PL89964B1 - - Google Patents

Description

The present invention relates to a process for the preparation of cephalosporins of the general formula I, which exhibit a broad spectrum of antibacterial activity against numerous species of gram-positive and gram-negative bacteria. For this reason, these compounds are useful as therapeutic and, to a lesser extent, prophylactic agents, for humans and There are a number of commercially available semi-synthetic cephalosporins with a broad spectrum of activity, but no cephalosporin showing a clinically useful level of antimicrobial activity against all pathogenic organisms important in clinical practice is sought. The invention relates to a process for the preparation of cephalosporins of the general formula I or their pharmacologically acceptable salts or esters, in which the cephalosporins are of the general formula I or their pharmacologically acceptable salts or esters. m Y is oxygen or sulfur, R1 is an organic radical of no more than 20 carbon atoms, R2 is an alkyl group of 1-3 carbon or enzyl atoms, or R1 and R2 together with the carbon and nitrogen atoms to which they are attached form 5-, 6- or 7-membered ring, R3 represents a phenyl group, a phenyl group substituted with one or more functional groups such as hydroxyl, halogen, nitro, 1-3 carbon alkoxy and amino, 2- or 3- thianyyl, cycloalkyl with 3-7 carbon atoms or alkyl with 1-4 carbon atoms and R4 is acetoxy or carbon, nitrogen or sulfur nucleophile. Preferably Y is oxygen. The group R1 may be an alkyl group of 1-10 atoms, among others carbon, alkenyl group with 1-10 carbon atoms, ara, alkyl or aralkenyl, in which the alkyl and alkenyl radicals contain 1-10 carbon atoms, and the aryl radicals are phenyl, thienyl, furyl, pyridyl or substituted phenyl groups, 2 89964 in which the there are groups such as alkyl 1-13 carbon atoms, alkoxy with 1-3 carbon atoms, halogen, nitro and ammonium groups, alkoxy with 1-10 carbon atoms, cycloalkoxy with 5-7 carbon atoms, alkylamino with 1-10 carbon, phenyl, furyl, oxygen, pyridyl, substituted phenyl, the substituents of which are 1-3 carbon alkyl, 1-3 carbon alkoxy, halogen, nitro and amino, substituted alkyl 1-10 carbon atoms in which the functional substituents are groups such as alkylthio group with 1-3 carbon atoms, alkoxy group with 1-3 carbon atoms or phenoxy group. In particular, the group R1 may be methyl, ethyl, n- or isopropyl, n-secondary or tertiary butyl, n-pentyl, n-hexyl, n + ieptyl, co-methylheptyl, noctyl, co, cj-dimethyloctyl, propenyl-2,3-methylpropenyl-2, 1-methylpropenyl , butenyl-2, octenyl-2, 2-phenylethyl, 2-phenylvinyl, 2-J21-methoxyphenyl) vinyl, 2- (4! -nitrophenyl) vinyl, 2- / 31,41,51 -trimethoxyphenyl / vinyl, 2- (furyl-2y); (enyl, 3-phenyl-propyl, 1-methyl-2-phenylvinyl, 4-phenylbutenyl-2, 5-) phenylpentenyl-2,1-methyl-5-phenylpentyl-2, methoxy, ethoxy, n- or secondary propoxy, n-, secondary or tertiary butoxy, n-pentoxy, n-hexyloxy, cyclohexyl, methylamine, phenethylamine, dimethylamine 2-methoxyphenyl, 2-chlorophenyl Iowa, 2-ethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-nitrophenyl, 2-methylphenyl, 4-methylphenyl, methoxVfiiethyl, ethoxymethyl, ethoxymethyl, methylthiomethyl, phexymethyl group. in others a methyl, ethyl or benzyl group, preferably R2 is methyl. y Groups with the symbols R2 and R3 together with the carbon and nitrogen atoms to which they are attached can form a ring of formula 7, 81 9 or 10, where n means the total numerical value 3-5, m means the total numerical value 2-4 I Ra is hydrogen, alkyl 1-3 carbon atoms, acyl 1-3 carbon atoms or alkylsulfonyl 1-3 carbon atoms. Preferably the ring is an imidoazolidine-2-onoyl-1,3-acetylimidazolidine-2-anil-1,3-methylsulfonylimidazolidine-2-onil-1 or hexahydrazepine-2-onoyl-1 ring. The group with the symbol R3 may be between in others, phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-nitrophenyl, 2-thienyl, 3-thienyl, cyclopropyl, cyclohexyl, 1,4-cyclohexadienyl, propyl or methyl. Preferably R3 is phenyl, 4 + hydroxyphenyl, 3-oro-4-hydroxyphenyl or 3-thienyl. The R4 group may include a strong carbon, nitrogen or sulfur nucleophile, among others. Such nucleophiles move the acetoxyl group from the 7- acid ring. of the aminocephalosporan and this shift has been observed by the action of various pyridine derivatives (Hele et al., Biochcm. J. 79, 403 (1961) and Spencer et al., J.Org.Chem., (USA), 32, 500 (1967); others heterocyclic aromatic compounds (Hale et al., loc. cit); Kariyone et al., J. Antibiotics, 23, 131 (1970), and Spencer et al. loc. cit (xanthogenates - dithioaramates) Van Heynjngen et al. J. Chem Soc (London), 5015 (1965), and aniline derivatives (Bradshaw et al., J. ChemSoc, (London), 80 I (1968). In particular, the R4 group may be a radical of formula 11, 12, 13, 14 , 15,16,17,18,19,20 or 21. Preferably R4 is 2-methyl-1,3,4-thiadiazolylthio-5,1-methyl- (1H) -1,2,3-tetrazolylthiol- wa-5,2-methyl-1,3,5-o xadiazolylthiol-5 or (1HH, 2,4, -triazolylthio-5) Preferably the carbon atom to which the R3 group is attached has the D configuration. Suitable pharmacologically acceptable salts are the sodium, potassium, calcium, magnesium, aluminum, ammonium or substituted salts ammonium, i.e. salts with trialkylamines such as triethylamine, procaine, dubenzylamine and triethanolamine. In the case of compounds of formula I having a basic nitrogen binding site in the side chain, inorganic acid addition salts such as sulfate, nitrate, phosphate may also be formed , borate, and hydrohalides such as hydrochloride, hydrobromide and hydroiodide, and organic salts such as acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, ascorbate and methanesulfonate. Suitable pharmacologically acceptable esters are above all those that decompose easily in the human body, releasing the parent acid such as acyloxyalkyl esters such such as acetoxymethyl, trimethylacetyloxymethyl, α-acetoxymethyl, α-acetoxybenzyl and α-trimethylacetyloxymethyl and alkoxycarbonylalkyl esters such as methoxycarbonyloxymethyl or α-methoxycarbonyloxyethyl. Other easily hydrolyzable esters are lactone, thiolactone and dithiolactone, i.e. the compounds of formula 1 in which the 4-carboxyl group is esterified to the group of formula 6, where X1 and Y1 are oxygen or sulfur and Z1 is a divalent radical, and in particular phthalide and substituted phthalide esters such as 5,6-dimethoxyphthalide esters. 89964 Compounds of general formula I are divided into two classes depending on their structure. One class includes compounds in which the group marked with the symbol R1 is linked to a carbonyl group by a CC bond, and the second class includes those compounds in which the group marked with the symbol R1 is linked to a carbonyl group by an NC bond. consists in that a compound of formula II or a salt or ester or silyl derivative thereof, in which formula II the dotted lines represent a bond at positions 2 or 3, n is 0 or 1 IR4 is as defined above, is reacted with N- an acylating derivative of the acid of formula III, in which Y, R1, R2 and R3 are as defined above, and in which reactive groups, such as amino and hydroxyl groups, can be blocked, and then, optionally, A * -isomer is converted into a given A9-isomer, removes silyl groups by alcoholization or hydrolysis, reduces the sulfoxide to the desired sulfide, and removes the blocking groups in the acyl side chain R and converts the ester to the free acid or its salt. The term "silyl derivative" "a" compound of formula II is the reaction product of a compound of formula II with a silylating agent such as halide dialkylsilane, halo trialkylsilane, halide dialkoxysilane and halo tralkoxysilane, or the corresponding aryl or aralkyl silane, and compounds such as hexylsilane methyl dihydroxy compounds of formula 2. The effect of moisture and hydroxyl compounds and after reacting them with an N-acylating acid derivative of formula 2, the silyl groups can be removed from the acylated intermediate by hydrolysis or alcoholysis. The method of the invention uses a reactive N-acylating acid derivative of formula 2. Selection the reactive derivative depends on the chemical nature of the substituents in the acid. If the acid contains only stable acid groups, a suitable N-acylating derivative is an acid halide, preferably an acid chloride. Such reagents are avoided when a labile acid group is present in the acid of formula III. In such cases, a suitable N-acylating derivative is a mixed anhydride. Alkoxy formic anhydrides are particularly preferred mixed anhydrides for this purpose. Other alternative N-acylating derivatives of the acid of formula III are the active esters. Esters such as, for example, an ester formed by reaction with 1-hydroxybenzotriazole or N-hydroxysuccinimide are obtained in situ by reacting the acid with the appropriate hydroxy compound in the presence of a carbodiimide, preferably dicyclohexylcarbodiimide. To other reactive N-acylic acid derivatives, 2 are reactive intermediates formed by in situ reaction with carbodiimide or carbonyldiumidazole, but the literature on the preparation of semisynthetic penicillins gives examples of other reactive N-acylating acid derivatives suitable for coupling with 6-APA. When the free acid of formula 1 or salt thereof, it is also convenient to acylate with an ester of a compound of formula II, followed by removal of the ester group. Conversely, when it is necessary to obtain an ester, it is convenient to carry out the acylation with 7-ACA or a salt thereof followed by esterification of the free acid. In the process of the invention, if it is necessary to block the reactive substituent in the acid of formula III, it is usually possible to use blocking groups. Free amino groups can be blocked by converting them into tertiary butyloxycarbonyl or benzyloxycarbonylamino groups. In another way, the amino group can be blocked as a nitro group and then converted to an amino group. If the compound formed by the N-acylation contains a sulfoxide group at the 1-position of the cephemic ring, it can be reduced by one of the known methods, for example described in the British in Patent No. 1,280,693. One such method involves the action of triphenylphosphine with acetyl chloride. When the compound obtained is an A2-cephem, the desired A3-cephem can be obtained by treatment with an A2-base compound such as potassium hydroxide or a tertiary amine such as pyridine and triethylamine, or by oxidation to A2-cephem sulfoxide followed by reduction to A3 cephem. The method of converting an ester to free acid or a principle depends on the type of ester in question. You can use acidic, alkaline or enzymatic hydrolyze. However, to reduce isomerization and side reactions, avoid aqueous solvents. The preferred de-esterifying agents are Lewis acids. Another method of preparing a compound of Formula 1 is to treat a compound of Formula 4 or a salt, ester or silyl derivative thereof, wherein the dotted line represents a bond at the 2 or 3 positions, R3. | R4 are as defined above for the compound of formula 1, the reaction with the compound of formula 5, in which Y, R1, R2 and IR3 have the above meanings, and then optionally transforming the A2-isomer into the given A3-isomer, removing the silyl groups by alcoholize or hydrolysis, reduces the sulfoxide to the desired sulfide, and removes the blocking groups in the acyl side chain R, and converts the ester to the free acid or its salt. The compounds prepared according to the invention are broad-spectrum cephalosporins, i.e. such cephalosporins that exhibit activity not only against gram-positive bacteria, but also against numerous4,89964 important gram-negative bacteria in clinical practice. The distinctive compounds according to the invention are active against such important organisms as Pseudomonas spp. Against which the commercially available cephalosporins are usually inactive. Furthermore, these compounds are active against numerous gram-negative cephalosporin-producing organisms, such as Enterobaoter spp. Serratia spp., Indole-positive Proteus. The following examples illustrate the method according to the invention without limiting its scope. Example I. Preparation of Dnx sodium salt - (N-imidazolidinone-2Hl-carbonylamino) -benzyl-cephalosporin. 2.2 g of D-α-aminobenzyl cephalosporin dihydrate were dissolved in 30 ml of water, 5 ml of acetone and 0.7 ml of triethylamine. A solution of 0.75 g of imidazolidinone-2-ylcarbonyl chloride in 20 ml of dry acetone was slowly added to the solution along with a further 0.7 ml of triethylamine while maintaining the addition rate so as not to exceed the pH of the reaction mixture between 7.5-8.0 . The addition time was about 5 minutes, and the mixture was then mixed for 1 hour with slight changes in pH. The acetone was removed under reduced pressure, the aqueous concentrate was covered with a layer of 35 mL of ethyl acetate, and both layers were cooled to 0 ° C. With vigorous stirring, the pH of the mixture was carefully adjusted to 1.5 with dilute HCl. The layers were separated and the aqueous phase was immediately re-extracted with 15 ml of fresh ethyl acetate. The combined organic layers were washed with 20 ml of water and then twice with 50 ml of saturated sodium chloride aqueous solution. The organic phase was filtered through siliconized paper to remove the last traces of an aqueous saturated sodium chloride solution and then mixed with 5 ml 1.0N sodium 2-ethylcaproate in isopropanol with stirring. The yellowish precipitate was filtered off, thoroughly washed with dry diethyl ether and dried under reduced pressure to give 1.2 g of the set cephalosporin.IR and: * max / nuJ ° D 1768 cm -1) / Haktam CO). Iodometric test: 54%. Chromatographic paper: - Rp ¦ 0.23 (butanol-ethanol-water). The starting compound, cephalosporin, showed R p = 0.19). Example. Preparation of sodium salt of Da-IN-3-cinnamoyl-3-methylreido) benzyl cephalosporin. For solution 2 2 g of Da-aminobenzyl cephalosporin in 30 ml of water, 5 ml of acetone and 0.7 ml of triethylamine were added a solution of 1.12 g of N-chloroformyl-N-methyl-cinnamamide in 25 ml of dry acetone, with a further 0.7 ml of triethylamine, at a speed such as to maintain the pH of the reaction mixture at 7.5-8.0 The addition time was about 5-8 minutes, the mixture was stirred for 1 hour, and then the acetone was removed by extraction with 2 x 100 ml. diethyl ether, the yellowish aqueous phase was covered with 40 ml of ethyl acetate, cooled to 0 ° C and Constant vigorous stirring was carefully brought to a pH of 1.5 with dilute hydrochloric acid. The layers were separated and the aqueous phase was re-extracted with 20 ml of fresh ethyl acetate. The combined organic layers were washed with 20 ml of water and then twice with 50 ml of saturated sodium chloride aqueous solution, the last traces of which were removed by filtering through a silicone filter paper. Then 5 ml of 1.0N sodium 2-ethylcaproate in isopropanol was added with stirring. Gestures, the white precipitate was filtered off, thoroughly washed with dry diethyl ether and dried under reduced pressure to give 2.8 g of the desired compound. IR: * max (nuJ ° 0 17 · 0 cm -1 (/ Mactam CO). Iodometric test: 58%. Paper chromatography: Rp = 0.51 (butanol - ethanol - water). Example III Preparation of the sodium salt of Da- (3-ethoxycarbonyl) -3-methyluretho) benzylcephalosporin. 2.2 g of D-aminobenzylcephalosporin dihydrate and 1 5 ml of triethylamine in 30 ml of anhydrous dichloromethane is stirred for 2 hours with 2.0 g of a 4 A molecular sieve. The mixture is filtered, cooled in an ice bath and treated with a solution of 0.84 g of ethyl N-chloroformyl-N-methyl carbonate in 15 ml of dichloromethane. The solution was stirred for 2 hours at room temperature, then evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of water, washed twice with 50 ml of ethyl acetate, covered with 50 mJ of ethyl acetate and acidified with normal hydrochloric acid to pH value 1.5, then sift to remove insoluble substances. The acetate layer was separated and the aqueous layer was re-extracted twice with 50 ml of water and 50 ml of saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, diluted with 100 ml of anhydrous ether and treated with 2N sodium 2-ethylcaproate in methyl isobutyl ketone until it subsided. precipitation. The sodium salt of the cephalosporin was collected on a filter, washed with anhydrous ether, and dried in vacuo over phosphorus pentoxide. The yield was 1.25 g, 43.1%. NMR: [(CD3) 2SO + D20] • 8 - 7.55) 5 H, A, aromatic protons 5.9-5.6 (2 H, m # protons a I C7, 3-4.7 (3H, m, C $ and CH2OCOCH3 protons), 4.38 [2H, q4J = 7Hz), NC02CH2 CH3], 2.13 (3H, S, -OCOCH3), 1 , 41 (3H, t (J = 7H2) - CO2CH2CH3). Paper chromatography: single zone Rp = 0.49 (butanol-ethanol-water). 89964 Example IV. Preparation of D-α (3-cyclohexylcarbonyl-3-methylureido) benzylcephalosporin sodium salt. 2.2 g of D-aminobenzylcephalosporin dihydrate was reacted as described above in Example III with 1.1 g of cyclohexyl-N-chloroformyl-N-methylcarbonate to give a yield of 32% 1.01 g of cephalosporin sodium.NMR: [(CD3 ) 2SO + D20], 8 - 7.40 / 5 H, s, aromatic protons), 5.8-5.4 / 2 H, m, C7 protons and a (5.3-4.5) 4 H, m, C6 proton, -CH2OCOCH3 and cyclohexylmethinium), 3.5-3.0 (2H, m, C2 protons), 3.10 / 3H, s,, N-CH3, 2.01) 3H, s, - OCOCH3), 3.1-1.2) 10 H, m, cyclohexylmethylene protons). Paper chromatography: a single spot with Rp = 0.60 (butanol-ethanol-water). Example 5 Preparation of the sodium salt of D-α (2,4-dimethylallophanamide) benzyl cephalosporin. 0.005 mole of anhydrous triethylammonium Da-aminobenzylcephalosporate, prepared from D-Aminobenzylcephalosporin dihydrate as described above in Example III, in 30 ml of dichloromethane, cooled in an ice bath, and then a solution of 2,45 g of fluoro-dimethyl chloride was added in 15 ml of dichloromethane. The solution was stirred for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of water, washed with 2 times 50 ml of ethyl acetate, covered with 50 ml of fresh ethyl acetate and acidified with 1N hydrochloric acid to a phi value of 1.5. The mixture was filtered to remove insolubles, the acetate layer was separated, and the aqueous layer was extracted with 50 mL of ethyl acetate. The combined acetate solutions were washed with 2 times 50 ml of water, 50 ml of saturated sodium chloride aqueous solution each time, and then dried with anhydrous magnesium sulfate. After the magnesium sulfate was filtered off, the acetate solution was concentrated to a volume of about 25 ml under reduced pressure and 1–5 ml of a 2N solution of sodium 2-ethylcaproate in methyl isobutyl ketone was added. The precipitated sodium salt was collected on a filter, washed with anhydrous ether, and dried in vacuo over phosphorus pentoxide. The yield was 1.29 9.492%. NMR: [(CD3) 2SO + D20], 5 = 7.38 (5H, s, aromatic protons 5.9-5.3) 2H, m, protons and C7aa (5, 2-4.6) 4 H, m, C6 proton and -CH20COCH3), 3.5-2.9 (2H, m, C2 methylene protons, 3.13 (3H, t, N-CH3), 2.73 (3H, s, -NHCH3 /, 2.01 / 3H, s, -OCOCH3 / UV: Xmax26t, 5 nm (e = 7 276), (95% ethanol). Paper chromatography: single zone with Rp = 0, 41 (n-butanol-ethanol-water). Example VI. Preparation of the sodium salt of Da- (hexahydroreazepinone-2-yl-1-carbonylamino) -benzyl cephalosporin. The compound was prepared from 1-chlorocarbonyl hexahydrozepine-2 and Dtx-aminobenzyl cephalosporin dihydrate as described above in the example V.3% above in the example above. NMR: [(CD3) 2SO + D2O], δ = 7.44 (5H, s, aromatic protons), 5.7-5.5 (2H, m, proton versus C7 proton I), 5.2- 4.6 (4H, m, C6 proton and ^ CH2OCOCH3), 4.1-3.8 (2H, m, C3 methylene broader azepinone), 3.5-2.1 (2H, m, C2 methylene) , 3.0-2.6 (2H, m, methylene C7 hexahydrozepinone), 2, D1 (3H, s, -OCOCH3), 1.9-1.4 (6H, m, C4, Cs methylene protons and C6 of hexahydroazepinone). UV: Xmax 263.5nm (e = 6509), (95% ethanol). Paper chromatography: single zone with Rp value of 0.58. Example VII. Preparation of the sodium salt of Da- (3-cinnamoyl-3-methylureldo) benzyl cephalosporinate. The compound was obtained from cinnamic acid N-chlorocarbonyl-N-methylamide and D -aminobenzyl cephalosporin dihydrate as described above in Example 37.5. %. NMR: [(CD3) 2SO + D20], 5 = 8.0-7.1 (12H, m, aromatic and olefinic protons), 5.8-5.5 ftm, C7 protons and a) 5 , 3-4.6 (3H, m, C6 protons and -CH2OCO- (, 3.35 (5H, singlet overlapping with multiplet, C2 methylene and J N-CH3), 2.04 (H, s, -0 -COCH3) .UV: Xmax279 nm (e = 18326), 95% ethanol). Paper chromatography: single zone with Rp = 0.52. Example 8 Preparation of the sodium salt Da- (3-crotonoyl-3-methylureido) - benzylcephalosporins. The compound was prepared from crotonic acid N-chlorocarbonyl-N-methylamide and D-amino-benzylcephalosporin dihydrate as described above in Example V, yielding 24%. NMR: [(CD3) 2SO + D20], 6 = 1 , 89 (3H, s, = CHCH3), 2.02 (3H, s, -OCO-CH3), 3.23 (3H, singlet cover as with a multiplet, ^ N-CH3 and methylene protons (^ (4.85-4.95) 3H, m, C6 and -CH2OCOCH3), 5.5-5.7 / 2 H, m, C7 protons and a (6 , 7-7.5) 2 H, m, protons oWnowef? Fldjb H, s, aromatic protons. UV Xmax 265 nm (e = 8.684), 95% ethanol). Paper chromatography: single zone Rp = 0.48. Example IX. Preparation of the sodium salt of Da (3-methyl-3-phenylpropionoloureldo) benzyl cephalosporin. The compound was prepared from propionic acid N-chlorocarbonyl-N-methylphenylamide and D-amlnobenzyl cephalosporin dihydrate as described above in Example V, with a yield of 55.5%. 6 89 964 NMR: [(CD3) 2SO + D 2 O], 8 - 1.03 (3H, s, -OCOCH3), 23-3.5 (9H, m, N-CH3, -OCH2CH2 and C2 methylene protons ), 4.8-5.0 (3H, m, C6 proton and -CH2OCO- (5.5-5.7) 2H, m, C7 protons and a, 7.30 (5H, A, Aromatic protons, 7.40 5 H, s, Aromatic protons UV: Xmax 264 nm (e = 7.300), (95% ethanol) Paper chromatography: single zone Rp = 0.63 Example X Preparation of sodium salt Da- [3-methyl-3 -) - o-methoxycinnamoyl) ureidojbenzyl cephalosporin. The compound was prepared from N-chlorocarbonyl-N-methyl-methoxy-cinnamamide and D-aminobenzyl cephalosporin dihydrate as described above in Example V in Example 34 , 3%. NMR: [(CD3) 2SO + D20], 8 = 2.03 (3H, s, -OCOCH3), 3.3 6 (3H, s -OCH3), 3.75 (5H, slnglet coincident with the multiplet,; N-CH3 and C2 methylene 4.85-5.05 (3H, m, C6 proton and -CH2OCO-), 60-5.80 (2Hjr., M, C7 protons and a / 7.0-8, 2/11 H, m, olefinic and aromatic protons). UV: Xmax229 (e = 17,856), (95% ethanol), 277 (e = 17,767), (95% ethanol) and 331 nm (e = 11,249), (95% ethanol). Paper chromatography: single zone with Rp value = 0.38. Example XI. Preparation of the sodium salt of D-3-methyl-3- (2'-thienyl) acryloylureidobenzyl cephalosporin. The compound was prepared from N-chlorocarbonyl-N-methyl- (2-thienyl) amide of acrylic acid and D-aminobenzylcephalosporin dihydrate as described above in example V, with a yield of 26.3%. NMR: [(CD3) 2SO + D20], 6 = 2.03 (3H, s, -OCOCH3), 3.32 (5H, m, ^ N-CH3 3 and methylene protons 0 ^ 4.7-5.1 (2H, m, C6 proton and -CH2OCO-), 5.5-5.8 (2H, m, C7 protons and a (6.8-8, 1 (10H, olefinic and aromatic protons) UV: Xmax267 (e = 12843) and 322.5 nm (e = 15 205), (95% ethanol) Paper chromatography: zone with Rp value = 0.63 Example XII. Preparation of Da- [3-methyl-3- (p-nitrocinnamoyl) ureido] benzyl cephalosporin. The compound was prepared from N-chlorocarbonyl-N-methyl-p-nitramide of cinnamic acid and D-aminobenzyl cephalosporin dihydrate as described above in the example above , yielding 13%. NMR: [(CD3) 2SO + D20], S = 1.97 (3H, s, OCOCH3, 2.74 (5H, m, 4N-CH3 and methylene protons (4 , 7 -5.2 (3H, m, -CH2OCO- and C6 proton (5.5-6jD (2H, m, C7 protons and a (7.0-8.3) 11H, m, aromatic and olefinic protons) . UV: Xmax 266 nm (e = 13,797), (95% ethanol). Paper chromatography: - zone with Rp value = 0.57. Example XIII. Preparation of the sodium salt of Da- [3-methyl-3- (α-methylcinnamoyl) ureido] benzylcephalosporin. The compound was obtained from N-chlorocarbonyl-N-methyl-α-methylamide cinnamic acid and D-aminobenzyl cephalosporin dihydrate as described above in the example above V, yield 33 J5%, 1 NMR: [(CD3) 2SO + D20], δ = 2.03 (3H, s, OCOCH3), 2.10 (3H, d, CH3-CH =), 3 , 25 (3H, s, N-CH3), 3.2-3.5 (2H, m, methylene C2 4.8-5.0 (3H, m, -CH2OCO- and proton C6 \ 5, 5-5.7 (2H, m, C7 protons and a 6.80 (1H, m,) Nc = CH- 7.3-8.1 (10H, m, aromatic protons) .UV: Xmax266 nm ) = 13797). Paper chromatography: zone with Rp = 0.67. Example XIV. Preparation of sodium salt of Da- (3-benzyl-3-cinnamoylureido) benzylcephalosporin. The compound was obtained from N-chlorocarbonyl-N-benzylamide of cinnamic acid and dihydrate Da-amino-benzylcephalcsporin as described above in Example V, yielding 49.5%. NMR: [(CD3) 2SO + D20], 5 = 2.03 (3H, s, CH3OCO), 3.33 (2 H, m, C2 methylene protons), 4.95 (3 Htr, m -CH2OCO- and proton C6), 5.28 (2H, m, PhCH2 -), 5.67 (1H, d, C7 proton), 5.72 (1H, s, protoha), 7.40 ( 17 H, m, aromatic and olefinic protons). UV: Xmax 289 nm) (e = 14,100), (95% ethanol). Paper chromatography: zone with value Rp = 0.64. Example XV. Preparation of the sodium salt of D4 - [3- (3 ', 4' ^ '- trimethoxybenzoyl) -3-methylureido] benzylcephalosporin. The compound was obtained from N "chlorocarbonyl-N-methyl-3,4,5-trimethoxyamide of benzoic acid and dihydro D-aminobenzylcephalosporin knit as described above in example V, yielding 27%. NMR: [(CD3) 2SO + D20], 6 = 2.03 (3H, s, CH3OCO-), 3.17 (5 H, mN-CH3 and C2 methylene), 3.83 (9H, m, 3XCH30-), 4.96 (3H, m, -CH2OCO- and proton C6), 5.63 (1H, d, proton C7) # 5.68 (1H, s, proton a), 6.88 (2H, s, trisubstituted phenyl protons), 7.40 (5H, s, Ph-), UV: Xmax265 nm (e = 11 832). Paper chromatography: zone with Rp = 0.42. Example XVI. Preparation of the sodium salt of Da- [3- (3- (3-3-dimethylacryloyl) -3-methylureido] benzylchalosporin. The compound was obtained from N-chlorocarbonyl-N- acrylic acid methyl-β3 / 3-dimethylamide and Da-aminobenzylcephalosporin dihydrate as described above in Form V, yield 24.7% .89 964 7 NMR: [(CD3) 2SO + D20], δ = 1.9- 2.1 (9H, m, / CH3 and -OCOCH3), 3.20 (2H, O N-CH3), 3.2-3.4 = c --¦ \ CH3 (2H, m, methylene C2 (4.8-5 , 0) 3 H, m, -CH2DCO- and proton C6 (5.6-5.8) 2 H, m, C7 protons and a (6.20) 1H, m, -CH = CC (7.42 ) 5 H, s, aromatic protons). UV: Xmax 227 nm (e = 18,460), (95% ethanol). «'Paper chromatography: zone with Rp = 0.62. Example XVII. Preparation of the sodium salt of D-methyl-3- (3 ', 4' ^ '- trimethoxycinnamoyl) uraidobenzyl cephalosporin. The compound was prepared from N-ch | orocarbonyl-N-methyl-3,4,5-trimethoxyamide of cinnamic acid and Da dihydrate -aminobenzyl cephalosporins as described above in Example V, yielding 33.5%. NMR: [(CD3) 2SO + D20], 6 = 2.03 (3H, s, -OCOCH3), 3.2-3, 5 (2H, m, C2 methylene), 3.36 (3H, s, N-CH3 3.77 (3H, s, -OCH3), 3.87 (3H, s, -OCH3), 3, 96 (3H, s, - (CH3), 4.8-5.0 (3H, m, C6 and -CH2OCO-), 5.5-5.7 (2H, m, protons a and C7), 7 , 1-7.7 (9H, m, aromatic iolefin protons) .UV: Xmax235 / 5nm) te = 21,396) and 320nm (e = 17,935), (95% ethane <). Paper chromatography: zone with Rp = 0.63. Example XVIII. Preparation of sodium salt of DtH2-imidazolidinocarbonylamino) benzyl cephalosporin. A solution of 1.32 g, 0.005 mol of Da * (2-imidazolidinocarbonylamino) phenylacetic acid in 20 ml of anhydrous tetrahydrofuran was cooled to <= -10 ° C and treated with 1 drop of N- methylmorpholne, 0.71 ml of triethylamine and 0.48 ml of ethyl chloroformate. The suspension formed was stirred for 15 minutes at <-10 ° C, then an ice-cold solution of 1.36 g, 0.005 mol of 7-aminocephalosporanic acid and 0.71 ml of triethylamine in 30 ml of 50% aqueous tetrahydrofuran was added. The solution was stirred for 3 hours at room temperature, then the tetrahydrofuran was removed under reduced pressure and the residue was dissolved in 100 ml of water. The aqueous solution was washed with 2 X 50 ml of ethyl acetate and acidified with 1N hydrochloric acid to a pH of 1.5. The precipitate was collected and dried in vacuo to give 0.87 g of product which was suspended in 10 ml of water and 0.95 equivalents of 1 normal sodium bicarbonate solution was added. The solution was filtered and the filtrate was evaporated under reduced pressure to dryness. The yield was 0.70 g, 26%. NMR: [(CD3) 2SO + D20] * 5 = 9.17) [1H, d) J = 8Hz), NH-], 7.41 (5H, s , aromatic protons), 9-5.4 (2 H, m, C7 protons and a), 5.3-4.6 (3 H, m, C6 protons and -CH2OCO-), 4.1-3, 1 (6 H, m, C2 methylene and imiazolidone methylene), 2.01 (3 H, s, - (COCH3). UV: Amax264 nm (e = 6,527), (95% ethanol). Paper chromatography: single zone with Rp = 0.32 (n-butanol-ethanol-water). Example 19 Preparation of sodium salt of D- (3-cinnamoyl-3-methylureido) benzyl cephalosporin. Solution 1.69 g, 0.005 mol, acid D-ar ( 3-methylureido) phenylacetic acid in 15 ml of anhydrous acetone was cooled to <-10 ° C, then 1 drops of N-methylmorpholine, 0.71 ml of triethylamine and 0.48 ml of ethyl chloroformate were added and the suspension formed was stirred for 15 minutes at temperature. <-5 ° C, then a cooled to 0 ° C solution of 1.36 g, 0.005 mol of 7ic acid and 0.71 ml of triethylamine in 30 ml of 50% aqueous acetone was added. The solution was stirred for 3 hours at temperature.at room temperature, then the acetone was removed under reduced pressure and the residue was diluted with approximately 50 mL of water. The aqueous solution is washed with 2 times 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate, acidified with 1N hydrochloric acid to a pH of 1.5. The layers were separated and the aqueous phase was extracted with 50 mL of ethyl acetate. The combined organic layers were washed twice with 50 ml of water and 50 ml of aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, concentrated under reduced pressure and treated with 1.5 ml of 2N sodium 2-ethylcaproate solution in methyl isobutyl ketone. The precipitate was collected on a filter, washed with anhydrous ether and dried under reduced pressure. The yield was 0.70 g, 223%. NMR: [(CD3) 2SO + D20], 8 = 8.0-7.1 (12H, m, aromatic iolefin protons), 5.8-5.4 (2H , m, C7 protons and a) 5.2-4.7 (3H, m, C6 protons and -CH2OCO-), 3.34 (5H, singlet matching the multiplet, ^ N-CH3 and C2 methylene), 2.05 (3H, s, -OCOCH3). UV: Xmax 275 nm (e - 17119), (95% ethanols. Paper chromatography: single zone Rp = 0.52. Example XX. Preparation of sodium salt DtH3-furylacryloyl-3-methylureido) benzyl cephalosporin. Compound obtained from acid Dtr (3-furylacrylyl-3-methyluro | to) -phenylacetic acid and 7-aminocephalosporanic acid as described in example XIX, yielding 14%. NMR: [(CD3) 2SO + D20], 6 - 2.03 ( 3 H, $, - OCOCH3 3.32 (5 H, singlet overlapping t with multiplet, ^ N-CH3 and C2 methylene protons), 4.8-5.1 (3 H, m, -CH2OCO- and CJ proton, bjó 5.8 (2 H, m, 889,964 C7 protons and a) 6.6-7.9 (10 H, m, furyl, olefinic and aromatic protons). Paper chromatography: • zone with Rp value - 0.58 Example XXI Preparation of the sodium salt of Da (3'-cinnamoyl-3'-methylurea) 4-hydroxybenzyl-cephalosporin. The compound was obtained from DtK- (3'Hsinnamoyl-3'-methylureido) ^ 4-hydroxyphenylacetic acid and 7 -emitocephalosporan as described in example XIX, with a yield of 35.9%. NMR: [(CD 3) 2SO + D20], 8 - 8.0-6.6 (11H, m, aromatic and olefinic protons), 53-5 / * (2H, m, C7 protons and a), 5.1-4 , 7 (3H, m, C6 and -CH2OCO -), 3.35 (5H, s, N-CH3 and methylene (^. 205 (3H, s, -OCOCH3). UV: max225 (24,468 (and 282 nm (-19,152), (95% ethanol). Paper chromatography: - single zone with Rp = 0.65. Example XXII. Preparation of 7- [Da- (3'-cinnamoyl) -3'-methylureido) phenylacetamido] -3- (2 "-methyl- # ^", 4 "-thiadiazoyl-5" -thio) -methylcephem-4-carboxylate sodium. Solution 0 ^ 5 g, 0 0.0025 mol, D-tt- (3-cinnamoyl-3-methylureido) phenylacetic acid in 10 ml of benzhydrate acetone was cooled to <-10 ° C, then 1 drops of N-methylmorpholine, 0.35 ml of thiethylamine were added, and 0.24 ml of ethyl chloroformate The suspension formed was stirred for 15 minutes at <-10 ° C, and then a solution of 0.86 g, 0.0025 mol of 7-amino-3-acid, cooled to 0 ° C, was added. - (2 'Methyl-1, 3 #, 4 # -thiadiazoyl-5'-thio) -methyl-cephem-3-carboxylic-4 10.35 ml triethylamine in 15 ml 50% aqueous acetone The solution was stirred for 2 hours at room, then acetone was removed under reduced pressure, the residue was diluted with approximately 50 mL of water and washed with is 2 times 50 ml of ethyl acetate. The aqueous phase is covered with 50 ml of ethyl acetate and acidified with 1N hydrochloric acid to a pH of 1.5. The acetate layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined acetate solutions were washed twice with 50 ml of water, 50 ml of aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and treated with 0.7 ml of 2N sodium 2-ethylcaproate solution in methyl isobutyl ketone. The precipitated sodium salt was collected in a filter bag, washed with anhydrous ether and dried under vacuum. The yield was 0.53 g, 30.9%. NMR: [(CD3) 2SO + D20], 8 - 8.0-7.0 (12H, m, aromatic and olefinic protons), 53-5.4 ( 2 H, m, C7 protons and a (5.1 -4.8 (1H, m, C6 proton 4.8-4.0 (2H, m, -CH2-S- (3.34 (5 H , slnglet overlapping with multiplet, N-CH3 and C2 methylene), 2.67 (3H, s, methyl thiadiazole protons) .UV: Xmax219 nm (e = 24010) and 282 nm (e = 27901), 95% ethanol Paper chromatography: single zone RF '= 0.63. Example XXIII Preparation of 7- [Da- (3'-cinnamoyl-3'-methylureldo) phenylacetamido] -3- (1 "-methyl-r' Sodium H-tetrazoyl-5 "-thio) methylcephem-3-carboxylate4. To a solution of 0.85 g, 0.0025 mol of Da- (3-cinnamoyl-3-methylureido) phenylacetic acid in 20 ml of anhydrous acetone was added at < -10 ° 1 drops of N-methylmorpholjny, 0.35 ml of triethylamine and 0.24 ml of ethyl chloroformate, then stirred at this temperature for 15 minutes, then a solution of 0.82 g, 0.0025 mol, cooled to 0 ° C, was added, 7-amino-3- (1'-methyl-1'H-th. acid trazoyl-5'-thio) m-ethyl-cephem-3-carboxyl-4 I 0.35 ml triethylamine in 30 ml 50% aqueous acetone and the solution was stirred for 2 hours at room temperature. The acetone was removed under reduced pressure and the residue was diluted with 100 ml of water, then washed twice with 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate and acidified with 1N hydrochloric acid to a pH of 1.5. The layers were separated and the aqueous solution was extracted with 50 mL of ethyl acetate. The combined layers were washed twice with 50 mL of water, dried with anhydrous magnesium sulfate and treated with 0.8 mL of 2N sodium 2-ethylcaproate in methyl isobutyl ketone. The precipitated salt was collected on a filter, washed with anhydrous ether (dried under reduced pressure. Yield was 0.64 g, 38.2%. NMR: [(CD3) 2SO + D20,], 3-8.0-7.1 (12 H, m, aromatic and olefinic protons /, 5.8-5.5 / 2 H, m, C7a protons), 5.1-4.8 (1H, m, C6 proton (4.6-4, 1 (2H, m, -CH2S-), 3.95 (3H, s, tetrazole methyl protons), 3.33 (5H, singlet overlapping multiplet, y N-CH3 and C2 methylene protons). UV: Xmax 282 nm (e85 25 277), (95% ethanol). Paper chromatography: single zone with Rp-0.66. Example XXIV. Preparation of DtH3-benzoyl-3-methylureido) -benzyl cephalosporin sodium salt 0.005 mol of triethylammonium anhydrous salt D-craminobenzyl cephalosporin in 30 ml of dichloromethane, prepared from 2.2 g of D-AmInobenzyl cephalosporin dihydrate as described above in example III, cooled in an ice bath, then a solution of 0.98 g, 0.005 moles of N-chlorocarbonyl-N was added. - benzoic acid methylamide in 15 ml of dichloromethane It was stirred for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of water, washed twice with 50 ml of ethyl acetate and, in the presence of 50 ml of ethyl acetate added, 89964 9 was acidified with 1N hydrochloric acid to a pH value of 1.5. The organic layer was separated, the aqueous phase was extracted with 50 ml of ethyl acetate, then the combined acetate extracts were washed twice with 100 ml of water and 50 ml of saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solution was treated with 1.5 ml of 2N sodium 2-ethylcaproate in methyl isobutyl ketone, diluted with 200 ml of anhydrous ether, the precipitated sodium salt was collected and dried in vacuo. The yield was 1.68 g, 57.2%. NMR: [(CD3) 2SO + D20], 6 - 7.7-7.2 (10H, m, aromatic protons), 5.8-5.4) 2H, m, C7 protons and a, 5.2-4.6 (3 H, m, C6 proton and -CH2OCO -), 3.6-23 (2 H, m, C2 methylene protons), 3.08 ( 3 H, s, NCH3), 2.00 (3H, s, -OCPCH3). UV: Xmax 263 nm (e = 8,710), (95% ethanol). Paper chromatography: - a single zone with Rp = 0.52 (n-butanol-ethanol-water). Example XXV. Preparation of the sodium salt of D-cr (3-methyl | o-3-acetylureido) benzylcephalosporin. The compound was obtained from N-chlorocarbonyl-N-methyl-acetic acid amide and Dtfc-aminobenzyl-cephalosporin dihydrate in the manner as described above in Example XXIV, 27%. NMR: [(CD3) 2SO + D20], 6 = 7.43 (5H, s, aromatic protons), 6.8-6.5 (2H, m, C7 protons and a (6.2- 4.6 (3H, m, C * proton and -CHaOCO-), 3.7-2.7 (2H, m, C * methylene protons), 3.20 (3H, i, NCH3, 2.33 ( 3 H, i, -C0CH3), 2.03 (3H, s, -OC0CH3) .UV: Xmax266 nm) (e * 7920), (95% ethanol). Paper chromatography: single zone with Rp value: 0, 42. Example XXVI Preparation of the sodium salt of Da- [3- (2-methylcrotonoyl) -3-methyluretho] benzylcaphalosporin. The compound was prepared from N-chlorocarbonylHSJ-methyl-2-methylamide crotonic acid dihydrate D-aminobenzylcephalosporin by the method as described above in example XXIV, yield 37.4%. NMR: [(CD3) 2SO + D20], 5 = 1.5-2.2 (6H, m, = CHCH3 and -OCOCH3), 3.12 (3H, s, N-CH3), 3.2-3.4 (2 H, m, C2 methylene protons) 4.9 (3 H, m, C6 proton and -CH2OCO-) 5.6 (2 H, m, C7 protons and a) 7.4 (aromatic protons, 5H, m, UV : Xmax 257 nm (e-7,930), (95% ethanol). Paper chromatography: - a single zone with the value Rp = 0.62. Example XXVII. Preparation of the sodium salt of Da (3-phenylacetyl-3-methyluretho) benzylcephalosporin). The compound was obtained from acetic acid N-chlorocarbonyl-N-methylphenylamide and DtK-aminobenzyl cephalosporin dihydrate as described above in Example XXIV. , 5%. NMR: [(CD3) 2SO + 'Q20], 5 = 2.03 (3H, s, -OCOCH3), 3.29 (5H, singlet overlapping multiplet ^ NCH3 and C2 methylene protons) , 4.04 (2H, s, -COCH2Ph), 4.92 (3H, m, OCOCH2- and a C6 proton 5.7 (2H, m, C7 protons and a), 7.32-7.40 (10H, d, aromatic protons). UV: Xmax 264 nm (e = 5,720, (95% ethanol). Paper chromatography: zone with Rp = 0.51. Example XXVIII. Preparation of the sodium salt Dtr [3- ( 4-phenylbtanoyl) <3-methylureido] benzyl cephalosporin. The compound was prepared from N-chlorocarbonyl-N-methyl-4-phenylamide of butyric acid and Da-aminobenzyl cephalosporin dihydrate as described above in Example XXIV, with a yield of 49.2% NMR. : [(CD3) 2SO + D20], 5 = 2.02 (7H, sjnglet coinciding with multip letem, -OCOCH3 and -CH2CH2Ph), 2.7 (2H, m, -COCH2-), 3.18 (5H, singlet overlapping multiplet. NCH3 and C2 methylene protons), 4.92 (3H, m, -CH2OCO- and C6 proton), 5.65 (2H, m, C7 protons and a) 7.26 (5H, s, aromatic protons) , 7.40 (5H, s, aromatic protons). UV: X max 261 nm (e = 7 785), (95% ethanol). Paper chromatography: zone with Rp = 0.62. Example XXIX. Preparation of sodium salt of Da- (3-octene-2'-olo-3-methylureido) -benzylcephalosporine. The compound was prepared from 2-dehydrocaprylic acid N-chlorocarbonyl-N-methylamide and D-aminobenzylcephalosporin dihydrate as described above in Example XXIV. with a yield of 25%. NMR: [(CD3) 2SO + D20], 6 = 0.8-1.5 (9H, m, - (CH2) 3CH3), 2.02 (5H, singlet coinciding with the multiplet , -OCOCH3 and -CH2CH =), 3.25 (5H, singlet coinciding with multiplex; NCH3 and C2 methylene protons), 4.8-5.0 / 3H, m, C6 proton and -CH2OCO- /, 5.5-5.7 (2H, m, C7 protons and [alpha]), 6.5-7.5 (2H, m, olefinic protons), 7.42 (5H, s, aromatic protons). Paper chromatography: Rp = 0.58 zone. Example XXX. Preparation of the sodium salt of Da- (3-furoyl-3-methylureido) benzylcephalosporin. The compound was obtained from N-chlorocarbonyl-N-methyl-2-furamide and Da-aminobenzylcephalosporin dihydrate as described above in Example XXIV, with a yield of 55.0% .NMR: [(CD3) 2SO + D20], δ = 2.04 (3H, s, -OCOCH3), 3.37 (5H, singlet coinciding with the multiplet, ^ NCH3 and C2 methylene protons), 4, 8-5.0 (3H, m, -COCH2- and proton C6), 5.5-5.8 (2H, m, protons, C7 and ^ 6.6-8.0 (8H, m, protons aromatic and furyl. UV: Xmax268nm (e = 19,990), (95% ethanol). Paper chromatography: zone with Rp = 0.39. Example XXXI. Preparation of sodium salt DtH3-cinnamoyl-3-ethylureido) -benzyl cephalosporin. prepared from N-chlorocarbonyl-N-ethylamide of cinnamic acid and Dt ** amino-10 89 964 benzyl cephalosporin dihydrate as described above in Example XXIV, yield 27/4%. NMR: [(CD3) 2SO + D20], S - 1.2-1.4 (3H, m, CH3CH2-), 2.04 (3H, s, -OCOCH3), 3.2-3.5 (2H, m, C2 methylene protons), 3, 7 -4.2) 2 H, m, 1 H, CH 2 -, 4.9-5.05 (3 H, m, - (COCH 2 - and a C6 proton), 6-5.8 (2 H, m, C7 protons and a (7.3-8.0 (12H, m, lolefin aromatic protons), UV: Xmax285 nm (e-19370), (95% ethanol). Paper chromatography: zone with Rp = 0.57. Example XXXII. Preparation of sodium salt of DtH3-acetyl β-billazolidine-2Hlo-1 * arbonylamino) - benzylcephalosporin. The compound was prepared from 3-acetyl-1-chlorocarbonyl-imidazolydinone-2 and D-craminobenzyl-pyhosphinone dihydrate in the manner described above in the manner XXIV. 61 £%. NMR: [(CD3) 2SO + D20], 5 = 7.42 (5H, s, aromatic protons) 5.8-5.3 (2H, m, C7 protons and a), 2 -4.6 (3 H, m, C6 proton and -CH2OCO -), 3.73 (4 H, s, imidazolidinone methylene protons), 3.6-2.9 (2 H, m, C2 methylene protons) 2 , 42 (3H, s, / NCOCH3), 1.99 (3H, s, - (COCH3) .UV X max260 nm (e = 8 180), (95% ethanol). Paper chromatography: a single zone with the value Rp = 0.30. Example XXXIII Preparation of the sodium salt of Da- (3-methylsulfonylimidazolidinone-2-11-1-carbonylamino) -benzyl-cephalosporin. The compound was prepared from 11-chlorocarbonyl-3-methylsulfonylimidazolidinone-2 and Dt-amino dihydrate ¦benzylcephalosporin as described above in example XXIV, with an efficiency of 38.1%. NMR: [(CD3) 2SO + D20] 5 = 7.48 (5 H, s, aromatic protons), 5.7-5.4, (2 H, m, C7 protons and a), (4 H, s, aromatic protons), 57-5.4, ( 2 H, m, C7 protons and a) 5.2-4.5 (3 H, m, C6 proton and -CH2OCO-), 3.89 (4H, s, imidazolidinone methylene protons), 3.7-2 , 8 (2H, m, C2 methylene protons) 3.38 (3H, s # -SO2CH3), 2.03 (3H, s, -OCOCH3). UV: Xmax 262 nm (e = 7,825), (95% ethanol). Paper chromatography: single zone with Rp = 0.27. Example XXXIV. Preparation of sodium salt of DtH2,4,4-trimethylamphanamido) benzyl cephalosporin. The compound was prepared from 1-chlorocarbonyl-1- ^ 3-trimethylurea and DtK-aminobenzyl cephalosporin dihydrate as described above in Example XXIV, with a yield of 33.2%. : [(CD3) 2SO + D20], 6 = 2.02 (3H, s, -OCOCH3), 2.88 [6H, s, -N (CH3) 2], 3.0 (3H, s, NCH3 ), 3.33 (2 H, m, C2 methylene protons), 4.93 (3 H, m, C6 protons, and -CH2OCO-), 5.58 (2 H, m, C7 protons and a) 7.40 (5H, m, aromatic protons). UV: Xmax 266 nm (e = 6,890), (95% ethanol). Paper chromatography: Rp = 0.30 zone. Example XXXV. Preparation of the sodium salt of DtH3-phenoxyacetyl-3-methylureldo) benzylcephalosporin. The compound was obtained from N-chlorocarbonyl-N-methylphenoxyacetamide and Dtraminobenzylcphalosporin dihydrate in the manner as described above in Example XXIV: 62.1% yield NosMR. CD3) 2SO + D20], 6 = 2.01 (3H, s, -OCOCH3), 3.23, (5H, m, NCH3 and C2 methylene protons), 4.92 (3H, m, -CH2OCO - and proton C6), 5.10 (2H, s, PhOCH2-), 5.61 (2H, m, C7 pfte a protons), 6.9-7.5 (10H, m, aromatic protons) . UV: Xmax 266 nm (e = 9000), (95% ethanol). Paper chromatography: zone with Rp value = 0.50. R zy k l, a d XXXVI. Preparation of the sodium salt of Da [3- (2-chlorobenzoyl) -3-methylureido] benzyl cephalosporin. The compound was prepared from benzoic acid N-chlorocarbonyl-N-methyl-2-chloroamide and D-aminobenzyl cephalosporin dihydrate as described above in Example XXIV , yield 28.5%. NMR: l / (CD3) 2SO + D20], δ = 2.03 (3H, s, -OCOCH3), 3.01 (3H, s, ^ N-CH3), 3.2-3.5 (2 H, m, CJ methylene protons, 4.8-5.1 (3 H, m, -CH2OCO and C6 protons) 5.6-5.8 (2 H, m, protons C7 and a), 7.3-7.7 (9 H, m, aromatic protons). UV: Xmax266 nm (e = 7 920), (95% ethanol). Chromatography - paper: zone with Rp = 0, 58. EXAMPLE XXXVII Preparation of the sodium salt of Da- [3- (2-methylbenzoyl) -3-methylureldo) -benzylcephalosporin The compound was prepared from N-chlorocarbonyl-N-methyl-2-methyl-benzoic acid dihydrate and Da-aminobenzyl cephalosporin dihydrate in method as described above in example XXIV, yield 51%. NMR: [(CD3) 2SO + D20], 6 = 2.01 (3H, s, -OCOCH3), 2.28 (3H, s, benzoyl- CH3), 2.96 (3H, s , N-CH3), 3.2-3.4 (2H, m, C2 methylene protons), 4.9-5.1 (3H, m, -CH2OCO- and a C6 proton), 6-5, 8 (2H, m, C7 protons and a) 7.3-7.5 (9H, m, aromatic protons). UV: Xmax 260 nm (e - 8 310), (95% ethanol). Paper chromatography: zone with Rp value of 0.50. Example XXXVIII. Preparation of sodium 7 {Da- (3-cinnamoyl-3-methylure | to) phenylacetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-thio) -methylcephem-3-carboxylate-4-carboxylate. 89,964 11 Solution 1.77 g 0.003 mol of tf-a (trifluoroacetic acid) salt of 7- (D-aminophenylcetamido) -1-1,3,4-thiadiazolyl-5-thio) -methylcephem-3-carboxylic acid-4 I 1, 35 ml of triethylamine in 30 ml of dichloromethane was cooled in an ice bath and treated with a solution of 0.78 g, 0.0035 mol, N-chlorocarbonyl 1-methyl-cinnamamide in 10 ml of dichloromethane. The solution was stirred for 3 hours at room temperature, then evaporated to dryness under reduced pressure, the residue was dissolved in 50 ml of water (washed twice with 50 ml of ethyl acetate). The aqueous solution was covered with 50 ml of ethyl acetate, acidified with 1N hydrochloric acid to a pH of 1J5, filtered, the acetate layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined extracts were washed twice with 50 ml of water and 25 ml of a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and treated with 1.0 ml of 2N sodium 2-ethylcaproate in methylisobutyl ketone. 200 ml of anhydrous ether were then added and the precipitated sodium salt was collected and dried under reduced pressure. The yield was 0.96 g, 46.6%. NMR: [(CD3) 2SO + D20], 5 = 8.0-7.0 (12H, m, aromatic and olefinic protons), 5.8-5, 5 (2H, m, C7 protons and <*), 4.93 [1Hd,)] = 5 Hz), C6 proton], 4.7-4.1) 2H, m, -CH2S-), 3.8-2.9 (2 H, m, C2 methylene protons), 3.25 (3 H, A, 1 NCH 3), 2.67) 3 H, s, thiadiazole-CH 3). UV: Xmax 282 nm (e = 30 630), (95% ethanol). Paper chromatography; a single zone with the value Rp = o.65. Example XXXIX. Preparation of sodium 7-D- (3-cinnamoyl-3-methylureido) -phenylacetamido-3- (1-methyl-1H-tetrazoyl-5-thio) -methylcephem-3-carboxylate. The compound was obtained from the salt of t.f.a. Cinnamic acid 7- (D-aminophenylacetamido) -3- (1-methyl-1H-tetrazoyl-5-thio) methylcephem-3-carboxylic acid-4- and N-chlorocarbonyl-N-methylamide in the manner described for example XXXVI 11, with an efficiency of 50.7%. NMR: r (CD3) 2SO + D20], 8 = 7.9-7.1 (12 Hm, aromatic and olefinic protons), 5.8-5.5 (2 H, m, C7 protons and a (5.1-4.8 (1 Hm m, C6 proton) 4.7-4.0 (2H, m, -CH2S-) 3.93 (3H, s, tetrazole -CH3), 3.8-3.1 (2H, m, C2 methylene protons), 3.33 (3H, s, NCH3). UV: Xmax282 nm) (e = 24490), (95% ethanol). paper: single zone with Rp = 0.51. __ _ _ "Example xL. Preparation of 7- [D-cr (3-cinnamoyl-3H-thiethylureido) fen7loac» tamido] -3- (1H-1,2,4- sodium tri-azolyl-3-thio) methylcepham-3-carboxylate-4-carboxylate. The compound was obtained from the tfa salt of 7- (Da-aminophenylacetamido) -3- (1H-1,2,4-triazolyl-3-thio) - cinnamic acid methyl cephem-3-carboxylic-4 and N-chlorocarbonyl-N-methylamide as described in Example XXXVII I, yield 55.7% .N MR: (CD3) 2SO + D20, = 8.0-7.0 (13H, aromatic, olefinic and triazole protons), 5.7-5A (2H, m, C7 and a protons), 5.0- 4.3 (3H, m, C6 proton and -CH2S), 3.8-3.0 (2H, m, C2 methylene protons), 3.33 (3H, s, 1N-CH3). UV: Xmax 287 nm (e = 21,980), (95% ethanol). Paper chromatography: Rp value zone = 0.58. Example XLI. Preparation of sodium 7- [Dtx * (2,4 tadazolyl-5-thio) methylcephem-3-carboxylate. The compound is obtained from the salt of t.f.a. 7- (Da-aminophenylacetamido) -3- (2-methyl-1,3,4-thiadiazolyl-5-thio) -methylcephem-3-carboxylic acid4 and 2,4-dimethylallophanoyl chloride as described above in Example XXXVIII, yield 58.7%. NMR: [(CD3) 2SO = D20], δ = 7.7-7.1 (5H, m, aromatic protons 5.7-5.5 (2H, m, C7 protons and a), 5.0-4.8 (1H, m, C6 proton), 4.7-4.1 (2H, m, -CH2S-3.1- (3H, s, N-CH3) , 2.70 (6H, s, -NHCH3 and thiadiazo | -CH3). UV: Xmax 274 nm (e = 13,010), 95% ethanol). Paper chromatography: single zone Rp = 0.41. Example XLII. Preparation of 7- (Da- (2,4-dimethylallophanamido) phenylacetamido] -3- (1-methyl-1H-tetrazolyl-5-thio) methylcephemo- Sodium 3-carboxylate-4-carboxylate. The compound was prepared from the tfa salt of 7- (Da-aminophenylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thio) -methyllocephem-3-carboxylic acid 2, 4-dimethylallophanoyl as described in example XXXVIII, yield 53.0%. NMR: [(CD3) 2SO + D20], 5 = 7.42 (5H, s, aromatic protons), 5.7-55 (2 H, m, C7 protons and a), 4.88 [1H, d, (J = 5HZ), C6 proton], 4.6-4.0 (2H, m, -CH2S -), 3, 93 (3H, s, tetrazol-CH3), 3.8-3.1 (2H, m, C2 methylene protons), 3.10 (3H, s N-CH3), 2.70 (3H, s, -NHCH3), UV: Xmax268 nm (e = 8,020), (95% ethanol). Paper chromatography: single zone with Rp = 0.47. Example XLIII. Preparation of 7- [Da- (3-acetyl- Sodium 3-methylureldo) -phenylacetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-thio) methyl-cephem-3-carboxylate-4-carboxylate of sodium 12 89 964 Azek was obtained from the tf .a salt of 7- (Stk-aminophenylacetamido) -3- (2-methyl-1-34-thiadiazol-5-thio) -methyl-cephem-4-carboxylic acid and N-chlorocarbonyl-N-methylacetamide as described above in Example XXXVIII, yield 76.9%. NMR: [(CD3) 2SO + D20],? = 7.47 (5H, s, aromatic protons) 5.8-5.4 (2H , m, C7 protons and a), 4.93 [1H, d, (J - 5HZ), C6 proton], 4.7-4.0 (2H, m, -CH2S-), 3.8 -3.0 (2H, m, C2 methylene protons), 3.21 (5H, s, ^ N-CH3), 2.72 (3H, s, tladazole-CH3), $ 33 (3H, s , -COCH3. UV: Xniax 275nm), (c - 12,410), (95% ethanol). Paper chromatography: single zone with Rp = 0.31. Example XLIV. Preparation of sodium 7- [Da- (3-acetyl-3-methylureido) phenylacetamido] -3- (1 'methyl-m-tetrazoyl-5-t-methylcephem-3-carboxylate-4-carboxylate sodium. The compound was prepared from the tfa salt of 7- (D-aminophenylacetamide) -3- (1-methyl-1H-etrazolyl-B110) -methylcephem-3-carboxyl-4 and N-chlorocarbonyl-N-methylacetamide as described above in Example XXXVIII, with a yield of 24.8%. NMR: [(CD3) 2SO + D20], 8 = 7.40) 5H, singlet, aromatic protons), 5.7-5.4 (2H, m, C7 protons and a ), 4.89 [1H, d, (J = 5Hz), C6 proton], 4.6-4.0 (2H, m, -CH2S-), 3.94 (3H, s, tetrazole -CH3), 3.8-3.1 (2H, m, C2 methylene protons), 3.18 (3H, s, 1N-CH3), 2.30 (3H, s, -COCH3). UV Xmax265 nm) (e = 8,040). Paper chromatography: single zone with Rp = 0.33. Example XLV. Preparation of 7- [Da [3- (4-phenylbutyryl) -3-methylure] to] phenylacetamido] -3- (2-methyl-1, Sodium 3,4-thiadiazolyl-5-thio) methyl cephem-3-carboxylate. The compound was obtained from the tfa salt Acid 7- (D-amino-phenylacetamido) -3- (2-methyl-1 # 3,4-thiadiazolyl-5-thio) -methyl-cephemo-3- (3-carboxylic-4 and N-chlorocarbonyl-N-methyl-4-phenylamide) of butter as described above in Example XXXVIII, with a yield of 46.8%. NMR: (CD3) 2SO + D20, A = 1.8-2.2 (2H, m, PhCH2CH2-), 2.5 -2.9) 7 H, m, thladazole CH3, -COCH2CH2CH2Ph), 3.17 (3H, s, N-CH3), 3.3-3.5 (2H, m, C2 methylene protons), 4 , 2-4.7 (2H, m, -CH2S-), 4.8-5.0 (1H, m, C6 proton), 4.5-43) 2H, m, C7 and <* protons ), 7.27 (5 H, s, aromatic protons), 7.41 (5 H, s, aromatic protons). UV'Xmax 275 nm (e = 12,770), (95% ethanol). Paper chromatography: zone with value Rp = 0.62. P r z y k l a d XLVI. Preparation of sodium 7- [Da- [3- (4-phenylbutyryl) '3-methylure] phenylacetamido] -3- (1 - methyl-1H-tetrazolyl-5-thio) methylcephemor 3-4-carboxylate sodium. The compound was obtained from the tfa salt of 7- (D-aminophenylacetamldo) -3- (1Hf-dimethyl-1H-tetrazolyl-5-thio) methylcephem-3-carboxylic acid-4 as described above in Example XXXVIII, yield 17.5%. NMR: [(CD3) 2SO + D2O] * 8 = 1.7-2.2 (2H, m, PhCH2CH2CH2-), 2.5-2.7 (4H, m, PhCH2CH2CH2CO), 3.16 ( 3 H, s, N-CH3), 3.4-3.6 (2 H, m, C2 methylene protons), 3.94 (3 H, x, s, tetrazol-CH3), 4.3-4, 5 (2H, m, -CH2-S), 4.8-5.0, (1H, m, C6 proton), 5.5-5.8 (2H, m, C7 protons and a), 7.25 (5H, s, aromatic protons), 7.37 (5H, s, aromatic protons). UV: Xmax 270 nm (e = 8,410), (95% ethanol). Paper chromatography: zone with Rp = 0.47. Example XLVII. Preparation of sodium 7- [D α - [3- (2-methylcrotonoyl) -3-methylureido] phenylacetamido] -3- (1-methyl-1H-tetrazolyl-5-thio) methylcephem-3 "carboxylate. The compound was prepared from the tfa salt of 7- (Da-aminophenylacetamido) 3- (1-methyl-1H-tetrazolyl-5-thio-methyl-cephem-3-carboxylic acid-4-j and N-chlorocarbonyl-N-methyl-2-methyl crotonic acid amide in the manner of described above in Example XXXVIII, with an efficiency of 17.1%. NMR: [(CD3 / 2SO = D20], 5 = 1.6-1.9 (6H, m, 2X-crotonoyl <; H3), 3.11 (3 H, s, y N-CH3), 3.4-3.6 (2 H, m, C2 methylene protons), 4.96 (3Hfs, tetrazol-CH3), 4.2-4.4 (2 H , m, -CH2S -), 4.7-5.1 (1H, m, C6 proton), 5.5-6.0 (3H, m, -CH = C, C7 protons and a), 7 , 40 (5H, s, aromatic protons) .UV: Xmax270 nm) (e = 9,260), (95% ethanol). Paper chromatography: zone with Rp = 0/43. Example XLVIII. Preparation 7- [Da- [3- (2-methylcrossono || o) -3H-methylureido) phenylacetamido] - • 3- (2-methyl-1,3,4-thiadiazolyl-5-thio) methyl ocephem-3-carboxylate 4 - Compound obtained from tfa k 7- (D-amino-phenylacetamido) -3- (2-methyl-1, 4-tladazolyl-5-thio) c) nriethylcephem-3-carboxylic-4 and N-chlorocarbonyl N-methyl * 2-phenylamide crotonic acid as described above in Example XXXVI11, with a yield of 35.6% NMR: [(CD3) 2SO + D2O], 6 = 1.6-1.9 (6H, m, 2X crotonoyl-CH3), 2.69 ( 3 H, s, tladazole-CH3), 3.12 (3 H, s, y N-CH3), 3.4-3.6 (2 H, m, C2 methylene protons), 4.3-4.6 (2H, m, -CH2S-, 4.9-51 (1H, m, C6 proton), 5.5-6.0 (3H, m, -CH = C <. C7 protons and a), 7 / * 1 (5H, s, aromatic protons) .UV: Xmax275 nm) (e - 13470), (95% ethanol). Paper chromatography: zone with Rp = 0.52. Example XLIX. Preparation of sodium 7- [Da- [3- (3-phenylpropionyl) -3-methylureido] phenylacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-thimethylcephem-3-4-carboxylate) 89,964 13 The compound was prepared from the tfa salt of 7- (Da-aminophenylacetamido) -3- <2-methyl-1/3/4-ijadio-esolyl-5-thio) methylcephamo-3-carboxylic acid-4 N-chlorocarbonyl-N propionic acid-methyl-3-phenylamide as described above in Example XXXVIII, yielding 34.9%. NMR: [(CD3) 2SO + D20], 5 = 2.68 (3H, s, thi diazo | - CH3-, 2.94 (4H, s, -CH2CH2Ph) 3.19 (3H, s, ^ N-CH3), 3.3-3.5 / 2 H, m, C2 methylene protons /, 4.2 -4.5 (2H, m, -CH2S- 4.8-5.0 (1H, m, C6 proton) 5.4-5.7 (2H, m, C7 protons and a) 7, 28 (5 H, s, aromatic protons) 7.37 (5 H, s, aromatic protons). UV: Xmax 275 nm (e = 13500), (95% ethanol). Paper chromatography: zone with RF value = 0.61 Example L. Preparation of sodium 7-D-a3- (3-phenylpropionyl) -3-methylureido phenylacetamido-3- (1-methyl-1H-tetrazolyl-5-thio) methyl-cephem-3-carboxylate-4 sodium. zec was obtained from salt t.f.a. Propionic acid (7-D, α-aminophenylacetamido) -3- <1-methyl-1H-tetrazolyl-5-thio) -methyl-cephem-3-carboxylic acid 4 I N-chlorocarbonyl-N-methyl-3-phenylamide as described above in Example XXXVIII, yield 26.8%. NMR: [(CD3) 2SO + D20], δ = 2.94 (4H, s, -CH2CH2Ph), 3.19 (3H, s, N-CH3), 3.0-3.8 (2 H, m, C2 methylene protons), 3.95 (3 H, s, tetrazo | -CH3), 4.2-4.5 (2 H, - CH2S- 4.8-5.0 (1H, m, C6 proton, 5-5.8 (2H, m, C7 protons and α7.2-7.5 (10H, d, aromatic protons). UV: Xmax260 nm (e = 9120), (95% ethanol). Paper chromatography: zone with Rp = 0.54. Example LI. Preparation of 7- [Dxx- [3- (3-methylcrotonoyl) -3-methylureldo] phenylacetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-thio) methyl-cephem-3-carboxylate-sodium-4-carboxylate. The compound was prepared from the tfa salt of 7- (Da-arninophenylacetamido) -3- ( 2-methyl-1/3-4-thiadiazolyl-5-thio) methyl-cephem-3-carboxylic-4 and N-chlorocarbonyl-N-methyl-3-methyl crotonic acid amide as described above as above in example XXXVIII, yield 24.6%. NMR: [(CD3) 2SO + D20], 5 = 1.9-2.1 (6H, m, -CH = C (CH3] 2, 2.70 thiadiazole -CH3), 3.18 (3H, s, N-CH3), 3.3-3.6 (2H, m, C2 methylene protons) 4.3-4.5 (2H, m, -CH2S -) 4.8-5.0 (1H, m, C6 proton), 5.5-5.7 (2H, m, C7 protons and a), 6.1-6.3 (1H, m -CH = C <;) 7/11 (5H, s, aromatic protons). UV: Xmax270 nm) 6 = 11,870), (95% ethanol). Paper chromatography: value zone Rp = 0.56. Example LII. Preparation of sodium 7- [Da [3- (3-methylcrotonoyl) -3-methylureldo) phenylacetamido] -3- (1i methyl-1H'tetrazolyl-5-thio-methylcephem-3-carboxylate-4-carboxylate]. t.fa. 7 (Da-aminophenylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thio) methyl-cephem-3-carboxylic acid-4 and N-chlorocarbonyl-N-methyl-3-methyl crotonic acid amide as described above in Example XXXVIII, yield 56.7%. NMR: [(CD3) SO + D20], = 1.9-2.1 (6H, m, = CH = C (CH3) 2) , 3.18 (3H, s, N-CH3) 3.4-3.6 (2H, m methylene protons C2), 3.96 (3H, s, tetrazol-CH3 4.3-4.5 (2H, m, -CH2S- 4.9-5) (1H, m, C6 proton) 5.5-5.8 (2H, m, C7 protons and a), 6.1-6, 3 (1H, m, -CH = C4), 7.40 (5H, s, UV aromatic protons: Xmax274 nm (e = 10 130), (95% ethanol), Paper chromatography: RF zone = 0 , 40. Example LIII Preparation of sodium 7 {Da (3-furoyl-3-methylureido) phenylacetamido] -3- (2-methyl-1,3y4-tla-diazolyl-5-tyl) methylcephem-3-carboxylate. The compound was prepared from tfa salt of 7- (D- a-aminophenylacetamido) -3- (2 * methyl-1/3/1-thiadiazol-5-thi4- •., - methyl-cephomo-3-carboxylic-4 and N-chlorocarbonyl-N-methylfuramide as described above in Example XXXVIII , with a yield of 32.6%. NMR: [(CD3) 2SO + D2Oj, 5 = 2.69 (3H, s, thiadiazole-CH3), 3.35 (5H, singlet overlapping multiplet, ^: N -CH3 and C2 methylene protons), 4.2-4.5 (2H, m, -CH2S-) 4.9-5.1 (1H, m, C6 proton), 5.5-5.8 ( 2 H, m, C7 protons and a) 6.6-8.0 (8 H, m, aromatic ifuryl protons). UV: Xmax 272 nm (e = 25,690), (95% ethanol). Paper chromatography: Rp = 0.50 zone. Example LIV. Preparation of sodium 7- [D 1 - (3-crotonoyl-3H-methylureido) phenylacetamido] -3- (2-methyl-1,4-thiadiazolyl-5-thiolmethylcephem-3-carboxylate-4-carboxylate). The compound was obtained from the salt of tfa acid Crotonic acid 7- (D-amino-phenylacetamido) -3- (2-methyl-1- (4-thiadiazolyl-5-thio) -methylcephem-3-carboxylic-4 and N-chlorocarbonyl-N-methylamide crotonic acid as described above in Example XXXVIII , a yield of 38.8%. NMR: [(CD3) 2SO + D20], 6 1.8-2.1 (3H, m, crotonyl-CH3), 2.70 (3H, s, diazole-CH3 ) 3.25 (3H, s, N-CH3), 3.5-3.7 (2H, m, C2 methylene protons), 4.3-4.5 (2H, m, -CH2S-) , 4.9-5.1 (1H, m, C * proton), 5.5-5.8 (2H, m, C7 protons and a), 6.6-7.1 (2H, m , olefinic protons), 740 (5H, s, aromatic protons). UV: Xmax273 nm) = 14510), (95% ethanol). Paper chromatography: RF value zone - 0.65.14 89 964 Example LV. Preparation of 7- {Da- (3-crotonoyl-3-methylureldo) phenylacetamido] -3- (1-methyl-1H-te \ trazolyl-5-thio) sodium methylcephem-3-carboxylate-4-carboxylate. The compound was obtained from the tfa salt Crotonic acid 7- (D-amino-phenylacetamido) -3 * (1-methyl-1H-tetrazolyl-5-ijo) methyl-cephem-3-carboxylic acid4 and crotonic acid-N-chlorocarbonyl-N-methylamide as described in Example XXXVIII , yielding 30.6%. NMR: [(CD3) 2SO + D20], 6 = 1.9-2.1 (3H, m, crotonyl-CH3), 3.23 (3H, s, N- CH3), 3 / * - 3.7 (2 H, m, C2 methylene protons), 3.94 (3 H, s, tetrazol-CH3 (4.2-4.4 (2H, m, -CH2S) , 4.9-5.1 (1H, m, C6 proton (5.5-5.8 (2H, m C7 protons and α6.6-7.1 (2H, m, olefin protons), 7.39 (5H, s, aromatic protons) .UV: Xmax270nm) (e = 10,010), (95% ethanol). Paper chromatography: zone with Rp value = -0.45.P from yk M d LVI. Preparation of sodium 7-Da-3- (2-chlorobenzo) -3-methyluroro-phenylacetamido-3- (2-methyl-1,3,4-thiadiazolyl-5-thio-methylcephem-3-carboxylate-4-carboxylate) The compound was prepared from the salt of 7- (D "α-aminoaminophenylacetamido) -3- (2-methyl-1 / 3,4-ijadiazol-yl-5-thio) methylcecefem-3-carboxylic acid4 and N-chlorocarbonyl Benzoic acid -N-methyl-2-chloramide it as described above in Example XXXVI11, yield 31 JB%, NMR: [(CD3) 2SO + D2O],? = 2.68 (3H, s, thiadiazole-CH3), 2.98 (3H, s,? N-CH3-, 3.3-3.6 (2H, m C2 methylene protons (4.3-4.6 (2H, m, -CH2S- (4.8-5.0 (1H, m , C6 proton; (5.5-5.8 (2H, m, C7 protons and a) 7.3-7.7 (9H, d, aromatic protons) .UV: Xmax276 nm = 11910, (95% ethanol). Paper.chromazography: zone with value Rp = 0 ^ 4. Example LVII Preparation of 7 {D ^ J3- (2 ^ ethylbenzoyl) -3'methylure | to] -phenvlkflKJetam | to] -3- (2-. sodium methyl-1,3,4-thiadiazolyl-5-thio) methyl-cephem-3-carboxylate4. The compound was prepared from the tfa salt of 7- (da-aminophenylacetamido) -3- (2-methyl-1,4-thiadiazolylO'5 -thi4- i ;; methylcephem-3-carboxylic4 and N-chlorocarbonylb- N-methyl and benzoic acid 2-methylamide by the method as described above in Example XXXVI 11, yield 32.7%. NMR: [(CD3) 2SO + D20], 5 - 2.27 (3H, s, benzoyl-CH3), 2.68 (3H, s, thiadiazole-CH3 2.97 (3H, s, N-CH3 (3.3-3, 6 (2H, m, C2 methylene protons) 4.4-4.6 (2H, m, -CH2-5, 5.3-5.5 (1H, m, CJ proton 5.6-5, 8 (2 H, m, C7 protons and ot), 7.3-7.6 (9 H, m, UV aromatic protons: Xmax274 nm) = 12 19 0). (95% ethanol). Paper chromatography: zone with Rp = 0.62. Example LVIII. Preparation of 7- [D-α- (3-acetylimidazolidine-2-yl-1-carbonylamino) phenylacetics to sodium] -3- (2-methyl-1,3,4-tladazo | yl-5-thio) -methyl-cephem-3-carboxylate sodium. The compound was obtained from the thi.a salt of 7- (Dtx-aminophenylacetamido) - 3- (2-methyl-1- [1-thiadiazolyl-5-thio) methyl-cephem-3-carboxylic 4 and 3-acetyl-1-chlorocarbonylimidazolidinone-2 as described above in example XXXVIII, yield 74.3% .NMR : [(CD3) 2SO + D20], 5 = 7.43 (5H, s, aromatic protons), 5.7-5 / 4 (2H, m, C7 protons and a) 5.1-4.8 (1H, m, C6 proton 4.7-4.1 (2H, m, -CH2S-), 3.70 (4H, s, Imidazolidinone methylene protons), 3.8-3.0 ( 2 H, m, C2 methylene protons), 2.70 (3 H, s, thi-azole-CH3), 2.45 (3 H, s, # ICOCH3) .UV: ^ ¦max 274.5 nm (e - 10 270), (95% ethanol). Paper chromatography: single zone Rp = 0.43. Example LIX. Preparation of 7- [Da-) 3-acetylimidazolidinone-2-11-Hcarbonylamino) phenylacetics to -3- (1 - Sodium methyl-1H-totrazolyl-5-thio) methylcephem-3-carboxylate. The compound was obtained from the salt t.fa. 7- (Da-aminophenylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thio) -methyl-cephem-3-carboxylic acid-4 and 3-acetyl-1-chlorocarbonyl] -midozolidinone-2 as described in Example XXXVIII, with Yield 43.5%. NMR: [(CD3) 2SO + D20], 6 = 7.47 (5H, s, aromatic protons), 5.8-5.4 (2H, m, C7 protons and a) , 5.0-4.8 (1H, m, C6 proton), 4.7-4.0 (2H, m, -CH2S-), 3.96 (3H, s, tetrazol-CH3.3 . 70 (4H, s, Imidazolidinone methylene protons), 3.8-3.1 (2H, m, methylene protons (^ J, 2/15 (3H, s, ^ NCOCH3). UV: Xmax265 nm ( e = 8,400), (95% ethanol). Paper chromatography: single zone with Rp value of 0.38. Example LX. Preparation of sodium salt of Da- (imidazolidinone-2-yl-1-carbonylamino) benzylchalosporin. Anhydrous solution D-craminobenzyl-cephalosporin triethylammonium salt, prepared from 2.2 g of 0.005 mol, dihydrate as described above in example III, in 30 ml of dichloromethane, cooled in an ice bath, then a solution of 0.75 g. 0.005 mol 1 was added. chlorocarbon 2-yl-imidazolidinone and 10 ml of dichloromethane. The solution was stirred for 3 hours at room temperature, evaporated to dryness under reduced pressure and the residue dissolved in 100 ml of water. The aqueous solution was washed twice with 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate and acidified with 1N hydrochloric acid to a pH of 1.5. The precipitated cephalosporin acid was collected on a filter, washed with 100 ml of water and dried under reduced pressure. The free acid was suspended in 25 ml of water, the pH was adjusted to 6.5 with b normal sodium hydroxide solution, then the solution was filtered and lyophilized to give the sodium salt. The yield was 1.77 g, 68.4%. NMR: [(CD3) 2SO + D20], 8 = 7.43 (5H, s, aromatic protons (5.8-5.4 (2H, m, protons C7 and tx), 5.2-4.6 (3H, m, C6 proton and -CH2OCO-), 4.0-3.0 (6H, m, C12 and Imidazolidinone methylene protons) 2.00 ( 3 H * s, -OCOCH3) .UV: Xmax264nm (e = 6,950), (95% ethanol). Paper chromatography: single zone Rp = 0.27. Example LXI. Preparation of 7- (Da- (imidazolidinone- Sodium 2-yl-1-carboxylamino) phenylacetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-thio) methyl-cephem-3-carboxylate, sodium. The compound was prepared from 7- (Dt * -aminophenes | oacetamido) -3- (2-methyl-1,3,4-thiadiazolyl-5-thio) methylephem-3-carboxylic-4 and 1-chlorocarbonylimidazolidinone-2 in the manner as described above in Example LX, with the yield of 63.5%. NMR: [(CD3) 2SO + D20], 8 = 7.43 (5H, s, aromatic protons), 5.8-5.4 (2H, m, C7 protons and a), 4.88 [1H, d, (J = 5Hz), C6 proton], 4.8-4.1 (2H, m, -CH2S-), 4.0-3.0 (6H, m , C2 protons and imidazolidinone methylene protons), 2.69 (3H, s, thiadiazole-CH3). UV: Amax 275 nm) (e = 12,210, (95% ethanol). Paper chromatography: single zone with Rp = 0.38. Example LXII. Preparation of 7- [DtHimidazolindinone-2-11-carbonylamino) -3- Sodium (1-methyl-tetrazolyl-5-thiomethylcephem-3-carboxylate4.1.72 g, 0.003 mol, 7- (Sa-aminophen | oacetamido) -3- (1-methyltetrazolyl-5-thio) -methylcephemo -3-carboxylic-4 was acylated with 1-chlorocarbonylimidazolidinone-2 as described above in Example LX to give the free acid as a rubbery solid. Dissolved in 30 ml of acetone, dried with anhydrous magnesium sulfate and treated with 2 with a normal solution of sodium 2-ethylcarbonate in methyl isobutyric ketone The precipitated sodium salt was collected on a filter, washed with anhydrous ether and dried under vacuum (Yield 1.16 g, 65%) NMR: [(CD3) 2SO + D2O ], d = 7.43 (5H, s, aromatic protons), 53-5.4 (2H, m, C7 protons, and [alpha]), 4.88 [1H, d,) J = 5Hz), proton C6], 7-4.0 (2H, m, -CH2S-), 3.95 (3H, s, tetrazol-CH3), 4.0-3.0 (6H, m, C2 methylene protons and imidazolidinone). UV: Xmax 271 nm (e = 8600), (95% ethanol). Paper chromatography: single zone with Rp -0.24. Example LXIII. Preparation of the sodium salt of D, La (3-cinnamoyl-3-methylureido) -thienyl-2-methylchalosporin. Solution 1.72 g 0.005 mol of D, La- (3-cinnamoyl-3-methylureido) thienyl-2-acetic acid, 1 drops of N-methylmorpholine and 0.71 ml, 0.005 mol, triethylamine in 15 ml of anhydrous acetone, cooled to -10 ° C and treated with 0.48 ml, 0.005 mol, ethyl chloroformate. The solution was stirred for 20 minutes at -5 ° C to 10 ° C, then a solution of 1.36 g, 0/305 mol, 7-aminocephalosporanic acid and 0.71 ml of triethylamine in 30 ml of water, cooled to 0 ° C was added. acetone. The mixture was stirred for 2 hours at room temperature, then the acetone was removed under reduced pressure, 50 ml were added and washed twice with 50 ml of ethyl acetate. The aqueous solution was acidified with 1N hydrochloric acid to pH 1.5, in the presence of 50 ml of ethyl acetate, and extracted with 50 ml of additional ethyl acetate. The extracts were washed twice with 100 ml of water and 50 ml of aqueous sodium chloride solution, dried anhydrous. With magnesium sulphate, 1.8 ml of 2N sodium 2-ethylcaproate solution in methylisobutyl ketone were added and diluted with 200 ml of anhydrous ether. The precipitated sodium salt was collected in a filter bag, washed with ether and dried. The yield was 1.12 g, 36.1%. NMR: [(CD3) 2SO + D20], 6 = 8.0-6.7) 10 H, m, aromatic, olefinic and thienyl protons) 6.0-53 (1H, m, proton a), 5.7-5.3 (1H, m, C7 proton), 5.2-4.5 (3H, m, C6 proton plus -CH2OCO-), 3, 8-3.0 (2 H, m, C2 methylene protons), 3.33 (3 H, s, 1 N-CH 3), 2.01 (3 H, m, -OCOCH 3). UV: Xmax 286 nm) e (e = 21,650), (95% ethanol). Paper chromatography: single zone with Rp value of 0.53. Example LXIV. Preparation of sodium 7- (D, La- (3-cinnamoyl-3-methylureido) thienyl-2-acetamido] -3- (2-methyl-1H-tetrazolyl-5-thio) methylcephem-3-carboxylate-4-carboxylate sodium, Compound Prepared from 7-amino-3- (1-methyl-1H-tetrazolyl-5-ijo) -methylcephem-3-carboxylic acid, 4L of DL - - (3-cinnamoyl-3-methylurea) thienyl-2- acetic acid as described above in example LXIX, yield 34%. NMR: [(CD3) 2SO + D20], 5 = 8.0-6.8 (10, H, m aromatic, olefinic and thienyl protons), 6 , 0-5.7 (1H, m, proton a), 5.7-5.3 (1H, m, C7 proton), 5.1-4.8 (1H, m, C6 proton), 4.6-4.0 (2H, m, -CH2S-), 2.93 (3H, s, tetrazol-CH3, 3.8-3.1 (2H, m, C2 methylene protons), 3 , 34 (3H, s,., E N-CH3) .16 89064 UV: \ mtx285 (e - 25 190 (95% ethanol). Paper chromatography: single zone with Rp value of 0.52. Example LXL. sodium salt of Da- (3 * c / mimollo-3-butterflyurekio) -b © nzylocafalo $ porin. Solution 1.09 g 0.005 mol, Da- (3-cinnamoy | o-3-methylureido) phenylacetic acid 10.77 g, 0.005 mol, Myydroxybene anhydrate zotrosol in 10 ml t.h.f. (tetrahydrofuran) was cooled in an ice bath and then treated with 0.006 moles of dicyclohexylcarbodvulmide. The mixture was left for 16 hours at 5 ° C, then 4 drops of acetic acid were added, stirred at room temperature for 15 minutes, then the dicyclohexylurea was filtered off and washed with 5 ml of tetrahydrofuran. The filtrate was added to a solution of 1.36 g of 0.005 mol of 7 * minocepha) osporanic acid in 30 ml of 50% aqueous t.f.h. the pH of which was adjusted to 6.5 with N-methylmorpholjny. The solution was stirred for 3 hours, maintaining the pH at 6.5-7.0, after which the t.h.f. was removed. under reduced pressure and the residue was diluted with 50 ml of water. The sodium salt was isolated from this solution as described in example L, X! X. The yield was 1.21 g, 19.4%. NMR: [(CD3iSO + P20], 6- 8.0-7.0 (12 H, m, aromatic iolefin protons (5.8-5.5 (2H, m, C7 protons and a), 5.2-4.6 (3H, m, C 1 proton and -CHaOCCM, 3.8 -2.9 (2H, m, C * methylene protons). 3.33 (3H, s, N-CH3), 2.02 (3H, s, -OCOCH3) .UV: Xmax286 nm (95% ethanol). Paper chromatography: single zone with Rp = 0.54 PL

Claims (2)

Claims 1. A process for the preparation of cephalosporins of the general formula I or their pharmacologically acceptable salts or esters wherein Y is oxygen or sulfur, R1 is an organic radical of no more than 20 carbon atoms, R2 is an alkyl group of 1-3 carbon atoms or benzyl, or R1 and R2 together with the carbon and nitrogen atoms to which they are attached form a 5 *, 6-7-membered ring, R3 is a phenyl group, a phenyl group substituted with one or more functional groups, such as a hydroxyl group, a halogen atom , nitro alkoxy group with 1-3 carbon and amino atoms, 2- or 3-thienyl group, cycloalkyl group with 3-7 carbon atoms or alkyl group with 1-4 carbon atoms R4 is acetoxy group, or carbon, nitrogen or sulfur nucleophile, characterized by that a compound of formula II or a salt, ester or silyl derivative thereof, wherein the dotted line represents a bond at position 2 or 3, n represents an integer 0 or 1 and R4 is as defined above, a reaction with a reactive N-acylating derivative of the acid of formula III, in which Y, R1, R3 and R3 have the meaning given above, and in which reactive groups such as amine and hydroxyl can be blocked and the A2-isomer is optionally converted to the preset A3-isomer, removes SHYL groups by alcoholization or hydrolysis, reduces the sulfoxide to the desired sulfide, and removes the wacyl side chain blocking groups, R, and converts the ester to the free acid or salt thereof. 2. A method for the preparation of cephalosporins of the formula I or their pharmacologically acceptable salts or esters wherein Y is oxygen or sulfur, R1 is an organic radical of no more than 20 carbon atoms, R2 is an alkyl group of 1-3 carbon or benzyl atoms, or R1 and R3 racially with the carbon and nitrogen atoms to which they are attached form a 5-, 6- or 7-membered ring, R3 denotes a phenyl group, a phenyl group substituted with one or more functional groups, such as hydroxyl, halogen, nitro, 1-3 carbon alkoxy and amino, 2- or 3-thienyl, cycloalkyl 3-7 carbon atoms or alkyl 1-4 carbon atoms, R4 is acetoxy, or a carbon, nitrogen or sulfur nucleophile characterized by where a compound of formula IV or a salt thereof is an ester or a silyl derivative in which the dotted line represents a bond at positions 2 or 3, R3 IR4 are as defined above, is reacted with a compound of formula V in which Y, R1, R2 IR3 May the meaning given above, after which it eventually converts the A3-isomer to the desired A3-isomer, removes the silyl groups by alcoholization or hydrolysis, reduces the sulfoxide to the desired sulfide, and removes the blocking groups in the R acyl side chain, and converts the ester to a free acid or its soft. 89 964 i ^ ii / ¦ / • kiii n ri N-CO-NH-CH-CO-NH "J 7 A C0-NN / -CH2R4 C Formula / COOH (0) n H HI R / Y H2N ':' VA V p xc; ch / .N-CO-NH-CH-CO-OH C0-Nv JC-CH2R4 R2 C • LOOH Formula 3 Formula Z f (O) n hn-ch-co-nhV * f I- CO -N \ ^ C-CH FT C 2 COOH Formula A ^ N-COCl Formula 5 CO-O-CH-Z1 h I and X1 -C = Y 'Formula 689 964 O (CH2) n N- Formula 7 O mor 9 Nc ^ O (CH2), 2 / m N- # z0 / - fi S -r ^ 0 (CH2) m N- N- <"NL-T mor 13 IS s- mor W S03H mor 15 N — N ¦ON i A mar HN — N ne CO, H mór 11 N_M mor 12 mor 17 NN O 3 Formula 19 N_N ChLOCH- ^) -S- 2 2 b Formula 20 NN H3C-Nf "\ l - (] - S- / f ? 0 / - / a Sample 21 Works. Typographer. UP PRL circulation 120? 18 Price PLN 10 PL