R-aminothiazolyl, cyclaminothiazolyl or a group of the formula
where RJ is C-C-alkyl;
R is a carboxy group or an esterified carboxy group; A is methylene, substituted by a group of the formula N - OR in the form of a synisomer, where R is C-Cj-alkyl, substituted by a carboxy group or an esterified carboxy group. 04/21/80 with R - amino-1,2,4oxadiazolyl or di (C-C-alkyl) aminomethylamino-1, 2,4-oxadiazolyl; R is a carboxy group or an esterified carboxy group; A is methylene which may have a substituent selected from the group consisting of amino, acylamino, hydroxy, oxo, and a group of the formula -N-OR, as a synisomer, where R4 is a hydrogen atom, Cj is C-alkenyl, C is C-alkyn or C-C-alkyl, which may be substituted with one or two substituents selected from carboxy, esterified carboxy, amino, acylamino or pyridyl; or R is aminothiazolyl, acylaminothiazolyl or a group of the formula
RSSOzT H
de RJ is C-C4 alkyl;
R is a carboxy group or an esterified carboxy group; A is methylene, substituted by a group of the formula N - OR, in the form of syn-isomer, where R i is alkyl, substituted by two substituents selected from carboxy, esterified carboxy, amino and acylaminogr: ppa or C —Cj-alkyl, substituted by pyridyl .
14.07.80 in case of R. - aminothiazole, chlorine-substituted amino-diadiazolyl, aminooxadiamol, in addition to amino-1, 2,4-oxadiazolyl, aminopyridyl, aminopyrimidinyl, acylaminothiazol | di (-alkyl) aminomethylamino-1, 2,4-oxadiazolyl, acylaminopyridyl, tristamine thiadiazolyl, di (,) alkylaminomethylphenamine thiazolyl or acylaminothiadiazolyl; R is a carboxy group or etherified carboxy group; isomers, where R is a hydrogen atom, C2, -C4-a kenyl, which may be substituted by a carboxy group or an esterified carboxy group, C 2 -C 4 alkynyl or C-C alkyl,: which may be substituted with one or two substituents selected from the carboxy group, etherified carboxy group, amino, acylamino, cyano, phosphono, 0,0-di (C-C-alkyl) phosphonogroup and pyrcidyl, or R, - aminothiazolyl amino1, 2,4-oxadiazole1) acylaminothiazolyl, di (C -C-alksh1) aminomethyleneamino-1, 2,4- oxadiazolyl or a group of the formula
RaSOaNH- p
de RJ - C-C-alkyl;
RJ is a carboxy group or sterified carboxy group; A is methylene, substituted by a group of the formula N - OR, in the form of a sinisomer, where R is alkenyl, substituted by carboxy group or esterified carboxy group, or C-C-alkyl, substituted by cyano, phosphono or 0,0di (-alkyl) phosphono group.
This invention relates to a method for producing new cephalosporin antibiotics, namely, Z-vinylcephalosporins, or their pharmaceutically acceptable salts, which have antimicrobial activity and can be used: in medicine as a medicine. A known method for producing 7-acylaminocephalosporins by acylation of 10 7-aminocephalosporin with the corresponding carboxylic acid or its reactive derivative CO. Cephalosporin antibiotics are known to have activity 15 against both gram-positive and gram-negative pathogenic microorganisms 2}. However, the production of new antibiotics of the cephalosporin series to combat strains of microorganisms resistant to the known cephalosporin antibiotics remains relevant. The aim of the invention is to obtain new cephalosporic antibiotics of a new series, possessing activity against a wide spectrum of microorganisms and high efficiency of action. This goal is achieved based on the known reaction of the reaction of 7-aminocephalosporins with carboxylic acids or their reactive derivatives by the method of obtaining the 3-vinylcephalosporins of the formula Rf-A-CCNH-jf, R where R is an aminothiazolyl, possibly substituted by chlorine, aminothiadiase olylaminoacetylylsilyl, aminothyladiol, aminothylazolealkylsilyl, aluminothiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, amino-thiazolyl, aminothiazolyl, aminooxylamine, amino-thiazolyl, amino-thiazolyl, possibly substituted by chlorine, aminothiadiase olylaminoylsilylsilyl, aminothiazolyl, aminothiazolyl, amino-thiazolyl, possibly substituted by chlorine; aminopyrimidinyl, amine tetrazolac acylaminothiazolyl, possibly substituted by chlorine, DlS-C alkyl) aminomethylenamine thiadiazolyl, di (C -C-alkyl)
aminomethylene aminooxadiazolyl, acylaminopyridyl, tritylaminothiadiazolyl,; tritylaminotetrazolyl or a group of the formula
RjSOzNH,
where R is —C — C — alkyl,
R2 is a carboxy group or an esterified carboxy group; A - methylene, which can.
have a substituent selected from the group comprising amino, acylamino, hydroxy, oxo, and a group of the formula - OR, in the form of syn-isomer, where R ,. - hydrogen atom, C5.-C-cycloalkenyl 5 C -C-alkynyl, C2-C4-alkenyl, substituted by carboxy group or esterified by carboxy-group Cj-C alkenyl, C-C-alkyl or C -C-alkyl, substituted by one or two substituents selected from the group comprising a carboxy group, an esterified carboxy group, an amino, acylamino, cyano, phosphono, 0,0-di (C, -C-alkyl) phosphono group and pyridyl,
or a pharmaceutically acceptable salt thereof, such that a compound of the formula
  .
. (P)
R2
wherein R, has the indicated meanings, or its reactive derivative in the amino group, or its salt, is reacted with a compound of the formula
R - A - COOH, (III) where R and A have the indicated meanings either with its reactive derivative at the carboxy group, or with its salt in a solvent inert under the reaction conditions, such as water, adeton dioxane, acetonitrile, chloroform, benzene, methylene chloride , ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, hexamethylphosphoramide, or mixtures thereof, and, if necessary, in a compound of formula I, in which Ri is acyl amino thiazolyl, possibly substituted by chlorine, di (C-C-alkyl) aminomethylene aminothiadiazole diazole; di (C-C-alkyl) aminomethylamino oxadiazolyl, achschlaminopyridyl, tritylaminothiadiazolyl
or tritylaminotetrazolyl, cleave an amino-protecting group to form a compound of formula I, wherein R is aminothiazolyl; possibly substituted by chlorine, aminothiadiazolyl,
5 aminooxadiazolyl, aminopyridyl or aminotetrazolyl, in an inert solvent under reaction conditions, such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydro-furan, N, N-dimethylformamide, dioxane, methylene chloride, chloroform, diethylmethylchloride, chloroform, N, N-dimethylformamide, dioxane, methylene chloride, chloroform, diethylmethyl formamide, dioxane, methylene chloride, chloroform, N, N-dimethylformamide, dioxane, methylene chloride, chloroform and / or in a compound of formula I, in which R2 is an esterified carboxy group,
5 cleaves the ester part to obtain a compound of formula I, in which R is a carboxy group, in an inert solvent under the reaction conditions, such as water, methanol,
0 ethanol, propanol, t-butyl
alcohol, tetrahydrofuran, N, N-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or a compound of formula I,
2 wherein i is a carboxy group, is esterified to obtain a compound of formula 1, wherein Rj is an esterified carboxy group, in an inert under reaction conditions solvent, such as N, N-dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, or mixtures thereof and / or in the compound of the formula I, in which A is methylene, substituted by a group
5 of formula -N - OR, j, in the form of syn-isomer, where RI is C-C-alkyl, substituted by esterified carboxy group or 0,0-di (C1-C4-alkyl) phosphonogroup, or C .;; - C4 The alkenyl substituted by the esterified carboxy group cleaves the ester part to give a compound of the formula I in which A is methylene substituted by a group of the formula -N-OR in the form of syn-isomer, where R4 is alkyl substituted by carboxygram or phosphonogroup, or Cj -C-alkenyl, substituted by a carboxy group, in
51
an inert solvent under the reaction conditions, such as water, methanol, ethanol, pronanol, tert-butyl alcohol, tetrahydrofuran, N, N-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or in the compound of the formula I, in which the esterified carboxy group R is C-C alkoxycarbonyl, substituted acylamino and etarified carboxy group, is cleaved off the acyl and ester parts to obtain the compound of formula I, in which the esterified carboxy group Rji is C -C alkoxycarbonyl, amino, and carboxy groups, in an inert solvent under conditions of the reaction, such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, N, Ndimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof and / or in a compound of formula I, in which A is methylene, substituted by a group of formula -N in the form of syn-isomer, where R is C-C-alkoxycarbonyl C, -C alkyl, substituted by acylamino and esterified carboxy or C -C-alkyl, substituted acylamino. and esterified with carboxy groups, the acyl and ester parts are cleaved to obtain a compound of formula I, in which A is methylene, substituted by a group of the formula - OR, as a syn-isomer, where R is C.-C, -alkoxycarbonyl is an alkyl substituted by an amino group and a carboxy group or C-C-alkyl, substituted by an amino group and a carboxy group, in a solvent inert under the reaction conditions, such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, N, N-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or in a compound of formula I, in which A is methylene, the group substituted with a group, ly N - OR, as a syn-isomer, where R.- C — C-alkyl, substituted by a carboxy group or for a Phono group, or C2-C-alkenyl, substituted by a carboxy group, is subjected etherification to obtain a compound of formula I, in which A is methylene, substituted by a group of the formula - OR4,
60876
in the syn-isomer, where R C is CJ alkln, substituted by etherified carboxy, or 0,0-di (
C4-alkyl). a phosphonogroup, or alkenyl, substituted with a stericized carboxy group, in an inert under the reaction conditions solvent, such as N, N-dimethylformamide, tetrahydrofuran, dioxane; methanol, ethanol or mixtures thereof, and / or in a compound of formula I, in which A is methylene, substituted by an acylamino group, the acyl moiety is cleaved to obtain a compound of formula I, in which A is methylene, substituted by an amino group, under inert conditions reactions with a solvent such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, H, M-dimethyl formamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and the desired product in free form or in the form of a pharmaceutically acceptable salt.
Antimicrobial activity of in vitro compounds:
(3-methanesulfonamidophenyl) -glycine-amino-3-3-vinyl-3-cephem-4-carboxylic acid — compound A; 30 (2-aminothiazol-4-Sh1) acetamido 3-vinyl-3-cephem-4-carboxylic acid - compound B;
(2-aminothiazol-4-yl) glycolamido 3-vinyl-3-cephem-4-carboxylic acid — compound C;
7- 2- (2-formamidothiazol-5-yl) acetamido-3-vinyl-3-cephem-4-carboxylic acid — compound D; 7-H2- (2-aminothiazol-6-sh1) acetamido 4Q 3-vinyl-3-cephem-4-carboxylic acid — compound E; (2-methanesulfonamidothiazol-5yl) acetamido 3-3-vinyl-3-cephem-4-carboxylic acid — compound F; 45 (2-guanvdinothiazol-4-yl) acetamido -3-vinsh1-3-cephem-4-carboxylic acid - compound G ;,
7-G2- (2-aminothiazol-4-yl) acetamido 3-vinyl-3-cephem-4-k. Arboxylic acid — compound H;
7-C2- (2-aminothiazol-4-yl) -2-methoxyimnoacetamido) -3-vinsh1-3-cefem-4carboxylic acid (syn-isomer) compound I;
55 7- 2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide-3-winnp-3-cephem-4carboxylic acid (syn-isomer) compound J; 711860 (2-aminothiazol-4-yl) -2-hexyloxyiminoacetamido} -3-vinyl-3-cephem4-carboxylic acid (syn-isomer).  compound K; 7-t 2- (2-aminothiazol-4-yl) -2- (L-2-5 amino-2-carboxyethoxycarbonylmethoxyimino) acetamndo-3-vinyl-ceph-4-carboxylic acid (synisomer) - compound L; (2-aminothiazol-4-yl) -2-carboxy-10 meth 6 xymino acetamido 3-vinyl-3 cephaem-4-carboxylic acid (syn.  isomer) - compound M; (2-amino-5-chlorothiazol-4-yl) -2carboxyl methoxyimino acetamido 1-3- 5 vinyl-3-cephem-4-carboxylic acid (syn-isomer) - compound N; (2-aminothiazol-4-yl) -2- (trans3-carboxyalyloxyimino) acetamido 3-vinyl-3-cephem-4-carboxylic acid (syn-isomer) - compound Oj (2-aminothiazole-4-sh1 ) -2- (3-carboxypropoxyimino) -acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer) - Compound P- was determined by twofold dilution on an agar plate.  One loop of the overnight culture of each test strain in Tripti casesoy broth (approximately 10 30 viable cells in 1 ml) was introduced into the grooves of the heart infusion agar (H1-agar) containing certain concentrations of antimicrobial agents, and the minimum inhibitory concentration of 35 was determined ( MlC) in units of µg / ml after incubation at 37 ° C for 20 hours.  The results of the determination of antimicrobial activity are presented in table 40.  1-3.  91 and blood samples were taken from the heart.  Antimicrobial levels for each serum sample were determined using a disk method using standard solutions prepared from rat serum.  The average serum level, mcg / ml after 1 h - 38.5; after 2 h - 34.9; after 4 h, 31.0; after 6 h - 28.8.  Protective effect in experimentally infected mice.  1.3 x Yu of pathogenic microorganism cells (Escherichia coli) suspended in 2.5% mucin are injected intraperitoneally to younger mice (ICR strain, 4 weeks old, weight 20.0 + 1.5 g).  One hour after the injection, compound A was orally administered.  For this group of minors for 4 days I was monitored for survival, and an effective dose of 480 mg was determined.  The compounds of formula I and their pharmaceutically acceptable salts are used in the form of conventional pharmaceutical preparations that contain these compounds as active ingredients in admixture with pharmaceutically acceptable carriers, such as organic or inorganic agents, or solid medicaments suitable for oral, parenteral and topical use.  Pharmaceutical formulations can be in a solid form, for example, tablets, granules, powders.  capsules, as well as in liquid form, for example, solutions, suspensions, syrups, emulsions, soft drinks, etc. d.  If necessary, these pharmaceutical preparations may include auxiliary substances, stabilizing and wetting agents, as well as other commonly used. additives such as lactose, magnesium stearate, white clay, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, macaw, chisel oil, olive oil, mahelo cocoa, ethylene glycol, etc. P.  ; The dosage of the compounds of the formula I depends on the age, the condition of the patient, the type of disease, the type of compound (I) to be administered, and so on. d.  (the daily dose is 1-4000 mg, the average single dose 7 may be 50.100, 250, 500, 1000 and 2000 mg).  Preparation of raw materials.  To a solution of eth2-2- (2-formamidothiazol-4) -2-methoxyiminoacetate (syn-isomer ,. 19 g) in methanol (200 ml), 200 ml of 50% formic acid and 29 g of zinc are added and the mixture is stirred at.  within 6 hours  After filtration, the reaction mixture is evaporated, followed by dissolving the residue in water (150 ml).  The resulting aqueous solution is treated with a 4% aqueous solution of sodium hydroxide to adjust the pH of the solution to 6.5, followed by the addition of ethanol (150 ml), 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (18.2 g) and triethylamine (8 g) .  After stirring at ambient temperature for 24 hours, the reaction mixture is filtered, followed by removal of the organic solvent.  The remaining aqueous solution is washed with ethyl acetate, adjusted to pH 4 with 10% hydrochloric acid solution and then extracted with ethyl acetate.  The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure to obtain. the residue that is washed with diethyl ether and get N-tert-butoxycarbonyl-2 (2-formamidothiazol-4-yl) glycine (3.3 g).  IR (Nujol): 3250, 3180, 1720, 1700, 1670, 1640, 1540, 1510.  Obtaining target compounds.  Example 1  To a solution of NT-butoxycarbonyl-2 (3-methanesulfonamidophenyl) -D-glycine 4.13 g) and triethylamine (1.2 g) in tetrahydrofuran (40 ml) a solution of ethyl chloroformate i (1.3 g) in tetrahydrofuran (4 ml ) at (-5) - (-4) s for 5 min followed by (. stirring at (-5) - for 1 h and get a solution of activated acid.  7-Amino-3-Vinyl-Zepham-4-carboxylate hydrochloride (4.3 g) and trimethylsilylacetamide (7.9 g) are added to ethyl acetate (50 ml) and the mixture is stirred for 5 minutes.  To the resulting solution is added a solution of the prepared activated. th acid and the mixture is stirred at (-30) 0 ° C for 2 h.  After addition of ethylacetate (150 ml) and water, the organic layer was separated.  The remaining aqueous solution was extracted with ethyl acetate, and the combined ethyl acetate solution was washed with saturated sodium bicarbonate solution and aqueous sodium chloride solution, dried over. the anhydrous magnesium sulfate is then evaporated.  The residue is washed with diethyl ether and collected by filtration.  7-K-tert-butoxycarbonyl-2-C 3-methanesulfonamidophenyl) B-glycinamido3-3-vinsh1-3-cephem-4carboxylate (5.3 g) is added.  The diethyl ether washings are evaporated to dryness and the same compound is isolated (0.7 g). Total yield 6.0 g.  IR (Nujol): 3340, 3280, 3250, 1790 1710, 1690, 1670, 1520 cm - NMR spectrum; /, ppm (DMSO-d): 1.37 (9H, S); 2.97 (3N, S); 3.65 (2H, q, Hz); 5.12 (1H, d, Hz); 5.15 (1H, S); 5.25 (1H, d Hz); 5.58 (1H, d, Hz); 5.78 (1H, dd, Hz, 8 Hz); 6.70 (1H, dd, Hz, 17 Hz); 6.93 (1H, S); 7.00-7.60 (14H, t); 9.20 (1H, d, Hz); 9.70 (1H, S).  Example 2  Through a suspension of 2- (3-methanesulfonamidophen l) -D-glycine (. 2.44 g) in methylene chloride (25 ml) gas is bubbled with hydrogen chloride at 5-10 ° C for more than 5 minutes.  After the addition of phosphorus pentoxide (3.1 g), the mixture was stirred at 010 ° C for 5 h.  The precipitated solid is collected by filtration, washed with methylene chloride (5 ml, dried to give a residue (2.7 g).  The residue was added to a solution of 7-amorphyl 3-vinyl-3-cephem-4-carboxylic acid (1.8 g) and trimethylsilylacetamide (6.3 g) in methylene chloride (30 ml) at -15 ° C and with stirring.   Stirring is continued at (-5) for 3 hours.  Water is added to the reaction mixture (30 ml and shaken.  After separation of the aqueous layer, the pH is adjusted to 5 with 20% sodium carbonate solution and evaporated to dryness under reduced pressure.  A residue is obtained which is chromatographed on a Diaion HP-20 non-ionic adsorption resin (120m. After washing with water, the residue is boiled with 30% isopropyl alcohol, the fraction containing the desired compound is collected, and the mixture is reduced under reduced pressure.  The resulting residue is lyophilized and (3-methanesulfonamidophenyl) -D-glycinamido-3-vinyl-3-cephem-4-carboxylic acid is obtained.  IR (Nujol): 3300-3150, 1760, 1685, 1605 cm - Example3.  To a suspension of benzhydryl-7-n-tert-butoxycarbonyl-2- (3-methanesulfonamidophenyl) -glycine-amido-3-vinsh I-3-cepha-4 carboxylate (5.0 g) in methylene chloride (50 ml) are added anisole (6.0 d) and trifluoroacetic acid (16.0 g) under ice cooling.  The mixture is stirred at ambient temperature for 1 hour.  After removing the solvent, ice water and ethyl acetate are added to the residue, followed by adjusting the pH to 2.5 with 10% hydrochloric acid solution.  After washing with ethyl acetate, the pH of the aqueous solution is adjusted to 6 with an aqueous solution of sodium bicarbonate, followed by removal of the organic solvent.  The pH of the polished aqueous solution is adjusted to 3.6 with 10% hydrochloric acid solution and then subjected to chromatography on a Diaion HP-20 non-ionic absorption resin column (Mitsubishi Chemical Indust. Reese Limited) (120 ml).  After washing with water (240 ml), it is eluted with 30% isopropyl alcohol (180 ml), the eluate is evaporated and lyophilized to obtain 7-C2- (3-methanesulfonamidophenyl) -D-glycinamido-3-V-vinyl-Ceph-4-carboxylic acid ( 1.4 g)  IR (Nujol): 3300-3150, 1760, 1685, 16. 05 cm  NMR spectrum, A) ppm (D. 0): 3.08 (3N, S); 3.47 (2H, S); 4.73 (1H, d, Hz): 5.10 (1H, d, Hz); 5.32 (1H, S); 5.33 (1H, d, Hz); 5, 63 (1H, d, Hz); 6.73 (1H, dd, Hz, 17 Hz); 7.33 (4H, S).  Example 4  To a solution of 7-C2 (3-methanesulfonamidophenyl) -D-glycinamido-3-vinyl-3-cephem-4-carboxylic acid (3.6 g) in water (50 ml) is added sodium bicarbonate (0.668 g ) and the solution is filtered.  The filtrate liofilizir one and get sodium 7-C2 (3-methanesulfonamidophenyl) -D-glycinamido-3-vinyl-3-cephem-4-carboxylate (3.69 g).  To the obtained compound (1.5 g) in N, N-dimethylformamide (15 ml) was added a solution of iodomethyl pivalate (0.76 g) BN, N-dimethylformamide (2 ml) under ice cooling and the mixture was stirred at the same temperature for 10 min-.  After addition of ethyl acetate (80 ml), the reaction mixture was alternately washed twice with water (80 ml), three times with an aqueous 5% sodium bicarbonate solution and then dried over anhydrous magnesium sulfate.  Removal of the solvent gives a residue which is crushed with diisopropyl ether and gives pivaloyloxymethyl- - 2- (3-methanesulfonamidophenyl) -D-glidinimido-3-3 vinyl-3-cepheme-f-carboxylate (0.61 g).   IR (Nujol): 1775, 1475, 1670 cm Example 5. To a solution of diketone (1.26 g) in carbon tetrachloride (12 ml) is added a solution of bromine (2.40 g) in carbon tetrachloride (3 ml) at (-30) - (-25) 0 and the mixture is stirred at this, temperature for 1.5 hours to obtain a solution of 4-bromoacetoacetyl bromide.  This solution is added dropwise to a solution of benzhydryl-7-amino-3-vinyl-3-cephem-4-car hydroxylate of boxylate (6.43 g) and trimethylsilylacetamide (7.82 g) in ethyl acetate (129 ml) at (-ZO) - (-10) 0 for 2 h.  Water and ethyl acetate are added to the reaction mixture, followed by separating the organic layer, which is washed with water, alternately with an aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated.  The resulting residue was diluted with a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml), thiourea (3.42 g) was added to this solution, followed by stirring at ambient temperature for 1 hour.  After the reaction mixture was mixed, water and ethyl acetate were added to the residue and then the pH of the solution was adjusted to 7 with sodium bicarbonate. The separated ethyl acetate layer was washed with an aqueous solution of nancy 8714 chloride and dried with anhydrous magnesium sulfate, evaporated under reduced pressure and the resulting mixture was obtained from 1-7-2- (2- amino-.  thiazol-4-yl) acetamido 1 -3-vinyl-3 cefem-4-carboxylate (6.89 g).  IR spectrum (Nujol): 1760, 1740, 1650, 1610 cm - NMR spectrum, {Г рт (DMSO-d): 3.47 (2H, wide S); 3.80 (2H, t); 5.27 (1H, d, Hz); 5.35 (1H, d, Hz); 5.68 (1H, d, Hz); 5.87 (1H ,.  dd, Hz, 8 Hz); 6.33 (1H, S); 6.85 TS, dd, Hz, 18 Hz); 6.93 (2H, t); 7.02 (1H, S); 7.43 (UN, S); 9.00 (1H, d, Hz).  Example 6  Pivalo-oxymethyl-7- (2-aminothiazol-4-1b) -acetamido 3-vinyl-3-cephem-4-carboxylate is prepared according to the procedure described in Example 5.  IR (Nujol): 1770, 1750, 1650 cm P RIM e p 7.  To a solution of benzhydryl-7-amino-3-vinyl 3-cephem-4-carboxyl 1 (1.9 g) hydrochloride and.  trimethylsilylacetamide (4.6 g) in ethyl acetate (30 ml) was added at -30 ° C an activated acid solution, which was prepared by stirring 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetic acid (syn-isomer) ( 1.1 g), phosphorus oxychloride (0.81 g), N, N-dimethylformamide (O, 39 g) and ethyl acetate (20 ml) for 1.5 hours while cooling. ice, the mixture is stirred at (-30) (-10) C for 1 h  After adding ethyl acetate (100 ml) and water (50 ml), the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to dryness.  2.4 g of benzhydryl-7-2 (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido3-3-vinyl-3-cephem-4carboxylate (syn-isomer) are obtained.  IR (Nujol): 3250.1780.17 ° J, 1700, 1660, 1540 cm.  NMR spectrum d, ppm (DMSO-dj): 3.78 (2H, m); 3.95 (3N, S); 5.30 (1H, Hz); 5.32 (1H, d, Hz); 5.66 (1H, d, Hz); 5.96 (1H, dd, Hz, 8 Hz); 6.82 (1H, dd, Hz, 17 Hz); 7.00 (1H. S); 7, 17-7.73 (1H, t); 8.57 (1. H, S); 9.80 (1H, d, Hz); 12.7 (1H, broad S).  15 Example 8.  Benzhydryl-7- 2 (2-formamidothiazol-4-Sh1) -2-allipox iminecetamido J-3-vinyl-3-cephem-4carboxylate (syn-isomer, 3.1 g) is obtained by the reaction of benzhydryl hydrochloride 7-amino-3- Vinyl-3-cephem-4-carboxyl (2.15 g) with 2- (2-formamidothiazol-yl) -2-allyloxyiminoacetic acid (syn-isomer, 1.53 g) according to the procedure described in Example 7.  IR (Nujol): 3250, 1760, 1690, 1660, 1530 cm t / NMR spectrum, cL, ppm (DMSO-d (,): 3.75 (2H, q, Hz); 4.65 (2H d, Hz); 5.00-6.3 (7H, t); 6.77 (1H dd, Hz, 18 Hz); 6.97 (1H, S); 7.17-7.63 (11H, t); 8.53 (1H, S); 9.78 (1H, d, Hz), 12.7 (1H, broad S).  Example 9  Benzhydryl-7- 2 (2-formamidothiazol-4-yl) -2-propargy oxyiminoacetamido-3-vinyl-3-cephem 4-carboxylate (syn-isomer, 1.3 g) is obtained by the reaction of benzhydryl-7-amino-3 hydrochloride -vinyl-3-cephem-4carboxylate (1.0 g) with 2- (2-formamidothiazol-4-yl) -2-propargyloxyiminoacetic acid (syn-isomer) (6.71 g) according to the method described in example 7.  IR (Nujol): 3250, 1780, 1720, 1690, 1660, 1550 cm NMR spectrum, (G, ppm (DMSO-d): 3.38 (1H, t); 3.82 (2H, q, .  Hz) 4.82 (2H, t); 5.33 (1H, d, Hz), 5.35 (1H, d, Hz); 5.55 (1H, d, Hz); 5.98 (1H, dd, Hz, 8 Hz); 6.85 (1H, dd, Hz, 18 Hz 7.02 (1H, S); 7.17-7.82 (Yu, t); 7.55 (1H, S), 8.62 (1H, S ); 9.80 (1H, d, Hz); 12.60 (1H, broad S).  Example 10  Benzhydryl-7C (2-formamidothiazol-4-yl) glyoxylamido-3-vinyl-3-cephem-4-carboxyl (6.1 g) is obtained by reaction of benzhydryl-7-amino-3-vinyl-hydroxycetamine-4-carboxylate hydrochloride ( 6.0 g) with (2-formamidothiazol-4-yl) glyoxylic acid (3.93 g) according to the procedure of Example 7, t. square  141144 With (decomposition) ,.  . .  / IR spectrum (Nujol) - 3150.1780.1720 1695, 1670, 1620, 1520 cm NMR spectrum, cG, ppm (DMSO-d {): 3.78 (2H, q, Hz); 5.33 (1H, d, Hz); 5.33 (1H, d, Hz); 5.68 (1H, d, Hz); 5.93 (1H, 87 dd, Hz, 8 Hz); 6.87 (1H, du Hz, 17 Hz); 7.00 (1H, S) j 7.20-7.67 (YN, t), 8.50 (1H, S), 8.63 (1H, S), 9.97 (1H, a, Hz) , 12.82 (1H, broad S).  The compounds of Examples 11-20 are prepared by the reaction of derivatives.  7-amino-3 vinyl cephalosporanic acid with the corresponding acid in accordance with the procedure described in example 7.  Example 11  (2-Aminothiazol-4-Sh1) acetamido-3-vinsh-3 cefem-4-carboxylic acid.  . IR (Nujol): 3260, 1760, 1650 cm.  Example 12  (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido 3-Z-vinyl-3-cephem-4-carboxylic acid hydrochloride (syn-isomer).  IR (Nujol): 3260, 1775, 1720, 1660, 1645, 1600, 1550 cm.  Example 13  (2-Aminothiazol-4-yl) -2-allyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer).  IR spectrum (Nujol): 3250, 1770, 1655, 1605, 1545 cm - Example 14, (2-Aminothiazol-4-yl) -2-proparGyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn- isomer).  IR (NuoL): 3250, PBO, 1680, 1620, 1530 cm - Example 15.  7- (2-Aminothiazol-4-yl) glyoxylamido-3-vinyl 3-cephem-4-carboxylic acid.  IR (Nujol): 3300, 32003100, 1780, 1660, 1610, 1520 cm Example 16.  Pivaloyloxymethyl-7- 2- (2-aminothiazol-4-yl) acetamido-3-vinsh-3-cephem-4-carboxylate.  IR (Nujol): 1770, 1750, 1650 cm Example 17.  Pivaloyloxymethyl-7- 2- (2-aminothiazol-4-yl) -2propargyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (sinisomer).  IR (Nujol): 1770, 1740, 1670 cm.  Example 18  Pivaloyloxymethyl-7-2- (2-aminothiazol-4-sh1) glyoxylamido-3-vinyl-3-cephem-4 carboxylate.  IR (Nujol): 1775, 1660, 1745 cm Example 19.  Hexanoyloxymethyl-7- 2- (2-amino-thiazol-4-yl) -2-proparoxyiminoacetamido-3 vinyl-3-cephem-4-carboxylate (sinisomer).  IR spectrum of Snuyol): 1770 1650 cm Example 20.  Hexanoyloxymethyl-7-G (2-aminothiazol-4-yl) glyoxylamido 3-3-vinyl-3-cephem-4-carboxylate.  IR (Nujol): 1770, 1660 cm Example 21.  To a solution of benzhydryl-7- 2- (2-aminothiazol-4-sh1 acetamido-3-vinsh-3-cephem-4-carboxyl silate (6.79 g) in methylene chloride (68 ml) is added trifluoroacetic acid (29.1 d) and anisole (11.02 g) at O C.  The mixture was stirred at ambient temperature for 65 minutes.  Then, the reaction mixture is quenched, ethyl acetate and water are added to the residue, followed by adjusting the pH of the solution to 7 with an aqueous solution of sodium bicarbonate.  The separated aqueous solution is treated with a 10% hydrochloric acid solution to adjust the pH to 3.0.  The precipitated substance is collected by filtration.  (2-Aminothiazol-4yl) acetamido-3-vinyl-3-cephem-4-carboxylic acid (1.88 g) is obtained, t. square  104 116С (decomposition).  IR (nujol): 3260, 1760, 1650 cm NMR spectrum, s, ppm (DMSO-d): 3.47 (2H, S); 3.77 (2H, q, Hz) 5, 18 (1H, d, Hz); 5.35 (1H, d, Hz); 5.62 (1H, d, Hz); 5.73 (1H, dd, Hz, 8 Hz); 6.33 (1H, S); 6.75-7.15 (2H, t); 6.98 (1H, dd, Hz, 18 Hz), 8.95 (1H, d, Hz).  Example 22  To a suspension of benzhydryl-7- 2- (2-h |) ormamidothiazolst) -2-methoxyiminoacetamido-3-vinyl 3-cephem-4-carboxylate (syn-isomer 2.3 g) in methylene chloride (40 ml) is added anisole ( 3.3 g) and trifluoroacetic acid (8.7 g) while stirring and cooling with ice.  Stirring is continued at ambient temperature for 75 minutes.  After evaporation of the reaction mixture, water is added to the residue and this acetate, followed by adjusting the pH to 7 with a saturated aqueous solution of sodium bicarbon. Ethyl acetate is added to the separated aqueous solution, the pH is adjusted to 2 with 10% hydrochloric acid.  The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and then evaporated to dryness.  The residue is washed with diethyl ether.  1.45 g of (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido 3-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer) are obtained.  IR spectrum (Nujol): 3250, 1770, 1690, 1650, 1540 cm - NMR spectrum, cL, ppm (DMSO-d): 3, 70 (2H, q, Hz); 3.88 (3N, S); 5.20 (1H, d, Hz); 5.30 (1H, d, Hz); 5.55 (JH, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 6.93 (W, dd, Hz, 18 Hz); 7.45 (1H, S); 8.52 (W, S); 9.73 (1H, d, Hz).  Example 23  7-G2- (2-Formamidothiazol-4-yl) -2-allyloxyiminoacetamido3-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer) is obtained by reacting 3 g of benzhydryl-7-C2- (2-formamidothiazol-4- (yl) -2-all-1-hsiminoate tamids-3-vinyl-3-cephem-4 carboxylate (syn-isomer) with 10.8 g of trifluoroacetic acid in the presence of 4.0 g of anisole according to the procedure described in example 22.  1.7 g yield .  IR (Nujol): 3250, 1770, 1680 (shoulder), 1650, 1530 cm-.  NMR spectrum, L, ppm (DMSO-d;): 3.67 (2H, q, Hz); 4.60 (2H, di Hz); 4.83-6.33 (7H, t); 6.90 (1H, dd, Hz, 18 Hz); 7.38 (1H, S); 8.48 (1H, S); 9.70 (1H, d, - Hz); 12.62 (IHj wide S).  Example 24  (2-Formamidothiazol-4-Sh1) -2-propargyloxyiminoacetamido-3-vinyl-3-cephem-4carboxylic acid is obtained by the reaction of 1.2 g of benzhydryl (2-formamidothiazol-4-Sh1) -2-proparcicioxyimoacetamido-Z-3-V-4-Sh1) -2-propane-4-Sh1-2-propamine-3-Sh) α-cephem-4 carboxylate (syn-isomer) with 4.4 g of trifluoroacetic acid in the presence of 1.7 g of anisole according to the procedure described in Example 2.  .  IR spectrum (Nujol): 3250, 1680, 1660, 1550 cm-NMR spectrum, L, ppm (DMSO-d): 3.52 (1H, t); 3.77 (2H, q,.  Hz); 4.80 (2H, ha); 5.27 (1H, d, Hz); five. 37 (1H, d, Hz), 5.62 (W, d.   Hz); 5.87 (1H, dd, Hz, 8 Hz); 7.00 (W, dd, Hz, 18 Hz) 7.50 (1H, S); 8.57 (W, S); 9.83 (1H, d, Hz); . 12.77 (1H, broad S).  Example 25  (2-Formamido thiazol-4-yl) glyoxylamido-3-vinyl 3-cephem-4-carboxylic acid (3.0 g is obtained by the reaction of benzhydryl-7- (2-formamidothiazol-4-yl) -glyoxy-1-amido 3-vinyl-3-cephem- 4-carboxylate (6.0 g) with trifluoroacetic acid (23.7 g) in the presence of anisole (9.0 g) in accordance with the procedure described in example 22.  NMR spectrum, cr, ppm (DMSO-dg): 3.75 (2H, q, Hz); 5.27 (1H, d, Hz); 5.37 (W, d, Hz); 5.63 (1H, d, Hz); 5.83 (1H, dd, Hz, 8 Hz); 7.00 (1H, dd, Hz, 17 Hz); 8.50 (1H, S); 8.65 (1H, S); 9, 93 (1H, d, Hz); 12.8 (1H, broad S).  The compounds of Examples 26-29 are prepared by reacting the benzhydryl ester of the corresponding derivatives of cephalosporanic acid with trifluoroacetic acid in the presence of anisole according to the procedure described in Example 22.  Example 26  (2-Aminothiazol-4-nl) -2-methoxyiminoacetamide 3-vinsh-3-cephem-4-carboxylic acid (syn-isomer).  IR (Nujol): 3260, 1775, 1720, 1660, 1645, 1600, 1550 cm.  Example 27  (2-Aminothiazol-4-yl) -2-allyloxyiminoacetamido3-3-vinsh-3-cephem-4-carboxylic acid (C1-isomer).  IR (Nujol): 3250, 1770, I655j 1605, 1545 cm - EXAMPLE 28.  (2-Aminothiaeol-4-Sh1) -2-propargyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer).  IR (Nujol): 3250, 1760, 1680, 1620, 1530 cm Example 29.  7- (2-aminothiazol-4-yl) glyoxylamido-3-vinyl 3-, cephem-4-carboxylic acid.  IR (Nujol): 3300, 32003100, 1780, 1660, 1610, 1500.  Example 30  To a solution of 1,4 (2-formamidothiazol-4-yl) -2 methoxyiminoacetamido-3-vinsh-3 cefem-4-carboxylic acid (synisomer) in 30 ml of methanol with concentrated tetrahydrofzfane is added concentrated hydrochloric acid (1.0 ml) and the mixture is stirred at ambient temperature for 2.7 h.  After evaporation of the reaction mixture, the residue is flushed with tetrahydrofuran and 1.2 g of hydrochloride 7- (2- (2-aminothiazol-4yl) -2-methoxyiminoacetamido-3-cinvinyl-3-cephem-4-car6anoic acid (syn-isomer) are obtained.  IR (nujol): 3260, 1775, 1720, 1660, 1645, 1600, 1550 cm NMR spectrum, eG, rrga (DMSO-d): 3.75 (2H, q, J 18 Hz); 4.00 (3N, S); 5.25 (1H, d, Hz); 5.35. (1H, d, Hz); 5.60 (1H, d, Hz); 5.80 (1H, dd, Hz, 8 Hz); 6.98 (1H, dd, Hz, 18 Hz); 7.02 (1H, S); 9.87 (W, d, Hz). , Example 31.  A mixture of 1.6 g (2-formamidothiazol-4-yl) -2-allyloxyiminoacetamido-3-cephem-4carboxylic acid (syn-isomer) and 1.5 ml of concentrated hydrochloric acid in 30 ml of methanol is stirred at ambient temperature for 2 h  After bleeding, a saturated sodium bicarbonate aqueous solution is added to the reaction mixture, followed by removal of the insoluble matter by filtration.  The filtrate is treated with a 10% hydrochloric acid solution to bring the pH to 3.  The precipitated solid is collected by filtration and washed with water.  1.25 g of (2-aminothiazol-4-yl) -2-allyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer) are obtained.  IR (Nujol): 3250, 1770, 1655, 1605, 1545 cm - NMR spectrum, cL, ppm (DMSO-d): 3.75 (2H, q, Hz); 4.67 (2H, t); 5.00-6.5 (7H,. t); 6.80 (1H, S); 7.00 (1H, dd, Hz, 18 Hz); 9.67 (1H, d, Hz).  Example 32  0.5 g of (2-aminothiazol-4-yl) -2-propargyloxyiminoacetamido-3-vinyl-3cephamome-4-carboxylic acid (syn-isomer) is obtained by the reaction of (2-formamidothiazol-4-yl) -2-propargyloxyiminoacetamido-3 -Vinyl-3-cephem-4-carboxylic acid (syn-isomer) with concentrated hydrochloric acid (0.5 ml) in a mixture of methanol (14 ml) 21 and tetrahydrofuran (4 ml) in accordance with the procedure described in example 31.  IR spectrum (1; uyol): 3250, 1760, l680, 1620, 1530 cm-.  NMR spectrum: L, ppm (DMSO-d f): 3.43 (1H, rt); 3.68 (2H, q, Hz) 4.7 (2H, ha); 5.17 (W, d, Hz); 2, 28 (1H, d, Hz); 5.53 (1H, d, Hz); 5.73 (1H, dd, Hz, 8 Hz), 6.83 (1H, S), 6.92 (1H, dd, Hz, 18 Hz); 9.67 (1H, d, Hz).  Example 33  7- (2-Aminothiazol-4-yl) glyoxylamido-3-vinyl 3-cephem-4-carboxylic acid (0.76 g) is obtained by reacting 7- (2fs rmidothiazol-4-yl) glyoxy-amido 3-vinyl-3-cefem- 4-carboxylic acid (1.23 g) with concentrated hydrochloric acid (1.25 ml) in a mixture of methanol (25 ml) and tetrahydrofuran (10 ml) in accordance with the procedure described in example 31.  IR spectrum (iuyol): 3300, 32003100, 1780, 1660, 1610, 1520 cm-.  NMR spectrum, (/ -, ppm (DMSO-dt): 3.80 (2H, q, Hz); 5.28 (1H, d, Hz); 5.42 (1H, d, Hz); 5, 63 (1H, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 7.05 (1H, dd,.  Hz, 18 Hz); 7.92 (1H, S); 9.58 (1H, d, Hz).  The compounds described in Examples 34-38 are prepared by reacting the corresponding cephalosporanic acid derivatives, having a formamido group, with concentrated hydrochloric acid in accordance with the procedure described in Example 31.  Example 34  Pivaloyloxymethyl-7 2- (2-aminothiazol-4-yl) -acetamido -3-vinsh1-3-cephem-4-carboxyl IR spectrum (Nujol): 1770, 1750, 1650 cmL Example 35.  Pivaloyloxymethyl-7- 2- (2-aminothiazol-4-yl) -2 propargyloxyiminoacetamido-3-vinyl Z-cephem-4-carboxylate (syn-isomer).  IR (Nujol): 1770, 1740, 1670 cm - Example 36.  Pivaloyloxymethyl-7- (2-aminothiazo 1-4-yl) -glyoxylamido 3-3-vinyl-3-cephem-4-carboxylate.  IR spectrum (Nujol); 1775, 1745, 1660 cm- 7 Example 37.  Hexanoyloxy-. TSh1-7- f 2- (2-aminothiazol-4-Sh1) -2propargyloxyminoacetamido: 1-3-winnp-cephem-4-carboxylate (syn-isomer).  IR (Nujol): 1770, 1650 cm - Example 38. . Hexanoyloxymethyl-7-G (2-aminothiazol-4-yl) -glyoxylamido 3-3-vinsh-3-cephem-4-carboxylate.  IR (Nujol): 1770, 1660 cm-. .  Example 39  Sodium (2-aminothiazol-4-yl) acetamido-3-vinsh3-cephem-4-carboxylate (1.36 g), which is obtained from (2-aminothiazol-4-yl) acetamido 3-3. -vinyl-3-cephem-4carboxylic acid (1.33 g) and sodium bicarbonate (0.304 g), dissolved in N, N-dimethylformamide (14 ml).  To this solution iodomethyl pivalate (0.932 g) in N, N-dimethylformamide (3 ml) is added under ice cooling, followed by stirring at the same temperature for 10 minutes.  After adding ethyl acetate (80 ml), the reaction mixture was alternately washed with water (twice), three times with a 5% aqueous solution of sodium bicarbonate and twice with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure.  The residue is pulverized with diisopropyl ether.  Pivaloyloxymethyl-7-p (2-aminothiazol-4-yl) acetamido-3-vinyl-3-cephem-4-carboxylate (1.0 g) is obtained, t. square  128-138 ° C (decomposition).  IR (Nujol): 1770, 1750, 1650 cm-.  NMR spectrum ,. (L, Rrga (DMSO-d): 1.18 (9H, S); 3.42 (2H, S); 3.80 (2H, q, Hz); 5.18 (1H, d, Hz); 5.40 (1H, d, Hz); 5.68 (1H, d, Hz); 5.77 (1H, dd, Hz, 8 Hz); 5.87 (2H, S); 6.30 (1H , S); 6.87 (2H, broad S); 6.88 (1H, dd, Hz, 17 Hz); 8.93 (1H, d, Hz), Example 40.  1.64 g of pivaloyloxymethyl-7- 2- (2-aminothiazol-4-yl) -2-propane-thioxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer) is obtained by the reaction of sodium (2-aminothiazol-4- or -2-propargyloxyiminoacetamido3-3-vinyl-3-cephem4-carboxylate (syn-isomer) (2 g) with iodomethylpivalgate (1.21 g) according to the procedure described in the reamer 39, t. square  163-185С (separation).
IR (Nujol): 1770, 1740, 1670
NMR spectrum, o, ppm (DMSO-d): 1.22 (9H, S); 3.5 (1H, S); 3.85 (2H, q,); 4.75 (1H, S); 5.35 (1H, d, Hz); 5.45 (1H, d, Hz); 5.70 (1H, d, Hz), 5.85 (1H, Yu dd, Hz, 8 Hz); 5.92 (2H, S); 6.87 (1H, S); 6.88 (1H, dd, Hz, 18 Hz); 7.32 (2H, ha); 9.73 (W, d, Hz).
Example 41. Pivaloyloxy- 15 methyl-7-C (2-aminothiazol-4-yl) -glyoxylamido-3-vinyl-3-cephem-4-carboxylate (0.94 g) is obtained by reacting sodium 7- (2-aminothiazole 4-yl) glyoxylamido-3-vinyl-3-cephem-4-carboxylic acid (1.05 g) with iodomethyl pivalate according to the procedure described in Example 39, mp. 108115 ° C.
IR (Nujol): 1775, 1746, 25 1660 cm-
NMR spectrum, L, ppm (DMSO-d,): 1.12 (9H, S); 3.75 (2H, t); 5.22 (1H, d, Hz); 5.38 (W, d, Hz); 5.67 (1H, d, Hz); 5.78 (1H, 30 d, Hz, 8 Hz); 5.83 (211, S); 6.85 (W, dd, Hz, 18 Hz); 7.35 (2H, broad S); 7.83 (W, S); 9.80 (1H, d, Hz).
Ex 42 a solution of iodomethylhexanoate 40 (1.28 g) in N, N-dimethylformamide (4.0 ml) under ice cooling. The mixture is stirred at the same temperature for 15 minutes. Ethyl acetate (80 ml) 45 was added to the reaction mixture, followed by washing twice with water, three times with a 5% aqueous solution of sodium bicarbonate and twice with a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate and then evaporated to a residue, which was powdered with diisopropyl ether.
1.85 g of hexanoyloxymethyl 7-C2- (2-aminothiazol-4-yl) -2-proparo-55yloxyiminoacetamido-3-winsh-3 cefem-4-carboxylate (syn-isomer) are obtained, m.p. 98-109 C (decomposition).
IR (Nujol): 1770, 1650 cm-.
NMR spectrum, G, ppm (DMSO-d): 0.87 (3N, t, Hz); 1.38 (6H, t); 2.53 (2H, t); 3.47 (1H, S); 3.80 (2H, q, Hz); 4.72 (2H, S); 5.27 (1H, d, Hz); 5.42 (1H, d, Hz); 5.70 (1H, d, Hz); 5.88 (3N, m); 6.80 (1H, S); 6.80 (1H, dd, Hz, 18 Hz); 7.25 (2H, broad S); 9.70 (1H, d, Hz).
Example 43 Hexanoyloxymethyl-7-G (2-aminothiazol-4-yl) -glyoxylamido H-3-vinyl-3-Cephem-4-carboxylate (0.96 g) is obtained by reacting sodium 7-C (2-aminothiazol-4 -Shl) glyoxy-amido-3-vinyl-3-cephem-4-carboxylate (1.05 g) with iodomethylhexanoate (0.666 g) according to the procedure described in example 42, mp. 89-84 S.
IR spectrum, (Nujol); 1770, 1660 cm.
NMR spectrum, J, ppm (DMSO-d): 0.82 (3N, S); 1.30 (6H, m), 2, 30 (2H, t, Hz); 3.77 (2H, m); 5.22 (1H, d, Hz); 5.37 (W, d, Hz); 5.68 (1H, d, Hz); 5.77 (1H, dd, Hz, 8. Hz); 5.83 (2H, S); 6.88 (1H, dd, Hz, 18 Hz); 7.37 (2H, t); 7.83 (1H, S); 9.78 (1H, d, Hz).
Example 44. To a solution of benzhydryl-7-amino-Zvinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) and 2,6-lutidine (1.08 g) in methylene chloride (60 ml) is added -2- (2-formamidothiazol4-yl) glycine (3.0 g) and N, N-dicyclohexylcarbodiimide (2.06 g) with ice-cooling and stirring. Stirring is continued at the same temperature for 1 hour and at ambient temperature for another 3.5 hours. After adding methylene chloride (100 ml), the reaction mixture is washed with dilute hydrochloric acid, followed by removal of the precipitated material by filtration. The filtrate is washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, then evaporated to give a residue, which is triturated with dithyl ether.
251
Get 7-CN-TpeT-6yTOKCHKapDoil-2 (2- | rmamidothiazol-4-yl) -glycinamido-3-vinyl-3-cephem-4-carboxylate (5.7 g)
IR (Nujol): 3280, 1780, 1720, 1660, 1630, 1540 cm-.
NMR spectrum, cG, ppm (DMSO-di): 1.39 (9H, S); 3.65 (2H, q, Hz) 5.10 (1H, d, Hz); 5.19 (1H, S); 5.22 (1H, d, Hz); 5.59- (1H, d, Hz); 5.74 (1H, dd, Hz, 8 Hz); 6.68 (1H, dd, Hz); 6.93 (1H, S); 7.00-7.70 (12H, t); 9.24 (1H, d, Hz).
Example 45 Benzhydrsch1-7Cm-trg. T-butoxycarbonyl-2- 2- (2, 2, 2-trifluoroacetamido) thiazol-4-yl glycinamido. 1-3-vinyl-3-cephem-4-carboxlnat (4.1 d) is obtained by the reaction of be113 shchril-7-amino-3-vinyl-3-cephem4-carboxylate (3.4 g) with N-tertbutoxix1pO 1-2C2- (2, 2, 2-trifluoroacetamido) thiazol-4-yl glycine (3 , 3 g) in accordance with the procedure described in example 44.
IR (Nujol): 3270, 1780, 1720, 1670, 1560 cm-,
NMR spectrum, cL, rrga (DMSO-d): 1, 43 (9H, S); 3.77 (2H, t); 5.136, 0 (5H, t); 6.82 (1H, dd, Hz, 18 Hz); 7.00 (1H, S); 7, 107, 70 (11I-I, t); 9.27 (W, d, Hz)
Example 46. To suspension: benzhydryl-7-H-tert-butoxycarbonyl-2- (2-aminothiazol-4-yl) glycine odoj-3-vinyl-3-cethem-4-carboxy-III (3.9 g) in methylene chloride ( 20 ml) trifluoroacetic acid (13.7 g) and anisole (3.8 g) were added with ice cooling. The mixture was stirred at ambient temperature for 1 hour. After evaporation of the reaction mixture, water (100 mp) and ethyl acetate were added to the residue, followed by adjusting the pH of the solution to 7 with 2% aqueous sodium hydroxide solution. The precipitated solid is removed by filtration and the aqueous layer is separated. Ethyl acetate is added thereto, followed by adjusting the pH to 4 with 10% hydrochloric acid. After separation of the aqueous layer, the organic solvent is completely removed by evaporation and the pH of the resulting aqueous solution is adjusted to 4 with 10% hydrochloric acid solution with cooling followed by chromatography on non-ionic absorption
608726
Diaion HP-20 resin (120 ml). After washing with water, elution with 10% isopropyl is carried out. alcohol, then 30% isopropyl alcohol. The fractions containing the desired compound are collected, extruded under reduced pressure and the residue is lyophilized to obtain (2-aminothiazole 4-br1) glycinamido-3-vinyl-3-cephem-4carboxylic acid (0.8 g).
IR (Nujol): 3400-3100, 1760, 1670, 1610, 1520 cm
NMR spectrum, “L, rta (Dj O + NaHCO,):
5 3.68 (2H, broad S); 5.08 (1H, S); 5.08 (1H, d, Hz); 5.25 (1H, d, Hz), 5.40 (1H, d, Hz); 5.70 (1H, d, Hz); 6.73 (1H, S); 6.80 (1H, dd, Hz, 18 Hz).
 Example 47. A mixture of benzhydropyl-7 N-tert-bytoxycarbonyl-2- (2formamidothiazol-4-yl) glycinamido J-3 vinyl-3-cephem-4-carboxylate (5.6 g) and concentrated hydrochloric acid (2.6 ml) in methanol (60 ml) and tetrahydrofuran (15 ml) is stirred at ambient temperature for 2.5 hours. The precipitated substance is collected by filtration and
0 washed with a mixture of methanol and water (1: 2 by volume), and then with water, followed by drying ..
The benzhydryl-7-M-tert-butoxycarbonic-1-2- (2-aminothiazol-45 yl) -glncynamido 3-vinyl-3-cephem-4carboxylate (0.4 g) is obtained.
IR (Nujol): -3300, 1770, 1710, 1650, 1620, 1570, 1510 cm-. NMR spectrum, s, ppm (DMSO-dj):
Q 1.40 (9H, S); 3.67 (2H, broad S); 5.00-6.00 (511, t); 6.47 (1H, S); 6.97 (1H, S); 6.67-7.67 (12H, ha); 9.00 (1H, ha).
Example 48. A mixture of benzhyd5 ryl-7-Cm-tert-butoxycarbonyl-2-C2 (2,2,2-trifluoroacetamido) thiaeol-4yl glycine-amino 3-3-vinyl-3-cephem-4carboxylate (2.5 g) and sodium acetate (2.8 g) in tetrahydrofuran
0 (20 ml), acetone (20 ml) and water (40 ml) were stirred at ambient temperature for 2 hours. After evaporation of the reaction mixture, the residue was extracted with ethyl acetate.
5 The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, then evaporated to give a residue, which is chromatographed on silica gel (50 g). Elution is carried out with methyl chloride and a mixture of methylene chloride and diethyl ether (9: 1 by volume). The fractions containing the desired compounds are collected and evaporated. Benzhydryl-7-N-tert-butoxycarbon-1-4-sh1) glycinamido-3 vinyl-3-cephem-4-carboxylate (1.0 g) is obtained: IR spectrum (Nujol): 3300, 1770, 1710, 1650, 1620, 1570, 1510. Example 49. To a solution of 7- (aminothiazol-4-yl) glyoxylamido-3 vinyl-3-cephem-4-carboxylic acid (2.35 g) in methanol (100 ml) was added sodium borohydride (0.34 g) at 5 - (-10) and the mixture is stirred at this temperature for 5 minutes. After the pH of the reaction mixture is adjusted to 10 with 10% hydrochloric acid, the methanol is removed by melting and the pH is adjusted. solution to 5 with 10% hydrochloric acid solution and subjected to chromatography on a non-ionic absorption resin (Diaion HP-20 (70 ml). After washing with water (140 mp), elution is carried out with a 30% solution of isopropyl alcohol (140 -ml) and collecting the fractions containing the desired compounds. After removing the isopropyl alcohol, the remaining aqueous solution is lyophilized. 7- {2- (2-aminothiazol-4yl) -D-glycolimide J-3-vinyl-3-cepheme 4- is obtained. carboxylic acid (2.01 g). IR spectrum (Nujol): 1755, 1650 cm NMR spectrum, cA, ppm (DMSO-d): 3.48 (2H, t); 3.83 (1H, broad S ); 4.83 (W, S); 4.98 (LN, d, Hz); 5.2 (1H, -d, Hz); 5.47 (1H, d, v); 5.5-5.53 (1H, dd, Hz, 8 Hz); 6.37 (W, S); 6.85 (2H, t); 7.07 (1H, dd,. Hz, 18 Hz; 8, 17, 8.27 (1H, d, Hz). Example 50. 7-C2- (2-Aminothiazol-4-yl) glycinamido-3-vinyl-3 cefem-4-carboxylic acid is obtained by reaction 7 -amino-3-vinyl-3-cephem-4carboxylic acid with 2- (2-aminothiaz) glycine according to the method described in example 2. IR spectrum (Nujol): 3400-3100, 1760, 1610, 1520 cm - Example 51. A mixture of 2- (2-meta. Sulfonamidothiazol-4-yl) acetic acid (2.6 g), N, N-dimethylformamide (0.88 g) and phosphorus oxychloride, 85 g) in ethyl acetate (10 ml; and tetrahydrofuran (20 ml) is stirred under cooling ice for 30 minutes This solution is added to a solution of benzhydryl-7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) and trimethylsilylacetamide (7.9 g) in ethyl acetate (50 ml) at and Stirring is continued at (-20) for 2 hours. After adding water, tetrahydrophzfane and ethyl acetate, the reaction mixture is adjusted to pH 7 with a saturated aqueous bicarbonate solution. sodium sodium. The precipitated substance is collected by filtration. Benzhydryl-7-G2- (2-methanesulfonamidothiazol-4-yl) acetamido 3-vinyl-3-cephem-4-carboxylate is obtained (3.6 g). After adding ethyl acetate and tetrahydrofuran to the filtrate, the organic layer is separated, washed with an aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, followed by titration to obtain the same product (0.9 g). Total yield 4.5 g. IR (nujol): 3250, 1700, 1650, 1610, 1600 NMR spectrum, eL, ppm (DMSO-dg): 2.88 (3N, S); 3.75 (2H, q, Hz); 5.20 (1H, d, Hz), 5.23 (1H, d, J-11 Hz); 5.62 (1H, d, Hz), 5.77 (W, dd, Hz, 8 Hz), 6.51 (1H, S); 6.74 (1H, dd, Hz, 17 Hz); 6.94 (1H, S); 7,107, 54 (UN, t); 9.22. (1H, d, Hz). I Example 52. Benzhydryl-7-C2 (2-formamidothiazol-5-yl) acetamido-3 vinyl-3-cephem-4-carboxylate (11.48 g), mp. 173C (decomposition) is obtained by reacting benzhydryl-7-amino-3-vinyl-3-cephem-4-carboxylate chlorohydrate. (10.3 g) with activated acid, which is obtained from 2- (2-formamidothiazol-5-yl) acetic acid (C5.4 g), N, N-dimethylformamide (2.56 g) and phosphorus oxychloride (5.34 g), in the usual way - as described in Example 51. IR spectrum (Nujol): 3270, 1770, 1715, 1680 cm - NMR spectrum, CL, Ppm (DMSO-dj): 3.78 (2H, S); 3.79 (2H, q, Hz); 5.24 (W, d, Hz); 5.3-6.0 (3H, m); 6.5-7, 1 (1H, m); 6.87 (1H, S);
G, 2-7.7 (11P, m); 8.46 (1H, S); 9, 23 (1H, d, Hz).
When ep 53. Activated acid obtained in the usual way from 13.8 g of 2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazol4-yl) acetic acid (syn-isomer), N, N-dimethylformamide (3.66 d) and phosphorus oxychloride (7.7 g) in tetrahydrofuran (80 ml) are added to the solution of benzhydryl hydrochloride 7-amino-Zvinyl-3-cephem-4-carboxylate (15 p) and trimethylsilylacetamide (32 g) in ethyl acetate (150 ml) while stirring. Stirring is continued at the same temperature for 30 minutes. After water was added (100 ml), the ethyl acetate layer was separated and washed alternately with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and then with an aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent is removed by removing the oil, which is washed with diisopropyl ether.
23.1 g of benegryl-7-2t-butoxycarboxymetoxyimino-2 (2-formamidothiazol-4-yl) acetamido 3-vinyl-3-cephem-4-carboxylate (synisomer) are obtained, mp. (decomposition).
IR (Nujol): 3250, 1780, 1720, 1680, 1540 cm
NMR spectrum, cf; ppm (DMSO-d 4): 1.45 (9H, S); 3.77 (2H, q, J-18 Hz); 4.64 (2H, S); 5.32 (1H, d ,. Hz); 5.2-6.0 (2H, t); 5.97 (W, d, Hz, 8 Hz); 6.5-7.6 (1H, t); 6, 98 (1H, S); 7.2-7.8 (11H, t); 8.55 (1H, S); 9.68 (1H, d, Hz) .; 12.71 (1H, broad S).
Example 54. To a suspension of 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) in methylene chloride (100 ml) are added 2, b-lutzcin (1.08 g) with and stirred. To the resulting solution were added 2- (2-methanesulfonamidothiazol-5-III) acetic acid (2.6 g) and dicyclohexylcarbodiimide (.06.06 g) with ice-cooling and stirring. Stirring is continued at the same temperature for 1 hour and then at ambient temperature for another 3.5 hours. After adding water, the precipitated substance is removed by filtration. The filtrate is washed with 10% hydrochloric acid solution, the organic layer
is separated and washed with acetic acid water, with a saturated sodium bicarbonate solution and with an aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. After removal of the solvent, a residue is obtained which is washed with diethyl ether. Benzhydryl-7-C2- (2-methanesulfonamidothiazol-5-yl) acetamido-3-vinyl-3-cephem-4-carboxylate (1.8 g) is obtained. The same product (1.8 g) was extracted from the washing solutions. Total yield 3.6 g
IR (Nujol): 3320, 1770, 5 1710, 1660, 1620, 1570, 1520 cmH
NMR, ppm (DMSO-d,): 2.90 (3N, S); 3.67 (2H, in); ;. 5, 22 (1H, d,); 5.30 (1H,
d, J 1fHz); 5.62 (1H, d, Hz); 5.77 (1H, dd, Hz, 8 Hz); . 6.75 (1H, dd, Hz, 17 Hz); 6.95 (1H, S); 7.03 (1H, t); 7.177, 60 (UN, tp); 9, 15 (1H, dd, Hz, 8 Hz).
The following compounds are prepared by reacting 7-amino-Zvinyl-cephalosporanic acid derivatives with the corresponding acids according to the procedure described in Example 53. 0 EXAMPLE 55 7-C2- (2-Aminothiazol-5-yl) acetamido1-3-vinyl-Zepham-4-carboxylic Acid.
IR (Nujol): 3550, 3280, 1725, 1650, 1540. 5 Example 56. Hexanoyloxymethyl-7-2- (2-aminothiazol-4-yl) acetamido-3-vinyl-3-cephem-4-carboxol.
IR (Nujol): 3250, 1765, H 1655 cm-. .
j EXAMPLE 57 Phthalide-3-yl-7H2- (2-aminothiazol-4-sh1) acetamido J3-vinyl-3-cephem-4-carbox-1.
IR (Nujol): 3250, 1780, 5 1760, 1650 cm
Example 58 7-C2- (2-Hydrobromide, gaunidinothiazol-4-yl) acetamido-3-vinyl-3-cephem-4-carboxylic acid ...
0IR spectrum (Nujol): 3400-3100,
1760, 1680, 1660, 1620, 1540 cm
Example 59. Phthalide-3-yl 7- (2-aminothiazol-4-yl) glyoxyl. amido-3-vinyl-3-cephem-4-carbox-1, 5 IR spectrum (Nujol): 3300, 1770, 1650 cm-.
Example 60 Pivaloyloxymech1-1-7- 2- (2-aminothiazol-4-yl) -2-. 31 methoxyimino-acetamido 3-3-vinyl-Zepham-4-carboxylate (syn-isomer). IR (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530. See Example 61. Phthalide-3-yl-7 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3- vinyl-3-cephem-4carboxylate (syn-isomer). IR spectrum (Nujol): 3300, 1775, 1670, 16.10, 1530 cm; Example 62. Benzhydryl-7112- (2-aminothiazol-4-Sh1) -2-tertbutoxycarbonylmethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxyl (syn-isomer). IR (Nujol): 3440, 3260, 3100, 1780, 1720, 1660, 1530. Example 63. A mixture of (2-formamidothiazol-5-yl) acetamido-3-vinyl-3-cephem-4-carboxylic acid (4.67 g) and concentrated saline (4.67 g) in methanol (93 ml and tetrahydrofuran (46 ml) stirred for 4 hours. After removal of the organic solvent, water (70 ml) was added to the residue, followed by adjusting the pH to 6-7 with 10% sodium hydroxide aqueous solution. The insoluble matter was removed by filtration, the filtrate was treated with 10 % hydrochloric acid solution with cooling to bring the pH to 3, followed by stirring at the same temperature in t 20 min. The precipitated substance is collected by filtration, washed with water, dried and a residue is obtained, which is dissolved in an aqueous solution of sodium bicarbonate and then chromatographed on silica (12 ml), using a 5% aqueous solution of sodium acetate-sodium as eluant The fractions containing the desired compound are collected and acidified with 10% hydrochloric acid until pH 3.1. The precipitated substance is collected by filtration and dried. (2-Aminothiazol-5yl) acetamido-3-vinyl-3-cephem-4carboxylic acid is obtained. (1.52 g), m.p. 290C. IR spectrum (Nujol) :. 3550, 3280, 1725, 1650, 1540 sy NMR spectrum, cL, ppm (DMSO-d): 3.53 (2H, S); 3.70 (2H, q, Hz) 5.12 (1H, d, Hz); 5.2-5.8 (2H, sh 5.67 (1H, dd, Hz, 8 Hz); 7 6.73 (1H, S); 6.7-7.4 (1H, t)} 9, 07 (1H, d, Hz). Example 64. A mixture of 19 g of benzhydryl 7-C2-tert-butoxycarboni .. methoxyimino-2- (2-formamidothiazol-4-yl) acetamido 3-3-vinyl-3-cephem-4carboxylate (syn-isomer) and 11.6 g of concentrated hydrochloric acid in methanol (380 ml) are stirred at ambient temperature for 15 minutes. After adding water (200 mp), the reaction mixture is neutralized with sodium bicarbonate, followed by removal of methanol under reduced pressure. The resulting aqueous solution is extracted three times with ethyl acetate and the combined the extract is washed with water and an aqueous solution of sodium chloride, then dried over anhydrous magnesium sulphate. After removing the solvent, an oil is obtained, which is washed with diisopropyl ether. 15.3 g of benzhydryl-7-2 (2-aminothiazol-4-yl) -2-tert are obtained. -butoxycarbonylmethoxyiminoacetamido Z-vinyl-Z-cephem-4-carboxylate (syn-isomer). IR spectrum (Nujol): 3440, 3260, 3100, 1780, 1720 1660, 1530 cm. NMR spectrum, tf, ppm (DMSO- d): 1.44 (9H, S); 3.77 (2H, q, Hz); 4.58 (2H, S); 5.29 (1H, d, Hz); 5.1-5.9 (2H, t); 5.90 (1H, dd, Hz, 8 Hz); 6.5-7.8 (13H, t); 6.83 (1H, S); 6.93 (1H, S); 9.56 (1H, d, Hz). The following compounds are obtained by reacting 7-acylamino-3-vinylcephalosporanic acid derivatives having formamido groups with hydrochloric acid in accordance with the procedure. described in example 64. Example 65. Hexanoyloxymethyl-7-C2- (2-aminothiazol-4-yl) acetamido -3-vinyl-3-cephem-4-carboxylate. IR spectrum (Nujol): 3250, 1765i 1655. cmL Example 66. Phthalide-3-yl-7 2- (2-aminothiazol-4-yl) acetamido-3 vinyl-3-cephem-4-carboxyggat, IR spectrum ( Nujol): 3250 1780, 1760, 1650 cm Example 67. Phthalide-3-yl-7, (2-aminothiazol-4-yl) glyoxynpamidod3-vinyl-3-cephem-4-carboxylate.
331
IR (Nujol): 3300, 1770, 1650 cmL
Example 68 Pivaloyloxymethyl-7-C2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido J-3-vinyl-Zeph-4-carboxylate (syn-isomer).
IR (Nujol): 3400-3100, 1770, 1745 ,. 1670, 1610, 1530.
Example 69 Phthalide-3-Sh1-7C2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido3-3-vinyl-3-cephem-4carboxylate (syn-isomer)
IR (Nujol) .: 3300, 1775, 1670, 1610, 15.30 cm-
Example 70. 7-C2- (2-Aminothiazol-4-yl) -2-carboxymethoximinoacetam-3-vinyl-3-cephem-4carboxylic acid. (Syn-isomer).
IR (Nujol): 3350, 1770, 1680, 1640 cm-.
Example 71. Pivaloyloxymethyl-7-C2- (2-aminothiazol-4-yl) B-glycolamido-3-vinyl-3-cephem-4carboxylate.
IR (Nujol): 3370, 1780, 1750, 1680, 1620 si
Example 72 Phthalide-3-yl-7 2- (2-aminothiazol-4-yl) -bb-glycolamido 3-3-vinyl-3-cephem-4-carboxylate
IR (Nujol): 1770, 1740, 1660, 1610 cm.
Example 73. To a suspension of benzhydryl-7- 2- (2-methanesulfonamvdothiazol-4-Sh1) acetamido-3-vinyl 3-cephem-4-carboxylate (4.5 g) in methylene chloride (30. Ml) and anisole (4.6 d) 2,2,2-trifluoroacetic acid (16.8 g) is added under ice cooling and the solution is stirred at ambient temperature for t hours. After evaporation of the reaction mixture, water and ethyl acetate are added and the pH is adjusted to 7 with 1N. aqueous solution of sodium hydroxide. Ethyl acetate and tetrahydrofuran are added to the separated aqueous layer, followed by adjusting the pH to -2 with 10% hydrochloric acid solution.
The organic layer is separated and washed with an aqueous solution of sodium chloride, then dried over anhydrous magnesium sulphate. After removing the solvent, a residue is obtained which is washed with diethyl.
7-t2- (2-methanesulfonamvdothiazol-4-Sh1) acetamido-3-vinylZ-cephem-4-carboxylic acid (1.5 g) is obtained
608734.
IR (Nujol): 3260, 3140, 3080, 1770, 1700, 1660, 1610, 1540 cm.
NMR spectrum, G, ppm (DMSO-dt): 5 2.88 (3N, S): 3.53 (2H, S); 3.72 (2H, q, Hz); 5.13 (1H, d, Hz); 5, 30 (1H, d, Hz); 5.57 (W, d,. Hz); 5.68 (1H, d, 8 Hz); 6.50 (1H, S); 6.95 (W, dd ,, 10 Hz, 18 Hz); 9.07 (1H, d, Hz).
Example 74. 7-C2- (2-Methanesulfonamidothiazol-5-Sh1) acetamido-3 vinyl-3-cephem-4-carboxylic acid (2.1 g) is obtained by the reaction of benzhydryl15 (2-methanesulfonamidothiazole-5yl) -acetamido 3-vinyl -3-cephem-4carboxylic acid (3.6 g). With 2.2.2 trifluoroacetic acid (13.2 g) in the presence of anisole (3.7 g) according to the procedure described in Example 73.
IR (Nujol): 3250, 3110,, 1770, 1705, 1660, 1560, 1530 cm
NMR spectrum, cG, ppm (DMSO-d): 25 2.88 (3H, S): 3.58 (2H, S); 3.68 (2H, q, Hz); 5.13 (1H, d, Hz); 5.32 (1H, d, Hz); 5.56 (1H, d, Hz); 5.68 (1H, dd, Hz, 8 Hz); 6.95 (1H, dd, 30 Hz, 18 Hz); 7.07 (W, S); 9.20 (1H, d, Hz).
The following compounds are prepared by reacting 7-acylamino-Zvinyl cephalosporanic acid derivatives having benzhydryl ether with 2,2,2 trifluoroacetic acid in the presence of anisole in accordance with the procedure described in Example 73.
Example 75. 7-C2- (2-Amino 40 thiazol-5-yl) acetamido3-3-vinyl-3 cefem-4-carboxylic acid.
IR (Nujol): 3550, 3280, 1725, 1650, 1540 cm
Example 76. Hydrobromide (2-guanidinothiazol-4-yl) acetamido-3 vinyl-3-cephem-4-carboxylic acid.
IR (Nujol): 3400-3100, 1760, 1680, 1660, 1620, 1540 cm-V
Example 77. To a suspension of 50 benzg, idrSh1-7-C2- (2-formamido-thiazol5-yl) acetamido-3-vinsh1-3-cephem-4carboxylate (11.48 g) in methylene chloride (57.4 ml) and anisole (15 ml) was added 2,2,2-trifluoroacetic acid 55 (46 ml) while cooling with ice and the mixture was stirred for 15 minutes. The reaction mixture is poured into diisopropyl ether (600 ml) and stirred under ice cooling for 20 minutes. The insoluble matter is collected by filtration and washed with diisopropyl ether. This substance (11.4 g) is suspended in water (150 ml), adjusted to pH 2 with a 10% hydrochloric acid solution, the precipitate is collected by filtration, washed with water and dried. Receive (2-formamidothiazole 5-SH1) acetamido-3-vinyl-3-cephem-4carboxylic acid (5.88 g), so pl. 200s (decomposition). IR (Nujol): 3260, 3220, 3050, 1780, 1750, 1670, 1540 cm. NMR, cG, ppm (DMSO-dt): 3.71 (2H, q, Hz); 3.76 (2H, S) 5.15 (W, d, Hz); 5, 3-6.9 (3H, m) 6, -6-7.2 (1H, t); 7.29 (1H, S); 8.50 (1H, S); 9.24 (1H, d, Hz). Example 78. To a suspension of (2-aminothiazol-4-sh1) -Bb-glycol amido-3-vinyl-3-cephem-4-carboxylic acid (6.2 g) in water (60 ml) is added with stirring sodium bicarbon. (1.36 g) and stirring continue for some time. The resulting solution is lyrphilized to produce sodium (2-aminothiazol-4-yl Bb-glycolamido3-3-vinyl-3-cephem-4carboxylate (6.50 g) v Poly5 D1EN product (9.5 g) is suspended in N, N-dimethylformamide (95.0 ml) and the suspension is stirred under ice cooling in a stream of nitrogen for 5 minutes. A solution of iodomethyl pivalate (5.7 g) in N, N-dimethylformamide (10 ml) is added dropwise to the obtained solution while cooling with ice and the mixture is stirred at this temperature for 10 minutes, the mixture is poured into a mixture of water and ethyl acetate and stirred. The organic layer is separated, leaving The aqueous solution is extracted with ethyl acetate. The extract and the organic layer are combined, washed three times with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated. Diisopropyl ether is added to the residue and the suspension is stirred. three times. Pivaloyloxymethyl-7-2 (2-aminothiazol-4-yl) -DL-glycolamido-3-vinyl-3-cephem-4-carboxyl (8.8 g), T.Sh1 is obtained. 90-94C. IR spectrum, (Nujol): 3370, 1780, 1750, 1680, 1620 cm-. NMR spectrum, ppm (DMSO-d): 1.18 (9H, t); 5, 19 (1H, d, OHz) ;, 5.36 (1H, d,, 0 Hz); 5.606, 22 (4H, m), 6.43 (W, S); 6.84 (1H, dd, Hz, 18 Hz); 8.36 (1H, d,, 0 Hz); 8.47 (1H, d,, 0 Hz). Example 79 .. Sodium 7-l2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 2.9 g), obtained from 7-G2- ( 2-aminothiazol-4-sh1) 2-methoxyiminoacetamide (31-3-vinyl-3 J cephem-4-carboxylic acid and sodium bicarbonate as described in Example 78, dissolved in N, N-dimethyl Shformamide (30 mp) and added to the solution a solution of iodomethyl pivalate (1.62 g) in N, N-dimethylformamide (5 ml) is added dropwise with ice-cooling and stirring. The stirring is continued at this temperature for 10 minutes. To the reaction mixture are added ethyl acetate (200 ml) and water (150 ml) with followed by separating the organic layer, which is washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removing the solvent, an oil is obtained which is pulverized with diisopropyl ether. 4-yl) -2-methoxy-imino-acetate 4MY-OD-3-vinyl-3-cephem-4carboxylate (syn-isomer). IR spectrum (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cmL NMR spectrum, tf, ppm (DMSO-d j): 1.18 (9H, S); 3.77 (2H, q, Hz); 3.84 (3N, S); 5.23 (1H, d, Hz); . 5.38 (1H, d, Hz); 5.69 (1H, d, Hz), 5.64-6.00 (ЗН, m); 6.75 (1H, S); 6.82 (1H, dd, 18 Hz); 7.24 (2H, broad S), 9.60 (1H, d, Hz). Example 80. To a solution of sodium 7-C 2- (2-aminothiazol-4-un) -acetamido-3-vinyl-3-cephem-4-carboxylate (2.0 g) in N, N-dimethylformamide (20 mp) iodomethylhexanoate (3.4 g) and sodium iodide (3.1 g) are added under a stream of nitrogen and the mixture is stirred. at ambient temperature for 1.5 hours. The reaction mixture is poured into a mixture of ethyl acetate (200 ml /
37
and water (20.0 ml), the organic layer is separated, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, followed by treatment with charcoal. The filtrate is concentrated and diisopropyl ether is added to it. The precipitated substance is collected by filtration.
Hexanoyloxymethyl-7-2 (2-aminothiazol-4-yl) acetamido-3-vinyl-3-cephem-4-carboxylate (1.5 g,) is obtained
IR spectrum (Nujol). 3250, 1765, 1655 cm
NMR spectrum, s, ppm (DMSO-dt): 1.2 (UN, t); 2.41 (2H, ha); 3.40. (2H, S); 3.75 (2H, q, Hz); 5.15 (1H, d, Hz); 5.58 (3H, m), 5.82 (2H, S); 6.23 (1H, S); 6.72 (1H, dd, Hz, 18 Hz); 6, 90 (2H, t); 8, 87 (1H, d, Hz),
Example 81. To a solution of 7-C (2-aminothiazol-4-yl) glyoxylamido-3-vinsh-3-cephem-4-carboxylic acid (1.0 g) in N, N-dimethylformamide (10 ml) was added triethylamine (0.27 g), 3-bromophthalide (0.56 g) and sodium iodide (0.39 g) with stirring and 10 s. Stirring is continued at this temperature for 30 minutes. The reaction mixture is poured into water (50 ml), extracted with a mixture of tetrahydrofuran and ethyl acetate (1: 1 by volume). The extract is washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulphate, followed by evaporation, the oil is pulverized with diisopropyl ether.
Phthalide-3-yl-7- (2-aminothiazol-4-yl) glyoxylamido-3-vinyl 3-cephem-4-carboxylate (1.0 g) is obtained.
IR (Nujol): 3300, 1770, 1650 cm.
Example 82. To a solution of sodium (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-V-vinyl-Zeph-7-carboxyl (syn-isomer, 2.16 g) in N, N-dimethylformamide (20 ml) is added 3 bromophthalide (1.3 g) and sodium iodide (1.35 g) and the mixture is stirred at ambient temperature for 40 minutes. Ethyl acetate (100 ml) and water (50 ml) were then added, the separated ethyl acetate layer was washed with a complete aqueous solution and an aqueous solution of 608738
rum sodium chloride and then dried over anhydrous magnesium sulphate. After removal of the solvent, the residue (2.6 g) is chromatographed on silica gel (50 g) using a mixture of bazole and ethyl acetate as eluent. The fractions containing the target compound are collected and entrained. 1.4 g of ftapid-3-yl-7-f20 (2-aminothiazol-4-Sh1) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer) are obtained.
IR (Nujol): 3300, 1775, 1670, 1610, 1530 cm-.
15 NMR spectrum, (U, ppm (DMSO-dt):
3.80 (2H, t); 3.88 (3N, S); 5.23 (1H, d, Hz); 5.20-6.00 (ЗН, t); 6.78 (1H, S); 6.82 (W, S); 7.05 (1H, dd, Hz, 17 Hz); 7.65 (1H, S);
20 7.68 (1H, S); 7.67-8.10 (4H, ha); 9.67 (d, Hz) T, 9.70 (d, Hz))
Example 83. To a solution of 7-f225 (2-aminothiazol-4-Sh1) acetamido-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) in N, N-dimethylformamide (15 ml) is added triethylamine (0.55 g), 3-bromophthalide 3Q (1.2 g) and sodium iodide (0.82 g) in a stream of nitrogen. The mixture was stirred at ambient temperature for 30 minutes, then poured into a mixture of ethyl acetate (300 ml) and water (200 ml), the organic layer was separated, washed with water and saturated aqueous sodium porous solution and dried over anhydrous magnesium sulfate, followed by treatment with charcoal. The filtrate is concentrated and diethyl ether is added. The precipitated substance is collected by filtration.
Phthalide-3-sh-7-C2- (2-aminothiazol-4-yl) acetamido-3-vinyl 3-cephem-4-carboxylate (1.5 g) is obtained.
IR (Nujol): 3250, 1780, 1760, 1650 cm
NMR spectrum, f, ppm (DMSO-d,): 3.43 (2H, S); 3.80 (2H, m); 5.15 (lH, d, Hz); 5.6 (3N, m); 6.23 (1H, S); 6.87 (2H, m); 7.03 (1H, dd, Hz, 18 Hz); 7.60 (s),. „. 7.63 (s) j
7.8 (4H, m), 8.83 (d, Hz) I. . 558.86 (d, Hz)
Example 84. Phthalide-3-sh1-7 2- (2-amino-thiazol-4-yl) -Pb-glycolamCH3-CHO-3-vinyl-3-cephem-4-carboxylate was prepared according to the method described in Example 83. IR spectrum. (Nujol): 1770, 1740, 1660, 1610 Example ,, 85. To a solution of phthalide-3-yl-7 (2-aminothiazol-4-sh1) - glyoxylamido-3-vinyl-3-cephem-4 carboxylate (0.3 d) in methanol (9.0 ml) and tetrahydrofuran (3.0 ml) sodium borohydride (0.012 g is added while cooling with ice. The mixture is stirred at this temperature for 30 minutes. After removing the solvent, the residue is dissolved in a mixture of water (15 ml), tetrahydrofuran (15 ml) and ethyl acetate (15 ml) followed by pH adjustment with to 7.0-10% -HbD hydrochloric acid solution. The separated organic layer is washed twice with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removing the solvent, the mixture is chromatographed on silica gel using a mixture of ethyl acetate and chloroform (17 : 3 by volume) as eluent. The fractions containing the desired compound are collected and evaporated to dryness. The residue obtained is pulverized with diisopropyl ether and washed with it. Phthalide-3-yl-7- 2- (2-aminothiazol-4-Sh1) -DL-glycolimido J3-vinyl-3-cephem-4-carboxylate (0.14 g) is obtained, m.p. 118-120С (decomposition). IR spectrum (Nujol): 1770, 1740, 1660, 1610 cm - NMR spectrum, cG, ppm (DMSO-dp: 3.80 (2H, t); 4.84 (1H, t); 5, 14. (1H, d,, 0 Hz); 5.196, 04 (ZN, t); 6.38 (1H, S); 6.93 (1H, t); 7.54-8.04 (5H, ha); 8, 33 (1H, t). Example 86. Pivaloyloxymethyl-7- 2- (2-aminothiazol-4-yl) -Bb glycolamido-3-vinyl-3-cephem-4carboxylate is prepared in accordance with the procedure described in example 85. IR -spectrum (Nujol): 3370, 1780, 1750, 1680, 1620 cm. Example 87. Suspension with 7-but-3-vinyl-3-cephem-4-carboxylic acid (1.95 g) and trimethylsilylacetate amide (5 , 6 g) in ethyl acetate (20 ml) was stirred at 40 ° C (solution A), To a solution of diketone (0.87 g) in carbon tetrachloride (9 ml) d Bromine solution of bromine (1.65 740 in carbon tetrachloride (2 ml) at -20 ° C is added dropwise, the mixture is stirred at -10 ° C for 3.0 minutes (solution B). At (-20) - (-10) ° C. solution B was added to solution A and the mixture was stirred at the same temperature for 30 minutes. After adding ethyl acetate (80 ml) and water (80 ml) to the reaction mixture, the organic layer was removed and washed with an aqueous solution of sodium chloride. and then dried over anhydrous sulphate, magnesium, followed by heating under reduced pressure. The obtained 7- (4-bromo-3-oxo-butylamido) -3 vinsh-3-cephem-4-carboxylic acid (3.2 g) is dissolved in a mixture of tetrahydrofuran (50 ml) and ethanol (50 ml), added 1 -amidinium urea (1.7 g), followed by stirring for 24 hours. The precipitated substance is collected by filtration and drying .t. Hydrobromide (2guanidinothiazol-4-yl) acetamido-1-3 vinyl-3-cephem-4-carboxylic acid (O, 7, g) is obtained. IR (Nujol): 3400-3100, 1760, 1680, 1660, 1620, 1540 cm-. NMR spectrum, (, ppm (DMSO-d): 3.273, 95 (4H, t); 5, 1-5.9 (4H, t); 6.9 (1H, S); 7.1 (1H, dd, Hz, 17 Hz; 9.1 (1H, d, Hz). The following compounds were prepared by reacting 7-amino-3-vinyl cephalosporanic acid derivatives with diketone, bromine and tiamourea according to the procedure described in Example 87. Example 88 Hexanoyloxymethyl-7- 2- (2-aminothiazol-4-sh1) acetamido-3-vinyl-3-cephem-4-carboxylag. IR spectrum (Nujol): 3250, 1765, 1655 cm Example 89. Phthalide-3- W1-7 2- (2-aminothiazol-4-yl) acetamido-1-vinyl-3-cephem-4-carboxllate IR spectrum (Nujol): 3250, 1780, 1760, 1650 cm; Example 90vK suspension 15 g benzhydryl-7- 2- (2-aminothiazole4- 1) -2-tert-butoxycarbonylmethoxyiminoacetamido-3-vinyl-3-cephem-4 carboxylate (syn-isomer) in anisole is added with stirring and ice-cooling 2,2,2-trifluoroacetic acid (60 ml). Stirring is continued at 10- 15 C for 80 min.
The reaction mixture is poured into diisopropyl ether (600 ml), the insoluble matter is collected by filtration and dried. This substance - (11.2 g) is dissolved in an aqueous solution of sodium bicarbonate and the resulting solution is adjusted to pH 6.0, and then chromatographed on silica (44.8 ml) using a 5% aqueous solution of sodium acetate as eluent. The fractions containing the target compound are collected and evaporated to dryness.
3.55 g of (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamido-3-vinyl-3-cephem 74carboxylic acid (syn-isomer) are obtained, m.p. 250C.
IR (Nujol): 3350, 1770, 1680, 1640 cb.
NMR spectrum, cG, ppm (DMSO-dg):
3.70 (2H, q, Hz); 4.62 (2H, S); 5.21 (lH, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 5-6 (2H, t); 6.82 (1H, S); 7.22 (2H, broad S); 6.57, 5 (1H, t); 9.50 (1H, d, Hz).
Example 91. 2-, 2 g of benzhydryl-2- (2-formamidothiazol-4-yl) -2 methoxyimico-acetamido-3-triphenylphosphoranylidene-methyl-3-cephem-4-carboxylate (syn-isomer), 20 ml of 36% formaldehyde aqueous solution and 60 ml of tetrahydrofuran is stirred at ambient temperature for 12.5 hours. After adding ethyl acetate (100 ml) to the reaction mixture, the organic layer is separated, washed with 10% hydrochloric acid and with an aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. After removing the solvent, a residue is obtained which is pulverized with diethyl ether and chromatographed on silica gel using chloroform and then a mixture of chloroform and acetone (19: 1 and 9: 1 by volume) as eluent.
The fractions containing the desired compound are collected and evaporated.
0.25 g of benzhydryl-7-2 (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer) is obtained.
IR (Nujol): 3250, 1780, 1710, 1700, 1660, 15400 cm.
Example 92. Iodide {4-benzhydryloxycarbonyl-7-2-tertbutoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido-3-cephem-3-Sh1 methyl triphenylphosphonium (syn-isomer, .0.59 g ) is dissolved in a mixture of methylene chloride (20 ml), water (10 ml) and 36% aqueous formaldehyde solution (1 ml), followed by adjusting the pH to 8 with 20% -Hbw sodium carbonate (aqueous) solution.
After stirring for 3 hours at 30-35 ° C, the reaction mixture
 treated with 10% hydrochloric acid solution to pH 2, and then extracted with methylene chloride. The extract is washed with an aqueous solution of sodium chloride and dried over sulfate.
magnesium and evaporated. Remainder
(0.46 g) chromatographic on silica gel using a mixture of solvents of benzene and ethyl acetate (2: 1 by volume) as eluent.
About, 14 g of benzhydryl-7C2-tert-butoxycarbonylmethoxyimino2- (2-formamidothiazol-4-yl) acetamido} 3-vinyl-3-cephem-4-carboxylate (syn-isomer) are obtained.
IR (Nujol): 3250, 1780, 1720, 1680, 1540 cm
The following compounds were prepared by reacting 7-acylamino-triphenylphosphoranylidenemethyl cephalosporanic acid derivatives with an aqueous formaldehyde solution in accordance with the procedure described in examples 91 and 92.
Example 93: Benzhydryl-7-2 (2-methanesulfonamidothiazol-4-yl) acetamido-3-vinyl-3-cephem-4-carboxylate. - IR spectrum (Nujol): - 3250, 1760, 1700, 1650, 1610, 1600 cm Example 94. Benzhydryl-7-2 (2-formamidothiaz ol-5-yl) ace tamido -3-vinyl-3-cephem-4-carboxylate .
IR (Nujol): 3270, 1770, 1715, 1680 cm
Example 95. Benzhydryl-7- 2 (2-methanesulfonamidothiazol-5-Sh1) acetamido-3-vinyl-3-cephem-4-carc strength t.
IR (Nujol): 3320, 1770, 1710, 1660, 1620, 1570.1520 cm
Example 96. Pivaloyloxymethyl-7-2-(2-aminothiazol-4-yl) -DL glycrlyamido 3-3-vinyl-3-cephem-4carboxylate.
IR (Nujol): 3370, 1780, 1750, 1680, 1620 cm
Example 97. Pivaloyloxymethyl-7- 2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3 cefem-4-carboxylate (syn-isomer). IR (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm - Example 98, Hexanoyloxyme tyl-7-C2- (2-aminothiazol-4-yl) acetamido-3-vinyl-3-cephem -4-carboxyl IR spectrum (Nujol): 3250, 1765, 1655 cm-. Example 99 Phthalide-3-yl-7G (2-aminothiazol-4-yl) glyoxylamido Z-vinyl-3-cephem-4-carboxylate. IR (Nujol): 3300, 1770, 1650 cm. Example 100 Phthalide-3-yl-7 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer). IR (Nujol): 3300, 1775, 1670, 1610, 1530. Etc. and meper 101. Phtalide-3-yl-7 2- (2-aminothiazol-4-yl) acetamido-3 vinyl-3-cephem-4-carboxylate. IR (Nujol): 3250, 1780, 1760, 1650 cm-. Example 102 Phthalide-3-yl-7 2- (2-aminothiazol-4-sh1) -bb-glycolamidr-3-vinyl-3-cephem-4-carboxyl IR spectrum (Nujol): 1770, 1740, 1660, 1610. Example 103. To a solution of benhydri-1 -7-amino-3-vinyl-3-cephem-4 carboxylate (3.02 g) in methylene chloride (30 ml) was added a solution of 2- (2 formamidothiazol-4-yl) -2- ( Bb-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino) acetic acid (syn-isomer 5.5 g) and then N, N-dicyclohexyl-carbodiimide (1.81 g), followed by stirring at ambient temperature for 2 hours. Diethyl ether (100 ml) was added to the reaction mixture, and the precipitated material was removed by filtration. After removing the solvent by filtration, the residue is dissolved in ethyl acetate, washed with a 5% aqueous solution of sodium bicarbonate, then with an aqueous solution of chlorine and sodium, followed by drying over anhydrous magnesium sulfate. After removal of the solvent, a residue (10 g) is obtained, which is chromatographed on silica gel (200 ml), eluting with a mixture of solvents of diisopropyl ether and acetone. The fractions containing the desired compound are collected and evaporated. Get benzhydryl-7- (2-formamidothiazol-4-yl) -2- -L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarboxylate (sinisomer, 5.9 g), so pl. 87-94C. IR (Nujol): 3350, 1780, 1720, 1700 (wide) cm-. NMR spectrum, s, ppm (DMSO-dJ: 1.33 (9H, S); 3.57, 3.96. (2H, ABq, Hz); 4.53 (3N, t); 4.73 ( 2H, broad S); 5.3 (1H, d, Hz); 5.33 (1H, d, Hz); 5.53 (W, d, Hz); 6.00 (1H, dd, Hz, 8 Hz); 6.87 (1H, S); 7.00 (1H, S); 7.4 (20H, t); 7.50 (1H, S); 8.57 (W, S); 9, 80 (1H, d, Hz); 12.7 (1H, broad S). Example 104 To a solution of benzhydryl-7-amino-3-vinsh1-3-cefem4-carboxylate (3.54 g) in methylene chloride (55 ml) a solution of 2- (2-formamidothiazol-4-sh1) -2- (OH-3benzhydryloxycarbonyl-3-tert-butoxycarboNYlaminoproxyimino) acetic acid (syn-isomer, 6.0 g) in tetrahydrofuran (60 ml) and then N, N-dicyclohexylcarbodiimide (2.2 g) followed by stirring at a temp for 4 hours. The precipitated material is removed by filtration, the filtrate is evaporated to dryness and the following is obtained: the residue is chromatographed on silica gel, eluted with a mixed solvent of diisopropyl ether and acetone. The fractions containing the desired compound are collected and evaporated. 8 g benzhydrSh1-7-C2 (2-formamide Thiazol-4-sh1) -2- (DL-3benzhydridoxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer), t .pl. 153-158C. IR spectrum (Nujol): 3200, 1780, 1700 (wide) cm-. NMR spectrum, G, ppm (DMSO-d 4): 1.36 (9H, S); 2.1 (2H, t); 3.6 (2H, t); 4.2 (ЗН. Т); 5.2-6.1 (4H, t); , 8 (1H, S); 6.97 (1H, S); 6.8-7.2 (1H, m); 7.37 (20H, m); 7.43 (1H, S); 8.53 (1H, S); 9.75 (1H, d, Hz); 12, 7. (1H, wide S). Example 105. To a solution of N, N-dimethylformamide (1.10 ml) and tetrahydrofuran (6 ml), phosphorus oxychloride (1.30 ml) is added dropwise, followed by stirring for 10 minutes. After addition of tetrahydrofuran (25 m) and 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetic acid (syn-isomer, 2.96 g), the mixture is stirred at 5 ° C for 45 minutes to obtain an activated acid solution. This solution is added dropwise to a solution of L-2-benehydryl-oxycarbonyl-2-tert-butoxycarboxyaminoethyl-7-amino-3-vinyl-3-cephem-4-carboxylate (5.0 g) and trimethylsilyl acetamides, ca (9.05 g) in methylene chloride (50 ml) at -30 ° C for 5 minutes, followed by stirring at (-20) (-10) ° C for 30 minutes. The reaction mixture is poured into a mixture of ethyl acetate (300 ml) and V9DY (100 ml), and the pH is then adjusted to 7.5 with 10% aqueous sodium hydroxide solution and aqueous sodium bicarbonate solution. The separated ethyl acetate solution is washed with an aqueous solution of sodium chloride and cjraiaT over anhydrous magnesium sulfate. After removal of the solvent, a crude product (7.5 g) —L-2-benzhydryloxycarboni 2-tert-butoxycarbonylaminoethyl-712- (2-formamidothiazol-4-yl) -2-labels Siiminoacetamido-3-vinsh1 3-cephem-4 carboxylate (syn-isomer). IR (Nujol): 3280, 1782, 1709, 1689, 1656 cm - NMR spectrum, CL, ppm (DMSO-dt):, 1.40 (9H, S); 3.73 (2H, t); 3.92 (311, S); 4.56 (ЗН, t); 5.20 (1H, d, Hz); 5.33 (W, d, Hz); 5.65 (W, d, Hz); 5.75 (1H, dd, Hz, 8 Hz); 6.84 (1H, S); 6.93 (W, dd, Hz, 18 Hz); 7.3 (iOH, m); 7.43 (1H, S); 8.53 (1H, S 9.73 (1H, d, Hz); 12.7 (1H, sheath S). Example 106. To V.ilsmeier's reagent, which is obtained from N, N-dimethylformamide (1.44 d) and phosphorus pentachloride (1.71 g) in tetrahydrofuran (6 ml) in the usual way, 2-formamidothiazol-4-Sh1 glyoxylic acid is added. (3.108 g). The mixture is stirred, N, K-dimethylformamide (45 ml) is added. and tetrahydrofuran (60 ml) to prepare a solution of an activated sour solution. A solution of activated acid is added dropwise to a solution of L-2-benz hydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl-7-amino-3-vinyl3-cephemcarboxylate (4.5 g) and three methylsil of lacetamide (8.4 g) in methylene chloride (45 ml) at -30 ° C for 746 minutes 5 minutes To the reaction mixture is added ethyl acetate (400 ml) and the pH is adjusted to 7.5 with aqueous sodium bicarbonate solution, washed with an aqueous solution of chloride sodium, and dried over anhydrous magnesium sulphate. After removing the solvent, a crude product (8.0 g) —L-2benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl-7-C (2-formamidothiazol-4-yl) glyoxylamido j-3-vinylH3- is obtained. cephem-4-carboxylate. IR (Nujol): 1777, 1720, 1667 cm. NMR spectrum, L, ppm (DMSO-d): 1.37 (9H, S); 3.67 (2H, t); 4.43 (3N, wide S); 5.10 (1H, d, Hz); 5.20 (1H, d, Hz); 5.55 (1H, d, Hz); 5.58 (1H, dd, Hz, 8 Hz); 6.71 (1H, S); 7.23 (UN, t); 8.37 (1H, S); 8.47 (1H, .S); 9.77 (1H,. Dd, Hz); 12.7 (1H, broad S). Example 107. Benzhydryl-7C2- (2-formamidothiazol-5-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem4-carboxylate (syn-isomer, 2.9 g), T.Sh1. 208 C (decomposition) is obtained by reaction of benzhydryl-7-amino-3-cephem-4-carboxylate hydrochloride (2.28 g) with 2- (2-formamidothiazol-5-yl) -2-methoxyiminoacetic acid (sinisomer, 1.4 g) in according to the procedure described in examples 105 and 106. IR spectrum (Nujol): 3250, 1780, 1720, 1685, 1655, 1570 cm. NMR spectrum, cG, ppm (DMSO-d): 3.82 (2H, q, Hz); 3.92 (3N, S); 5.30 (W, d, Hz); 5.32 (1H, d, Hz); 5.67 (1H, d, Hz); 5.92 (1H, dd, 8 Hz); 6.85 (1H, dd, Hz, 17 Hz); 7.00 (1H, S); 7.2-7.6 (UN, t); 7.61 (1H, S); 8.62 (W, S); 9.98 (1H, d, Hz). Example 108 Benzhydryl-7 2- (2-formamidothiazol-5-sh1) -2-methoxyiminoacetamido-3-vinyl-3-cephem-. 4-carboxylate- (anti-isomer, 4.14 g) is obtained by reacting benzhydropyl-7-amino-3-vinyl-3-cepheme-4-carboxylate hydrochloride (3.26 g) with 2- (2-formavdothiazol-5-il) -2-methoxyiminoacetic acid (anti-isomer, 2.0 g) according to the procedure described in examples 105 and 106. IR spectrum (Nujol): 3250, 1780, 1720, 1685, 1660 cm
NMR spectrum, (DMSO-dfc):
3.79 (2H, q, Hz); 4.12 (3N, S); 5.34 (1H, d, Hz); 5.31 (1H, d, Hz); 5.65 (1H, d, Hz); 5.83 (1H, dd, Hz, 18 Hz);
7.00 (W, S); 7.42 (YUN, Broad S); 8.26 (1H, S); 8.62. (1H, S); 9.55 (1H, d, - Hz).
Example 109. Benzhydryl-7f (2-formamidothiazol-5-yl) glyoxylamido-3-vinyl-3-cephem-4-car .boxesh1at (3.0 g), mp. 178 C (decomposition) is obtained by reacting benzhydryl-7-amino-3-vinyl-3-cephem-4 carboxylate hydrochloride (2.68 g) with (2-formamidothiazol-5-yl) glyoxylic acid (1.5 g) according to with the method described in examples 105 and 106.
IR (Nujol): 3280, 1775, 1730, 1705, 1635, 1555 cm.
NMR spectrum, cG, ppm (DMSO-d,):
3.80 (2H, q, Hz); 5.34 (W, d, Hz); 5.70 (W, d, Hz); 5.35 (1H, d, Hz); 5.82 (W, dd, Hz, 8 Hz); 6.89 (1H, dd, Hz, 17 Hz); 7.2-7.8 (UN, ha); 6.99 (W, S); 8.58 (1H, S);
8.68 (1H, S); 9.92 (1H, d, Hz), 12, 98 (1H, wide S).
Example 110. Benzhydryl-7 2- (2-formamidothiazol-4-yl) -2-ethoxyiminoacetamido-3-vinyl-3 cefem-4-carboxylate (syn-isomer, 25 g) is obtained by the reaction of benzhydryl-7-amino-3-chloroprate Zepham-4-carboxylate (17.2 g) with 2- (2-formamidothiazol-4-yl) -2-ethoxyiminoacetic acid (syn-isomer, 8.8 g) according to the procedure described in examples 105 and 106.
IR (Nujol): 3260, 3150, 1770, 1720, 1700, 1660, 1620, 1560, 1540 cm
NMR spectrum, cL, ppm (DMSO-d): 1.27 (3N, t, Hz); 3.79 (2H, q, Hz); 4, 18 (2H, q, Hz); 5.32 (1H, d, Hz); 5.33 (1H, d, Hz); 5.65 (1H, d, Hz);
5.96 (1H, dd, Hz, 8 Hz); 6.78 (W, dd, Hz, 17 Hz);
6.97 (1H, S); 7.17-7.67 (1H, t); 9.73 (1H, d, Hz), 8.55 (1H, S); 12.70 (1H, broad S).
Example 111. Benzhydryl-7C2- (2-formamidothiazol-4-yl) -2-hexyloxyiminoacetamido-3-vinsh1-3cepheme-4-carboxylate (syn-isomer, 5.7 g) is obtained by reacting the hydrochloride
benzhydryl-7-amino-3-vinyl-3-cephem-carboxylate (4.29 g) with 2- (2-formamidothiazol-4-yl) -2-hexyloxyiminoacetic acid (syn-isomer, 3.29 g) according to with the method described in example 105 and 106.
IR (Nujol): 3250, 1770, 1710, 1700, 1650, 1570, 1535 cm
NMR spectrum, (f, ppm (DMSO-d): 0.87 (3N, t, Hz); 1.0-2.0 (8H, m); 3.75 (2H, ABq, Hz); 4 , 12 (2H, t, Hz); 5.28 (1H, d, Hz); 5.42 (1H, d, Hz); 5.62 (1H, d, Hz); 5.90 (W, dd , Hz, 8 Hz); 6.77 (1H, dd, Hz, 17 Hz); 6.97 (1H, S), 7.12-7.15 (11H, ha); 8.50 (W, S ); 9.52 (1H, d, Hz); 12, 70 (1H, broad S).
The following compound is obtained by reacting 7-amino-3-vinyl cephalosporanic acid derivatives with the corresponding acid chlorohydrate according to the procedure described in examples 105 and 106.,
PRI me R 112. (2-Aminothiazol-5-Sh1) -2-methoxyiminoacetamido-3-vinsh-3-cephem-4-carboxylic acid (syn-isomer), mp. 250C.
IR (Nujol): 3300, 1780, 1645, 1580, 1515 cm H
EXAMPLE 113. (2-Aminothiazol-5-yl) -2-methoxyimino acetamido-3-vinyl-3-cephem-4-carboxylic acid (anti-isomer), mp. . IR (Nujol): 3320, 1775, 1655, 1575, 1515 cm.
Example 114. 7-C (2-Aminothiazol-5-yl) glyoxy-1amido-3-vinyl 3-cephem-4-carboxylic acid, m.p. 250s
IR (Nujol): 3300, 3180, 1770, 1690, 1620, 1510, 1460 cm
Example 115. (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamido 3-vinyl-3-cephem-4-carboxylic acid (syn-isomer).
IR (Nujol): 3300, 1770, 1660, 1545 cm-.
Example 116. Pivalocloxymethyl-7-C2- (2-aminot1 | azol-4-sh1) -2 pivaloyloxymethoxycarbonylmethoxyimino) acetamido1-3-vinyl-3-cephem-4carboxylate (syn-isomer), mp. 115C (decomposition).
IR (Nujol): 3400, 3260,
3100, 1780, 1750, 1660, 1530 ctf-
Example 117.  Pivaloyloxymeth1-7-C2- (2-aminothiazol-4-ip) -249 ethoxyiminoacetamido J-3-vinyl-Zeph-4-carboxylic acid (sinisomer).  IR spectrum (Nujol). : 3300, 1780, 1740, 1670, 1610, 1530 cm-1 Example 118.  7-G2- (2-Amino thiazol-4-yl) -2-hexyloxyimino amido-3-vinc1-3-cephem-4-carboxylic acid (syn-isomer), t. square  147155s (decomposition).  IR (Nujol): 3250, 1770, 1660, 1530.  Example 119.  Acetoxymethyl (2-aminothiazol-4-yl) -2-methoxy iminoacetamido 3-vinyl-3-cephem-4 carboxylate (syn-isomer), m. square  78 83 ° C.  IR (Nujol): 3300, 1765 (wide), 1660, 1610, 1535 cm-.  Example 120  Propionyloxy methyl-7-C2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-C-3-vinyl-Zecem-4-carboxylate (syn-isomer), t. square  79-85C.   IR (Nujol): 3350, 1770 (wide), 1650, 1620, 1530 cmL Example 121.  Isobutyryloxymethyl-7- 2- (2-aminothiazol-4-yl, 2-methoxyiminoacetamido Z-3-vinyl 3-cephem-4-carbyoxylate (syn-isomer) t. square  92-100 ° C.  IR (Nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cm Example 122.  1-Acetoxypropsh-7-G2- (2-aminothiazol-4-yl) methoxyiminoacetamido3-3-vinyl-3cepham-4-carboxylate (syn-isomer), t. square  97-101C.  IR (Nujol): 3300, 1765, 1670, 1610 cm-.  Example 123  L-2-Amino-2carboxyethyl-7-G2- (2-aminothiazol4-yl) -2-methoxyiminoacetamido-3 vinyl-3-cephem-4-carboxylate (synisomer).  IR (Nujol): 3200, 1700, 1735 (shoulder), 1650 (wide).  Example 124  L-2-Benzhydr oxycarbonyl-2-tert-butoxycarbon aminoethyl-7- (2-aminothiazol-4-yl) glyoxyl Ilamido-3-vinyl-3-cephem-4carboxylate.  IR (Nujol): 3340, 1775, 1720, 1660, 1614 cmL in P and m e 125  Benzhydryl-7 2- (2-aminothiazol-4-sh1) -2- (b-2benzhydryloxycarbonyl-2-tert-butyoxycarbonylamino-tosoxycarbonyl 750-methoxyimino) acetamrado J-3-vinyl-Zeph-4-carboxylate (syn-isomer) . square  124-128 C.  IR (Nujol): 3360, 1750 (wide), see Example 126.  Benzhydryl-7G2- (2-aminothiazol-4-sh1) -2- (Bb-3benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer), t. square  119-122p.  IR (Nujol): 3300, 1780, 1719, 1680 cm-g Example 127.  To a suspension of 2- (5-amino-1,2,4-oxadiazol-3-yl) -2-methoxyiminoacetic acid (sinisomer, 2.23 g) in methylene chloride (70 ml) is added phosphorus oxychloride (7.2 g) followed by stirring at ambient temperature for 45 min.  N, N-dimethylformamide (4.4 g) was added at and the mixture was stirred at (-10) - 0 ° C for 1 hour to prepare an activated acid solution.  This solution is added to a solution of benzhydryl-7-amino-3-vinyl-Zeph-4-carboxylate hydrochloride (4.7 g) and trimethylsilyl acetamide (8.6 g) in ethyl acetate (50 ml) at -20 ° C and the mixture is stirred at (-20) C for 1 h.  After adding ethyl acetate (200 ml) and water (200 ml) to the reaction mixture, the ethyl acetate layer is separated, washed with a saturated aqueous solution of sodium bicarbonate and with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.  After removing the solvent, a residue is obtained which is chromatographed on silica gel, eluting with a mixed solvent of ethyl acetate and benzene (6: 4 by volume).  The first fractions containing the desired compound are collected and evaporated.  The benzhydryl-7- 2- (5-amino1, 2,4-oxadiazol-3-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, 2.4 g) is obtained.  IR (Nujol): 3250, 1770, 1710, 1670, 1600, 1550 cm NMR spectrum, s /, rrP1 (DMSO-d): 3.77 (2H, q, Hz); 3.97 (3N, S); 5.28 (1H, d, Hz); 5.28 (1H, d, Hz); 5.65 (1H, d, Hz); 5.92 (1H, dd, Hz, 8 Hz); 6.78 (1H, dd, Hz, 17 Hz); 51 6, 97 (1H, S); 7.17-7.67 (UN, m); 8.03 (2H, S); 9.77 (1H, d,.  Hz) Secondary fractions containing the desired compound are collected and evaporated.  .  Benzhydryl-7-f2-C5- (NNj N-dimethylaminomethylene) amino-1,2, oxadiazol-3-yl -2-methoxyiminoamide amido-3-vinyl-3-cephem-4-carboxyl is obtained (syn-isrmer, 2, 0 g).  IR (Nujol): 3200,. 1780, 1720, 1680, 1640, 1540 cm  NMR spectrum, cL, ppm (DMSO-d): 3.07 (3N, S); 3.22 (3N, S); 3.68 (2H, t) | 4.00 (3N, S); 5.30 (d, Hz); 5.32 (W, d, Hz); 5.67 (1H, d, Hz); 5.95 (1H, dd, Hz, 8 Hz); 6.80 (1H, dd, Hz, 17 Hz); 7.98 (1H, S); 7.20-7.67 (UN, t); 8.65 (1H, S); 9.83 (W, d, Hz).  Example 128  Benzhydryl-7 2- (5-amino-1,2,4-oxadiazol-3-yl) acetamido-3-vinyl-3-cephem-4-carbo silate (2.1 g) is obtained by reacting chlorine-hydrate benzhydryl-7- amino-3-vinyl 3-cephem-4-carboxylate (4.3 g) with 2- (5-amino-1,2, 4-oxadiazol-3-yl) -.  acetic acid (1.72 g) in accordance with the procedure described in example 127.  IR (Nujol): 3380, 3250, 3180, 3130, 1770, 1710, 1650, 1540 cm - NMR spectrum, cG, ppm (DMSO-d): 3.35 (2H, S); 3.78 (2H, q, Hz 5.23 (W, d, Hz); 5.32 (1H, d, Hz); 5.65 (W, d, Hz) 5.82 (W, dd, Hz , 8 Hz); 6.80 (1H, dd, Hz, 17 Hz); 7.00 (1H 7.20-7.67 (Yun, t); 7.73 (2H, S); 9, 18 ( 1H, d, Hz).  Example 129.  To a solution of benzhydryl-7-, 2- (2-formamidothiazole 4-sh1) -2- (L-2-benzhydryloxycarbonate 2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino) acetamido -3wins1-3-cephem-4-carboxylate (sinisomer, 6 ) in methanol (140 ml), concentrated hydrochloric acid (3.1 ml) was added, and the mixture was stirred at c.  for 90 minutes, the pH of the mixture is adjusted to 6.0 with a 5% aqueous solution of sodium bicarbonate and then diluted with water (200 ml).  After removal of methanol, an aqueous solution is obtained, which is extracted with ethyl acetate.  The extract is washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate, followed by removal of the solvent.  The residue is pulverized with diisopropyl ether and collected by filtration.  Benzhydryl-7- 2- (2-aminothiazol-4-sh1) -2- (L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyim but) acet-amide about -3-vinyl-3-cephem-4-carboxyl is obtained ( syn-isomer, 5.5 g), t. square  124-128 0.  IR (Nujol): 3360, 1750 (wide) AI.  NMR spectrum, 1, rrga (DMSO-d): 1.40 (9H ,.  S); 3.57, 3.98 (2H, ABq, Hz); 4.50 (3N, t); 4.63 (2H, broad S); 5.30 (1H, d, Hz); 5.31 (1H, d, Hz); 5.67 (1H, d, Hz); 5.95 (1H, dd, Hz, 8 Hz); 6.86 (2H, S); 6.8-7.20 (1H, t); 7.00 (W, S); 7.40 (UN, S); 9.65 (1H, d, Hz).  Example 130  To a solution of benzhydryl-7- 2- (2-formamidothiazol4-yl) -2- (B1-3-benzhydrSh1oxycarbonyl3-tert-butoxycarbonylaminopropoxyimino) acetamido3-3-winnl-3-cephem-4carboxylate (syn-isomer, 3.65 g) in methanol (109 ml), concentrated hydrochloric acid (1.96 ml) was added and the mixture was stirred at 35 ° C for 24 minutes.  The pH of the reaction mixture is adjusted to 6.5 with 10% aqueous sodium hydroxide solution and 5% aqueous sodium bicarbonate solution, followed by removal of methanol.  The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate.  After removal of the solvent gave a residue which was pulverized with diisopropyl ether to give benzgidrSh1-7- 2- (2-aminothiazol-4-w1) -2- (BL-3-benzgidrshtoksikarbonil-W-tert-butrksikarbonilaminopropoksiimino) acetamido-Winkle 3-cephem-W -4-carboxylate (sinisomer, 3.5 g), t. square  119-122 0.  IR spectrum, (Nujol): 3300, 1780, 1719, 1680 cm.  NMR spectrum, s, ppm (DMSO-dj): 1.37 (9H, S): 2.1 (2H, t), 3.7 (2H, t); 4.2 (ЗН, t); 5.2-6.1 (4H, t); 6.8 (2H, S); 6.8-7.2 (1H, t); 6.97 (1H, S); 7.37 (20H, S); 9.67 (1H, d.   Hz).  Example 131  To a solution of L-2 benzhydryloxycarboH1sh-2-tert-butok sicarbonylaminoethyl-7-C2- (2-forms of dotiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxyl (sio-isomer, 6 , 8 g) in methanol (300 ml) concentrated hydrochloric acid was added and the mixture was stirred for 1 hour.  After adding water (100 ml), the pH of the reaction mixture is adjusted to 5.5 with aqueous sodium bicarbonate solution, followed by removal of methanol.  The residue is dissolved in ethyl acetate, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate, followed by treatment with activated charcoal.  After removal of the solvent, L-2-benzhydryloxycarbonyl-2 tert-butoxycarbonylaminoethyl-7-C2 (2-aminothiazol-4-yl) -2-methoxyimino acetamido-3-vinyl-3-cephem-4-carboxyl silate (syn-isomer, 5.0 g)  IR spectrum (Nujol): 3370, 1775, 1730, 1616 cm - NMR spectrum, s, ppm (DMSO-d): 1.33 (9H, S); 3.83, 3.93 (2H, ABq, Hz) ;; 3.80 (3N, S); 4.47 (3N, wide S); 5.12 (1H, d, Hz); 5.23 (1H,. d, Hz); 5.60 (W, dd, Hz, 8 Hz); 5.66 (1H, d, Hz); 6.70 (1H, S); 6.77 (1H, S 6.8-7.2 (1H, t); 7.3 (Yun, broad S); 9.57 (1H, d, Hz).  . Example 132  To a solution of L-2 beishydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl-7- (2-formamidothiazol-4-Sh1) -glyoxylamido} -3 vinyl-3-cephem-4-carboxylate (8.7 g) in methanol (150 ml) was added hydrochloric acid (4.7 g) is added and the mixture is stirred at 35-40 ° C for 70 minutes.  The pH of the reaction mixture was adjusted to 5.0 with a 5% aqueous solution of sodium hydroxide with a 5% aqueous solution of sodium bicarbonate, followed by adding dropwise water (600 ml).  Precipitated solid. The property is collected by filtration, washed with water and dried.  L-2-benzhydryloxycarbon 2-tert-butoxycarbonylaminoethyl-7 (2-aminothiazol-4-yl) HJ is obtained by hydroxylamine J 3-vinyl-3-cephem-4-carboxylate (5.40 g).  IR (Nujol): 3340, 1775, 1720, 1660, 1614 cm NMR, t /, ppm (DMSO-di):. 1.37 - (9H, S); 3.47,  3.97 (2H, ABq, Hz); 4.53 (3N, m); 5.18 (1H, d, Hz); 5.33 (1H, d, Hz); 5.65 (1H, dd, Hz, 8 Hz); 5.68 (1H, d, Hz); 6.82 (1H, S); 6.92 (1H, dd, Hz, 18 Hz); 3.37 (YUN, S); 7.83 (1H, S); 9.80 (1H, d, Hz), Example 133.  A solution of 7-G2 (2-formamidothiazol-5-yl) -2-methoxyiminoacetamido-3-vinsh1-3-cephem-4carboxylic acid (syn-isomer, 1.9 g) and concentrated hydrochloric acid (1.36 g) are mixed at ambient temperature for 1.3 hours  After evaporation of the reaction mixture to dryness, the residue is suspended in water (35 ml) and the pH is adjusted to 7-8 with 10% aqueous sodium hydroxide solution and then to 3 with 10% hydrochloric acid.  The precipitated solid is collected by filtration, washed with water and dried.  (2-aminothiazol5-yl) -2-methoxyiminoacetamidoZ-Zvinyl-3-cephem-4-carboxylic acid (syn-isomer, 1.3 g) is obtained, t. square  7  JK-spectrum (Nujol): 3300, 1780, 1645, 1580, 1515.  NMR spectrum, d, ppm (DMSO-d): 3.76 (2H, q, Hz); 3.81 (3N, S); 5.23 (1H, d, Hz); 5.35 (1H, d, Hz); 5.60 (1H, d, Hz); 5.78 (1H, dd, 8 Hz); 6.98 (1H, dd, Hz, 18 Hz); 7.12 (1H, S); 7.60 (2H, broad S); 9.76 (1H, d, Hz).  Example 134  (2-Aminothiazol-5-yl) -2-methoxyiminoacetamido} 3-vinyl-3-cephem-4-carboxylic acid (anti-isomer, 1.27. d) is obtained by the reaction of (2-formamidothiazol-5-yl) 2-methoxyiminoacetamido-3-vinyl-Zeph-4-carboxylic acid (anti-isomer, 2.1 g) with concentrated hydrochloric acid (1.5 g) in accordance with the procedure described in example 133.  T. square  7  . . IR (Nujol): 3320, 1775, 1655, 1575, 1515 cm L NMR, cG, Rrga (DMSO-d): 3.76 (2H, q, J-20 Hz); 4.01 (3N, S); 5.23 (1H, d, Hz); 5.33 (1H, d, Hz); 5.58 (1H, d, Hz); 5.73 (W, dd, 8 Hz); 6.98 (1H, dd, Hz, 18 Hz); 7.72 (2H, broad S); 7.79 (1H, S); 9.27 (1H, d, Hz).  Example 135, 7-C2- (2-Aminothiazol-5-yl) glyoxylamido 3-vinyl 3-cephem-4-carboxy acid 1 (1.1 g produced by the reaction of 7- (2-formamidothiazol-5-yl) glyoxylamido-3-vinyl 3 -cepheme. -4-carboxylic acid (1.73 with concentrated hydrochloric acid (2.2 g) according to the procedure described in example 133.  T. square  250 IR (Nujol): 3300, 3180, 1770, 1690, 1620, 1510, 1460 cmL NMR spectrum, ppm (DMSO-dj; 3.75 (2H, q, Hz); 5.24 (1H, d, Hz; 5.35 (1H, d, Hz); 5.62 (ni, d, Hz); 5.73 (1H, dd, Hz, 8 Hz); 7.03 (1H, dd, Hz , 17 Hz); 8.28 (1H, S); 8.56 (2H, wide S); 9.54 (W, d, Hz).  Example 136.  (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamido 3-vinsh1-3-cephem-4-carboxylic acid (syn-isomer, 12.2 g) is obtained by the reaction of 7-C2- (2-formamidothiazol-4-yl) -2 - ethoxyminoacetamido -3.  vinsh-3-cephem-4-carboxylic acid (syn-isomer, 15.2 g) with concentrated. hydrochloric acid (14 ml) according to the procedure described in example 133.  IR (nujol): 3300, 1770, 1660, 1546 cm NMR spectrum, cL, pp1n (DMSO-d): 1.27 (3N, t, Hz); 3.77 (2H, q, Hz); 4.17 (2H, q, Hz); 5.23 (1H, d, Hz); 5.35 (1H, d, Hz); 5.62 (1H, d, Hz); 5.83 (1H, dd, Hz, 8 Hz); 6.78 (1H, S); 6.98 (1H, dd, Hz, 17 Hz); 9.63 (1H, d, Hz).  Example 137  (2-amino thiazol-4-yl) -2-hexyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid is obtained (syn-isomer, 2.1 g) by the reaction (2-formamidothiazol-4-sh1) - 2-Hexyloxyiminoacetate amido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 3.0 g) with concentrated hydrochloric acid (0.65 g) according to the procedure described in example 133.  IR (Nujol): 3250, 1770, 1660, 1530 cm NMR, eL, ppm (DMSO-dg): 0.84 (3N, t, Hz); 1.03-2.0 (8H, (2H, ABq, Hz). ; 4.07 (2H, t, Hz); 5.20- (1H, d, Hz /; 5.28 (1H, d, Hz); 5.55 (W, d, Hz); 5.77 (1H, dd, Hz, 8 Hz); 6, 70 (1H, S); 6.93 (1H, dd, Hz, 17 Hz); 9.58 (W, d, Hz); The following compounds are obtained by the reaction of 7-acylamino-Zvinyl-cephalosporanic acid derivatives having formamido group, with concentrated hydrochloric acid according to the procedure described in example 133.  Example 138  (5-amino1, 2,4-oxadiazol-3-yl) -2-methoxyiminoacetamido D-3-vinyl-3-cephem-4carboxylic acid (syn-isomer).  IR (Nujol): 3250, 1770, 1660, 1550 cm--.  Example 139.  7-C2- (5-Amino1, 2,4-oxadiazol-3-yl) acetamvdo-Zwinsh-3-cephem-4-carboxylic acid.  IR (Nujol): 3500-3200, 1770, 1690, 1670, 1565 cm - Example 140.  2-amino-2-carboxyethyl-7- 2- (2-aminothiazol-4-yl) 2-methoxyiminoacetamido-3-vinyl-Zecem-4-carboxylate (syn-isomer).  IR (Nujol): 3200, 1770,.  1735 (wide), 1650 (wide)  Example 141  2-amino-2-carboxystil-7- 2- (2-aminothiazol-4-sh1) Bb-glycolamido3-3-vinyl-3-cephem-4carboxylate.  IR spectrum (Nujol); 3300, 3180, 1760, 1720, 1628 cmL Example 142.  (2-Aminothiazol-4-yl) -2- (b-2-amino-2-carboxyethoxycarbonylmethoxyimino) acetamido3-3-vinsch-3-cephem-4-carboxylic acid (syn-isomer), t. square  158 C (decomposition).  IR (Nujol): 3200 (wide), 1760 (wide) cm Example 143.  (2-Aminothiazol-4-sh1) -2- (Въ-3-amino-3-carboxypropoxyimino) acetamido-3-vinyl 3-cephem-4-carboxylic acid (synisomer), t. square   (decomposition).  IR (Nujol): 3120, 1766, 1612 cm Example 14. - A solution of benzhydrSh1-7- 2- (2-formamidothiazol-5-Sh1) 2-methoxyiminoacetamido3-3-vinsh1-3cepheme-4-carboxylate (syn-isomer, 2.7 g) in anisole (3.5 ml) and trifluoroacetic acid (10.8 ml) is stirred under ice-cooling for 15 minutes.  The reaction mixture is poured into diisopropyl ether (140 ml) and the mixture is stirred for 10 minutes.  Precipitated solid ve. the substance is collected by filtration, washed with diisopropyl ether and dried.  Get 7-C2- (2-formamidothiazole 5-yl) -2-methoxyiminoacetamido-Z-nvinyl-3-cephem-4-carboxylic acid (syn-isomer, 2.0 g), t. square   .  (decomposition).  IR (Nujol): 3250, 3090, 1770, 1660, 1530 cm - NMR spectrum, 0, ppm (DMSO-d):.  3.78 (2H, q, Hz); 3.92 (3N, S) 5. 27 (W, d, Hz); 5.33 (1H, d, Hz); 5.58 (1H, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 6.97 (1H, dd, Hz, 17 Hz); 7.57 (1H, 8.57 (1H, S); 9.89 (W, d, Hz).  Example 145  (2-Formamidothiazol-5-Sh1) -2-methoxyiminoacetamido-3-vinsh-3-cephem-4-carboxylic acid (anti-isomer, 2.35 g, t. square  165 ° C) is obtained by the reaction of benzhydryl-7- 2- (2-foryamidothiazol5-W1) -2-methoxyiminoacetamido3-3-vinyl-3-cephem-4-carboxylate (anti-isomer, 3.0 g) with trifluoroacetic acid (12 ml) in the presence of anisole (3.9 ml) in accordance with the method described in example 144.  IR (Nujol): 3260, 1780, 1730, 1690, 1670, 1575, 1520 NMR spectrum, (/ ppm, (DMSO-d (. ): 3.75 (2H, q, Hz); 4.14 (3N, S) 5. 28 (W, d, Hz); 5.35 (1H, d, Hz); 5.62 (1H, d, Hz); 5.77 (1H, dd, Hz, 8 Hz); 7.02 (1H, dd, Hz, 18 Hz); 8.23 (1H, S); 8.60 (1H ,.  S); 9.48 (1H d, Hz).  Example 146.  7-C2-Formamidothiazol-5-yl) -glyoxylamido-3-vinyl-3-cephem-4-carboxylic acid (2.1 g, t. square  157C with decomposition) is obtained by the reaction of benzhydryl-7-. (2formamidothiazol-5-yl) glyoxylamido 3-vinyl-3-cephem-4-carboxylate (2.9 g) with trifluoroacetic acid. acid (11.6 ml) in the presence of anisole (3.8 ml) in accordance with the procedure described in example 144.  IR (Nujol): 3270, 1775, 1700, 1655, 1535, 1470 cm NMR spectrum (H ppm (DMSO-d: 3.73 (2H, q, Hz); 5.24 (1H, d, Hz); 5.34 (1H, d, Hz); 5.60 (1H, d, Hz); 5.73 (W, dd, 8 Hz); 7.00 (1H, dd,. - 17 Hz); 8.57 (1H, S); 8.68 (1H, S); 9.87 (1H, d, Hz).  PRI me R 147.  (2-Formamidothiazol-4-yl) -2-ethoxyimino-acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 15.3 g) is obtained by the reaction benzhydryn-1-7-2 (2-formamidothiazole) 4-yl) -2-ethoxyiminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, 2.4 g) with trifluoroacetic acid (45.6 g) in the presence of anisole (17 g) in accordance with the procedure described . in the example of G44.  IR7Spectrum (NUYOL): 3250, 1770, 1690, 1660, 1540 cm NMR spectrum, cL, ppm (DMSO-d g): 1.30 (ZN, t, Hz); 3.77 (2H, q, Hz); 4.22 (2H, q, Hz); 5.27 (1H, d, Hz); 5.36 (1H, d, Hz); 5.62 (1H, d, Hz); 5.88 (1H, dd, Hz, 8 Hz); 6.98 (1H, dd, Hz, 17 Hz); 7.43 (W, S); 8.55 (1H, S); 9.70 (W, d, Hz); 12.47 (1H, broad S).  Example 148.  (2-Formamidothiazol-4-ml) -2-hexyloxyiminoacetamido3-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 3.1 g) is obtained by the reaction of benzhydryl-7-2 (2-formamidothiazol-4- (yl) -2-Hexyloxyiminoacetamido-3-vinyl-3-cephem4-carboxylate (syn-isomer, 5.5 g) with trifluoroacetic acid (9.3 g) in the presence of anisole (3.5 g) in accordance with the procedure described in example 144.   .  IR (Nujol): 3250.1780.1700, 1685 (shoulder), 1650,. , 1550 cm-NMR spectrum, s, ppm (DMSO-d g):.  0.88 (3N, t, Hz); 1.07-2.0 (8H, w); 3.72 (2H, ABq, Hz); 4.13 (2H, t, Hz); 5.23 (1H, d, Hz); 5.37 (1H, d, Hz); 5.60 (1H, d, Hz); 5.83 (1H, dd, J-5 Hz, 8 Hz); 6.97 (W, dd, Hz, 17 Hz); 7.40 (1H, S); 8.53 (W, S); 9.65 (1H, d, Hz); 12.62 (1H, broad B).  The following compounds were prepared by reacting 7-acylamino-Zvinyl cephalosporanic acid derivatives having benzhydryloxycarbonyl with trifluoroacetic acid in the presence of anisole according to the procedure described in Example 144.  59 example 149.  7-C2- (2-Aminothiazol-5-yl) -2-methoxyiminoacetamide 3-vinyl-3-cephem-4-carboxylic acids (syn-isomer), t. square  7  IR (Nujol): 3300, 1780, 1645, 1580, 1515 cm L PR EXAMPLE 150.  7-C2- (2-Aminothiazol-5-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (anti-isomer), t. square  250 ° C.  IR (Nujol): 3320, 1775, 1655, 1575, 1515 cm - Example 151-.  7- (2-Aminothiazol-5-yl) glyoxy-amido-J-3-vinyl 3-cephem-4-carboxylic acid, t. square  7  IR (Nujol): 3300, 3180, 1770, 1690, 1620, 1510, 1460 cm - Example 152.  7-C2- (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamido 3-vinyl-3-cephem-4-carboxylic acid (syn-isomer).  IR (Nujol): 3300, 1770, 1660, 1545 cm.  Example 153  (2-Aminothiazol-4-Sh1) -2-hexyloxyiminoacetamido 3-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer), t. square  147155 С (decomposition).  IR (Nujol): 3250, 1770, 1660, 1530 cm Example 154.  To a suspension of benzhydryl-7- 2- (5-amino-1,2,4oxadiazol-3-yl) -2-methoxyiminoacetate amido 3-3-vinyl-3-cephem-4-carboxylate (2.4 g) in methylene chloride (15 ml and anisole (1.8 g) was added trifluoroacetic acid (4.9 g) and the mixture was stirred at ambient temperature for 1 hour.  Diisopropyl ether (150 ml) is added to the reaction mixture, the precipitated product is collected by filtration, followed by suspension in a mixture of ethyl acetate and water, the pH of the mixture is adjusted to 7 with 10% aqueous sodium hydroxide solution.  Ethyl acetate is added to the separated aqueous solution and saturated with sodium chloride.  After adjusting the pH of the mixture to 1.5 with a 10% hydrochloric acid solution, the ethyl acetate solution is separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate.  After removal of the solvent, a residue is obtained, which is washed with distiff zfir.  76C (5-amino-1,2,4-oxydiazol-3-yl) -2-methoxyiminoacetamido-3-3-vinyl-3-cephem-4-carboxylic acid, a new acid (syn-isomer, 1.6 g) is obtained.  IR (nujol): 3250, 1770, 1660, 1550 ctf NMR spectrum, A, ppm (DMSO-dg): 3.77 (2H, q, Hz); 4.00 (3N, S); 5.23 (1H, d, Hz); 5.37 (1H, d, Hz); 5.62 (1H, d, Hz); 5.85 (1H, dd, Hz, 8 Hz); 7.00 (1H, dd, Hz, 17 Hz); 8.07 (2H, S); 9.78 (1H, d, Hz).  Example 155  7- (2- 5-CN- (N, N-Dimethylaminomethylene) amino -1,2,4-cadiazol-3-sh-2-methoxyimino-acetamido) -3-vinyl-3-cethem-4-carboxylic acid (syn-isomer, 2.2 g) is obtained by the reaction of benzhydryl-7-2 / 5- {N- (N, N-dimetsIminomethyl) amino 1,2,2-oxadiazol-3-sh1 / -2-methoxyiminoacetamido3-3-vinyl-3-cephem -4 carboxylate (syn-isomer, 3.3 g) with trifluoroacetic acid (5.93 g) in the presence of anisole (2.2 g) in accordance with the procedure described in example 154.  IR (nujol): 3200.1770.1700, 1660, 1640, 1530 ctf NMR spectrum, cL, ppm (DMSO-df) j 3.08 (3N, S); 3.23 (3N, S); 3.75 (2H, q, Hz); 4.00 (3N, S); 5.23 (1H, d, Hz); 5.37 (1H, d, Hz); 5.60 (1H, d, Hz); 5.85 (1H, dd, Hz, 8 Hz); 6.99 (1H, dd, Hz, 17 Hz); 8.65 (1H, S); 9.78 (W, d, Hz).  Example 156.  (5-Amino, 2,4-oxadiazol-3-yl) acetamido-3wins1-3-cephem-4-carboxylic acid (0.55 g) gives the reaction benzhydryl-7-2- (5-amino-1,2, 4-oxadiazol-3-yl) acetamido-3-vinyl-Zepham-4-carboxylate (2.05 g) with trifluoroacetic acid (9.0 g) in the presence of anisole (2.5 g) in accordance with the procedure described in example 154.  IR (Nujol): 3500-3200, 1770, 1690, 1670, 1565 cm-H NMR, CL, ppm (DMSO-d): 3.50 (2H, S); 3.73 (2H, q, Hz) j 5.18 (1H, d, Hz); - 5.35 (1H, d, Hz); 5.62 (W, d, Hz); 5.75 (1H, dd, Hz, 8 Hz); 7.02 (1H, dd, Hz, 18 Hz); 7.8 SG (2H, S); 9.22 (W, d, Hz).  Example 157.  (2-Aminothiazol-4-yl) -2-carboxymethoxyimino acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 1.8 g) and sodium bicarbonate (667 mg) are dissolved in water (0 ml), the solution is lyophilized dried to obtain the disodium salt (2 aminothiazol4 yl) -2-carboxymethoxyiminoacetamido3-3-vinsh-3-cephem-4-carboxylic acid (syn-isomer, 1.9 g), t. pl, 250С.  IR (nujol): 3300 (wide), 3180 (wide), 1750, 1660, 1535 NMR spectrum, aA, ppm (DMSO-d): 3.42 (211, wide S); 4.37 (2H, broad S); 5.10 (1H, d, Hz); 4.65, 9 (ЗН, t); 6.89 (W, S); 6.6-7.3 (W, t); 7.33 (2H, broad S).  To a solution of compound (1.8 g) in N, N-dimethylformamide (18 m was added iodomethyl pivalate (1.84 g) in N, S and dimethyl formamide (1.8 ml) under ice cooling, followed by stirring at this temperature for 15 minutes.  The reaction mixture is poured into a mixture of ice water and ethyl acetate, the organic layer is separated. The remaining aqueous layer is extracted with ethyl acetate and the combined ethyl acetate solution is washed with an aqueous solution of sodium bicarbonate and with an aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate.  After removing the solvent, a residue is obtained, which is pulverized with diisopropyl ether.  . The filtrate is collected and pivaloyloxy methyl-7-L 2- (2-aminothiazol-4-yl) -2 is obtained (pivaloyloxymethoxycarbonylmethoxy.  imino) acetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, 0.9 g), t. square  115 ° C (decomposition).  IR Spectrum (Nujol):. 3400,3260,310 1780, 1750, 1660, 1530 cm.  NMR spectrum, L, ppm (DMSO-dg): 1.06 (18H, S); 3.77 (2H, q, Hz 4.76 (2Y, S); 5.25 (1H, d, Hz); 5.4-6.1 (7H, m); 6.5-7.2 ( W, m); 6.82 (W, S); 7.24 (2H, broad S); 9.59 (1H, d, Hz).  Example 158.  To a solution of sodium 7-C2- (2-aminothiazol-4-yl) -2 methoxyiminoacetamido3-3-vinyl. p-3 cepheme-4-carboxylate (syn-isomer, 2.2 g) in N, N-dimethylformamide (25 ml is added dropwise a solution of iodoethyl acetate (1 g) in N, N-dimethyl ormamide (3 ml) at a temperature below in for 2 minutes and the mixture is stirred at this temperature for 15 minutes.  The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (50 ml) and the separated aqueous solution was extracted with ethyl acetate (30 ml).  The combined ethyl acetate solution is washed twice with a 5% aqueous solution of sodium bicarbonate and twice with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.  After removal of the solvent, the residue is pulverized with diisopropyl ether and collected by filtration.  Acetoxymethyl-7-C2- (2-amino-thiazol-4-yl) -2-methoxyimoacetate-J-3-vinyl-3-cefem-4-carboxyl is obtained (syn-isomer, 1.6 g), t. square  78-83 0.  . IR (Nujol): 3300, 1765 (wide), 1660, 1610, 1535 cm-.  NMR spectrum, d, ppm (DMSO-dg): 2.10 (3N, S), 3.77 (2H, ABq, Hz); 3.87 (3N, S); 5.25 (1H, d,); 5.38 (1H, d, Hz); 5.67 (1H, d, Hz); 5.85 (3N, m); 6.77 (1H, S); 6.90 (1H, dd, Hz, 17 Hz); 9.80 (1H, d, Hz).  Example 159.  Propionyloxymethyl-7- 2- (2-aminothiazol-4-sh1) -2 methoxyimino acetamido-3-vinyl-3 cefem-4-carboxylate (syn-isomer, 1.5 g), t. square  79-85 s is obtained by reacting sodium (2-aminothiazol-4-yl) 2-methoxyiminoacetamido-3-vinyl-3 cefem-4-carboxylate (syn-isomer, 1.5 g) with iodomethyl propionate (0.82 g) according to the procedure described in example 158.  IR (Nujol): 3350, 1770 (wide), 1650, 1620, 1530 cm-H NMR spectrum, “H, ppm (DMSO-d): 1.03 (3N, t, Hz); 2.40 (2H, q, Hz); 3.77 (2H, ABq, Hz); 3.85 (3N, S); 5.38 (1H, d, Hz); 5.62 (1H, d, Hz); 5.85 (ЗН, t); 6.75 (1H, S); 6.85 (W, dd, Hz, 17 Hz); 9.62 (W, d, Hz).  Example 160  Isobutyryloxymethyl-7- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido3-3-vinyl-3cepham-4-carboxyl-1 (syn-isomer, 2.3 g), t. square  92-100 C (decomposition) is obtained by the reaction of (2-aminothiazol-4-yl) -2-methoxyimine acetamido 3-vinyl-3-tseph-4-carboxylate (CI isomer, 3.0 g) with iodomethyl eobeutyrate (1.7 g) in accordance with the method described in example 158.  IR (Nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cm ---.  NMR spectrum, cG, ppm (DMSO-d): 1.1 (6H, d, Hz); 2.3-2.9 (1H, m) 3.46-4.23 (2H, m); 3.85 (3N, S); 5.25 (1H, d,. r4); 5.38 (1H, d, Hz); 5.52-6.0 (2H, t); . 5.87 (2H, S); 6.77 (1H, S); 6.85 (1H, dd, Hz, 17 Hz); 9.63 (1H, d, Hz).  Example 161  Pivaloyloxymethyl-7- 2- (2-amino-Thiazol-4-yl) -2-ethoxyiminoacetamido-3-vinyl-Zecem-4-carboxylate (syn-isomer, 2.6 g) is obtained by reacting sodium (2-aminothiazol-4-yl) - 2-ethoxyiminoacetamido-3-cephem-4-carboxylate (syn-isomer, 3.65 g) with iodomethyl pivalate (1.94 g) according to the procedure described in Example 158.  IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530 cm - NMR spectrum, (G, ppm (DMSO-d): 1.17 (9H, S); 1.23 (ZN, t , Hz); 3.77 (2H, q, Hz); 4.12 (2H, q, Hz); 5.23 (1H, d, Hz); 5.38 (1H, d, Hz); 5, 62 (1H, d, Hz); 5.73- (ZN, t); 6.73 (1H, S) 6.83 (1H, dd, Hz, 17 Hz); 9.57 (1H, d, Hz ).  Example 162  Hexanoyloxymethyl-7- 2- (2-aminothiazol-4-yl) -DL glycolamido-3-vinyl-3-cephem-4carboxylate is prepared by reacting sodium 7- (2- (2-aminothiazol-4-sh1) -Bb-glycol amido - 3-vinst-3-cephem-4-carboxyl (2.0 g) with iodomethylhexanoate (1.3 g according to the procedure described in example 158, t. square  65-70s.  IR (Nujol): 3300, 1770, 1680, 1619 ctf NMR spectrum, (, ppm (DMSO-d): 0.61 1.80 (9H, t); 2.37 (2H, t,, 0 Hz 2.40 (1H, ha); 3.78 (2H, q, Hz 4.90 (1H, d ,, OHz); 5.23 (1H, d, J-4.0 Hz); 5.41 (1H, d,, 0 Hz); 5.53-6.13 (4H, m); 6.45 (1H, S); 6.88 (1H, dd,, 0 Hz, 18.0 Hz), 8.44 (d,, 0 Hz) 1 (.  8.56 (d, 0 Hz)) The following compounds were prepared according to the procedure described in Example 158.  Example 163  1-2-Benzgidrosh1oxycarbonyl-2-tert-butoxycarbonylaminoethm1-7-2- (2-formamidothiazol4-yl) -2-methoxyiminoacetamido-3vinyl-3-cephem-4-carboxylate (sinisomer).  IR (Nujol): 3280, 1782, 1709, 1689, 1656 Example 164.  L-2-Benzgidrosh1oxycarbonyl-2-tert-butoxycarbonylaminoethyl-7-, (2-formamidothiazol-4yl) glyoxylamido-3-vinyl-3-cephem4-carboxylate (syn-isomer).  IR (Nujol): 1777, 1720, 1667 cmH Example 165.  Sodium 7-G2- (2-aminothiazol-4-sh1) -2methoxyiminoacetamido-3-vinsh1-3cepheme-4-carboxylate (syn-isomer, 2.0 g) was added to the solution in S, N-dimethylformamide (40 ml) Sodium iodide (0.8 g) and 1-bromopropyl acetate (0.9 g) are added with ice-cooling and stirring.  Re-mixing is continued at this temperature for 30 minutes.  The reaction mixture is poured into a mixture of water and ethyl acetate.  The separated organic layer is washed twice with saturated.  an aqueous solution of sodium chloride and twice with water, followed by drying over anhydrous magnesium sulphate.  After removing the solvent, the residue is pulverized with diisopropyl ether and chromatographed on silica gel with a mixture of ethyl acetate and chloroform (4: 6 - 6: 4 by volume).  The fractions containing the desired compound are collected.  After removal of the solvent, the residue is pulverized with diisopropyl ether and collected by filtration.  A 1-acetoxypropyl-7-2 (2-aminothiazol-4-yl), -2-methoxyiminoacetamido3-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 0.62 g) is obtained, t. square  97-10Gs.  IR (nujol): 3300, 1765, 1670, 1610 cm H NMR, eL, ppm (DMSO-d): 0.95 (3N, t); 1.87 (2H, t); 2.07 (3N, S); 3.48-4.23 (2H, t); 3.85 (3H, S); 5.25 (1H, d,, 0 Hz); 5.25-5.98 (ЗН, t); 6.74 (1H, S); 6.53-7.38 (4H, t); 9.58 (1H, d,, 0 Hz).  Example 166.  1-Acetoxypropyl (2-aminothiazol-4-nl) Bb-glycolamido3-3-vinsh1-3-cepam-4carboxylate (0.68 g) is obtained by the reaction of sodium 7-C2- (2-aminothiazol-yl) -DL-glycrlamido3- H-vinyl-Zepham-4-carboxylate (2, O g) with 1-bromopropyl acetate (1.0 g) in the presence of sodium iodide (0.8 g) according to the procedure described in Example 65.  IR (Nujol): 3300, 1770, 1680, 1629 cmH NMR, G-, ppm (DMSO-dc): 0.71-.  1, 12 (ЗН, t); 1.81 (2H, ha); 2.05 (ЗН, S) ;, 3.76 (2H, q,, 0 Hz); four. 91 (1H, ha); 5.20 (1H, d, Oz 5.23-5.96 (GH, t); 6.41-7.51 (GH, t. 8.33 (G, t). .  Example 167.  To a solution of L-benzhydryloxycarbonyl-2-tert-butoxycarboiyl-amino-ethyl-7- (2-aminothiazol-4-yl) -glyoxylamido-3-vin 3-cephem-4-carboxyl 1 (5.4 g) in methanol add a little sodium borohydride (0.417) d) at 5c, the mixture is stirred at the same temperature for 15 minutes.  After adjusting the pH of the reaction mixture to 5.0, it is concentrated. hydrochloric acid is concentrated to dryness under reduced pressure and a residue is obtained which is a chromatog. Refined on silica gel (100 ml), eluting with a mixture of benzene and acetone.  The fractions containing the desired compounds are collected and exchanged.  2-benzhydryl-1-carboxycarbon-2-tert-bytoxycarboxylaminoeth w 7-2-C2-aminothiazol-4-yl) -bh-glyco-amido-3-vinyl-3-cephem-4-carboxyl (2.5 g) is obtained.  IR (Nujol): 3340, 1774, 1715 cm-H NMR spectrum, cL, ppm (DMSO-d): 1.33 (9H, S); 3.30 (W, S); 3.46, 3.90 (2H, ABq, Hz), 4.50 (3H, 4.83 (S) f.  four. 92 (s) l 5.1-6.0 (3H, m); 5.11 (1H, d, D 6.41 (W, S); 6.77 (1H, S); 6.88 (1H, dd, Hz, 18 Hz); 7.37 (UN, S); 8.36 (d, Hz) i,.  8.46 (d, Hz) J Example 168.  A solution of benzgshfil-7- (4-bromo-2-methoxy-schnoacetoacetamido) -3-vinyl-3-cephem-4carboxylate (syn-isomer, 1.2 g), thiourea (0.5 g) and sodium acetate (trihydrate, 0.7 g) in water (20 ml) and. tetrahydrofuran (20 ml) was stirred for 3.5 h.  The reaction mixture is extracted with ethyl acetate, the extract is washed with water and dried over anhydrous magnesium sulfate.  After removal of the solvent, the residue is pulverized with distil ether and benzhydryl-7-2- (2amidothiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxes at (syn-isomer, 1.05 g) is obtained.  IR (Nujol): 3230.1780, 1720, 1650, 1620, 1580, 1540 cm.  NMR, cG, ppm (DMSO-d): 3.78 (2H, q, Hz); 3.87 (3N, S); 5.28 (1H, d, Hz); 5.32 (1H, d, Hz); 5.65 (1H, d, Hz); 5.72 (1H, dd, Hz, 8 Hz); 6.80.  (1H, S); 6.80 (1H, dd, Hz, 17Hz); 6.97 (1H, S); 7.20-7.67 (UN, t); 9.67 (1H, d, J-8 Hz).  Example 169.  (2-Aminothiazol-4-yl-2-methoxyiminoacetamidoZ3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 0.8 g) is obtained by the reaction of 7- (4-bromo-2-methoxyiminoacetoacetamido) -3-vinyl -Z-cephem-4-carboxylic acid (syn-isomer, 1.5 g) with thiourea (0.8 g) in accordance with the procedure described in example 168.  IR (Nujol): 3400-3100, 1780, 1660, 1630, 1540 cm-.  NMR, cG, ppm (DMSO-d): 3.72 (2H, q, Hz); 3.87 (3N, S); 5.20 (1H, d, Hz); 5.33 (W, d, Hz); 3.58 (1H, d, Hz); 5.78 (1H, dd, Hz, 8 Hz); 6.77 (1H, S); 6.95 (1H, dd, Hz, 18 Hz); 9.62 (W, d, Hz).  The following compounds were prepared by reacting the corresponding 7-acyl-amino-3-vinyl-cephalosporanic acid derivatives with thiourea in accordance with the procedure described in Example 168.  Example 170.  L-2-Benzhydryloxycarbonyl-2-tert-butoxycarbonyl-aminoethyl-7-f2-ata (2-aminothiazol-4-shl) 2-methoxy-thyminotrocetamide-3-vinyl-3-ref-4-box-4-box-3-vinyl-3-vinyl-3-reflux-3-vinyl-3-tetrame-4-carboxamide-3-vinyl-3-phase-4-box;  IR (Nujol): 3370, 1775, 1730, 1616 cm - Example 171.  (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamido 3-vinyl-3-cephem-4-carboxylic acid (syn-isomer), IR spectrum (Nujol): 3300, 1770, 1660, 1545 cm R and m e p 172.  7-C2- (2-Aminothiazol-4-yl) -2-hexyloxyiminoacetamide-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer), t. square  147155 s (decomposition).  IR (Nujol): 3250, 1770, 1660, 1530 cm - Example 173.  Pivaloyloxymethyl-7- 2- (2-aminothiazol-4-yl) -2 (pivaloyloxymethoxycarbonylmethoxy imino) acetamido3-3-vinyl-3-cephem-4carboxylate (syn-isomer), t. square   (decomposition).  IR (Nujol): 3400, 3260, 3100, 1780, 1750, 1660, 1530 cm.  Example 174.  Acetoxymethyl-2- (2-aminothiazol-4-yl) -2-methoxy-imino-acetamido-3-vinyl 3-cephem-4 carboxylate (syn-isomer), t. pl, 7883С.  IR (Nujol): 3300, 1765 (wide), 1660, 1610, 1535 cm.  Example 175  Propionyloxymethyl-7- 2- (2-aminothiazol-4-Sh1) -2-methoxyimino-acetamido-3-V-vinyl-3-cephem-carboxylate (syn-isomer), t. square  79-85 S.  IR (Nujol): 3350, 1770 (wide), 1650, 1620, 1530 cm.  Example 176  Isobutyryloxy methyl 7- | 2- (2-aminothiazol-4-yl) -2 methoxyiminoacetamido 3-3-vinyl-Zeph-4-carboxylate (syn-isomer), t. square  92-100С (decomposition).  IR (Nujol): 3400-3100, 1780-1740, 1670,. 1610, 1530 cm Example 177.  Pivalonloxymethyl-7- 2- (2-aminothiazol-4-Sh1) -2-ethoxyiminoacetamido3-3-vinsh1-3cepheme-4-carboxylate (syn-isomer).  IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530 cm-.  Example 178.  1-Acetoxypropyl-7- 2- (2-aminothiazol-4-Sh1) -2-methoxyimino-acetamido3-3-vinyl-3 cefem-4-carboxylate (syn-isomer), t. square  97-101C.  IR (Nujol): 3300, 1765, I 1670, 1610 cm-.  Example 179.  To a mixture of trifluoroacetic acid (28.8 ml) and anisole (4.8 ml) was added L-2-benzhydryl-1-carbonyl-2-tert-butoxycarbon-1 aminoethyl-7-2- (2-aminothiazol-4-yl) 2-methoxyimo-acetamido 3 -3-vinyl-zecem-4-carboxylate (4.8 g) at and the mixture is stirred for 30 minutes.  The reaction mixture is added dropwise to diisopropyl ether (900 ml), the precipitated substance is collected by filtration, and water (100 ml) and ethyl acetate (100 ml) are added to it.  The separated aqueous solution was washed with ethyl acetate (50 ml), followed by complete removal of ethyl acetate by evaporation.  The resulting aqueous solution is treated with 5% aqueous sodium bicarbonate solution and adjusted to pH 3.0 followed by removal of the precipitated substance. - An aqueous solution is chromatographed on a non-ionic absorption resin (100 ml) Diaion HP-20 (Mitsubishi Chemical Industries Ltd.). ).  After washing with water (300 ml), elution is carried out with a 30% aqueous solution of isopropyl alcohol and the fractions containing the desired compound are collected.  After removal of the solvent, the residue is lyophilized and dried.  B-2-amino-2-carboxyethyl-7-C2- (2-aminothiazol-4-yl) -2methoxyiminoacetamido-3-vinsh1-3cepheme-4-carboxylate (syn-isomer, 1.5 g) is obtained.  IR spectrum (Nujol): 3200, 1770, 1735 (shoulder), 1650 (wide) cs.  NMR spectrum, s, ppm (DCI + DjO): 3.73, 3.94 (2H, ABq, Hz); 4, 13 (3N, S); 4.5-4.9 (ЗН, t); 5.30 (1H, d, Hz); 5.56 (1H, d, Hz); 5.77 (1H, d, Hz); 5.80 (1H, d, Hz); 7.11 (1H, dd, Hz, 18 Hz); 7.19 (1H, S).  Example 180  A solution of L-2benzhydryloxycarbonyl-2-tert-butoxycarbonyl-aminoethyl-7- 2- (2-aminothiazol-4-yl) -Bb-glycolamido-3-vinyl-3-cephem-4-carboxylate (2.2 g) and anisole (5 ml) in trifluoroacetic acid (20 ml), stirred at 5 ° C for 30 minutes.  The reaction mixture is added dropwise to diisopropyl ether (600 ml), the precipitated substance is collected by filtration and washed with diisopropyl ether, followed by dissolution in water (50 ml).  After adjusting the pH of the mixture to 3.5 with a 5% aqueous solution of sodium bicarbonate, an aqueous solution. chromatographic on non-ionic absorption resin Diaion HP-20 (80 ml).  After washing with water (240 ml), elution was carried out with a 10% aqueous solution of isopropyl alcohol and the fractions containing the desired compound were collected.  After removing the solution, the residue is lyophilized and then dried.
B-2-amino-2-carboxyethyl-7-C2- (2-aminothiazol-4-U1) -DL glycolamido-3-vinyl-3-cephem-4 carboxylate (1.1 g) is obtained.
IR (Nujol): 3300, .3180, 1760, 1720, 1628 cm-
NMR spectrum, dl, rrga (DMSO-d): 3.55, 3.97 (2H, ABq, Hz); 4.34, 83 (ЗН, t); 4.88 (1H, S); 5.18 (1H, d, Hz); 5.77 (1H, t); 6.43 (1H, S); 6.98 (1H, dd, Hz 18 Hz)
8.4 (d, Hz) 1,. 8.47 (d, Hz)
Example 181. A mixture of benzhydryl-7- 2- (2-aminothiazol-4-yl) -2 (L-2-benzhydryloxycarbonyl-2-tertbutoxycarbonylaminoethoxycarbonylmethoxyimino) acetamido-3-vinyl-3zefem-4-carboxylate (syn isomer) , 4 g), trifluoroacetic acid (21.6 ml) and anisole (5.4 ml) is stirred for 70 minutes. The reaction mixture is added dropwise to diisopropyl ether (1000 ml) and the precipitated substance is collected. After washing with diisopropyl ether, this substance is dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). The separated aqueous solution was washed with ethyl acetate, which was then completely removed by evaporation. The pH of the resulting aqueous solution was adjusted to 3.0 with 5% sodium bicarbonate solution and then chromatographed on Diaion HP-20 non-ionic adsorption resin (100 ml). After washing with water (300 ml), elution is carried out with a 20% aqueous solution of isoproshm alcohol and fractions containing the desired compound are collected. After removal of the solvent, the residue is lyophilized.
(2-Aminothiazol4-yl) -2- (L-2-amino-2-carboxyethoxycarbonylmethoxyimino) acetamido 3 vinyl-3-cephem-4-carboxylic acid, (syn-isomer, 1.7 g), m.p. 158 C (decomposition).
IR (Nujol): 3200 (wide), 1760 (wide) see
NMR spectrum, J, ppm (DMSO-d): 3.51, 3.75 (2H, ABq, Hz); 4.3-4.8 (5Y, t); 5.13 (1H, d, Hz); 5.19 (1H, d, Hz); 5.44 (1H, d, Hz); 5.72 (1H,
dd, Hz, 8 Hz); 6.79 (1H, S); 6.93 (W, dd, Hz, 18 Hz);
9.66 (1H, d, Hz).
Example 182, A mixture of benz5 hydryl-7-C2- (2-aminothiaz6l-4-yl) -2 (DL-2-benzhydryloxycarbonyl-3-tertbutoxycarbonylaminopropoxyimino) acetamido -3-vinyl-3-cephem-4-carboxylate , 3.3 g), trifluoroacetic acid (20 ml) and anisole (3.3 ml) was stirred at 15-10 ° C for 1.5 hours. The reaction mixture was added dropwise to diisopropyl ether (300 ml), precipitated the substance is collected by filtration and then washed with diisopropyl ether followed by dissolving in water (50 ml). The aqueous solution is washed with ethyl acetate (50 ml x 2) and then
 ethyl acetate is completely removed by evaporation. The pH of the resulting aqueous solution was adjusted to 3.1 with a 5% aqueous solution of sodium bicarbonate and chromatographed on Diaion HP-20 non-ionic adsorption resin (100 ml). After washing with water (300 ml), elution is carried out with a 20% aqueous solution of isopropyl alcohol, fractions containing the desired compound are collected, which are then treated with activated charcoal. After removal of the solvent, the residue is lyophilized.
(2-Aminothiazol5 4-yl) -2- (DL-3-amino-3-carboxypropoxyimino) acetamido-3-vinyl-Zeph-4-carboxylic acid (10, sinusomer, 0.7 g) is obtained, m.p. 145 ° C (decomposition).
- IR spectrum (Nujol): 3120, 1766, 1612.
NMR spectrum, cL, ppm (D O + DCl): 2.53 (2H, t); 3.82 (2H, broad S); 4.31 (1H, t, Hz); 4.57 (2H,
5 t, Hz); 5.32 (1H, d, Hz); 5.53 (W, d, Hz); 5.73 (1H, d, Hz); 5.82 (1H, d, Hz); 7.13 (1H, dd, Hz, 18 Hz); 7.25 (W, S).
0 Example 183. To a suspension of vilsmeier reagent, prepared from N, N-dimethylformamide (1.8 g), and phosphorus oxychloride (3.7 g), 2- (25 formamidothiazol-4 -yl) -2- (2-pyridylmethoxyimino) acetic acid (syn-isomer 6.74 g) with ice-cooling with stirring. Stirring is continued at the same temperature for 30 minutes. An activated acidic solution is obtained, which is added to a solution of benzhydryl-7-amino-3-vinsh1-3-cephem-4 carboxylate chlorohydrate (8.6 g) and trimethylsilylacetamide (15.7 g) in ethyl acetate (100 ml) at -20 ° C, the mixture was stirred at (-20) (-5) C for 2 hours. To the reaction mixture was added ethyl acetate and. water followed by separation of the ethyl acetate layer. The ethyl acetate solution is washed with a saturated aqueous solution of sodium bicarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate. After removing the solvent, the residue is pulverized with diisopropyl ether to give benzhydryl-7-C2- (2-forms
thiazol-4-yl) -2- (2-pyridylmethoxyimino) acetamido 1-3-vinyl-3-cephem-4carboxylate (syn-isomer, 13.6 g).
IR (Nujol): 3250, 1760, 1720, 1660, 1580, 1560, 1540 cm
NMR spectrum, cr, ppm (DMSO-d): 3.77 (2H, q, Hz); 5.33 (4H, ha); 5.63 (1H, d, Hz); 6.03 (1H, dd, Hz, 8 Hz); 6.80 (1H, dd, Hz, 17 Hz); 7.00 (1H, S); 7.13-8.00 (14H, t); 8.53 (1H, t); 8.53 (1H, S); 10.07 (1H, d, Hz); 12.7 (1H, S).
Example 184. Benzhydryl-7C2- (2-formamidothiazol-4-yl) -2- (3-. Pyridylmethoxyimino) acetamido -3 vinyl-3-cephem-4-carboxylate (sinisomer, 8.7 g) is obtained by the reaction of benzhydryl hydrochloride1-7 -amino-3-vinyl-3-cephem-4-carboxylate (8.6 g) with 2- (2-formamidothiazol-4-yl) -2 (3-pyridylmethoxyimino) acetic acid (syn-isomer, (6,74) , in accordance with the procedure described in Example 183. N-jpC-CONH-Tr. NSHR-II. coaxial Benzhydryl-7- 2- (2-formamidothiazol-4-yl) -2- (2-pyridylmethoxyimino) acetamido - 3-vinsh-3-cephem-4 ambient temperature for 1.5 hours. After removing the solvent to the residue ethyl acetate and water are added, followed by adjusting the pH to 7 with 20% sodium carbonate aqueous solution. The separated ethyl acetate solution is washed with an aqueous solution of sodium chloride and then dried over anhydrous sulfate
magni. After removal of the solvent, benzhydryl-7-C2- (2-aminothiazol-4-sh1) -2- (2-pyridylmethoxyimino) acetamido2-3-vinsh3-3-cephem-4carb oxylate (syn-isomer, 4.6 g) is obtained.
IR Spectrum (Nujol):. 3240, 1775, 1720, 1670, 1610, 1590, 1540 cmL
NMR spectrum, c, ppm (DMSO-dt): 3.73 (2H, q, Hz); 5.28 (2H, S); 5.28 (2H, ha); 5.63 (W, d, Hz);
5.98 (1H, dd, Hz, 8 Hz); 6.82 (1H, dd, Hz, 17 Hz); 6.85 (W, S); 7.00 (1H, S); 7.1-8.00 (13H, t); 8.53 (W, dd, Hz, 6 Hz); 10.00 (W, d, Hz).
Example 186. 772 IR spectrum (nujol): 3260, 1770, 1710, 1690, 1650, 1580, 1570, 1530 cm — 5 Gp spectrum, cr, ppm (DMSO-d) S 3.75 (2H, q, Hz ); 5.27 (2H, S); 5.30 (1H, d,); 5.30 (1H, d, Hz); 5.67 (1H, d, Hz); 5.97 (1H, dd, Hz, 8 Hz); 6.78 (1H, dd, Hz, 17 Hz); 6.97 (1H, S); 7.20-7.67 (12H, t); 7.87 (1H, t); 8.53 (1H, S); 8.47-8.70 (2H, t); 9.88 (1H, d, Hz); 12.67 (1H, broad S). Example 185. A mixture of benzhydryl-7-C2- (2-formam 1 Pdiazol-4-P1) 2- (2-pyridylmethoxyimino) acetamido 1-vinyl-3-cephem-4-carboxylate (syn-isomer, 5.45 g) concentrated salt Acidic acid (5 ml) and methanol (150 ml) was stirred at N-rpC-CONH-TY CONHA J C axis - / l coaxial {-O) 2 ° li / cH3SO, e ®cc carboxylate (syn-isomer, 2, 72 g) is added to a solution of dimethyl sulfate (O, 95 g) in tetrahydrofuran 73 (12 SML and the mixture is stirred at 43-46 C for 25 hours. After removing the solvent, the residue is dissolved in a mixture of water (30 ml), tetrahydrofuran (30 ml). ml) and ethyl acetate (50 ml) followed by separation of water About the layer. The remaining organic solution is extracted with water, ethanol is added to the combined aqueous solution. After removal of the solvent, the residue is washed with a mixture of dimethyl ether and 1-methyl-2 (1- (2-formamidothiazol-4-yl) -1- CH (4-benzhydr oxycarbonyl-3-vinyl 3-cephem-7 or N -pC-CONH rf nsoshA 1 cn, -O I O 0 1 / Lf CH 3 CH 3 SO 3)
A solution of the compound obtained above (1.6 g) and concentrated hydrochloric acid in methanol (30 ml) and tetragvdrofuran (20 ml) is stirred at ambient temperature for 5 hours. After removing the solvent, the residue is dissolved in tetrahydrofuran and ethanol, then concentrated and a residue is obtained which is pulverized with diethyl ether.
1-Methyl-2- {1 (2-aminothiazol-4 -) (4-benz hydryloxycarbonyl-3-vinyl-3-cephem-7-yl) carbamoyl methylenaminooximeNc-SOS-jY is obtained. . - .- c-CONH-rr
HCONHl JJlo Ny-CH CH2 HCONHJljTllo s
S -n
Ar, np4C- / Vk.S W
W-Q
1-Methyl-3t1- (2-formamidothiazol4-yl) -1-Sy- (4-benzhydryloxycarbonylZ-vinyl-3-cephem-7-yl) carbamoyl methyleneaminoxymethyl-pyridine methyl sulfate (syn-isomer) is obtained by the reaction of benzhydryl-7- 2- (2-formamidothiazol-4-Sh1) | -2- (3-pyridylmethox RP1 Mino) tc11 - pyridine methyl sulfate (sinisomer, 1.5 g).
IR (Nujol): 1780, 1720, 1680, 1630, 1585, 1545, 1500 cm
NMR spectrum, s, ppm (DMSO-d): 3.43 (3N, S); 3.80 (2H, t); 4.40 (3N, S); 5.33 (1H, d, Hz); 5.33 (1H, d, Hz); 5.57 (1H, d, Hz); 5.73 (2H, S); 5.83 (1H, dd, Hz, 8 Hz); 6.82 (1H, dd, Hz, 17 Hz); 6.97 (1H, S); 7.07 (1H, S); 7.17-7.67 (UN, t); 7.93-8.80 (ЗН, t); 9.17 (1H, dd, Hz, 6 Hz), 10.08 (W, d, Hz)
Example 187
I / l
SNSNZZO
acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 3.4 g) with dimethyl sulfate (1.26 g) in accordance with the procedure described in example 186,
IR (nujol): 1770, 1720, 1670, 1550 (m 774 carbamoyl 1-methylamino-oxymethyl pyridium "methyl sulfate (syn-isomer, g). IR spectrum (nujol): 3180 j 1770, 1710, 1670, 1625, 1540 cm NMR spectrum, dL, ppm (DMSO-dj): 3.40 (3N, S); 3.73 (2H, t); 4.38 (3N, S); 5.33 (1H, d, Hz ); 5.35 (1H, d, Hz); 5.65 (1H, d, Hz); 5.75 (2H, S); 6.02 (1H, dd, Hz, 8 Hz); 6, 80 (1H, dd, Hz, 17 Hz); 6.98 (1H, S); 7.2-7.70 (UN, ha); 7.57 (1H, S); 8.55 (1H, S ); .7.93-8.63 (ZN, ha); 9.13 (1H, dd, Hz, 6 Hz); 10.00 (1H, d, Hz). N - pc: -osh -% „D J II o NyJ-№CH, Mch. HjN SN T WO °°.... 1. CH 3 CH 2 3 3 NMR spectrum, cG, ppm (DMSO-d): 3.42 (3N, S); 3, 80 (2H, m); 4.40 (3H, S); 5.33 (1H, d, Hz); 5.38 (1H, d, Hz); 5.52 (2H, S); 5.70 (1H, d, Hz); 5.95 (1H, dd. I -jT-v. -Wi nT-g 5. N e-coNHn-r, HCONH-JI ,, COOCH (- /) HC l.. , 1 g) is obtained by reacting the compound (1.5 g) described above with concentrated hydrochloric acid (1.2 ml) in accordance with the procedure described in example 186. IR spectrum (Nujol): 3400-3100, 1760 , 1660, 1600, 1530 cm-NMR spectrum, sG, ppm (DMSO-d): 3.40 (3N, S); 3.73 (2H, broad S); 4.45 (3N, S); 5.20 (1H, d, Hz); 5.38 (1H, d, Hz); 5.47 (2H, S); 5.63 (1H, d, Hz), 5.80 (1H, dd, Hz, 8 Hz); 6.7-7.7 (11H, t); 6.97 (1H, S); 7.12 (1H, S); 8.17 (1H, t); 8.7 (1H, t); 9.00 (1H, t); 9.17 (1H, broad S); 10.02 (1H, d, Hz). Example 188. To a solution of benzhydryl-7- 2- (2-aminothiazol-4-yl) 2- (2-pyridsh1methoxyimino) acetamido 3-vinyl-3-cephem-4-carboxylate (sinisomer, 4.6 g) in methylene chloride ( 20 ml) and anisole (3.0 g) are added trifluoroacetic acid (11.2 g) with stirring and ice-cooling C-CONH-pf N-C-AT II / -coaxial (- / 3 OCHH / ®CH3CbbSoi hydrochloride 1-methyl-2- {1- (2-aminothiazol-4-yl) (4-benzhydr 11yloxy 118 6087 C-CONH-rY NOY-CH-CH r COOCHf-- ocH, - / 3 SND-SN3BO. Stirring is continued at ambient temperature in over 1.5 hours. The reaction mixture is added dropwise to diisopropyl ether (300 ml) and oselenated crystals. the steels are collected by filtration followed by suspending in water (70 ml). The pH is adjusted to 7.5 with 1N aqueous sodium hydroxide solution and the resulting aqueous solution is washed with ethyl acetate. The pH of the aqueous solution is adjusted to 3.4 with 10% hydrochloric acid, precipitated crystals collected, 7-C2- (2-aminothiazol-4yl) -2- (2-pyridylmethoxyimino) acetamido-3-vinsh1-3-cephem-4-carboxylic acid is obtained (syn-isomer, 1.8 g). IR (Nujol): 3300, 1770, 1650, 1620 (shoulder), 1540 cm NMR spectrum, (G, ppm (DMSO-d): 3.70 (2H, q, Hz); 5.23 (1H , d, Hz); 5.30 (2H, S); 5.32 (1H. d, Hz); 5.60 (1H, d, Hz); 5.85 (1H, dd, Hz, 8 Hz) ; 6.82 (1H, dd, Hz, 17 Hz); 6.82 (W, S); 7.00-8.10 (GH, ha); 8.57 (1H, d, Hz); 9, 97 (1H, d, Hz). EXAMPLE 189. -D. J 11 S Nf ppv / -h HCIOCH-O I CH 3 carbonyl-3-vini.n-3-cephem-7-yl) cabamoyl methylene aminooxymethyl pyridine methyl sulfate (syn-isomer, 2.6 g) was suspended in methylene chloride (20 ml) and anisole (1, A g) and trifluoroacetic acid (5.8 g) was added thereto under ice-cooling and with stirring, followed by stirring at a temperature surrounding with for 1.5 hours. The reaction mixture is added dropwise to diisopropyl ether (250 ml), the precipitated substances are collected by filtration and dissolved in water (20 ml). The pH of the aqueous solution is adjusted to 6.5 1 n. aqueous solution of sodium hydroxide and washed with ethyl acetate, then adjusted to pH 2 with a 10% hydrochloric acid solution, followed by chromatography on a nonionic adsorption resin Diaion HP-20 (100 ml). After washing with water, elution is carried out with a 30% aqueous solution of isopropiC-SOSH-pY
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CHj-CHjSO 7- {2 (2-aminothiazol4-nl) -2-C (1-methyl-3-pyrvdino) methox-imino J acetamido-3-vinyl-3-cephemD-carboxylate hydrochloride (syn-isomer, 0.4 d) receive the reaction of 1-methyl-3- {1- (2-aminothiazol-4-yl) hydrochloride (4-benzhydryloxycarbonyl-t3-vinyl 3-cephem-7-sh1) carbamoyl metstenaminooxymethyl pyridine methyl sulfate (syn-isomer, 1 g) with trifluoroacetic acid (2.8 g) in the presence of anisole (O, 52 g) in accordance with the procedure described in example 189, IR spectrum (Nujol): 3400-3100, 1760, 1660, 1600, 1530 cm. NMR spectrum, Lpp1p (DjO): 3.67 (2H vs S); 4.43 (3N, S); 5.25 (1H, d, J-5 Hz); 5.30 (1H, d, Hz); 5.43 (1H, d, Hz); 5.50 (2H, S) 5.80 (1H, d, Hz); 6.83 (1H, dd, TC, 17 Hz); 7.02 (1H, S); 8.10 (1H, t); 8.78-8.90 (2H, t); 8.90 (1H, S). EXAMPLE 191: Benzhydryl-7 2- (2-formamidothiazol-4-yl) -2- (1 tert-butoxycarbonyl-1-methylethoxynmino) acetamido3-vinyl-3-cephem-4carboxylate (syn-isomer, 4.93 d) to
alcohol, fractions containing the desired compound are collected and evaporated. The resulting residue is lyophilized.
7- {2- (2-am1 notiazol-4-Sh1) -2-f (1-methyl-2-pyridino) methoxyimino acetamido-3-vinsh1-3cephem-4-carboxylate hydrochloride (syn-isomer, 1,2 d).
IR (Nujol): 1770, 1720, 1670, 1630, 1540 cm-.
NMR spectrum, ppm (): 3.60 (2H wide S); 4.38 (3N, S); 5.22 (1H, d, Hz); 5.25 (1H, d, Hz); 5.40 (1H, d, Hz); 5.70 (2H, S); 5.82 (1H, d,. Hz); 6.82 (1H, dd, Hz, 17 Hz); 7.03 (1H, S); 7,808, 73 (ЗН, t); 8.87 (1H, dd, Hz, 6 Hz).
Example 190.
C-CONH-r-
and about "-lnsn,
  xy
7 these
OSI is obtained by the reaction of benzhydryl-7-amino-3-v-nyl-3-cephem-4 carboxylate hydrochloride (3.2 g) with 2- (2-formamidothiazol-4-sh1) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino a) acetic acid (syn-isomer, 2.9 g) in accordance with the procedure described in example 103. IR spectrum (Nujol): 3150, 1780, 1720, 1690 cm. NMR spectrum, cG, ppm (DMSO-d): 1.271, 81 (15H, m), 3.81 (2H, q,, 0 Hz); 5.34 (W, d, Hz); 5.22-6.18 (3N, m); 6.79 (1H, dd,, 0 Hz, 18 Hz); 7.00 (1H, S); 7.13-7.75 (1Ш, m); 8.54 (1H, S); 9.58 (1H, d,, 0 Hz). Example 192. BenzhydrSh1-712- (2-formamidothiazol-4-sh1) -2- (1 tert-butoxycarbonyl ethoxyimino) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 5.62 g) is obtained by reaction of hydrochloride benzhydryl-7-amino-3-vinsh-3-cephem-4-carboxylate (3.4 g) with 2- (2-formamidothiazol-4-yl) -2- (1-tert-butoxycarbrynyl ethoxy-shno) acetic acid ( syn-isomer, 3.0 g) in accordance79; P
VII with the method described in example 103.
IR (Nujol): 3250, 3150, 1780, 1720, 1680.
NMR spectrum, e, ppm (DMSO-d): 1.23-1.72 (12H, m); 3.78 (2H, q,, 0 Hz); 4.66 (1H, q,, 0 Hz); 5.33 (1H, d,, 0 Hz); 3.276, 16 (1H, m); 6.79 (1H, dd,, 0 Hz, 18.0 Hz); 6.98 (1H, S); 7.18-7.82 (11H, t); 8.56 (1H, S), 9.59 (d, 0 Hz) 1
(1H) 9.67 (d,, 0 Hz) j
Example 193. Benzhydryl-7C2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyimino-adamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 6.4 g) is obtained by the reaction of benzhydryl-7amino-3-vinyl hydrochloride -3-cephem-4-carboxylate (4.29 g) with 2- (2-formamidothiazol4-yl) 2-ethoxycarbonylmethoxyiminoacetic acid (syn-isomer, 3.8 g) in accordance with the procedure described in example 103.
IR (Nujol): 3250, 1780, 1710, 1690, 1660, 1540 cm-H
NMR spectrum, cG, ppm (DMSO-d): 1.20 (3N, t, Hz); 3.77 (2H, t); 4.15 (2H, q, Hz); 4.75 (2H, S); 5.28 (1H, d, Hz); 5.30 (1H, d, Hz); 5.65 (1H, d, Hz);
5.97 (1H, dd, Hz, 8 Hz); 6.82 (1H, dd, Hz, 17 Hz); 6.97 1H, S); 7.17-7.67 (11H, t); 8.55 (1H, S); 9.73 (W, d, Hz); 12.67 (1H, broad S).
Example 194. (2-Formamidothiazol-4-yl) -2-tert-butoxycarboxymethoxyiminoacetamido-3 vinyl-3-cephem-4-carboxylic acid (syn-isomer, 2.7 g) is obtained by reaction of 7-amino-3-vinyl-3 -cephem-4-carboxylic acid (2.26 g) with 2- (2-formamidothiazol-4-yl) -2-tert-butoxycarbonylmethoxyiminoacetic acid (syn-isomer, 3.29 g) according to the procedure described in example 103..
IR (Nujol): 3230, 1780, 1720, 1680, 1542 cm.
NMR spectrum, cL, ppm (DMSO-d j): 1.45 (9H, S); 3.73 (2H, q, Hz) 4.63 (2H, S); 5.23 (1H, d, Hz); 5.30 (1H, d, Hz); 5.58 (1H, d, Hz); 5, 85 (1H, dd, Hz); 5.85 (1H, dd, Hz, 5 Hz);
6.98 (1H, dd, Hz, 18 Hz);
608780
7.46 (1H, S); 8.53 (1H, S); 9.53 (1H, d, Hz); 12.73 (1H, broad S).
Example 195. Benzhydryl-75 C2- (2-amino-thiazol-4-yl) -2- (1-tert-butoxycarbonyl-1-methyl-toxothiimino) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 4.03 d) semi-reacted by reaction of benzhydryl-7-2g- (210 formamidothiazol-4-sh1) -2- (1-tertbutoxycarbonyl-1-methylethoxyimino) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 4, 8 g) with concentrated hydrochloric acid
15 (1.4 g) in accordance with the procedure described in example 129.
IR (Nujol): 3260, 1780, 1720, 1680, 1620 cmL
NMR spectrum, (L, ppm (DMSO-dg):
20 1.21-1.70 (15H, m); 3.83 (2H, m); 5.30 (W, d,, 0 Hz); 5.16-6.10 (2H, m); 6.94 (1H, dd,, 0 Hz, 8.0 Hz); 6.44-7.04 (1H, ha); 6.74 (1H, S); 6.96 (1H, S); 7.07-7.66
25 (YUN, m); 9.41 (1H, d,, 0 Hz).
Example 196. Benzhydryl-7C 2- (2-aminothiazol-4-sh1) -2- (1-tertbutoxycarbonylethoxyimino) acet-. amido-3-vinyl-3-cephem-4-carboxyl 130 at (syn-isomer, 4.81 g) is obtained by the reaction of benzhydrin 1-7-C2- (2-formamidothiazol-4-yl) -2- (1-tert-butoxycarbonyl ethoxyimino ) acetamido-3-vinyl-3-cephem-4-carboxylate (syn35 isomer, 5.5 g) with concentrated hydrochloric acid (1.6 g) according to the procedure of example 129.
IR (Nujol): 3250, 1780. 1720, 1780, 1640, 1620 cm-
40 NMR spectrum, L, ppm (DMSO-d): 1.27-1.50 (12H, m); 3.78 (2H, tp); 4.65 (1H, q,, 0 Hz); 5.18-5.86 (ЗН, t); 5.93 (1H, dd,, 0 Hz, 8.0 Hz); 6.80 (1H, S); 6.96 (1H, S);
45 7.07-7.67 (UN, t); 9.44 (d, 0 Hz)
(W) 9.54 (d,, 0 Hz)
Example 197. Benzhydryl-7 2- (2-aminothiazol-4-Sh1) -2-ethoxycar bonylmethoxyimino) acetamido -3 vinyl-3-cephem-4-carboxylate (synisomer, 5.45 g) is obtained by the reaction of benzhydryl1-7-2- (2-formamidothiazol4-Sh1) -2-ethoxycarbonylmethoxyimino) acetamido3-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 6.2 g) d with concentrated hydrochloric acid (3.8 ml) in accordance with the procedure Example 129. IR (Nujol): 3250, 1780, 1720, 1662, 1620, 1535. NMR spectrum, cL, ppm (DMSO-d): 1.2 (3N, t, Hz); 3.68 (2H, t); 4.15. (2H, q, Hz); 5.28 (1H, d, Hz); 5.65 (W, d, Hz); 5.95 (1H, dd, Hz, 8 Hz); 6.82 (1H, dd, Hz, 17 Hz); 6.87 (1H, S); 7.00 (1H, S); 7.30-7.70 (UN, ha); 9.65 (1H, d, Hz). Example 198 7-C2- (2-Aminothiazol-4-Sh1) -2-tert-butoxycarbonyl methoxyiminoacetamido-3-vinyl-3cepham-4-carboxylic acid (sinisomer, 1.7 g) is obtained by reaction (2-formamidothiazol-4 -yl) -2-tert-butoxycarbonylmethoxyiminoacetamido -3-vinsh1-3-cephem-4-carbonic acid (syn-isomer, 2.1 g) with concentrated hydrochloric acid (1.2 ml) in accordance with the procedure described in example 129 IR (Nujol): 3300, 1770, 1925, 1680, 1610, 1530. NMR spectrum, (G, ppm (DMSO-d): 1.45 (9H, S); 3.72 (2H, q, Hz) 4.58 (2H, S); 5.22 (1H, d, Hz) 5.33 (1H, d, Hz); 5.58 (1H, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 6.82 (1H, S); 6.98 (1H, dd Hz, 18 Hz); 9.52 (1H, d, Hz). Example 199. To a mixture of benzG1edrt-7-2- (2-aminothiazol-4-yl) -2 (1-tert-butoxycarbonyl- 1-methylethoxyimino) acetamido-3-vinyl-3 cepheme-4-carboxylate (syn-isomer, 3.9 g) and anisole (3.9 ml) was added trifluoroacetic acid (15.6 ml) with ice cooling and the mixture was stirred at ambient temperature for 1 hour. Diisopropyl ether is added to the reaction mixture and the precipitated crystals are collected by filtration, and then bromine is diisopropyl ether. Ethyl acetate and water are added to the crystal, followed by adjusting the pH to 7.5 bicarbonate.
naty natri. The separated aqueous solution is washed with ethyl acetate and then the pH is adjusted with a 2.510% hydrochloric acid solution. The precipitated crystals are collected by filtration, washed with water and dried.
(2-aminothiazyl-4-yl) -2- (1-carboxy-1-methylethoxyiminoacetamido-3-vinyl-3-cephem-4carboxylic acid (syn-isomer, 3.2 g) is obtained by the reaction of benzhydryl-2- (2-aminothiazole -4-yl) -2-ethoxyiminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, .5.2 g) with trifluoroacetic acid (12.8 g) in the presence of anisole (3.4 g) in the corresponding ) acetamido 3-3-vinyl-3-cephemcarboxylic acid (syn-isomer-, 1.09 g), m.p. 173-177 ° C (decomposition). The filtrate and washings were combined and saturated with sodium chloride, followed by extraction with tetrahydrofuran. The extract is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, then evaporated to dryness to give a residue, which is pulverized with diisopropyl ether and collected by filtration to obtain the same title compound (0.59 g). Total yield 1.68 g. IR spectrum (Nujol): 3300, 3200, 1770, 1670, 1640 cm NMR spectrum, cG, rrga (DMSO-d s): (6H, S); 3.76 (2H, q, OHz); 5.24 (W, d, ... Hz); 5.18-5.98 (ЗН, t); 6.79 (W, S); 6.95 (1H, dd,, 0 Hz, 18.0 Hz); 9.41 (1H, d,, 0 Hz). Example 200. (2-Aminothiazol-4-Sh1) -2- (1-carboxyethoxyimino) acetamidoJ-3-vinyl-3-cephem-4carboxylic acid (syn-isomer, 0.73 g) is obtained by the reaction benzhydryl-2- (2 -aminothiazol-4-yl) -2-- (1-tertbutoxycarbonylethoxyimino) acetamido J3-vinyl-3-cephem-4-carboxylate (4.7 g) with trifluoroacetic acid (18.8 ml) in the presence of anisole (4.7 ml) in accordance with the procedure described in Example 199. IR spectrum (Nujol): 3260, 3160, 1770, 1670 cm-. NMR, cG, ppm (DMSO-d): 1.44 (3N, d, 00 Hz); 3.73 (2H, S); 4.66 (W, q, ... Hz); 5.23 (1H, d,, 0 Hz); 5.33 (1H, d, 5 Hz); 5.63-6.00 (2H, t); 6.81 (2H, t); 6.81 (W, S); 6.97 (1H, dd, 5 Hz, 18.0 Hz); 9.44 (W, d, ... Hz); 9.49 (1H, d,, 0 Hz). . Example 201. (2-Aminothiazol-4-yl) -2-ethoxycarbonylmethoxy with the procedure described in Example 144. IR spectrum (Nujol): 3250, 1770, 1670, 1530 CNf HMP-cneKTp ,, ppm (DMSO-di ):, 22 (W t, Hz); 3.70 (2H, broad S); 4.17 (2H, q, Hz); 4.75 (2H, S); 5.23 (1H, d, Hz); 5.35 (1H, d, Hz); 5.58 (W, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 6.88 (1H, S); 6.98 (W, d, Hz, 17 Hz, 9.63 (1H, d, Hz). Example 202. Bin 3 hydrochloride-7-amino-3-vinyl-3-cephemcarboxylate (2.3 g) is dissolved in cjrxoM ethyl acetate, (50 ml) and trimethylsilyl acetamide (4.9 g) at 40 s. To the Vilsmeier reagent obtained by the reaction of dry H, H-dimethylformamide (0.5 g) with phosphorus oxychloride (1.1 g) in dry ethyl acetate (2.0 ml) in the usual manner, dry tetrahydrofuran (20 ml) and; 2- (3-tert-butoxycarbonylpropoxyimin) -2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer 2.1 g) followed by stirring at (-3) -. An activated acidic solution is obtained, which is added to a solution of ethyl acetate at -10 ° C with stirring. Stirring is continued at (-10) - (-5) 0 for 30 minutes. Water is added to the reaction mixture and the separated organic layer is washed with saturated sodium bicarbonate solution and saturated water. After removing the solution, the residue is pulverized with diisopropyl ether. (3-tert-butoxycarbonylpropoxyimino) -2- (2-form shdothiazol-4-III) acetamido-T-3-vinyl 3-cephem-4-carboxylate (syn-isomer 3.63 g) is obtained. IR (nujol): 3280, 3150, 1780, 1720, 1660 cm. NMR spectrum, (G, ppm (DMSO-d): 1.43 (9H, S), 1.97 (2H, t); 2.38 (2H, t ,., 0 Hz); (2H, q,, 0 Hz); 4.18 (2H, t,, 0 Hz); 5.33 (1H, d, J-11.0 Hz), 5.34 (1H, d,, 0 Hz); 5.67 (1H, d, Oz 5.97 (1H, dd,; 0 Hz, 8 Hz); 6.82 (1H, dd, , 0 Hz, 17.0 Hz); 7.00 (1H, S); 7.19-7.73 (11H, t); 8.57 (W, d); 9.77 (W, d, 0 Hz.) 784 Example 203. Benzhydryl-7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (10.6 g) is dissolved in methylene chloride (100 ml) and trimethyl-silylacetamide (20, 6 g) at 25 C. To a suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (syn isomer, 4.0 g) in methylene chloride (100 ml) is added phosphorus oxychloride (12.1 g) followed by Stir at ambient temperature for 1.5 hours. Add H, K-dimethylformamide (8 ml) at (-12) - (-10) C and stir the mixture at (-10) (-8) s for 45 min to obtain an activated acid solution. An activated acidic solution is added to the methylene chloride solution obtained with and with stirring. Stirring is continued at -15 ° C. for 45 minutes. The reaction mixture is poured into a saturated solution (aqueous) sodium bicarbonate (300 ml), followed by stirring for 30 minutes. While stirring, the pH was adjusted to 7.5 with sodium bicarbonate, ethyl acetate (500 ml) was added and the insoluble matter was removed by filtration. The separated organic layer is washed with aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue is pulverized with diethyl ether to give benzhydryl-7-C2- (5-amino1, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido 1-3-vinsh1-3-cephem-4-carboxylate (syn- isomer, 6.3 g). IR (nujol): 3300, 3175, 1770, 1720, 1670, 1610, 1510 cmH NMR spectrum, cG, ppm (DMSO-dj): 3.77 (2H, t); 3.93 (3N, S); 5.25 (W, d, Hz); 5.27 (W, d, Hz); 5.62 (1H, d, Hz); 5.92 (1H, dd, Hz, 8 Hz); 6.77 (1H, dd, Hz, 17 Hz); 6.97 (W, S); 7.38 (UN, t); 9.62 (1H, d, Hz. Example 204. The Vilsmeier reagent obtained from K, H-dimethylformamide (0.37 ml) and phosphorus oxychloride (0.44 ml) in a conventional manner, is suspended in dry tetrahydrofuran (20 ml) , 2- (tertbutoxycarbonylmethoxyimino) -2- (6formamidopyridin-2-yl) acetic acid (syn-isomer, 3.0 g) is added with ice cooling and stirring. Stirring is continued at this temperature for 1 hour to obtain an activated acid solution which is added to a solution of benzhydr-7-amino-3-vinyl-3-cephem-4 carboxylate (2.72 g) and trimethylsilylacetamide (5.5 g) in methylene chloride with stirring. Stirring is continued at (-20) (-10) s for 1 h. Water (50 ml) and ethyl acetate (200 ml) are added to the reaction mixture, the separated organic layer is washed with 5% aqueous sodium bicarbonate solution and then ferment with the whole sodium chloride aqueous solution, followed by drying over magnesium sulphate. After removing the solvent, benzyl-SCHR-7-2- (tert-butoxycarboiylmethoxynmIlO2) -2- (6 formamide pyridarP1-2-yl) acetamide-3- kinil-3cepham-4-carbox1shat (syn-kzoker, 4.8 g), m.p. 154 157С. IR spectrum (Nujol): 3240, 1777, 1745, 1715, 1689, 1667 cm - NMR spectrum, s, ppm (DMSO-d): 1.40 (9H, S); 3.50, 3.93 (2H, ABq, Hz) ;. 4., 60 (2H, S); 5.20 (1H, d, Hz); 5.25 (1H, d, Hz); 5.56 (1H, d, Hz); 5.95 (1H, d Hz, 8 Hz); 6.9 (W, S); 7.3 (yun, t); 7.3-8.3 (ЗН, t); 9.4 (1H wide S); 9.53 (W, d, Hz); 10.6 (W, d, Hz). Example 205. Benzhydryl-72- (trans-3-tert-bztoxycarbonylallyloxyimino) -2- (2-formamidothiaz 4-yl) acetamido-2-3-vinyl-3-cephem-4carbovsilat (syn-isomer, 4.83 g) is obtained by reaction of benzhydryl hydrochloride -7-amino-3-vinyl-3-cephem-4carboxylate (3.0 g) with 2- (trans-3 i tert-butoxycarbonyl alyloxy (2-formamidothiazol-4-Sh1) acetic acid (syn isomer, 2, 7 g) in accordance with the procedure described in examples 202-204. IR spectrum (Nujol): 3250, 1780, 1710, 1660 cm 2 NMR spectrum 5 cG, ppin (DMSO-d): P47 (9H, S) ; 3.79 (2H, q, J-18, OG 4.89 (2H, ha); 5.34 (W, d, OG 5.35 (1H., D, 0 Hz); 5.68 (1H, d,., 0 Hz); 5.86-6.30 (2H, t); 6.52-7.22 (2H, t); 7.00 (W, S); 7.21 - 7.74 (11H, t); 8.58 (1H, S); 9.91 (1H, d,, 0 Hz); 12.73 (1H,. wide S), Example 206. Benzhydryl-7C2-cyanomethoxyimino-2- (2- formamidothiazol-4-yl) acetamido-7-vinyl-3-defem-4-carboxylate (sio-isomer, 3.1 g) is obtained by the reaction of benzhydryl-7-amino-3-vinyl-zecem-4-carboxylate hydrochloride (2.5 g ) with 2 cyanomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer, 1.6 g) in accordance with the procedure described in examples 202-204. IR spectrum (Nujol): 3180, 1770, 1720, 1680 cm - NMR spectrum, cG, ppm (DMSO-d): 3.77 (2H, t); 5.03-6.10 (5H, ha); 5.81 (1H, dd,, 0 Hz, 8.0 Hz); 6.43-7.13 (1H, t); 6.96 (W, S); 7.35 (UN, S); 7.56 (1H, S); 8.53 (1H, S); 9.93 (1H, d,, 0 Hz). Example 207, Benzhydryl-7 2-tert-butoxycarbonylmethoxyimino2 - (5-chloro-2-formamidothiazol-4-yl) acetamido3-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 5.6 g) is obtained by reaction benzhydryl-7amino-3-vinsh-3-cephem-4-carboxylate hydrochloride (3.43 g) with 2-tert-butoxycarbonylmethoxyimino-2- (5-chloro-2-formamidothiazol-4-yl) acetic acid (sinisomer, 3 , 2 g) in accordance with the procedure described in examples 202-204. IR (nujol): 3200, 1780, 1720, 1680, 1606, 1540 cm NMR spectrum, c1, ppm (DMSO-d): 1.43 (9H, S); 3.77 (2H, t); 4.67 (2H, S): 5.30 (1H, d, Hz); 5.32 (1H, d, Hz); 5.65 (1H, d, Hz); 6.03 (1H, dd, Hz, 8 Hz); 6.83 (1H, dd, Hz, 18 Hz); 7.02 (1H, S); 7.23-7.8 (UN, t); 8.60 (1H, S); 9.73 (1H, d, Hz). Example 208, Benzhydryl-7C 2- (6-formamidopyridine-2-Sh1) -2 methoxyimino acetamido-3-vinyl-3ceph-4-carboxyl 1 (syn-isomer, 5.7 g), mp, 154-159 ° C, is obtained by the reaction of benzhydryl-7-amino-3-vinyl-3-cephem-4-carboxylate (3.8 g) with 2- (6-formamidophene-2-yl) -2 methoxyiminoacetic acid (sinisomer, 3.0 g) in accordance with the procedure described in examples 202-204. IR (Nujol): 3350, 1770, 1720, 1670, 1613 cm. NMR spectrum, G, ppm (DMSO-d): 3.78 (2H, m); 4.0 (3N, S); 5.30 (1 d, Hz); 5.63 (W, d, Hz), 6.0 (1H, dd, Hz, 18 Hz); 7.0 (IH, S); 7.4 (UN, m); 7.08, 0 (3N, m); 9.3 (IH, S wide); 9.7 (1H, d, Hz); 10.7 (1H, d Hz). The following compounds were prepared by reacting 7-amino-3-vinyl cephalosporanic acid derivatives with the corresponding acylating agents in accordance with the procedure described in Examples 202-204. Example 209. Benzhydryl-7 2- (2-aminothiazol-4-yl) -2- (3-tertbutoxycarboiylpropoxyimino) acetamido2-3-vinyl-3-cephem-4-carboxyl (si-isomer). IR spectrum (Nujol): 3340, 3250, 1780, 1720, 1680, 1620 cm - Example 210. Benzhydryl-7 2- (2-aminothiazol-4-yl) -2- (trans-3 tert-butoxycarbonyl-lilloxyimino acetamido-3 -Vinyl-3-cephem-4-carboxylate (syn-isomer). IR spectrum (Nujol): 3250, 1770, 1700, 1670, 1610 cm - Example 1111. Benzhydrch1-7L2- (6- aminopyridin-2-yl) -2-tertbutoxycarbonylmethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxyl (syn-isomer). IR spectrum (Nujol): 3350, 1778, 1721, 1682, 1615 cm - Example 212. Benzhydryl -7C2- (2-aminothiazol-4-yl) -2-cyanomethoxyiminoacetamido-3-vinyl-Zepham-4-carboxylate (syn-isomer). IR spectrum (Nujol): 3430, 3250, 1780, 1720, 1680, 1660 cmh prime 213, Benzhydryl-7 2- (2-amino-5-chlorothiazole) -4-yl -2-tert-butoxycarbonylmethoxyiminoacetamido-3-winsh-3-cephem-4-carboxylate (syn-isomer). IR spectrum (Nujol): 3425 , 3270, 1780, 1720, 1675, 1620, 1540 cn Example 214. Benzhydryl-7H2- (6-aminopyridin-2-yl) -2-methoxy iminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer). IR (Nujol): 3250, 1775, 1720 (shoulder), 1680 (wide) cm Example 215. (5-Amino 1,2,4-thiadiazol-3-yl) -2-methoxymia acetamido-3-vinyl- 3-cephem-4-carboxylic acid (syn-isomer). 788 IR spectrum (Nujol): 3350, 3250, 1770, 1670, 1670, 1620, 1530. Example 216. (2-Aminothiazol-4-pc) -2-cyanomethoxyiminoacetamido 1-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm Example 217. (6-Aminopyridin-2-yl) -2-methoxyimino acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer ). IR (nujol): 3350, 3250, 1780 (wide), 1667 (wide) cm Example 218. Pivaloyloxymethyl-7-C2- (5-amino-1,2,4-thiazol3-yl) -2-toximino aminoacetamido -3 vinyl-3-cephem-4-carboxylate (sinisomer). IR (Nujol): 3400-3100, 1770, 1760, 1680, 1620, 1530 cm Example 219. Add phosphorus oxyl chloride to a suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) - 2 tert-butoxycarbonylmethoxyiminoacetic acid (syn-isomer, 2.0 g) in methylene chloride, the mixture is stirred at ambient temperature for 1.5 hours, N, N-dimethylformamide (4.0 ml) is added at -15 ° C followed by stirring at (-15) - (-5) ° C for 4Q minutes to obtain an activated acid solution. To a suspension of benzhydryl-7-amino-3-vin1-3-cephem-4-carboxylate hydrochloride (2.6 g) in methylene chloride (26 ml) is added trimethylsilylacetamide (5.5 g) and the mixture is stirred at 35–40 ° C for 10 min Prepared solution of activated acid is added to the mixture with and stirred at (-10) (-5) C for 30 minutes. A saturated sodium chloride aqueous solution (150 ml) and ethyl acetate (150 ml) are added to the reaction mixture and the pH adjusted to 7.5 with a saturated sodium bicarbonate aqueous solution. The separated organic layer was washed with a full aqueous sodium chloride solution and then dried over magnesium sulfate. After removal of the solvent, benzhydryl1-7-2- (N, Ndimethylaminomethylene) -aminoZ-1,2,4-thiadiazol-3-ylJ-2-tert-butoxycaobonylmethoxyiminoacetamido J-389; one
inyl-3-cephem-4-carboxylate (synzom p, 4, 13.d).
IR (Nujol): 1770, 1710, 1620 cm-g
NMR ,, pp1p (DMSO-df): 1.47 (9H, S); 3.09 (3N, S); 3.20 (3N, S); 3.2 (2H, S); 4.71 (2H, S); 5.17-6.17 (GH, m); 5.32 (1H, d, 5.0 Hz); 6.80 (W, dd, 12.0 Hz, 18.0 Hz); 6.80 (1H,
d,, 0 Hz, ta, O Hz); 7.00 (1H, S); 7.43 (YUN, S); 8.50 (1H, S); 9.69 (1H, d,, 0 Hz).
Example 220. To a solution of enzhydryl 77-C2-tert-butoxycarbon1-shmethoxyimino-2- (2-formamidothiazol 4-yl) acetamido-3-vinyl-3 cefem-4-carboxylate (syn-isomer, 2.5 g) in anisole ( 2.5 ml) and methienchloride (5 ml) was added trifluoroacetic acid (10 ml) under ice cooling, the mixture was stirred at ambient temperature for 2 hours. Diisopropyl ether was added dropwise to the reaction mixture, the precipitated crystals were collected by filtration and washed with diisopropyl ether.
7-2-carboxymethoxy-Shno-2- (2-fluoroamidothiazol-4-yl) acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 1.57 g) is obtained.
IR (Nujol): 3130, 1770, 1670 cm -
NMR spectrum, cG, ppm (DMSO-d): 3.71 (2H, q,, 0 Hz) ,; 4.66 (2H, S); 5.22 (1H, d,, 0 Hz); 5.22-5.85 (211, m); 5.84 (1H, dd, 0 Hz, 8.0 Hz); 6.93 (1H, dd, 0 Hz, 18.0 Hz); 7.44 (1H, S); 8.50 (1H, S); 9.59 (1H, d,, 0 Hz); 12.30 (1H, broad S).
Example 221, To a solution of benzhydryl-7- 2- (2-amino-thiazol-4-yl) -2- (trans-3-tert-butoxycarbon-1-hallyloxy-sew) acetamido-3-vins-1-cephem-4-carboxylate (synomer, 4.4 g) and anisole (4.4 ml) in methylene chloride (9.0 ml) was added trifluoroacetic acid (17.6 ml) while it was cooled with ice and the mixture was stirred at ambient temperature for 2 hours. Diisopropyl ether is added to the reaction mixture, the precipitated material is collected by filtration and washed with diisopropyl ether. Ethyl acetate and water were added to this solution, setting as 608790
The pH of the solution is 7.5 with saturated aqueous sodium bicarbonate solution. The separated aqueous layer was washed with ethyl acetate, the ethyl acetate remaining in the aqueous solution was completely removed by evaporation, and then adjusted to pH 2.2 with a 10% hydrochloric acid solution. The precipitated substance is collected by filtration and dried.
fO 7-C2- (2-aminothiazol4-Sh1) -2- (trans-3-carboxy-allyloxyimino) acetamido} -3-vinyl-3-cephem-4carboxylic acid (syn-isomer, 2.31 g) is obtained.
15 IR spectrum (Nujol): 3250, 1760, 1690, 1650 cm-
NMR spectrum, tf, rrga (DMSO-dp: 3.73 (2H, q,, 0 Hz); 4.84 (2H, t); 5.24 (1H, d,, 0 Hz);
20 5.34 (1H, d,, 0 Hz); 5.476, 23 (3N, go); 6.63-7.34 (2H, t); 6.83 (1H, S); 9.77 (1H, d,, 0 Hz).
Example 222, at ambient temperature stirred
for 1 h, a mixture of benzhydryl-7G2- (6-aminopyrin-2-yl) -2-tert-butoxycarbonylmethoxyiminoacetamido 3-3 vin1-3-cephem-4-carboxylate
(syn-isomer, 6.0 g), anisole
(10 ml) and trifluoroacetic acid (60 ml). The reaction mixture is poured into diisopropyl ether (600 ml) with stirring, the precipitated substance
It is collected by filtration, washed with diisopropyl ether and then dissolved in water (100 ml), adjusted to pH 7.5 with a 5% aqueous solution of sodium bicarbonate and washed with ethyl acetate (50 ml). The resulting aqueous solution is treated with concentrated hydrochloric acid to adjust the pH to 2.5 and extracted with ethyl acetate (200 ml) and tetrahydrofuran.
(200 ml). Adjusting the pH of the remaining aqueous solution to 1.5 with concentrated hydrochloric acid and extracting with tetrahydrofuran (100 ml). Combined Extracts
washed with saturated aqueous sodium chloride solution and dried over magnesium sulphate. After removing the solvent, the residue is washed with acetone and diisopropyl ether.

Receive (6-aminopyridin-2il) -2-carboxymethoxyiminoacetamido 3-vinsh1-3-cephem-4-carboxylic acid 1, syn-isomer, 2.4 g), so pl. 173178 C (decomposition).
IR (Nujol): 3300, 1763 (wide), 1660 (wide).
NMR spectrum, L, ppm (DMSO-dg): 3.68 (2H, t); 4.77 (2H, broad S); 5.25 (1H, d, Hz); 5.30 (1H, d, Hz); 5.87 (W, d, Hz); 5.83 (1H, dd, Hz, 8 Hz); 6.58, 0 (3N, t); 9.7 (1H, d, Hz).
EXAMPLE 223. (2-Aminothiazol-4-b1) -2- (3-carboxy-propoxyimino) acetamido-3-vinyl-3-cephem-4 carboxylic acid (syn-isomer, 1.75 g) is obtained by the reaction of benzhydryl- 7- 2- (2-aminothiazol-4-yl) -2- (3-. Tert-butoxycarbonylpropoxyimino) acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 3.2 g) with trifluoroacetic acid (12.8 ml) in the presence of anisole (3.2 ml) in accordance with the procedure described in examples 220-222. . IR (Nujol): 3300, 1760, 1660 cm- ..
NMR spectrum, cL, ppm (DMSO-d): 1, 95 (2H, t); 2.37 (2H, t ,, OHz); 3.73 (2H, q,, 0 Hz); 4.13 (2H, t,, 0 Hz); 5.23 (1H, d ,, 0 Hz); 5.23-6.00 (ЗН, t); 6.79 (1H, S); 7.00 (1H, dd, 0 Hz, 18.0 Hz); 9.65 (1H, d,, 0 Hz).
Example 224. (2-Amin.o5-chlorothiazol-4-yl) -2-carboxymethoxyiminoacetamido1-3-vinyl-3-cephem-4carboxylic acid (syn-isomer, 2.2 g) is obtained by the reaction of 7-t2- (2-amino- 5-chlorothiazol-4-yl) -2-tertbutoxycarbonylmethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 4.6 g) with trifluoroacetic acid (14.4 g) in the presence of anisole (2.7 g) in accordance with the methodology described in examples 220-222.
IR spectrum (Nujol): 3400, 3180, 1770, t685, 1650, 1610 cm. NMR spectrum, (f, rrga (DMSO-d): 3.70 (2H, q, Hz); 4.63 (2H , S); 5.18 (1H, d, Hz); 5.33 (1H, d, Hz); 5.56 (1H, d, Hz); 5.83 (1H, dd, TC, 8 Hz) ; 6.95 (1H, dd, Hz, 18 Hz); 9.45 (1H, d, Hz).
Example 225. Trifluoroacetic acid. (16.0 ml) is added to a solution of benzhydryl-7- (LY (L, LH-dimethylaminomethyl) aminoZ-1,2,4-thiadiazol-3-yl-2-tert-butoxycarbonylmethoxyiminoacetamido) -3-vynyl-Zecem -4-carboxylate (syn-isomer 4.0 g) in methylene chloride (8 ml) and anisole (4 ml) under ice cooling, the mixture is stirred at ambient temperature for 1.5 hours. The reaction mixture is added dropwise to diisopropyl ether (200 ml of the precipitated substance is collected by filtration and then added to a mixture of water and ethyl acetate, followed by adjusting the pH to 7.5 with a saturated aqueous solution of bicarbonate The separated aqueous layer is saturated with sodium chloride, adjusted to pH 2.5 with 10% hydrochloric acid, followed by extraction with a mixture of ethyl acetate and tetrahydrofuran (1: 2 by volume). The extract is washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate After removing the solvent, the residue is washed with diethyl ether and collected by filtration.
7-C2- (5-formamido-1, 2,4-thiadiazol-3-yl) -2-carboxymethoxyiminoacetamido 2-3-vinyl-3-cephem-4carboxylic acid (syn-isomer, 1.75 g) is obtained.
IR (Nujol): 3200, 1770, 1670 cm -
NMR, cG, ppm (DMSQ-d): 3.70 (2H, t); 4.75 (2P, S); 5.24 (1H, d,, 0 Hz); 5.33 (1H, d,, 0 Hz); 5.61 (1H, d,, 0 Hz); 5.91 (1H, dd,, 0 Hz, 8.0 Hz); 6.96 (1H, dd,, 0 Hz, 18.0 Hz); 8.87 (W, S); 9.70 (1H, d, J-8.0 Hz) 13.47 (1H, broad S).
Example 226. To a solution of benzhydryl-7-C2-tert-butoxycarbonyl, methoxyimino-2- (2-formamidothiazol4-yl) acetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, 2.0 g) and anisole ( 8.0 ml) in dioxane (8 ml) and tert-butyl alcohol (8 ml) p-toluenesulfonic acid (2.2 g was added, followed by stirring at 60 ° C for 5 hours. To the reaction mixture was added ethyl acetate and water The pH is adjusted to 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and washed with ethyl acetate, ethyl acetate and tetrahydrofuran are added, the pH is adjusted to 2.2 with a 10% solution of salt. After saturation of the aqueous layer with sodium chloride, the organic layer is separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. After removing the solvent, the residue is pulverized with diisopropyl ether and collected by filtration, water is added and the pH is adjusted to 5.5 with 2 N an aqueous solution of sodium hydroxide. The aqueous solution is subjected to chromatography on a nonionic adsorption resin Diaion HP-20 (20 ml), eluted with water (40 ml). Ethyl acetate and tetrahydrofuran are added to the cell and the pH is adjusted to 2.2 with 10% hydrochloric acid solution. After the aqueous layer is saturated with sodium chloride, the organic layer is separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. After removing the solvent, the residue is pulverized with diisopropyl ether and collected by filtration. (2-Aminothiazol-4yl) -2 carboxymethoxyiminoacetamido 3-vinyl-3 cephem-4-carboxylic acids (syn-isomer, 0.31 g) are obtained. IR (Nujol): 3350, 1770, 1680, 1640 cm - NMR spectrum, 0, ppm (DMSO-d): 3.70 (2H, .q, Hz); 4.62 (2H, S) 5.21 (1H, d, Hz); 5.82 (1H, dd, Hz, 8 Hz), 5-6 (2H, ha); 6.82 (1H, S); 7.22 (2H, broad S); 6.5--7.5 (W, t); 9.5 (1H, d, Hz) The following compounds were obtained by reacting 7-acylamino-Zvinyl-3-cephalosporanic acid derivatives having a formamido group, tert a butoxycarbonyl group and a benzhydryl ester with p-toluenesulfonic acid in the presence of anisole in accordance with the procedure described in example 226. Example 227. (2-Aminothiazol-4-yl) -2- (trans-3-carboxyallyloxyimino) acetamido-3-vinsh1; 3-cephem-4-carboxylic acid (synisomer). IR (Nujol): 3250, 1760, 1690, 1650 cm Example 228. (6-Aminopyri, rank-2-yl) -2 carboxymethoxyiminoacetamido-3-vinyl-3-cephem 4carboxylic acid (syn-isomer). IR (Nujol): 3300, 1763 (wide 10, 1660 (wide). Example 229. 7-C2- (2-Aminothiazol-4-yl) -2- (3-carboxypropoxyimimino) acetamido 3-3-vinyl-3 -cephem-4carboxylic acid (syn-isomer). IR spectrum (Nujol). 3300, 1760, 1660 cm- Example 230. 7-G2- (2-Amino-5-chlorothiazol-4-yl) -2-carboxymethoxyiminoacetamido-3 -Vinyl-3-cephem-4carboxylic acid (syn-isomer). IR spectrum (Nujol): 3400, .3180, 1770, $ 168, 1650, 1610 cm - Example 231. A mixture of benzhydryl-7-C2- (3- tert-butoxycarbonylpropoxyimino) -2- (2-formamidothiazol4-yl) acetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, 3.5 g), concentrated hydrochloric acid (1.0 g), ethanol (30 ml) and tetrahydrofuran (15.0 ml) was stirred at ambient temperature for 2.5 hours. Ethyl acetate was added to the reaction mixture, followed by adjusting the pH to 7.5 with saturated aqueous sodium bicarbonate. The separated organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulphate. After removing the solvent, the residue is pulverized with diisopropyl ether. (3-tert-Butoxycarbonylpropoxyimino) -2- (2-aminothiazol-4-yl) acetamido3-3-vinylcepham-4-carboxylate (syn-h isomer, 3.33 g) is obtained. IR (nujol): 3340, 3250, 1780, 1720, 1680, 1620 cm NMR spectrum, (G, ppm (DMSO-d): 1.40 (9H, S); 1.87 (2H, t) ; 2.35 (2H, t,, 0 Hz); 3.76 (2H, m); 4.11 (2H, t, Hz); 5.30 (1H, d,, 0 Hz); 5.32 (1H, d, 0 Hz); 5.66 (1H, d, Hz); 5.91 (m, dd, 0 Hz, 8.0 Hz); 6.78 (1H, S); 6, 79 (1H, dd,, 0 Hz, 18.0 Hz); 6.98 (W, S); 7.39 (YUN, S); 9.66 (1H, d ,, Oru) Example 232. Mixture benzhydryl -7-G2- (trans-3-tert-butoxycarbonyl-allyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido3-3-vinyl 3-cephem-4-carboxylate (syn-isomer, 4.7 g) concentrated salt hydrochloric acid (1.34 g), methanol (30 ml) and tetrahydrofuran (10 ml) is stirred at ambient temperature for 2.5 hours. To the reaction add Distil the ethyl acetate and adjust to pH 7.5 with saturated aqueous sodium bicarbonate solution. The separated organic layer is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. After removing the solvent, the residue is pulverized with diis propyl ether.
Benzhydryl-7- 2- (trans3-tert-butoxycarbonylallyloxyimino) -2- (2-aminothiazol-4-yl) acetamido D-3-vinyl-3-cephem-A-carboxylate (syn-isomer, 4.50 g) is obtained.
IR (Nujol): 3250, 1770, 1700, 1670, 1610 cm
NMR spectrum, c (, ppm (DMSO-d): 1.45 (9H, S); 3.76 (2n, ha); 4.86 (2H, t); 5.34 (1H, d, 0 Hz); 5.35 (1H, d,, 0 Hz); 5.68. (1H, d,, 0 Hz); 5.77-6.30 (2H, t); 6.54-7, 17 (2H, t); 6.86 (1H, S); 7.00 (1H, S); 7.17-7.70 (Yun, t); 9.81 (1H, d, 0 Hz ), Example 233. To a suspension of benzhydr1sh-7- 2- (6-formamido-4-yl-2-yl) -2-three-butyl-3-vinyl-3-cephem-4-carboxylate (I-3-isomer-3-vinyl-3-cephem-4-carboxylate (I-isomer, 3-vinyl-3-cephem-4-carboxylate). 300 ml) was added concentrated hydrochloric acid (2.88 ml) and the mixture was stirred for 1 hour. The reaction mixture was adjusted to pH 5.5 with 5% aqueous sodium bicarbonate solution and the methanol was removed by distillation under reduced pressure. osleduyuschim extraction with ethyl acetate (300 mL) nassh1ennym extract was washed with aqueous sodium chloride and dried over magnesium sulfate.
After removal of the solvent, benz hydrogen-7- 2- (6-aminopyridin-2-yl) -2-tert-butoxycarbonylmethoxyiminoacetamido3-3-vinyl-3-cephem-4carboxylate (syn-isomer, 4.5 g) is obtained, m.p. 125-129 6.
IR (Nujol): 3350, 1778, 1721, 1682, 1615 cm
NMR spectrum, (, ppm (DMSO-d t): 1.45 (9H, S); 3.55, 3.97 (2H, ABq, Hz); 4.65 (2H, broad S); 5, 29 (1H, d, Hz); 5.95 (1H, d, Hz); 5.98 (1H, dd, Hz, 8 Hz); 6.9 (1H, ha); 6.97 (1H, S ); 6.8-7.7 (GH, t); 7.4 (YUN; ha); 9.47 (W, d, Hz).
Example 234. Benzgndryl-712- (2-aminothiazol-4-yl) -2-cyanomethoxyiminoacetamido-3-vinyl-3cepham-4-carboxylate (syn-isomer, 5 2.17 g) is obtained by reaction of benzhydryl-7-C2- ( 2-formamidothiazol-4-sh1) 2-cyanomethoxyiminoacetamido3-3-vinil-3-cephem-4-carboxstat (sinisomer, 3.0 g) with concentrated
0 hydrochloric acid (0.35 g) in accordance with the procedure described in, for example, measures 231-233.
IR (Nujol): 3430, 3250, 1780, 1720, 1680, 1660 cm
5 NMR spectrum, (G, ppm (DMSO-d): 3.77 (2H, ha); 5.02 (2H, S); 5.106, 08 (2H, t); 5.28 (1H, d, , 0 Hz); 5.85 (W, dd,, 0 Hz, 8.0 Hz); 6.83 (W, dd,, 0 Hz, 18.0 Hz);
0 6.89 (1H, S); 6.95 (1H, S); 7.097, 63 (UN, t); 9.83. (W, d ,, 0 Hz).
Example 235. Benzhydryl-7t2- (2-amino-5-chlorothiazol-4-yl) -2-tert-butoxycarbonylmethoxyimino5 acetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer 4.6 g) is obtained by the reaction of benzhydryl- 7-C2- (2-formamido-5-chlorothiazol-4-yl) -2-tertbutoxycarbonylmethoxyiminoacet0 amido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 5.5 g) with concentrated hydrochloric acid ( 2.3 ml) in accordance with the procedure described in examples 231-233.
5 IR spectrum (Nujol): 3425, 3270, 1780, 1720, 1675, 1620, 1540 cm.
NMR spectrum, cG, rrga (DMSO-d (): 1.43 (9H, S); 3.77 (2H, ha); 4.63 (2H, S); 5.30 (1H, d, Hz );
0 5.32 (1H, a, Hz); 5.68 (1H, d, Hz); 6.00 (1H, dd, Hz, 8 Hz); 6.85 (1H, dd, Hz, 17 Hz); 7.03 (W, S); 7.22-7.90 (UN, ha); 9.60 j: iH, d, Hz).
5 Example 236, Benzhydryl. -72- (6-aminopyrimidin-2-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4carboxylate (syn-isomer, 4.5 g), mp. 183-188 0, produced by the reaction
0 benzhydryl-7-C2- (6-formamidopyridine-2-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (sinisomer, 5.7 g) with concentrated hydrochloric acid (4.3 ml) in accordance with the technique described in examples 231-233. IR spectrum (Nujol): 3250, f775, 1720 (shoulder), 1680 (wide) cm-. HMP-cneKTpjcA.ppm (DMSO-dfi): 3.8 (2H, m); 3.93 (3H, S); 5.3 (1H, d, Hz); 5.3 (1H, d, Hz); 5.63 (1H, d, Hz); 5.95 (1H, dd, Hz, 18 Hz); 6.5-8.2 (ЗН, ha); .6.9 (1H, m); 7.0 - (IH, S); .7.4 (UN, ha); 9.57 (1H, d, Hz). The following compounds were prepared by reacting 7-acylamino-2-vinylcephalosporanic acid derivatives having formamido groups with concentrated hydrochloric acid according to the procedure described in Examples 231-233. Example 237. Benzhydryl-7t 2 (5-amino-1,2,4-thiadiazol-3-ml) methoxyimine-acetamide-J-3-vinyl-3 ceph-4-carboxylate (syn-isomer). IR (nujol): 3300, 3175, 1770, 1720, 1670, 1610, 1510 cm L Example 238, 7-C2- (5-Amino1, 2,4-thiadiazol-3-yl) -2-methoxyimine acetamido -3 -vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm L Example 239. (2-Aminothiazol-4-yl) -2-cyanomethoxyiminoacetamido-3-vinsh-3-cephem-4-carboxylic acid (syn isomer). IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm Example .240. (6-aminopyridium-2-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (Nujol): 3350, 3250, 1780 (wide), 1667 (wide). Example 241. (2-Aminothiazol-4-yl) -2- (trans-3-carboxyalyloxyimino) -acetamido-3-vinyl 3-cephem-4-yarboxylic acid (sinisomer). IR (Nujol): 3250, 1760, 1690, 1650 cm-. Example 242. (6-.A plnopyridin-2-ip) -2-carboxymethoxyiminoacvtamido-3-vinyl-3-cephem-4carboxylic acid (syn-isomer). IR (Nujol): 3300, 1763 (wide), 1660 (wide) cm, Example 243. (2-Aminotnazol-4-yl) -2- (3-carboxypropoxyimino) acetamido2-3-vinyl-3-cephem 4-carboxylic acid (syn-isomer). IR spectrum (nuisl); 3300, 1760, 1660 cm. Example 244. 7-C2- (2-Amino5-chlorothiazol-4-yl) -2-carboxymethoxyiminoacetamido-3-vinyl-3-cephem-carboxylic acid (syn-isomer). IR (Nujol): 3400, 3180.1770, 1685, 1650, 1610 cm-g. Example 245, Pivaloyloxymethyl-7-C2- (5-amino-1,2,4-thiadiazole-3-yl) -2-methoxyimine-etomideoJ- 3-vinyl-3-cephem-4-carboxylate (sinisomer). IR (nujol): 3400-3100 ,, 1770, 1760, 1680, 1620, 1530 cm Example 246. To a suspension of benzhydryl-7-G2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylate (syn-isomer, 6.2 g) in methylene chloride (60 ml) anisole (9.3 g) and trifluoroacetic acid (24.5 g) are added and the mixture is stirred at ambient temperature for 1.5 hours. After removal of the solvent, the residue is added dropwise to diisopropropyl ether (600 ml) and the scavenged material is collected by filtration. The filtrate is suspended in water (50 ml) and adjusted to pH 7.5 with 2 n. an aqueous solution of sodium hydroxide followed by washing twice with a mixture of ethyl acetate (50 ml) and tetrahydrofuran (50 ml). Ethyl acetate (50 ml) and tetrahydrofuran (50 ml) were added to the resulting aqueous solution. The mixture is saturated with sodium chloride and adjusted to pH 1.0 with a 10% hydrochloric acid solution. The organic layer is separated and the remaining aqueous solution is extracted twice with a mixture of ethyl acetate and tetrahydrofuran. The combined organic solution is washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After removal of the solvent, the residue is pulverized with diethyl ether. 7-C2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyp1Minoacetamido3-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 3.9 g) is obtained. IR (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm--. NMR spectrum, s, ppm (DMSO-d): 3.71 (2H, t); 3.93 (3N, S); 5.18 (1H, d, Hz); 5.32 (1H, d, Hz); 5.55 (1H, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 6.95 (1H, dd, Hz, 17 Hz); 9.58 (1H, d, Jf8 Hz). Example 247. (2-Amino thiazol-4-yl) -2-cyanomethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 0.92 g) is obtained by the reaction of benzhydryl-7-f2 (2 -aminothiazol-4-yl) -2-cyanomethoximinoacetamido3-3-vinyl-3-cephem-4carboxylate (syn-isomer, 2.1 g) with trifluoroacetic acid (8.4 ml in the presence of anisole (2.5 ml) in according to the method described in example 246. IR spectrum (Nujol): 3300, 2020, 1770, 1670, 1620 cm - NMR spectrum, cG, ppm (DMSO-d): 3.73 (2H, q,, 0 Hz; 5.02 (2H, 5.23 (1H, d,, 0 Hz); 5.34 (1H, d,, 0 Hz); 5.37-6.80 (1H, m); 5, 79 (W, dd, 0 Hz, 8.0 Hz); 6.63-7.38 (1H, t); 6.91 (1H, S); 9.83 (1H, d,, 0 Hz) Example 248. (6-Amino Pyridin-2-i l) -2-methoxy-amino-acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 0.85 g), mp 183-188 s, is obtained by the reaction of benzhydryl-7-C2- (6- aminopyridine-2il) -2-methoxyiminoacetamido 3-vin Z-cephem-4-carboxylate (syn-isomer 4.5 g) with trifluoroacetic acid (15 ml) in the presence of anisole (5 ml) in accordance with the procedure described in example 246 IR (nujol): 3350, 3250, 1780 (wide), 1667 (wide) cm NMR, cG, ppm (DMSO-d): 3.58, 3.97 (2H, ABq, Hz); 4.12 (3N, S); 5.28 (1H, d, Hz); 5.36 (1H, d, Hz); 5.62 (1H, d Hz); 5.87 (1H, dd, Hz, 8 Hz); 6.7-8.2 (6H, t); 9.93 (1H, d, Hz). Example 249. To a suspension of 7-C2-methoxyimino-2- (5-amino-1,2,4 thiadiazol-3-yl) acetamido-3-vinyl 3-cephem-4-carboxylic acid (sinisomer, 2.3 g) in Sodium bicarbonate (0.47 g) is added to water (30 ml) and stirred. The insoluble material is removed by filtration, the filtrate is lyophilized, and the sodium salt of the indicated acid (2.0 g) is obtained, which is dissolved in Na, N-dimethylformamide (3 ml) under ice-cooling, followed by stirring at a temperature below 5 ° C for 10 minutes . Ethyl acetate (50 ml) and water (50 ml) are added to the reaction mixture, the organic layer is separated and washed three times with a saturated aqueous solution of sodium bicarbonate (30 ml) and three times with an aqueous solution of sodium chloride (30 ml), followed by drying over sulfate magni. After removal of the solvent, the residue is pulverized; Pivaloyloxymethyl-7-C 2 methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3-vinyl-3 cephaem-4-carboxylate (syn-isomer, 1.4 g) is obtained, t. square 125-133 C (decomposition), IR spectrum (Nujol): 3400-3100, 1770, 1760, 1680, 1620, 1530 cm NMR spectrum, cG, ppm (DMSO-d): 1.15 (9H, S) ; 3.77 (2H, q, Hz); 3.93 (3N, S); 5.23 (1H, d, Hz); 5.38 (1H, d, Hz); 5.7 (1H, d, Hz); 5.7-6.1 (3N, m), 6.85 (1H, dd, Hz; 17 Hz); 8.15 (2H, broad S); 9.67 (1H, d, Hz). Example 250. 2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-tert-butoxycarbonylmethoxyimino) acetic acid (syn-isomer, 2.5 g) is added to a solution of phosphorus pentachloride (1 , 7 g) in methylene chloride, followed by stirring at (-5) - (-15) C for 1 hour. After drying, diisopropyl ether (75 ml) is added to the mixture at (-10) - (-5) C and stirred at ambient temperature for 10 minutes. The precipitates are collected by filtration and then washed with diisopropyl ether. To a suspension of benzhydryl-7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.7 g) in methypenchloride (27 ml), trimethylsilylacetamide (5.8 g) is added, followed by stirring. The precipitated substances are added to this solution with and the mixture is stirred at the same temperature for 30 minutes. To reaction-. Water (80 ml) and ethyl acetate (200 ml) were added to the mixture, followed by separation of the organic layer. Water is added thereto and the mixture is adjusted to a pH of 7.5 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer is washed with an aqueous solution of sodium chloride and then dried over D with magnesium sulfate. After removal of the solvent, benzhydryl-7- 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-tert-butoxycarbonylmethoxyiminoacetamido-3-vinyl-3cephamo-4-carboxylate (syn-isomer, 3.53 g ).
IR (Nujol): 3400, 1770, 1720, 1670, 1620
NMR spectrum, (Y, pp1p (DMSO-d .;): 1.46 (9H, S); 3.77 (2H, q,, 0 Hz); 4.67 (2H, S); 5.30 (1H, d, 0 Hz); 5.33 (W, d, 0 Hz); 5.66 (W, d, 0 Hz); O 5.96 (W, dd, 0 Hz, 9 , 0 Hz); 6.80 (W, dd,, 0 Hz, 17.0 Hz); 6.99 C1H, S); 8.23 (2H, broad S); 7.43 (UN, S); 9.63 (1H, d,, 0 Hz).
Example 251. To a suspension of 2- (4-aminopyrimidin-2-yl) -2-tertbutoxycarbonylmethoxyiminoacetic acid (syn-isomer, 1.3 g) in ethyl acetate (25 ml) was added hydroxy-20 phosphorus chloride (O, 5 ml) under ice cooling and stirring, which is continued for 30 minutes, then trimethylsilylacetamide (28 mg) is added and the mixture is stirred at the same temperature
within 30 min. Phosphorus oxychloride (0.5 ml) is added to the mixture at 0–5 ° C, followed by stirring at the same temperature for 30–15 min, then N, M-dimethylformamide (0.37 ml) is added at 0–5 ° C followed by stirring under ice cooling for 30 minutes to obtain an activated 35 acid solution. This solution is added to a solution of benzhydryl-7-amino-3-vinyl 3-cephem-4-carboxylate (1.32 g) and trimethylsilylacetamide (3.5 g) in methylene chloride (30 ml) at -20 ° C with 4th
followed by stirring for 40 min. The reaction mixture was poured into ethyladetate, the separated organic layer was washed with 5% aqueous sodium bicarbonate solution and 5% aqueous sodium chloride solution, followed by drying over magnesium sulfate. After removal of the solvent, the residual oil is subjected to chromatography on silica gel 50 (100 ml) using a mixed solvent of diisopropyl ether and ethyl acetate as eluent. The fractions containing the desired compound are collected, evaporated, and benzhydryl-7- 2- (4-aminopyrimidin-2-yl) -2-tert-butoxycarbonyl- is obtained. methoxyiminoacetamido -3-vinsh1-3cepheme-4-carboxylate (syn-isomer, 0.4 g), m.p. 155-158 C.
IR (Nujol): 3250, 1780, 1723, 1690, 1628 cm.
. NMR spectrum, g; ppm (DMSO-d): 1.46 (9H, S); 3.44, 3.66 (2H, ABq, Hz); 4.78 (2H, S); 5.90 (1H, d, Hz); 5.27 (1H, d, Hz); 5.40 (1H, d, Hz); 6.10 (1H, dd, Hz, 8 Hz); 6.67 (1H, d, Hz); 6.96 (1H, S); 6.98 (1H, dd, J.11 Hz, 18 Hz); 7.3 (yun, t); 8.28 (1H, d, Hz); 8.50 (W, d, Hz).
Example 252. Benzhydryl-7 2- (0,0-diethylphosphonometoxyimino) 2- (2-formamidothiazol-4-yl) acetamide-J3-vinyl-3-cephem-4-carboxylate (sinisomer, 5.3 g), mp. 135-142 C is obtained by reacting benzhydryl-7-aminoZ-vinyl-3-cephem-4-carboxylate (4.7 g) with an activated acid solution, which is obtained from 2- (0.0diztilphosphonomethoxyimino) -2- (2-formamidothiazol-4- or) acetic acid (syn-isomer, 5.5 g), phosphorus oxychloride (2.07 ml) and N, N-dimethylformamide (1.75 ml) in tetrahydrofuran (55 ml) according to the procedure described in Examples 250 and 251 .
IR (Nujol): 3400, 3160, 1785, 1723, 1675 cmL
NMR spectrum: sG-, ppm (DMSO-df): 1.25 (6H, t, Hz), 3.73 (2H, t); 4.13 (4H, t); 4.57 (2H, d, Hz); 5.28 (1H, d, Hz); 5.2-5.8 (2H, ha); 5.90 (1H, t); 6.80 (1H, dd, Hz, 18 Hz); 6.95 (1H, Yu; 7.37 (YUN, t); 7.47 (1H, S); 8.53 (1H, S) 9.80 (1H, d, Hz); 12.7 (1H wide s)
Examples are p 253. Trifluoroacetic acid (13.6 ml) is added to a solution of benzhydryl-7- 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-tert-butoxycarbonate-methoxy-imino-ethophamide-J-3-vinyl-3 cefem- 4-carboxylate (syn-isomer, 3.4 g) in methylene chloride (7.0 ml) and anisole (3.4 ml) with ice cooling, followed by stirring at ambient temperature for 1.5 h. The reaction mixture is added dropwise to diisoproxy ether (150 ml), the precipitated substances are collected by filtration and then added to a mixture of water and ethyl acetate. After adjusting the pH to 7.5 with aqueous solution 1 with sodium bicarbonate solution, the aqueous layer is separated and then adjusted to pH 2.0 with 10% hydrochloric acid solution. The precipitated substance is collected by filtration, washed with water and then dried.
7-C2- (5-amino-1,2,4-diazol-3-ShI) -2-carboxymethyl-3-vinyl-3-cepheme-4-carboxylic acid (syn-isomer, 1.39 g) is obtained.
IR (Nujol): 3380, 3280, 1760, 1720, 1670 cm-L
NMR spectrum, cffppm (DMSO-d): 3.73 (2H, q, 5 Hz); 4.69 (2H, S); 5.21 (1H, d,, 0 Hz); 5.33 (1H, d,, 0 Hz); 5.60 (1H, d,, 0 Hz); 5.86 (W, dd,, 0 Hz; 8.0 Hz); 6.98 (1H, dd,, 0 Hz, 18.0 Hz); 8.16 (2H, broad S); 9.56 (1H, d,, 0 Hz).
Example 254. To a solution of benzhydryl-7-C2- (0,0-diethylphosphonomethoxyimino) -2- (2-formamidothiazol4-yl) acetamido j-3-vinyl-3-cephem-4carboxylate (syn-isomer, 4.2 g) in methylene chloride (20 ml) and anisole (2 ml), trifluoroacetic acid (5 ml) is added under ice-cooling. followed by stirring at Yu for 1.5 hours. The reaction mixture is added dropwise to diisopropyl ether (400 ml), the precipitated substances are collected by filtration and washed with diisopropyl ether, followed by drying under reduced pressure.
7-1 | 2- (0,0-diethylphosphonomethoxyimino) -2- (2-formamidothiazol-4-yl) -acetamido-3-vinyl-3-cefem-4-carboxylic acid (syn isomer, 2.8 g) are obtained, m.p. . 173-176 C.
IR (Nujol): 3160, 1775 (wide), 1680 (wide) cm
NMR spectrum, (G, ppm (DMSO-dfe):
1.28 (6H, t, Hz); 3.76 (2H, t); 4.17 (4H, t); 4.58 (2H, d, Hz); 5.23 (1H, d, Hz); 5.36 (1H, d, Hz); 5.63 (1H, d, Hz); 5.87 (1H, dd, Hz, 8 Hz); 7.0 (1H dd, Hz, 18 Hz); 7.70 (1H, S); 8.56 (W, S); 9.82 (1H, d, Hz); 12.7 (1H, broad S).
Example 255. To a solution of (0,0-diethylphosphonomethoxyimino) 2- (2-formamidothiazol-4-yl) acetamido} 3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 1.725 g) in methylene chloride (26 ml ) Bis- (3methylslc) -acetamide (3.05 g) and trimethylsilyl iodide (3.0 g) are added at 25-28 seconds, followed by stirring at ambient temperature for 18 hours. After removing the solvent, the residual oil is dissolved in methanol (25 ml), the mixture is stirred at 2 hours after addition of concentrated hydrochloric acid (2 ml). After removing the solvent, the residue was dissolved in water (50 ml) and adjusted to pH 5.5 with 1N. aqueous solution of sodium hydroxide. This solution is chromatographed on Diaion HP-20 non-ionic adsorption resin. After flushing with water, elution with 10% aqueous soluble methanol is carried out. The eluates containing the desired compound are collected and lyophilized.
7-C2-phosphonomethoxyimino-2- (2-aminothiazol-4-yl) acetamido 3-vinyl-3-cephem-4-carboxylic acid (syn-isomer, 1 g) is obtained, m.p. 185s (decomposition).
IR (Nujol): 3300 (wide) 1780, 1658, 1660 cmH
NMR spectrum, cL, ppm (D O + NanCOj): 3.70 (2P, t); 4.32 (2H, d, HzU; 5.28 (1H, d, Hz); 5.43 (1H, d, Hz); 5.50 (1H, d, Hz); 5.83 (1H, d , Hz); 6.93 (1H, dd, Hz, 18 Hz), 7.00 (W, S).
The following compounds were prepared by reacting 7-acylamino-Zvinylcephalosporanic acid derivatives having formamido groups with concentrated hydrochloric acid in accordance with the procedure described in Examples 231-233.
Example 256. (5-Amino, 2,4-thiadiazol-3-yl) -2-carboxymethoxyacetamido-3-vinyl-3-cephem4-carboxylic acid (syn-isomer),
IR (Nujol): 3380, 3280, 1760, 1720, 1670 ctf
Example 257. To a suspension of 0.9 g of benzhydryl-7- 2- (2-amin6-thiazol-4-yl) -2-methoxyimine-acetamido J3-Binyl-3-cephem-4-carboxylate in 10 ml of methylene chloride and 0.66 g of anisole gain 2.5 g of trifluoroacetic acid are cooled with ice and then stirred for 1 hour at room temperature. The reaction mixture is added dropwise to 100 ml of diisopropyl ether, the precipitate is filtered off and suspended
The mixture is diluted with a mixture of ethyl acetate and water, and the pH is then adjusted to 7 with a saturated aqueous solution of sodium bicarbonate. The separated aqueous solution is saturated with sodium chloride, and then a mixed solvent consisting of ethyl acetate and tetrahydrofuran in a ratio of 8: 2 by volume is added. After the pH was adjusted to 3.2 with 10% hydrochloric acid, the organic layer was separated, washed with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After removing the solvent, the residue is washed with diisopropyl ether.
0.4 g of the syn-isomer (2-aminothiazole-A-1m) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid is obtained.
IR (Nujol): 3400-3100, 1780, 1660, 1630, 1540 cm.
NMR spectrum, cf, ppm (DMSO-d): 3.72 (2H, q, Hz); 3.87 (3N, S) 5.20 (1H, d, Hz); 5.33 (1H, d, Hz); 5.58 (1H, d, Hz); 5.78 (1H, dd, Hz, 8 Hz); 6.77 (1H, S); 6.95 (1H, dd, Hz, 18 Hz); 9.62 (1H, d, Hz).
Example 258. A Bilsmeier reagent was prepared from 1.8 g of phosphorus oxychloride and 0.8 g of K, H-dimethylformamide in 3.2 ml of ethyl acetate using a conventional procedure. 2.7 g of sinisomer 2- (2-cyclopenten-1-yloxyimino) --2- (2-formamidothiazol-4-yl) acetic acid are added to the stirred suspension of the Vilsmeier reagent in 30 ml of dry tetrahydrofuran with ice and mixed with ice and stirred 30 min at the same temperature (solution A). 8.1 g of trimethylsilylacetamide — to a stirred suspension of 2.0 g of 7-amino-3-vinyl 3-cephem-4-carboxylic acid in ethyl acetate are added, the mixture is stirred for 10 minutes at 35–40. 10 ° C and stirred at the same temperature for 0.5 hours, 40 ml of water are added to the reaction mixture and the separated organic layer is added to water; The pH of the mixture is adjusted to 7.5 with a saturated sodium bicarbonate aqueous solution. Set the pH to 2.0 of the separated aqueous layer with
6087106
with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.
According to | yachayut 3.20 g syn-isomer 7-C2 (2-cyclopenten-1-yloxyimino) -2- (2 formamidothiazol-4-sh1) acetamido. -3wins-3-cephem-4-carboxylic acid.
ten
IR (Nujol): 3200, 1780, 1680, 1650 cm-.
NMR spectrum, cL, pp1p (DMSO-dg): 1.79-2.78 (4H, t); 3.73 (2H, q, Hz); 5.22 (1H, d,, 0 Hz); 5 5.33 (W, d,, 0 Hz); 5.60 (1H, d,, 0 Hz); 5.71-6.28 (4H, ha); 6.96 (1H, dd,, 0 Hz, 18.0 Hz); 7.40 (1H, S); 8.53 (1H, S); 9.63 (1H, d,, 0 Hz).
20
Example 259. Obtain 5.1 g of benzhydryl-7-C2- (5-tritylamino-1,2, 4-thiadiazol-3-yl) acetamido2-3-vinyl3-cephem-4-carboxylate when interacting with 3.17 g of monohydrochloride
5 benzhydryl-7-amino-3-vinyl-3-tsefem4-carboxylate with an acid chloride derived from 2.7 g of 2- (5tritylamino, 2,4-thiadiazole-3-yl) acetic acid and 1.75 g of Type of phosphorus chloride in accordance with the procedure of Example 258.
IR Spectrum (Nujol): 1760, 1710, 1670 cm -
NMR spectrum, (G, ppm (DMSO-d g): 3.35 (2H, m); 3.73 (2H, m); 5.18
5 (1H, d, Hz); 5.27 (1H, d, Hz); 5.62 (1H, d, Hz); 5.72 (1H, dd, Hz, 8 Hz); 6.77 (1H, dd, Hz, 18 Hz); 6.93 (1H, S); 7.3 (YUN, S); 7.63 (1H,
0 d, Hz); 8.05 (1H, S).
Example 260. To a suspension of 2.15 g of benzhydryl-7-amino-3-vinsch-3-cephem-4-carbox-15-at-monochlorohydrate in 100 ml of methylene chloride was added, with ice-cooling, 0.54 g of 2,6-lutidine. 2.4 g of 2- (5-tritylamino-1, 3,4-thiadiazol-2-yl) acetic acid, 1.03 g K, K-di0 cyclohexylcarbodiimide, 200 ml tetracycrofuran and 60 ml K, were added to the solution obtained. N-dimethylformamide, the mixture is stirred at room temperature for a day. After removing the solvent
5 to the residue was added a mixed solvent of ethyl acetate, tetragvdrofuran and water. Filtered off
insoluble substances are washed through the diltrate with dilute hydrochloric acid and saturated aqueous solution. sodium bicarbonate and an aqueous solution of sodium chloride, and then dried over magnesium sulfate. After removing the solvent, the residue is washed with diisopropyl ether.
2.6 g of benzhydrip-7-2 (5-tritylamino-1,3,4-thiadiazol-2-yl) acetamido-3-vinyl-3-cephem-4 carboxylate are obtained.
IR (Nujol): 3300-3150, 1780, 1720, 1660, 1620, 1510 cm.
Example 261. 4.4 g of benzhydryl-7-C2- (5-tritylamino-2H-tetrazol-2-yl) acetamido 3-3-vinyl-Zecem-4-carboxylate are obtained by reacting benzhydryl-7-amino-3-vinyl-3-monohydrochloride cephem-4-carboxylate (3.5 g) and 3.5 g of 2- (5-tritylamino-2H-tetrazol-2-yl) acetic acid in the presence of 0.9 g of 2,6-lutidine and 1.7 g of N, N-dicyclohexylcarbodiimide in accordance with the method of example 260.
IR (Nujol): 3325, 1780, 1710, 1620, 1560 cm
NMR spectrum, eG, ppm (DMCO-dt): 3.78 (2H, br); 5.02-5.92 (6H, ha); 6.78 (1H, dd, Hz, 17 Hz); 6.97 (1H, S); 7.05-7.65 (25H, ha); 9.33 (1H, d, Hz).
Example 262. A mixture of 3, t g of syn-isomer (2 cyclopenten-1-yloxyimino) -2- (2 formamidothiazol-4-yl) acetamido3-3 vinyl-3-cephem-4-carboxylic acid in 22 is stirred at room temperature for 2.5 hours. ml of methanol, 10 ml of tetrahydrofuran and 1.3 g of concentrated hydrochloric acid. The reaction mixture was added to a mixture of ethyl acetate and water, adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The pH of the separated aqueous layer is adjusted to 3.0 with 10% hydrochloric acid. The precipitate is filtered off, washed with water and dried over phosphorus pentoxide in vacuo. . 2.7 g of the syn-isomer (2-cyclopenten-1-yloxyimino) -2 (2-aminothiazol-4-yl) acetamido-3-winch-3-cephem-4-carboxylic acid are obtained.
IR (Nujol): 3270, 1765, 1650 cm -
NMR spectrum, s, ppm (DMCO-dj): -1.92-2.75 (4H, t); 3.73 (2H, q.
, 0 Hz); 5.21 (1H, d,., 0 Hz); 5.21-6.33 (6H, t); 6.80 (1H, S); 6, 96 C1H, dd, 0 Hz, 18.0 Hz); 9.62 (W, d,, 0 Hz).,
Example 263. To a suspension of 2.6 g of benzhydryl-7-G2- (5-tritylamino1, 3,4-thiadiazol-2-yl) acetamido 3-3 vinyl-3-cephem-4-carboxylate in 30 ml of methylene chloride and 2, 1 g
anisole was added 7.6 g of trifluoroacetic acid with ice and then stirred for 1.5 hours at room temperature. The reaction mixture is drunk in 300 ml of diisopropyl ether, the precipitate is filtered off and suspended in 40 ml of water. After adjusting the pH to 7 with a 10% aqueous solution of sodium hydroxide, the solution is washed with ethyl acetate and then adjusted to pH 5 with 10% hydrochloric acid. The residue of organic solvent is completely removed by evaporation and set
J The pH of the resulting aqueous solution is 4 with diluted acetic, - acid, and the solution is chromatographed on Diaion HP-20 non-ionic adsorption resin (50 ml). After washing with water, elution is carried out with 30% isopropyl alcohol, fractions containing the desired compound are collected. then concentrate them under reduced pressure, the concentrate is lyophilized.
5 0.31 g of (5-amino 1, 3,4-thiadiazol-2-yl) acetamido-3 vinyl-3-cephem-4-carboxylic acid is obtained.
IR (Nujol): 3300, 3200, 1760, 1650, 1610, 1600, 1550,
Q 1510 cm
NMR spectrum, G, ppm (DMCO-dt): 3.55 (2H, wide S) -; 3.88 (2H, S); 5.05 (1H, d, Hz); 5.05 (lH, d, Hz) i 5.30 (1H, d, Hz); 5.55 (1H, dd, Hz, 8 Hz); 7.17 (tH, dd, 17 Hz); 9.27 (1H, d, J-8 Hz).
Example 264. Obtain 0.55 g of (5-amino-1,2,4-thiadiazal-3-yl) acetamido3-3-vinsh1-3-cephem-4-carboxylic acid by reacting 5 g of benzhydryl-7-2- ( 5-tritylamino-1, 2,4-thiadiazol-3-yl) acetamido-3-vinyl-3-cephem-4-carboxyl 1 and
14.7 g of trifluoroacetic acid in the presence of 5.57 g of anisole according to the procedure of Example 263.
IR (nujol): 1760, 1640 cm NMR spectrum, ppm (DMCO-d): 3.55 (2H, S); 3.68 (2H, m); 5.13 (1H, d, Hz); 5.28 (1H, d, Hz); 5.55 (1H, d, Hz); 5.68 (1H, dd, Hz, 8 Hz); 6.95 (tH, dd, Hz, 18 Hz); 7.9 (2H, broad 9.05 (1H, d, Hz). Example 265. 0.7 (5-amino-2H-tetrazol-2-Sh1) acetamido3-3-vinyl-3-cephem-4 -carboxylic acid, mp. 230-242 C (with decomposition) with isomeric action of 8.3 g of benzhydryl-7-G2- (5-tritylamino-2H-tetrazol-2-yl) acetamvdo 2 vinyl-3-cephem-A- carboxylate and 24.9 g of trifluoroacetic acid in t the presence of 9.4 g of anisole according to the procedure of Example 263. IR spectrum (Nujol): 3400-3100, 1770, 1680, 1620, 1550 cm. NMR spectrum, 1: L, ppm (DMSO-d) .3.7 (2H, t); 4.8-6.05 (6H, t); 7.00 (1H dd, Hz, 17 Hz); 9.57 (W, d, Hz). Example 2b6: 0.18 g of concentrated hydrochloric acid is added to a solution of 3.0 g of the syn-isomer benzohydryl-7- 2- (tert-butoxycarbo-methoxyimino) -2- (2-aminothiazol-4-yl atsvtamido-3-vinyl-3-cephem-4-carboxylate in 12 ml of formic acid, and stirred for 2.5 hours at room temperature. Reak tional mixture was poured into 100 ml of diisopropyl ether. Otfiltrovgaayut precipitate promgoayut diisopropyl ether and dried. 1.6 g of 7-monohydrochloride C2-carboxymethoxyimino-2- (2-ami thiazol-4-yl) atsetamidoZ-3-vinyl-3- cepheme-4-carboxylic acid (synisomer) on the IR spectrum (Nujol): 1760, 1670, 1630 cm - NMR spectra p, A, ppm (DMCO-d): 3.7 (2H, t); 4.75 (2H, S); 5.25 (W, d, 0 Hz); 5.36 (1H, d, Hz); 5.61 (1H, d,, 0 Hz); 5.80 (1H, dd,, 0 Hz, 8.0 Hz); 6.70-7.47 (1H, t); 7.06 (1H, S), 78 (1H, d, 0 Hz). This reaction can be carried out with the use of reagents and solvents presented in table. 4. Table 4 Sol on acid-acetic acid (concentrated) p-Toluenesulfonicity Acidic acid Acetic acid Methanesulfonic acid Acid Acetic acid Example 267. Add 1.7 g of 2-amino-acetic acetic acid chloride to a solution of 2.0 g 7- (2-aminothiazol-4-yl) -glyoxylamido-3 vinyl-3-cephem-4-carboxylic acid and 0.7 g of sodium acetate trihydrate in 40 ml of water, set the pH of the mixture to 5.2 with 10% aqueous hydroxide solution sodium and stirred for 3.5 hours at 50 ° C. While stirring, adjust the pH of the mixture to 5,, 4 in the same way. Then the pH of the reaction mixture paBHbiM 2.2 is adjusted with IOZ-hydrochloric acid under ice cooling. The precipitate is filtered off, washed with water, then dried over phosphorus pentoxide in vacuo. 1.13 g of 7-C2- (2-aminothiazol-4-yl) -2-carbomethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer) are obtained. IR (Nujol): 3350, 1770, 1680, 1640 cm-. The following compounds were obtained by reacting oxacompound derivatives of 7-acylaminocephalosporanic acid with the corresponding 0-substituted hydroxylamines by the procedure of Example 267. Example 268. 7-C2- (2-Amino-, thiazole-4-sh1) -2-methoxyimine racetamido-3- vinkl-3-cephem-4-carboxylic acid (syn-isomer). Ill IR (Nujol): 3400-3100 1780, 1660, 1630, 1540 cm-g Example 269. Pivaloyloxymethyl 7-C2 (2taminotiaeol-4-yl) -2MeTOKCHHMHHoa4eTaMHfloJ-3-BHHHn-3tsefem-4-karbokssh1at ( syn isomer). IR (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm - Example 270. Acetoxymethyl (2-aminothiazol-4-yl) -2-methox-iminoacetamido-3-vinsh-3-cephem-4carboxylate (syn-isomer). IR (Nujol): 3300, 1765 (wide), 1660, 1610, 1535 cm-. Example 271. Propionyloxy methyl 7-12-- (2-aminothiazol-4-yl) -2 methoxyimino acetamido-3-vinyl-3 cefem-4-carboxylate (syn-isomer). IR (Nujol): 3350, 1770 (wide), 1650, 1620, 1530 cm Example 272. Isobutyryloxymethyl-7-t2- (2-aminothiazol-4-yl) 2-methoxyiminoacetamido-1-3-vinylZ-cephem-4- carboxylate (syn-isomer) IR spectrum (nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cd Example 273. 1-Acetoxypro-dyl-7-2- (2-aminothiazol-4-yl) -2methoxyiminoacetamido -3-vinyl-3 cefem-4-carboxylate (syn-isomer). IR (Nujol): 3300, 1765, 1670, 1610 cm Example 274. L-2-Amino-2carboxyethyl-7-2- (2-aminothiazol4-yl) -2-methoxyiminoacetamido -3 vinyl-3-cephem-4-carboxylate (synomer). IR (Nujol): 3200, 1770, 1735, 1650 (wide) see Example 275. Phthalide-3-yl-7-L2- (2-aminothiazol-4-yl) -2-methox-iminoacetamido-3-vinyl-3-cephem-4 carboxylate (syn-isomer). IR (Nujol): 3300, 1775, 1670, 1610, 1530 cm-. Example 276. (2-Amino thiazol-4-yl) -2-allyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (Nujol): 3250, 1770, 1655, 1605, 1545. Example 277. (2-Amino thiazol-4-yl) -2-propargyloxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (nujol): 3250, 1760, 1680, 1620, 1530 cm7112 Example 278. 7-C2- (2-Aminothiazol-4-sh1) -2-ethoxyiminoacetamido, 3-vinsh1-3-cefen-4-car6anoic acid (syn-isomer). IR spectrum (yuyol): 3300, 1770, 1660, 1545 cm L Example 279. Pivaloyloxymethyl-7-2 (2-aminothiazol-4-yl) 2 ethoxyiminoacetamto 3-3-vinyl-Zecepham-4-carboxylate (syn-isomer) . IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530. Example 280. 7-G2- (2-Aminothiazol-4-yl) -2-hexylimoxyiminoacetamido-3-vinsh1-3-cephem-4-carboxylic acid (syn-isomer). IR spectrum (Nujol): 3250, 1770, 1660, 1530 cm - Example 281. (2-Aminothiazol-4-yl) -2- (1-carboxyethoxyimino) acetamido-3-vinyl-3-cephem-4 carboxylic acid (syn isomer). IR spectrum (Nujol) :. 3260, 3160, 1770, 1670 cm - Example 282. 7-C2- (2-Aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamidoj-3-vinyl-Zepham-4-carboxylic acid ( synisomer). IR (Nujol): 3300, 3200, 1770, 1670, 1640 cti. Example 283. 7-1; 2- (2-Aminothiaz ol-4-yl) -2- (3-carboxypropoxyiminoacetamido-3-vinyl-3-cephem-4carboxylic acid (syn-isomer). IR spectrum (Nujol): 3300, 1760, 1660 cm. Example 284. (2-Aminothiazol-4-yl) -2-ethoxycarboxymexyimino-amino-acetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR spectrum (Nujol): 3250, 1770, 1670, 1530 cm. Example 285. Benzhydryl-7 2- (2-aminothiazol-4-yl) -2- (3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino) acetamido 3-vinyl-3-cephem 4-carboxylate (sinisomer). IR spectrum (Nujol): 3300, 1780, 1719, 1680 cm. Example 286. Benzhydryl-7 2- (2-aminothiazol-4-yl) -2- (2-b nshydryloxycarbonsh1-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino) acetamido3-3-vinyl-3-cephem-4carboxylate (syn-isomer) .JJ3 IR spectrum (nujol): 3360, 1750 (pink) CNT Example 287. 7-C2- Amino thiazol-4-yl) -2- (pyridine 2-Sh1methox imino) acetamido L-3-vinip-3-cephem-4 carboxylic acid (syn-isomer). IR cneKfp (Nujol): 3300, 1770, 1650, 1620, 1540 cm. Example 288. 7-C2- (2-Amino t and 3 ol-4-yl) -2-methoxyimino acetates H-vinyl-3-cephem-4-carboxylic acid (syn-isomer)., IR spectrum (nujol): 3300, G / 80, 1645, 1580, 1515 cm - Example 289. (2-Amino thiazole-4-sh1) -2-cyanomethoxyimino; eTaM4qo3-3-BHHiiH-3-4e (J) eM- 4-Kap6o new acid (with in-isomer). IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm-H Example 290. 7-f2- (2-AMHHo thiazol-4-yl) -2- (3-kyrboxyalllylox-iminoacetamidoZ-3-vinsh-3 -cephem-4carboxylic acid (syn-isomer). IR spectrum (Nujol): 3250, 1760, 1690, 1650 cm L Example 291. (2-Amino 5-chlorothiazol-4-yl) -2-carboxymethomines iminoacetamido-3- Vinsh1-3-cephem-4carboxylic acid (syn-isomer) IR spectrum (Nujol): 3400, 3180, 1770, 1685, 1650, 1610 cm - Example 292. (2-Formamidothiazol-4-Sh1) -2- ( 0,0-dizti.phosphonometoksiyimino) acetamidoJ-3vinyl-3-cephem-4-k. Arboxylic acid (syn-isomer). IR spectrum (Nujol): 3160, 1775 (wide), 1680 (wide). Example 293. (2-Amino thiazol-4-yl) -2- (2-cycle penten-1iloxyimino) acetamido 1-3-vinyl 3 cepheme-4-carboxylic acid (syn isomer). IR spectrum (Nujol): 3270, 1765, 1650 cmH Example 294. (5-amino 1,2,4-thiadiazole- 3-yl) -2-methoxyiminoacetamido-3-vinyl-3-cephem-4carboxylic acid (syn-isomer). IR spectrum (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm Example 295, Pyvaloyloxymethyl-7 - 2- (5-amino-1,2,4-thiadiazo 4-yl) -2-methoxyiminoacetamido-3 vinyl-3-cephem-4-carboxylic acid (syn-isomer). 7 And spectrum (Nujol): 3400-3100, 1770, 1760, 1680, 1620, 1530 cm. Example 296. 7-C2- (5-Aninog 1,2,4-thiadiazol-3-yl) -2-carboxymethoxyiminoacetamido D-3-vinyl-Zdefem-4-carboxylic acid (syn-isomer). IR (Nujol): 3380, 3280, 1760, 1720, 1670 cm-. . Example 297. (5-Amino1, 2,4-oxadiazol-3-yl) -2-methoxy, imino acetamido3-3-vinyl-3-cephem-4carboxylic acid (syn-isomer). Example 298. (6-Aminopyridin-2-Sh1) -2-methoxyiminoacetamido 3-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (Nujol): 3350, 3250, 1780 (wide), 1667 (wide) see Example 299. (6-Aminopyridin-2-yl) -2-carboxymethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn-isomer). IR (Nujol): 3300, 1763 (wide), 1660 (wide) cm Example 300. Benzhydryl-7 {2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido-3-vinyl-3-cefem4- carboxylate (syn-isomer). IR (Nujol): 3250, 1780, 1710, 1700, 1660, 1540 cm- / Example 301. Benzhydryl-7G 2- (2-formamidothiazol-4-yl) -2-tertbutoxycarbrynylmethoxyiminoacetamido-3-vinyl-3-cefem -4-carboxyl 1 (syn-isomer). IR spectrum (Nujol): 3250, 1780, 1720, 1680, 1540 cm - Example 302. Benzhydryl-7 2- (2-aminr-thiazol-4-yl) -2-tertbutoxycarbonylmethoxyiminoacetamido 3-vinyl-3-cephem-4-carboxylate (synomer). IR (Nujol): 3440, 3260, 3100, 1780, 1720, 1660, 1530. Example 303. 2.2 g syn-isomer of 2- (1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetic acid are added to a stirred suspension of 1.6 g p phosphorous phosphorus in 22 ml of methylene chloride at, the mixture is stirred for another 30 minutes at (-5) (-15) ° C. Dry diisopropyl ether is added to the reaction mixture and the precipitate is filtered off and washed with dry diisopropyl ether. 1151186087 11 brewed from 5.4 g of trimethylsilyl-pH of acetamide to a stirred suspension of 2.5 g of benzhydrash-7-amine H-vinyl-3-cephem-4-carboxylate hydrochloride in 25 ml of methylene chloride. The previously obtained precipitate is added to the resulting solution with and stirred at (-5) - (-10) s for 40 minutes. Water is added to the solution, and the separated aqueous layer is removed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous chloride solution. sodium, dried over magnesium sulphate and evaporated; 2.51 g of the syn-isomer, benzhydryl-7- 2- (1-tert-bytoxycarbonate Iethoxymino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamidoJ-3 vinyl-3-cephem-4 are obtained carboxylate. IR (Nujol): 1770, 1720, 1680, 1610 cm-. Example 304. 0.95 g of the syn-isomer (4-tert-butoxycarbonylaminothiazol-2-sh1) -2-methoxy-imino-acetamido-3-vinyl-3-cephem-4-carboxylic acid is obtained by reacting 0.7 g of 7-amino-3- Vinyl-3-cephem-carboxylic acid and 0.9 g of a sinisomer of 2- (4-tert-butoxycarbonylaminothiazol-2-yl) -2-methoxyiminoacetic acid according to the method of example 7. IR spectrum (Nujol): 3250, 1785, 1720, 1690, 1600, 1535 cm NMR spectrum, (U, ppl (DMCO-d): 1.45 (9H, S); 3.72 (2H, q, Hz) 3.95 (ZN, S); 5, 18 (1H, d, Hz); 5.28 (1H, d, Hz); 5.52 (1H, d, Hz); 5.82 (1H, dd, Hz, 8 Hz); 5.90 (1H , dd, Hz, 17 Hz) 7.28 (1H, S); 9.71 (1H, .d, Hz) 10.27 (1H, S). Example 305. Add 9.6 ml of trifluoroacetic acid. acid to a solution of 2.4 g of the syn-isomer benzhydryl-7- 2- (1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3-vinyl- 3 cem-4-carboxylate in 5 ml of methylene chloride and 2.4 ml of anisole are cooled with ice and the mixture is stirred for 1 hour at room temperature. The resulting solution is added dropwise to 100 ml of diisopropyl ether, and the precipitate is filtered. The precipitate is added to a mixture of water and ethyl acetate, then set to 116 7.5 with 10% aqueous sodium hydroxide solution. The separated aqueous layer is saturated with sodium chloride, adjusted to pH 1.5 with 10% hydrochloric acid, and extracted with a mixed solvent consisting of ethyl acetate and tetra-tetrafluran 1: 1 by volume. The extract is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent, 0.55 g of the syn-isomer of (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido-3-vinyl 3-cephem-4-carboxylic acid is obtained. IR (Nujol): 3330, 3200, 1770, 1670, 1610 CM-t NMR spectra, G, ppm (DMCO-d): 1.37 (ZN, t); 3.70 (2H, t); 4.80 (1H, t); 5.07-6.07 (4H, t); 6.96 (1H, dd,, 0 Hz, 18.0 Hz); 8.17 (2H, broad S); 9.47 (d, 0 Hz) I 9.55 (d, 0 Hz) Example 306, Added to 2 liters of ethanol 70 g of the syn-isomer (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamido - H-vinyl-Zeph-4-carboxylic acid and stir the mixture at 40 ° C. for 30 minutes. Filter out insoluble substances and pursue ethanol. The washings were combined with the filtrate, 4.2 l of water were added thereto at 40 ° C, then stirred for 1 hour at room temperature. The precipitate is filtered off. 61.6 g of crystalline a (2-aminothiazol4-yl) -2-carboxymethoxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid trihydrate are obtained. X-ray spectrum: 20 1/1 o (relative: 20 17 26.1 0.43 24.7 0.42 23.7 0.53. 1186087118 17.50.1023.40008.08.90.95 15.40.4823, 10,507,50,15 15,00,9322,70,695,80,34

权利要求:
Claims (1)
[1]
A method for producing 3-viniltsefalosporinov general formula I wherein 1C - aminothiazol optionally substituted by chlorine, aminotiadiaz olil, aminooksadiazol yl, aminopyridyl, Aminopyrimidinyl, aminotetraz olil, atsilaminotiazolil optionally substituted by chlorine, Diss ^ -C ^ alkyl) aminometilenaminotiadiazolil, di (C _l —C ₆ -alkyl) aminomethyl enaminooxadiazolyl, acylaminopyridyl, tritylaminothiadiazolyl, tritylaminotetrazolyl or a group of the formula
R3SO2NH where Rg is C, -C ₄ alkyl;
Ra is a carboxy group or an esterified carboxy group g pa;
A is methylene, which may have a substituent selected from the group consisting of amino, acylamino, oxy, oxo group of the formula ~ N - 0R ₄ , in the form of a syn-isomer, where R4 is a hydrogen atom, CyC ^ cycloalkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ alkenyl substituted with a carboxy group or an esterified carboxy group C ₂ -C ₄ alkenyl, C-C-alkyl or C, -C ^ -alkyl substituted with one or two substituents selected from the group consisting of carboxy, eteryfitsirovannuyu carboxy, amino, acyl ♦ amino, cyano, phosphono, 0.0 * -di (C ₄ -C 4 alkyl) phosphono group and pyridyl ', or range atsevticheski acceptable salts, characterized in that a compound of general formula II
And ₂ where K, has the indicated meanings, or its reactive derivative at the amino group; or a salt thereof, is reacted with a compound of the general formula III
R ₄ - A - COOH, where R ₍ and A have the indicated meanings, either with its reactive derivative at the carboxy group or with its salt in an inert solvent under the reaction conditions, such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride , ethylene chloride, tetrahydrofuran, ethyl acetate, Ν, Ν-dimethylformamide, pyridine, hexamethylphosphoramide, or mixtures thereof and, if necessary, a compound of formula I in which R ₄ is acylaminothiazolyl, optionally substituted with chlorine, di (C ₄ -C ^ -alkyl ) aminomethyleneaminothiadiazolyl, di (C ₄ ~ C ς -alkyl) aminomethyleiamine ooxadiazolyl, acylaminopyridyl, tritylaminothiadiasis olyl or tritylaminotetrazolyl, the amino protecting group is cleaved to give a compound of the formula, wherein ^ is aminothiazolyl, possibly substituted with chlorine, aminothiadiazolyl, aminooxadiazolyl, aminotetrazole, such as water, a reaction solution such as ethanol, aminotetrazole, such as water, ethanol, ethanol, aminotetrazole, propanol, tert-butyl alcohol, tetrahydrofuran, Ν, Ν-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or in a compound of formula I in which R ₂ is esterified bath carboxy group, the ester part is cleaved to give a compound of formula I in which R ^ is a carboxy group in an inert solvent under the reaction conditions, such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, N, N-dimethylformamide, dioxane , methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or an IPC compound of the formula I in which R _{2 is a} carboxy group, are esterified to obtain a compound of the formula I in which R ₂ is an esterified carboxy group in an inert solvent under the reaction conditions, such as , Ν-dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, or mixtures thereof, and / or in a compound of formula I, in which A - methylene substituted with a group of formula -N · - 0R _4, in the form of syn-isomer, wherein R ₄ -C ₁ ~ C _t -alkyl substituted with an esterified carboxy group or 0,0 ¹ -di (C ₄ -C ₄ -alkyl) phosphono group, or C ₂ -C ₄ alkenyl substituted with an esterified carboxy group, the ester moiety is cleaved to give a compound of the formula I, in which A is methylene substituted by a group of the formula = N - 0R ₄ , in the form of a syn-isomer, where R ₄ -C _n -Cς -alkyl substituted with a carboxy group or pho sphono group, or C ₂ -C ₄ alkenyl substituted with a carboxy group in an inert solvent under the reaction conditions, such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, Ν, Ν-dimethylformamide, dioxane, methylene chloride ,! chloroform, diethyl ether, or mixtures thereof, and / or in a compound of formula I in which the esterified carboxy group R ^ is C ₄ -C ^ alkoxycarbonyl substituted with an acylamino group and the esterified carboxy group, the acyl and ester moieties are cleaved to give a compound of formula I, in esterified carboxy wherein R _J, is a C ₄ -C ^ alkoxycarbonyl, carboxy and substituted amino, in a reaction-inert solvent such as water, methanol, ethanol, propanol, tert-butyl alcohol, tetrahydrofuran, Ν, Ν-di etilformamid, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or in a compound of formula I, in which A - methylene substituted with a group of formula -N - 0R _4, in the form of syn-isomer, wherein R ₄ represents a C ₄ -C ₆ -alkoxycarbonyl-C ₂ -Cj-alkyl. substituted by an acylamino group and an esterified carboxy group or C ₄ ~ C ₆ -alkyl substituted by an acylamino and esterified carboxy group, the acyl and ester moieties are cleaved to give a compound of formula I in which A is methylene substituted by a group of formula sN - 0R ₄ , as the syn1186087 isomer where R ", - C, -Cg is alkoxycarbonyl-C, -C _ς alkyl substituted with an amino group and a carboxy group, or (C-C _алки alkyl substituted with an amino group and a carboxy group in a solvent inert under the reaction conditions, such as water, Methanol, ethanol, propanol, tert-butyl lactic alcohol, tetrahydrofuran ', Ν, Ν-dimethylformamide, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and / or in a compound of formula I in which A is methylene substituted with a group of the formula = N-OR ₄ , in the form syn isomer, where R ₄ is C ^ C ^ alkyl substituted with a carboxy group or phosphono group, or -C ₄ ~ alkenyl substituted with a carboxy group is esterified to give a compound of formula I in which A is methylene substituted with a group of formula = N- OR ₄ , in the form of a syn-isomer, where R ₄ is C ^ -C ^ -alkyl substituted with an esterified carboxy group or 0,0'-di (C, -C ₄ -al keel) phosphono group, or C ₂ -C ₄ ~ alkenyl substituted with an esterified carboxy group in an inert solvent under the reaction conditions, such as N, N-dimethylformamide, tetrahydrofuran ·, dioxane, methanol, ethanol, or mixtures thereof, and / or in the compound of formula I in which A is methylene substituted with an acylamino group, the acyl moiety is cleaved to give a compound of formula I in which A is methylene substituted with an amino group in a solvent inert under the reaction conditions, such as water, methanol, ethanol, propanol, tert- butyl alcohol, tetrahydrofuran, N, N-dimethylform mid, dioxane, methylene chloride, chloroform, diethyl ether, or mixtures thereof, and the target product is liberated in free form or in the form of a pharmaceutically acceptable salt.

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KR870002166B1|1987-12-14|Process for preparing antibiotic compounds

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同族专利:

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公开号 | 公开日

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EP0244637B1|1993-03-17|

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US4423213A|1983-12-27|

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EP0123024B1|1988-09-07|

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NO803470L|1981-07-02|

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NO160921C|1989-06-14|

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DK491780A|1981-06-19|

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ES8300112A1|1982-10-01|

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GR71596B|1983-06-17|

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MX158337A|1989-01-26|

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AT86987T|1993-04-15|

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EP0244637A1|1987-11-11|

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PT72079A|1980-12-01|

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ES8204739A1|1982-05-01|

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FI74970C|1988-04-11|

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JPH0710870B2|1995-02-08|

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DE3071939D1|1987-05-07|

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NL930045I1|1993-08-02|

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EP0030630A2|1981-06-24|

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US4487927A|1984-12-11|

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HK11888A|1988-02-16|

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AT26280T|1987-04-15|

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JPH06279452A|1994-10-04|

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IE53271B1|1988-09-28|

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US4409214A|1983-10-11|

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AU6444280A|1981-05-28|

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EP0123024A2|1984-10-31|

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EP0030630B1|1987-04-01|

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HU186753B|1985-09-30|

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SG61787G|1988-04-15|

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ES496948A0|1982-05-01|

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DE3072207T2|1993-07-15|

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PT72079B|1981-09-29|

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CA1235414A|1988-04-19|

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AU543301B2|1985-04-18|

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MX158338A|1989-01-26|

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US4585860A|1986-04-29|

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MY101359A|1991-09-05|

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FI74970B|1987-12-31|

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EP0030630A3|1981-09-09|

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DE3072207D1|1993-04-22|

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DE3072122D1|1988-10-13|

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EP0123024A3|1985-03-13|

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NL930045I2|1994-01-03|

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US5110921A|1992-05-05|

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NO160921B|1989-03-06|

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ES507972A0|1982-10-01|

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US4960889A|1990-10-02|

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IE802347L|1981-05-19|

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AT37028T|1988-09-15|

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AR248139A1|1995-06-30|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB7939985|1979-11-19|

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GB8004335|1980-02-08|

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GB8012991|1980-04-21|

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GB8022920|1980-07-14|

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