SU1118289A3 - Method of obtaining cephalosporin derivatives - Google Patents

Abstract

1. METHOD FOR PRODUCING CEFALOSPORIN DERIVATIVES of formula I "4 (ONH-f-rN 0 y (lH, R, where R. and R have the indicated meanings; Y is a hydrogen atom or a group protecting the carboxy group or its reactive derivative is reacted with a substituted ureidophenyl acetic acid) acid of general formula III / L-juice-juice-sn-Soon Ki where R, R., R and p have the indicated values, or with its reactive derivative in an inert organic solvent at a temperature of -30 to 35 C for 0, 5-48 hours, if necessary, remove the carboxy group protecting group. upp, and isolate the desired product.

Description

2. The way pop. IfOTnHuara u and in order to use the anhydride, ester or amide thereof as the p6-reactive derivative of the substituted ureidophenylacetic acid of general formula III.

Priority signs: 22.06.78 when - methyl;

R is a hydrogen atom or hydroxy group} hydroxy group and. R

hydroxy groups are in position 3.4;

R. is a hydrogen atom;

RM.- 1-methyltetrazol-5thylthiomethyl;

R; j is a hydrogen atom or methyl;

hydrogen atom or hydroxy group; hydroxy or acetoxy and, moreover, both Rj groups are bonded to adjacent carbon atoms of the core;

a hydrogen or methoxy-atom atom; acetoxy group or a group of the formula

-S-R,

V

where R is 1,3,4-thiadiazol-2-shI, 5-methyl-t, 3,4-thiadiazol-2-yl, 1,2,3triazol-5-yl or 1-methyltetrazol

- 5 - Il.

The invention relates to methods for the preparation of new antibiotics of the cephalosporin series, which can be used as medicines in medicine. A known method for the preparation of biologically active derivatives of 7- (2-amino-p- (p-hydroxyphenyl) acetamido-3C1, 2, 3-triazol-5-yl) thiomethl-3 cefem-4-carboxylic acid by acylation of the corresponding 7-amino cephaposporin with a reactive JeK- Joifhi

de R is a hydrogen atom, or methyl;

Hydrogen atom or hydroxy group; Choxy or acetoxy and, with both R groups bound to adjacent carbon atoms of the core;

RX is a hydrogen atom or methoxy group;

RC acetoxy group or a group of the formula

-S-R6,

where Rg is 1,3,4-thiadiazol-2-yl, 5-. methyl-1,3,4-thiadiazol-2-yl, 1,2,3triazol-5-yl or 1-methyltetrazol-5-yl, concluding that 7-ai HHocephalosporin of the general formula

  s.

.

COOY with 2-amino-2- (p-hydroxyphenyl; acetic acid ij). The aim of the invention is to obtain new antibiotics of the cephalosporin series that expand the arsenal of effects on a living organism. This goal is achieved based on the known 7-aminocephalosporins acylation reaction by the proposed method creep of cephalosporin derivatives of the formula R4 OUN-dHoU

where R.j and R g have the indicated meanings;

Y is a hydrogen atom or a group protecting the carboxy group or its reactive derivative j is reacted with a substituted uredophenylacetic acid of the general formula

R2

where R, R D, and p have specified

meanings

or with its reactive derivative in an environment of an inert organic solvent at a temperature of from -30 to 35 ° C for 0.5-48 hours, if necessary, remove the group protecting the carboxy group, and isolate the desired product.

As a reactive derivative of the substituted ureidophenylacetic acid of the general formula III, its anhydride, ester or amide is used.,

Reactive derivative

7-aminocephalosporin of formula II means a derivative in which the 7-amino group is activated into the reactive form, for example, by introducing a trimethylsilyl group into the 7-amino group.

When a compound of formula II has a pregroup group Y, examples of such a group can be groups that form an ester with a carboxyl group, such as a trimethylsilyl or benzhydryl group. The trimethylsilyl group bound to the carboxyl group is easily removed by treatment with water or alcohol, and the benzhydryl group is easily removed with trifluoroacetic acid. Other examples of protecting group Y are organic or inorganic bases capable of forming salts with a carboxyl group with a strong group, such as alkaline alkaline earth metals or tertiary amines, such as triethylamine N-methylpiperidine, N-methylmorpholine or pyridine. The salt forming bases are removed by treatment with acid.

The reactive derivative of a substituted urediphenylacetic acid of formula III means a derivative of this acid in which the carboxyl group is activated for the reaction. Examples of such derivatives are anhydride, reactive ester or amide. The anhydride may be a mixed anhydride with aliphatic carboxylic acids such as pivalic acid, trichloroacetic acid or pentanoic acid; with alkylcarbonate, with phenylformate acid, with an aromatic carboxylic acid, the ester may be such as 1-hydroxybenzotriazolyl, 2,4-dinitrophenyl, N-oxysuccinimide, N-hydroxyphthalimide, pentachlorophenyl, phenylazophenylide cyanomethyl, or methoxymethyne, pentachlorophenyl, cyanomethyl, cyanomethyl, cytomethyleneimide, pentachlorophenyl, cyanomethyl, cyanomethyl, nitroxymethyl, pentachlorophenyl, pentachlorophenyl, cyanomethyl, nitroxyphenylcate, N-hydroxyphthalimide, pentachlorophenyl, pentachlorophenyl, N-hydroxybenzamide The amide may be the same as the amide with imidazole, triazole or. Tetrazol.

When a compound of formula II is used in which Y is a protecting group for the carboxyl group, the amide formation reaction can be carried out more efficiently by using a condensing agent such as carbodiimide, for example, N, N-dicyclohexylcarbodiimide, N, N-diethylcarbodiimide, N cyclohexyl -N-morofolinoethylcarbodiimide or K, H-diisopropylcarbodiimide, without first converting the substituted ureidophenylacetic acid into its reactive derivative.

The amide formation reaction is carried out in a solvent environment, in particular an inert organic matter is used. A non-solvent such as acetone, tetrahydrofuran, dimethylformamide, pyridine, acetonitrile, dioxane, chloroform, dichloromethane or ethyl acetate. Water miscible solvents can be used as aqueous mixtures.

Although the reaction is usually carried out with cooling or at ambient temperature, it can be carried out with heating, depending on the reagents taken.  Usually the temperature varies from -30 to 35 ° C. preferably from -20 to 20 C.  Although the reaction time varies depending on the temperature, reagents and solvent used, it is. may vary. from several tens of minutes to several tens of hours.  It is usually S from 0.5 to 48 h, preferably i-24 h.  The selection of the α-target compound and the reaction mixture can be carried out, for example, by extraction with an organic solvent (such as dichloromethane, chloroform or ethyl acetate), by chromatography on silica gel using ion exchange resins, crosslinked dextrins, highly porous styrene polymers or acrylate ester .   An optical isomer, for example, the D and L-isomer of the desired compound of formula I, can be obtained by using an optically active starting compound, such as oi amine phenylacetic acid or substituted ureidophenylacetic acid.  The target compounds can be mixed in formulations with various pharmaceutical preparations adapted for different variants of the administration of pharmaceutical compositions for humans or animals.  Preparations are obtained using pharmaceutical carriers, diluents and / or excipients.  In particular, emulsions, solutions or suspensions in water or oil can be mixed for injection, as well as suppositories such as cocoa butter or other glycerides are used.  The content of active compound varies depending on the method of administration, but usually exceeds 0.1%, such as, for example, 5-99%, preferably 10-60%.  The amount administered for humans is typically 100-3000 kg per day for adults.  The preferred daily dose for adults is 500-2000 mg, although this amount may vary depending on.  body weight, age, symptom, mode or frequency of administration.  Upon preparation of the proposed compounds, thin layer chromatography was performed using silica gel as a carrier (pre-coated plates manufactured by E. Merkk,  Darmstadt); as a developer, mixtures of ethyl acetate-etaol-acetic acid (25: 5: 1 by volume), ethyl acetate-ethanol-acetic acid-water (10: 4) are used. 2: 1 by volume).  9 Example 1.  Step 1, A solution of 6.04 g of triethylamine in dry dichloromethane (20 ml) is added dropwise at room temperature to a solution of H-methyl-3,4-diacetoxybenzamide (15.0 g) and triethylsilyl chloride (6.49) in dry dichloromethane (70 ml).  After the mixture was boiled under reflux for 30 minutes, a solution (82 ml) of phosgene (42 ml) in dry dichloromethane was added to the mixture at a temperature of from -5 to 5 ° C, followed by gradually bringing the temperature of the mixture to room temperature.  Excess phosgene and solvent used are removed by evaporation under reduced pressure to give crude K- (3,4-diacetoxybenzoyl) -Y-methylcarbamoyl chloride.  The product is dissolved in cold dried dichloromethane (50 ml) and, after removing the insoluble matters by filtration, the solution is ready for the subsequent reaction.  Stage 2.  Na, 0-bis- (Trimethylsilyl) acetamide (44.3 ml) is added to a suspension of DY- / phenylglycine (14.0 g) in dried dichloromethane (150 ml) at room temperature, followed by stirring the mixture until it is homogeneous.  Under stirring, a solution of N- (3,4-diacetoxybenzoyl) -Y-methylcarbamoyl chloride in high dichloro-, methane, previously prepared in step 1, is added dropwise to this mixture.  After stirring for 1.5 hours at 5-10 ° C, the mixture is evaporated to dryness at room temperature under reduced pressure, and after the dried methanol is added to the residue, the mixture is again evaporated to dryness under the same conditions.  Ethyl acetate (500 ml) and cold 1 n.  hydrochloric acid solution is added to the residue, the organic layer is separated.  This layer was washed with a cold, saturated aqueous solution of sodium chloride (500 ml) and extracted three times with a cold, saturated aqueous solution of sodium bicarbonate (total amount of 700 ml).  The aqueous layer was taken up, washed with ethyl acetate (100 ml).  The pH of the aqueous layer is adjusted to 2.5 with 2N.  hydrochloric acid solution and extracted with 500 ml of ethyl acetate.  The organic layer applied is washed with a cold, saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and dried dry under reduced pressure to give 15.0 g of p / - / - o-3- (3,4-diacetoxybenzoyl) -3-methyl-i -ureido-phenylacetic acid in the form of a white powder.  Thin-layer chromatography (TLC) Rf 0.52, developer I.  IR spectrum:,: 3700, 2400, 1775, J740, 1700, 1510.  Spectrum NMR; (DMCO-de, 60 MHz), §G (million shares): 2.29 (6H, singlet); / 3.12 (SA, singlet); 5.5 (1H, doublet, T 7 Hz); 7 , 2-7.6 (8H, multiplet); 9.65 (1H, doublet, Hz).  The specified connection receive the following way.  To a mixture of tetrahydrofuran (50 ml) of trimethylsilyl chloride (7 g) and D / - / - 5 (r (3-methyl-T-ureido) phenylacetic acid (6.4 g) obtained by the interaction of D - / - phenylglycine and methyl-lysoxy 6.4 g of triethylamine are added dropwise at a lower temperature and stirred.  After the addition is complete, the mixture is stirred at 40-50 ° C for 1 hour and the temperature is cooled below.  To a mixture of PO, a solution of 7.9 g of 3,4-diadetoxybenzoyl chloride in 20 ml of tetrahydrofuran is added, and then the mixture is stirred for 2 hours at.  After cooling the mixture to a temperature below 10 ° C, small amounts of methanol are added to the mixture and insoluble substances are removed by filtration.  The filtrate is evaporated dry at room temperature and reduced pressure, and the residue is purified by chromatography on a silica gel column (WaKooel C-200, manufactured by WaKO WhipuakiK. To Japan), using 3-4% methanol in chloroform.  5 g of product are obtained in the form of a white powder.  Stage 3.  To a solution of D / - / - oi-f3,4 diacetoxybenzoyl) -3-methyl 1-ureido phenylacetic acid (2.0 g) in methanol (20 ml) was added dropwise 4 ml of 29% aqueous ammonia while cooling ice water.  The mixture is stirred for 30 minutes. its temperature gradually reaches room temperature, then the mixture is concentrated at room temperature and reduced pressure.  Too ml of ethyl acetate and 70 ml of cold saturated aqueous sodium bicarbonate solution are added to the residue.  The pH of the aqueous solution is adjusted to 8.5.  The aqueous layer was separated and after adjusting its pH to 2.5 with cold 2N.  The hydrochloric acid solution is extracted with 200 ml of ethyl acetate.  The separated organic layer is washed with cold sodium chloride aqueous solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give (1.3 g) B - / - / - o - 3- (3, A-dioxybenzoyl) -3-methyl -1-ureido phenylacetic acid as a white powder.  Stage 4.  B / - / - o - 3- {3,4-g1-oxybenzoyl) -3-methyl-1-ureido-L-phenylacetic acid (4.0 g), completely dried over phosphorus pentoxide, dissolved in dried tetrahydrofuran ( 60 ml), containing 1.57 g of 1-hydroxybenzotriazole.  To this solution, 20 ml of a solution of N, N -dicyclohexylcarboxydim (2.87 g) in dried tetrahydrofuran at 0 ° C in an ice bath under a nitrogen atmosphere are added dropwise.  Stirring is continued while the temperature of the mixture gradually rises to room temperature over 2 hours and the resulting N, N-cyclohexyl urea precipitate is separated by filtration.  The filtrate containing 1-benzotriazole ester.  D / - / - oi- 3- (3,4-dioxybenzoyl) -3methyl-1g-ureido-phenylacetic acid, you are ready for the subsequent reaction.  Stage 5.  B, 0-bis (Trimethylsilyl) acetamide (11.5 ml) is added under a nitrogen atmosphere at room temperature to a suspension of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (6.32 g) in dried dichlorg methane (100 ml), followed by stirring the mixture until it becomes homogeneous.  To this solution is added dropwise the entire solution in tetrahydrofuran, preliminarily obtained in stage 4, while maintaining the temperature of the mixture between 5 and, followed by stirring for 8 h.  The mixture is then evaporated to dryness at room temperature, under reduced pressure, and after adding dried methanol to the residue, it is again evaporated to dryness under reduced pressure.  To the residue was added 100 ml of ethyl acetate, a cold, saturated sodium bicarbonate solution (150 ml) and the mixture was thoroughly mixed.  After removal of non-dissolved substances by filtration, the pH of the filtrate is adjusted to about 1.0 with cold 2 N hydrochloric acid solution.  The precipitate was filtered, washed with water (100 ml) and dissolved in acetonate (70 ml).  The solution is processed activated. bone char and evaporated, dry at room temperature and reduced pressure.  5 ml of acetone was added to the residue and the mixture was treated with 50 ml of diethyl ether to obtain 3.5 g of (-) (3,4-dioxybenzoyl) -3-methyl-1-ureidoabophenylacetamide-3-acetoxymethyl-3-cephem -4 carboxylic acid (compound A) in the form of light yellow amorphous crystals.  g TLC: Rf 0.45, promoter II.  IR spectrum: KBG, 4d, o, 1cc cm 2300, 1775, 1675, 1520.  Nuclear Magnetic Resonance Spectrum (DMCO-d ,, 60 MHz), 8 (million shares): 2.02 (GZ, singlet); 3.12 (SN, singlet); 3.47 (2H, br.  glet); , 2 (3N, multiplet); 5.5-5.9 (2H, multiplet); 6.8-7.6 (8Y, multiplet).  UV spectrum (E OH) d, o nm: 265, 290 (very).  Color reactions with ferric chloride - positive (dark green staining).  a) The procedure described is repeated with the exception that the direct intermediate compound is obtained - D / - / - oi- 3 (3,4-diacetoxybenzoyl) -3-methyl-1ureido cC- (4-hydroxyphenyl) acetic acid, which has the following Characteristics: TLC: Rf 0.51, manufacturer I.  IR spectrum: KBG, max 37002300, 1770, 1740, 1700-1680, 1510.  NMR spectrum: (DMSO-d, 60 MHz), (million fractions): 2.2 (6H, singlet): 3.12 (3N singlet); 5.23 (1H, hollow T 7 Hz); 6.6-7.6 (7H, multiplet 9.50 (1H, doublet, T 7 Hz); and as a result, (-) (3,4-dioxybenzosch1) -3-meTyl-1-ureido-and- ( 4-oxyphensh1) ycetamido Zetsesoksimenl-y-3-cephem-4-carboxy acid (compound B) in the form of light yellow amorphous crystals.  TLC: Rf 0.42, Proponent II.  IR spectrum, KVG,} motsssm: 37002300, 1775, 1675, 1510.  NMR spectrum (DMCO-d 60 MHz), 8 (million shares): 2.01 (EF, singlet); 3.19 (ZN singlet): 3.5 (2H, br. singlet); 4.80-5.15 (GZ, multiplet); 5.5-6.1 (2H, multiplet); 6.7-7.6 (7H, multiplet).  UV spectrum (US), d ,, d (, d nm: 267, 292 (shoulder).   Color reaction with ferric chloride is positive (dark green color).  b) B / - / - (| 1-Гз- (3,4-Diokg. ibenzoyl) 3-methyl-1-ureido phenylacetic acid, sex -1-ene at stage 3, interacts with 7-amino-3- (5-methyl1, 3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid according to the described method with the formation of 7-Gu (()) (((3,4-dioxybenzene) -3-methyl-1ureido-CI-phenylacetamide 3- (5-methyl1, 3,4-thiadiazol-2-ylthiomethyl) -3 -cepheme-4-carboxylic acid (compound B) in the form of light yellow amorphous crystals.  TLC: Rf 0.40, Proponent II.  LC spectrum,, 37002300, 1775, 1680, 1515, 5СРР spectrum: (DMCO-d, 60 MHz), (million shares): 2.69 (ZN, singlet) 3.19 (ZNu singlet); 3.68 (2H, br.  singlet); 4.4 (2H, br.  singlet); 5.04 (1H, doublet, T 5 Hz); 5.66, 1 (2H, multiplet); 6.9-7.7 (8H, multiplet).  UV spectrum (E2PH),;), d.  nm: 272.  The color reaction with ferric chloride is positive (dark. staining).  c) According to the described procedure, D / - / - oiСЗ- (3,4-hydroxybenzoyl) -3-methyl-1-ureido-A- (4-hydroxy-1) acetic acid interacts with 7-amIno-3- (5-methyl- 1, 3,4-thiadiazol-2-ylthiomethyl) 3-cephem-4-carboxylic acid yielding 7- {in (-) - oC (3- / 3,4-dkoxybenzoyl / -3-methyl-1-ureido) -oC- (4-hydroxyphenyl) acetamido J -3- (5-methyl-1,3,4-ti-azol-2-ylthiomethyl) -3-cephem-4-carboxylic acid (compound D) as light yellow amorphous crystals.  TLC: Rf 0.39, Proponent II.  IR spectrum,. , cm: 37002300,. 1775, 1680, t5tO.  NMR spectrum (r) MCO-d,), S (ppm) shares): 2.70 (ZN, singlet)} 3, t8 (ZN, singlet); -3.7 (2H, br.  singlet), 4.4 (2H, shir. ); 5.05 (1H, doublet, T 5 Hz); 5.5-6.0 (2H, multiplet) ji 6.7-7.5 (7H, multiplet).  11 UV spectrum (E OHH-A.  nm: 270, rx hR WCltC 280 (shoulder).  The color reaction with the chloric gland is positive (dark green color).  d) B (-) - go1- 3- (3,4-dioxib. Enzoyl 3-methylureido | phenylacetic acids are reacted with 7-amino-3- (1-methyl-1H-tatrazol-5-ylthiomethyl) -3-cephem of 4-carboxylic acids in the same manner as in Example 1 to obtain (-) - o (. (3,4-Dioxybenzoyl) -3-methyl-1 -ureido-oi-phenyl acetamido-3- (1-methyl-1 H-tetrazol5-ylthiomethyl) -3-cephem-4-carboxylic acid (compound D) as light yellow amorphous crystals.  TLC: Rf 0.40, prod. Ii.  IR spectrum, KVG: - / iax.  cm: 3700 2300, 1775, 1680, 1615.  NMR spectrum (DMCO-dg), 5 (million shares): 3.10 (SN, singlet); 3.6 {2H, shir. ); 3.93 (SA, singlet); 4.31 (2 br.  singlet); 5.1 (1H, doublet, T 5 Hz); 5.4-5.8 (2H, multiplet 6.8-7.6 (8H, multiplet).  UV spectrum () ,, nm: 265 285 (shoulder).  .  Color reaction with ferric chloride is positive (dark green (Dyeing).  e) According to the method described in Example 1, they are subjected to the interaction D (-) - “. (3,4-Dioxybenzosh1) -3methyl-1-ureido - - (X- (4-hydroxyphenyl) acetic acid with 7-amino-3- (1methyl-1H-tetrazol-5-ylthiomethyl) -3-hey) em-4- carboxylic acid, to obtain 7-fD (-) -d-C3- (3,4-dioxybenzosch1) 3-methyl-1-ureido -oC (4-hydroxyphenyl) acetamido-3- (1-methyl-1H-tetrazole 5- Š1thiomethyl) -Z-cephem-4-carboxylic carbon (compound E) in the form of light yellow amorphous crystals.  TLC: Rf 0.39, Proponent II.  IR spectrum, KVG, „ox.   3,700,200, 1770, 1675, 1510.  NMR spectrum (DMCO-dg), 8 (million shares); 3.11 (SA, singlet); 3.6 (2H, width ); 3.95 (ZN, singlet), 4.31 (2H, shir.  singlet); 5.1 (1H, duplet T 5 Hz); 5.3-5.9 (2H, multi plet): 6. 5-7,5 (7H, multi-flash).  UV-spectrum (EiOH) ,, nm: 265 280 (shoulder), 29. 0 (shoulder).  Color reaction with ferric chloride is positive (dark green color).  9 e) D (-) - o ((3,4-Dioxybenzoyl) 3-methyl-1-ypeICo.Phenylacetic acid is reacted with 7-amino-3 (1,3,4-tnadiazol-2-ylthiomethyl) -3-cephem- 4-carboxylic acid in the same manner as in Example 1, yielding 7-fD (-) - c ((3,4-dioxibenzoyl) -3-methyl-1-yreido-o-phenylacetamido-3- (1,3, 4-thiadiazole-2ylthiomethyl) -3-cephem-4-carboxylic acid (compound X) in the form of light yellow amorphous crystals.  TLC: Rf 0.50, Proponent II.  IR spectrum, KBr, cm 37002300, 1775, 1680, 1520.  NMR spectrum (DMCO-dg), 8 (million shares): 3.17 (GZ, singlet); 3.7 (2H, br. ); 4; 5 (2H, br. ); 5.04 (1H, doublet, T 5 Hz); 5.6-6.0 (2H, multiplet), 6.9-7.7 (3N, multiplet), 9. 36 (1H, singlet).  UV spectrum (E | OH), | nm: 268.  . . /, Front, d ,.  Color reaction with ferric chloride is positive (dark green color).  g) D (-) - ((3,4-Dioxybenzoyl) 3-methyl-1-ureido - (, - (4-hydroxyphenyl) acetic acid is reacted, as in Example 1, with 7-ino-3- (1.3 , 4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid to give (-) 3- (3,4-dioxybenzoyl) -3-methyl-1-ureido-1 -o. - (4oxyphenyl) acetamidou-3- (1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid (compound 3) as light yellow amorphous crystals.  TLC: Rf 0.38, Proponent II.  IR spectrum, KBr, g |, 37002300, 1775, 1680, 1510.  NMR spectrum (DMCO-dg), 8 (million shares): 3.18 (GZ, singlet); 3.7 (211, br. singlet); 4.5 (2H, br. ); 5.05 (1H, doublet, T 5 Hz); 5.5-6.0 (2H, multiplet); 6.7-7.5 (7H, multiplet); 8.37 (1H, singlet).  UV spectrum (E.  OH) m: 270, 280 (shoulder).  Color reaction with ferric chloride is positive (dark green color).  h) D (-) (3,4-Dioxybenzosch1) 3-metsh1-1-ureido (4-hydroxyphenyl) acetic acid is reacted, as in Example 1, with 7-amino-3- (1,2,3-triazole -5-ylthiomethyl) -3 cefem-4-carbonic acid, semi-t3-1 cha (. ), 4 dioxenzoyl 3-methyl-1-ureidoT-1- (4-hydroxyfluyl).  - Aceta shdT-3 (1,2,3-triazole-5-sh1-.  ti “1otil) -3-tsefem-4-carboxylic acid (compound I) in the form of a light yellow powder.  , TLC; Rf 0.39, proponent II.  JK-spectrum, KVg, 4yadk 5/37002300, 1770 ,.  1680, 1515.  NMR spectrum (DMSO-dg) S (million shares): 3.11 (GZ, singlet); 3 6 (2H, width satellite mode 60 MHz); 3.95 (2H, br.  singgling); 5.03 (1H, doublet T 5 Hz); 5.4-5.9 (2H, multiplet); 6.6-7.5 (7H, multiplet; 7.95 (1H, singlet) UV1-spectrum (E. HE),. ,, nm: 272, 280 (shoulder).    Color reaction, with hlrny iron - is positive (dark green coloring).  and) D (-) - with (((3,4-Diacetoxybenzoyl) -3-methyl-1-5feids-a- (4-oxIphenyl) acetic acid is reacted, as in Example 1, with 7-amino-3- ( 1,2, 3-triazol-5-ylthiomethyl) -3-depem-4-carboxylic acid to give 7- | T) (-) - ((3,4-diacetox benzoyl) -3-methyl-1-ureido - a- (4-hydroxyphenyl) acetamido-3- (1,2,3-triazole 5-ylthiomethyl) -3-cephem-4-carboxylic acid (compound I) in the form of a bright yellow powder.   .  TLC: Rf 0.40, Proponent II.  IR Spectrum, KBr ,, oifeC 37002300, 1770, 1760, 1680, 1510.  NMR spectrum (acetone-dg, 60 MHz), (million fraction): 2.26 (6H, singlet); 3.20 (SA, singlet); 3.6 (2H, width ); 4.1 (2H, shir,); 5.01 (1H ,.  doublet, T 5 Hz); 5.5-6.0 (2H, multiplet) 6.7-7.7 (7H, multiplet); 7.86 (1H, singlet); - UV spectrum () (; im: 268, Example 2.  Stage 1, oxalyl chloride (5.3 g) is added to a solution of 4.0 g of 2,3-diacetoxybenzamide in 1,2-dichloroethane (40 ml) with stirring and cooling.  The mixture is gradually heated to boiling point and allowed to react at reflux for 10 hours, then the solvent is then removed from the oxalyl chloride under a lower pressure to obtain 2,3-diacetoxybenzoyl isocyanate, which is dissolved in dried dichloromethane (40 ml) for the subsequent reaction.  9 . Stage 2  H, 0-bis (Trimethylsilsh1) acetamide (19 ml) is added dropwise at room temperature to a suspension of B (-) - phen "shglycine (5.3 g) in youtaeHHoM dichloromethane (100 ml) at room temperature, followed by stirring until the mixture becomes homogeneous. To a clear solution with rto drops to-.  Bavl solution, previously crawled in stage 1.  After stirring the mixture for 1.5 hours at the same temperature, the mixture was dry at room temperature and noHirateHHOM pressure.  Dried methanol is added to the residue and evaporated dry under reduced pressure, cold dilute aqueous hydrochloric acid solution (200 ml) is added to the residue, and the mixture is stirred for 5-10 minutes.  The resulting white precipitate was collected by filtration and dissolved in cold saturated aqueous sodium bicarbonate solution (250 ml).  Insoluble materials are removed by filtration.  The filtrate is washed with 250 ml of ethyl acetate after adjusting its pH to approximately 1.0 with cold SALT. H acid (2N, solution), a white precipitate formed, was collected by filtration, washed with water :, then with diethyl ether and dried in air, obtaining 4.5 D - (-) - (; ((2,3-diacetoxybenzoyl) -1- ureido phenylacetic acid in the form of a white powder, T, mp, 200-201 C (decomp.), Calculated,%: C 57.97; H 4.38 N 6.76 Found,%: C 57.64; H 4.39 N, 6.65, Step 3, D (-) - ((2,3-Liacetoxybenzoyl) -1-yreidoJphenylcyclic acid (2.0 g) is suspended in methanol (20 ml) and 2 are added dropwise to the suspension 5 ml of 29% aqueous ammonia while cooling with ice water, the mixture is stirred at 5-10 seconds for 30 minutes and concentrated at room temperature and reduced pressure.  50 ml of ethyl acetate and 100 ml of cold saturated sodium bicarbonate solution and water are added to the residue.  The aqueous layer is separated and, after removing insoluble substances by filtration, its pH is adjusted to approximately 2.5 using a 2N pit.  hydrochloric acid.  The resulting white precipitate is collected by filtration, washed with water, then with diethyl ether and dried in air, obtaining 1.4 g of P (-) (2,3-dioxybenzoyl) 1-ureido-7-phenyl acetic acid in the form of a white powder.  T. square  211-212 ° C (times ).  Calculated,%: C 55.17; H 4.63; N 8.04 C bN hOb Found;%: C 55.44; H 4.38; N 8.08.  Stage 4.  In (-) (2,3-Lioxybenzoyl) -1-urexto, phenylacetic acid (4.0 g) and 1-hydroxybenzotriazole (1.63 g) are dissolved in dry tetrabandrophenum (100 ml) and added dropwise to the solution at 0-5 C, a solution of N, N -dicyclohexylcarbodiimide (2.99 g) in 20 ml of dry tetrahydrofuran.  The mixture is stirred while its temperature gradually rises to room temperature; after about 2.5 hours, the precipitated dicyclohexyl urea is removed by filtration.  The filtrate, containing 1-benzoriazolyl ether (P) (-) - ((2,3 dioxynbenzoyl) -1-ureido phenylacetic acid, is used for the subsequent reaction.  .  Stage five.  M, 0-bis (Trimethylsil 1) acetamide (7; 8 ml) at room temperature I was added to a suspension of 7-amino-3- (1-methyl-1H-tetrazole-5ylthiomethyl) -3-cephem-5-carboxylic acid ( 5.2 g) in 200 ml of dry dichloromethane, followed by stirring until the mixture is homogeneous.  To this homogeneous mixture is added dropwise. Obtained previously in step 4.  the tetrahydrofuran solution, maintained at a temperature of 5-10 ° C, with stirring, to obtain a siege.  Y, 0-bis (trimethylsilyl) acetamide is added again until the mixture is homogeneous, then stirring is continued at the same temperature for 8 hours.  The mixture is then evaporated dry at room temperature and reduced pressure, and after adding dry methanol to the residue, the mixture is again evaporated dry under reduced pressure.  To the residue add 200 ml of etthtacetate and 200 ml of cold saturated aqueous sodium bicarbonate solution, followed by thorough stirring.  After removal, not 89.  16 solutes by filtration the pH of the aqueous layer is adjusted to approximately 1.0 with a cold 2 N.  hydrochloric acid.  The precipitates are filtered, washed with water; (100 ml) and dissolved in acetone (150 ml).  The solution is treated with activated charcoal and evaporated to dry at room temperature and reduced pressure.  The residue is treated with 70 ml of diethyl ether to give 4.0 g of (-) - S-C3- (2,3-dioxybenzoyl) -1-ureido -o-phenylacetamido 3- (1-methyl-1P-tetrazol-5-ylthiomethyl) 3 cefem-4-carboxylic acid (substance k) as a light yellow powder.  TLC: Rf 0.38, Proponent II.  IR spectrum, KVG, - MA1: CM: 37002300,.  1775, 1680, 1530, 1490.  NMR spectrum (acetone- (,), 8 (million shares): 3.7 (2H, shir. ); 3.96 (SA, singlet); 4.37 (2H, br.  singlet); 5.05 (lEi, doublet, T 5 Hz); 5.66, 0 (2H, multiplet); 6.8-7.7 (8H, multiplet).  UV spectrum (nm: 256, 280 (shoulder), 310 (shoulder).  Color reaction with ferric chloride is positive (dark green color).  a) The procedure described in example 2 (in stage 1-4) is repeated with the difference that 3,4-diacetoxybenzamide is used instead of the 2,3-diacetoxybenzamide used in this example in stage 1 and 1-benzotriazole ester P is obtained (-) (3,4-Dioxybenzoyl) -1-ypeido J -ct-phenylacetic acid.  This abir is reacted with 7-amIno-3- (5methyl-1, 3,4-thiadiazol-2-ylthiomethyl) 3 cefem-4-carboxylic acid and treated: as in Example 2 (step 5), to give 7 -{by(. (3,4 Dioxybenzoyl) -1-ureido-sb-phenylacetamido-3- (5-metsh-1,3,3-thiadiazolyl-2 thiomethyl) -3-cephem-4-to carboxylic acid (compound L) as . , light yellow powder.  TLC: Rf 0. 36, proponent II.  3700 cm-spectrum, KBG, -9d, 2200, 1770, 1675, 1525.  dTR spectrum (acetone-d /), S (mln.  up to it): 2,69 (ZN, singlet); 3.72 (2H, br.  dinglet); four. 4 (2H, width ); 5.13 (1H, doublet, T 5 Hz); 5.5-5.9 (2H, multiplet); 6.8-7.7 (8H, multiplet); UV spectrum (E, OH) -A. . .  , nm: 268, 290 (shoulder).    Color reaction with ferric chloride is positive (dark green color).  b) D (-) (2,3-diacetoxybenzoyl) -1-Ureido - ((, - fenylacetic acid, obtained in Example 2 (in Step 2), is reacted with 7 amino-3- (1-methyl-1H- tetrazol-5-shlthiomethyl) 3-cepheme-4-carboxylic acid as in Example 2 (steps 4 and 5) to give 7- {in (-) OC- 3- (2,3-diacetoxybenzoyl) -1 - Ureido-Qt-Phenylacetamide, about-3- (1-methyl 1H-tetrazol-5-ylthiomethyl) -3-cephem4-carboxylic acid (compound M) in the form of a pale yellow powder, IR spectrum, KVg, -) l, h " , cm 37002300, 1775, 1690, 1530, 1490.  NMR spectrum (acetone-d), 5 (million up to): 2.28 (6H, singlet); 3.75 (2H, br.  singlet); 3.95 (SA, singlet); 4.4 (2H, br.  singlet); 5.07 (1H, doublet, T 5 Hz); 5.6-6.0 (2H, multiplet); 7.2-8, O multiplet).  PRI me R 3.  Stage 1.  Triethylamine (10.2 g) is added dropwise to a suspension of 7-amino-3-acetoxymethyl-3-cephem-4carboxylic acid (8.2 g) in dry dichloromethane (80 ml) at room temperature, followed by stirring the mixture in for 30 minutes at the same temperature.  The mixture obtained is used for the subsequent transformation of Step 2.  B (-) (3,4-Diacetoxybenzoyl) -3-methyl-1-ureidoDt-phenylacetic acid (8.6 g), semi.  Example 1 (stage 2) and pivaloyl chloride (3.0 g) were dissolved in dry dichloromethane (40 ml) and added to this solution dropwise.  gr9 ethylamine (2.4 g) at a temperature below -15 ° C.  After stirring the solution at the same temperature for 1 hour, Hbrt and dichloromethane lacTBOp are added to the solution prepared in advance at stage 1, and stirring is continued at temperatures below for 1-1.5 hours.  The solution was dry-dried under reduced pressure, and 200 ml of ethyl acetate and a cold, saturated sodium bicarbonate aqueous solution (200 ml) were added to the residue (200 ml). After removal of the undissolved substances by filtration, the pH of the aqueous solution was adjusted to 1.0 using a cold 2 n.  hydrochloric acid solution, and extracted with ethylacetate (200 ml).  The organic layer is washed with a cold, saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and distilled under reduced pressure to remove the used solvent.  The residue is purified by chromatography on a column filled with Diaion-HP-20 resin (trade name of a resin suitable for phase-inverted chromatography, manufactured by Mitsubishi Kasei Kogyo Kabushiki Kays, Japan).  The fractions eluted with methanol-water (3: 1 by volume) were collected and distilled under reduced pressure in order to remove the used solvent.  7.0 g of 7-Gu (-) - L-) 3- (3,4-diacetoxybenzoyl-3methyl-1-ureido-1 x3 phenylacetamido 3-acetoxymethyl-3-cephem-4-carboxylic acid (compound H) were obtained as white powder.  Rf 0.62, Proponent II.  IR spectrum, KBG, - / io1x 37002300, 1780, 1745, 1695 1510.    NMR spectrum (Acetop for 60 MHz) S- (ppm) shares): 2.00 (EIT, singlet); 2.28 (6H, singlet); 3.15 (SA, singlet); 3.5 (2H, br.  singlet), 4.65, 3 (3N, multiplet); 5.5-6.0 (2H, multiplet); 7.2-7.7 (8H, multiplet).  a) According to the method of Example 3, 7-amino 3-acetoxymethyl-3-cephem-4-carboxylic acid, which was used after silylation of H, 0-bis (trimethylsilyl) acetamide, is reacted with P (-) - o ((3.4- diacetoxybenzoyl) -3-methyl-1 -ureido -ab- (4-hydroxyphenyl) acetic acid, prepared as described in example 1a, and treated to obtain 7-Gb (-) -: ol 3- (3,4-diacetoxybenzoyl) -3 -methyl-1-ureido-ot-(4-hydroxyphenyl) acetamido1-3-acetoxymethyl 3-cephem-4-carboxylic acid (compound o) as a white powder.  Purification is carried out chromatographically with a column filled with silica gel.  Instead of Diaion HP-20, the eluent is a mixture of methanol and chloroform (1:20 by volume). ,

TLC: Rf 0.54, Proponent II.

IR spectrum, KBG, 9 “,. 3,700,200, 1775, 1740-1670, 1510.

NMR spectrum (acetone-d), S (mln oli): 2.00 (3N, singlet); 2.28 (6H, singlet); 3.16 (SA, singlet); 3.5 (2H, broad singlet); 4.6-5.3 (EIT, multiplet); 5.5-6.1 (2H, multiplet); 6.7-7.7 (7H, multiplet).

b) According to the procedure described in prier 3 (in stages 1 and 2), P is treated (3,4-diacetoxybenzoyl) -3-methyl-1-ureido-phenylacetic acid and 7-amino-3- (5- Mets 11, 3,4-thiadiazol-2-ylthiomethyl) -3 cefem-4-carboxylic acid to give (-) -ct-3- (3,4-di-acetoxybenzoyl) -3-methyl-1 -ureido-cC-phenylacetamido -3- (5-metsh1-1,3,4-thiadiazol-2-methylthiomethyl) -3-cephem-4-carboxylic acid (compound P); in all light yellow powder. . TLC: Rf 0.50, Proponent II.

IR spectrum: KBG, m 37002300, 1775, 1690, 1510.

.ShR spectrum (acetone-dg, 60 MHz) 8 (ppm): 2.28 (6H, singlet);

2.67 (ZN, singlet); 3.15 (SA, singlet); 3.74. (2H, broad singlet);

4.44 (2H, AB 5.2 (tH, doublet,

T 5 Hz); 5.6-6.0 (2H, multiplet);

7.2-7.7 (8H, multiplet).

c) According to the described and example. According to the method, D (-) (3,4 diacetoxybenzonl) -3-methyl-1-ureido is treated

- (4-hydroxyphenyl) acetic acid and 7-amino-3- (5-methyl-1,3,4-thiadi sol-2-ylthiomethyl) -3-cephem-4-carboxylic acid to give 7-Gb (-) -oC - f3- (3,4diacet6xybenzoyl) -3-methyl-1-ureidoT - (4-hydroxyphenyl) acetamido-3- (5-methyl-1, 3,4-thiadiazol-2-ylthiomethyl) 3 cephem-4-carboxylic acid (compound P) in the form of a white powder. TLC: Rf 0.48, developer II. MK-spectrum, KBr ,, t 37002300, 1775, 1685, 1510.

NMR spectrum (acetone-dg 60 MHz) S (ppm): 2.28 (6H, singlet;

2.68 LPN, singlet); 3.14 OZN, singlet); 3.65 (2H, br; singlet); 4.41 (2H, AB); 5.03 (1H, doublet,

T 5 Hz) 1; 5.5-6.0 (2H, multiplet), 6.6-7.6 (7H, multiplet).

g) According to the method described in example 3 (at stages 1 and 2) P (-) t. (3,4-diacetoxybenzoyl) -3-methyl-tureido phenylacetic acid and 7-amino-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid are treated to obtain (-) - d-3- (3,4-diacetoxybenzoyl) 5 3-methyl-1-urevdo-oi-phenylacetamido 3- (1-methyl-1H-tetrazol-5-ylthiomethyl) 3-cephem-4-carboxylic acid (compound C) in the form of a white powder. TLC: Rf 0.55, proponent II. About IR spectrum: KVg, 9 / nax. cm: 37002300, 1775, 1690, 1510..

NMR spectrum (acetone-djg 60 MHz) b (ppm): 2.27 (6H, singlet); 3.13 (SA, singlet); 3.75 (2H, br. 5 singlet); 3.93 (SA, singlet); 4.37 (2H, bs, singlet); 5.11 (1H, doublet), 3 5 Hz); 5.6-5.9 (2H, multiplet); 7.2-7.7 (8H., Multiplet).

e) According to the procedure described in Example 3, D (-) - ot-f3 (3,4-diacetoxybenzoyl) -3-methyl-1ureido} -ot- (4-hydroxyphenyl) acetic acid and 7-amino-3 are treated - (1-methyl-TNterazol-5-ylthiomethyl) -3-cephem-4carboxylic acid to give 7-Gn (-) C- 3- (3,4-diacetoxybenzoyl) 3-methyl-1-ureido -o6 (4- hydroxyphenyl) acetamido {-3- (1-methyl-1H-tetrazol5-S1thiomethyl) -3-cephem-4-carboxylic acid 0 (compound T) as a white powder.

TLC: Rf 0.52, Proponent II. IR spectrum: KVG ,, d, 37002300, 1775, 1690, 1510 .. 5. NMR spectrum (acetone-dg 60 MHz), S (ppm): 2.29 (6H, singlet); 3, t6 (3N, singlet); 3.8 (2H, br); 3.98 (SA, singlet); 4.40 (2H, broad singlet); 5.09 (1H, doublet, 5 Hz). | 0 5.4-6.0 (2H, multiplet); 6.7-7.7 (7H, multiplet).

 Example 4: Pivaloyl chloride (1.14 g) is added dropwise to

. a solution of B (-) (3,4-dioxybenzoyl) -3-methyl-1-ureido-1-phenylacetic acid (3.25 g) obtained by the method of example 1 (at stage 3) and dry pyridine (0.9 g) in dry ethyl acetate (TOO ml) at a temperature of re from -10 to -15 ° C. The mixture is measured for 15 minutes at the same temperature. To this mixture is added dropwise a solution of benzhydryl eff-7 / α-amino-7-a-methoxy-3- (1 5 methyl-1H-tetrazole 5-ylthiomethyl) -3 cefem-4-carboxylic acid (3.3 g) in dry dichloromethane (35 ml) at a temperature of from -10 to -15s. The mixture was stirred at this temperature for 2 hours, at 0–10 ° C for 2 hours and then at room temperature for one hour, and evaporated to dry under reduced pressure. Residue: dissolved in a mixture of 50 ml water and 50 ml ethyl acetate and. The pH of the solution is adjusted to approximately: 1.5 with hydrochloric acid (2N solution). The ethyl acetate layer is added, washed with a cold saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and distilled under reduced pressure to remove the solvent used. The residue is subjected to chromatographic purification on a column of silica gel. The fractions eluted with ethyl acetate benzoyl (1: 1 by volume) were collected and distilled under reduced pressure to remove the elution solvent. 3.3 g of (-) - ", - C3- (3,4-dioxybenzoyl) -3-methyl-1 -ureido | -o (, -phenylacetate amido-7 C-methoxy-3- (1- Methyl-1, dividing 5-thiomethyl) -3-cephem-4-carboxylic acid as a light yellow powder. The product (0.5 g) was dissolved in dry dichloromethane (3 ml). 1.5 ml of anisole was added to the solution. and 3.0 ml of trifluoroacetic acid: while cooling with ice water, after the mixture has been stirred for 30 minutes at 0-5 ° C, the mixture is concentrated and dry under reduced pressure. The residue is treated with diethyl ether to obtain (-) Ot- 3,4-diox Ibenzoyl) - 3-methyl-1ureido} -oC-phenylacetamido r-itli- etokci-3- (1-methyl-1H-5-tetpazol iltiometil) -s-cephem-4-carboxylic acid (Compound Y) as a pale yellow powder. TLC: Rf 0.51, proponent II. IR spectrum, KBr, (o, KC 37002300, 1775, 1680, 1515. Nuclear Magnetic Resonance Spectrum (acetone-dg 60 MHz) S (ppm): 3.18 (ZN, singlet); 3.49 (ZN, singlet); 3.5 (2H, broad singlet); 3.94 (EH, singlet); 4.37 (2H, ABg-); 5.03 (1H, singlet) 5.70 (1H, doublet, J 7 Hz); 6.9-7.7 (8H, multiplet); vS, 6 (1H, singlet) 9.90 (1H, doublet, - 7 Hz). UV spectrum (),. Nm: 272,290 (shoulder). Color reaction with ferric chloride is positive (dark green is stained a) According to the procedure described in example 4, B (-) (3,4-dioxybenzoyl) -3-methyl-1-ureido-phenylacetic acid and benzhydryl 7-amino-7O1-methoxy-3- (5-methyl-1, 3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid ester bathe to obtain (-) -, (3,4-dioxybenzoyl) -3-methyl-1-ureifioj - "(.- phenylacetate amide - 7th-methoxy-3- (5-methyl-1,3,4-thiadiazol-2 -ylthiomethyl) -3-cephem-4-carboxylic acid (compound F) as a light yellow powder. TLC: Rf 0.52, developer II. IR spectrum, KBr, (icc 37002300, 1775, t680, 1515. Color reaction with ferric chloride is positive (dark green about inscription). b) According to the described procedure, D (-) (3,4-dioxibenzoyl) -3-methyl-1-ureido-phenylacetic acid and benzhydryl ether are treated; 7A-amino-7L-methoxy-3- (1,3,4-ty, adiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid to give (-) - (3 ((3,4-dioxybenzoyl) -3-metsh1-1-ureido-oC-phenylacetamido-76-methoxy3- (1,3,4-thiadiazol-2-ylthiomethyl) 3-cephem-4-carboxylic acid (compound X), in the form of a light yellow powder. TLC: Rf 0.52, developer II. IR spectrum, KBG,;, CMB 37002300, 1775, 1680, 1520. The color reaction with ferric chloride is positive (dark green staining). C) D ( -) - K-C3- (3,4-dioxybenzoyl) t 3-metsh1-1-ureidoZ-01- (4-hydroxyphenyl) acetic acid and benzhydryl ester 7 | -amino-7 "; - tags si-3- (1 -methyl-1N-tetrazol-5-ylthiomethyl) -3-cephem-4carboxylic acid to give 7l- {o (-) (3,4-dioxybenzoyl) -3-methieth-ureido -o (g (4 -oxiphenyl) acetamido 7c (, -methoxy-3- (1-methyl-1H-tetrazol5-ylthiomethyl) -3-cephem-4-carboxylic acid (compound C) as a light yellow powder. TLC: Rf 0.49, pro Infrared spectrum, KBG, 9 "Ax. 37002300, 1775, 1675, 1510. Color reaction with ferric chloride is positive (dark green color).

d) According to the described procedure, B (-) - o ((3,4-dioxybenzoyl 3-methyl-1 -ureido-oL- (4-hydroxyphenyl) acetic acid and 7B-amino-7c (, methoxy-3- ( 5-methyl1, 3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid to give () 39 Lioxybenzoyl) -3methyl-1 -ureido -oL- (A-hydroxyphenyl) acetamido -7 ° C-methoxy- 3- (5-methyl1, 3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid (compound III), in the form of a light yellow powder.

TGX: Rf 0.50, Proponent II.

IR spectrum, KBG, l, o, ks m 37002300, 1775, 1680, 1510.

Color reaction with ferric chloride is positive (dark green color).

e) According to the described procedure, D (-) -ot-3- (3,4-dioxybenzoyl 3-methyl-1-JHP o-species, - (4-hydroxyphenyl) acetic acid and benzhydryl ether- 7- | -amino -7y-methoxy-3- (1,3,4thiadiazol-2-ylthiomethyl) -3-cephem-4carboxylic acid to give (-) (OC-3- (3,4-dioxybenzoyl) -3-methyl-1 ureido oi- (4 hydroxyphenyl) -acetamido | 7 "-methoxy-37 (1,3,4-thiadiazole-2yl-thiometht) -3-cephem-4-carboxylic acid (compound S), in the form of a light yellow powder.

TLC: Rf 0.50, Proponent II.

IR spectrum, KBr, SMOKc m 37002300, .1775, 1680, 1510.

Color reaction with ferric chloride is positive (dark green color).

EXAMPLE 5 Dried dichloromethane (10 ml) containing ethyl chlorocarbonate (0.35 g) and dry dichloromethane (10 ml) containing N-methyl morpholine (0.32 g) are added dropwise. to a solution of D (-) - sCf3- (3,4-diacetoxybenzoyl) -3-methyl-ureido-phenylacetic acid (1.38 g) obtained in Example 1 (n stage 2) in dry dipormethane (30 ml) at a temperature varying from -20 to -15 ° C, with subsequent stirring at a temperature of from -10 to -15 ° C for 1 hour. After adding dropwise a solution of benzhydryl ester 7 | 3-amino-3-acetoxymethyl-7-6-methoxy-3- cefm-4-carboxylic isloty (1.50 g) in dry dichloromethane (10 ml) under a ra.stvoru

the temperature is in the range of -10 to -15 ° C and the mixture is stirred at the same temperature for 2 hours while for 1 hour the mixture is evaporated dry 5 under reduced pressure. The residue was dissolved in a mixed solvent: water (50 ml) + ethyl acetate (50 ml) and the pH of the solution was adjusted to approximately 1.5 with 2N. hydrochloric acid when cooled with ice water.

The ethyl acetate layer was washed first with a cold saturated aqueous solution of sodium bicarbonate, then with a cold saturated aqueous solution.

S solution of sodium chloride, dried over anhydrous magnesium sulphate and distilled under reduced pressure to remove the used solvent. The residue was purified by chromatography on a column of silica gel. The fractions eluted with ethyl acetate benzene (1: 2 by volume) are collected and evaporated under reduced pressure.

5 to remove the eluted solvent. 1.52 g of 7A-GB (-) o (- 3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido -oi-phenylacetamido to 7 ° C-methoxy-3-acetoxymethyl-3-cephem-

0 4-carboxylic acid, benzhydryl ether, in the form of a light yellow powder.

IR spectrum, KBG, Dlaks 3300. 1775, 1740-1680, 1510-1490.

/ NMR (CDdj, 60 MHz), 5 (ppm): 2.01 (3N, singlet); 2.28 (6H, singlet); 3.19 (SN, singlet); 3.2 (2H, br. Singlet); 3.51 (SA, singlet); 4.89 (2H, ABg), 5.02

1 (1H. Singlet); 5.62 (1H, doublet, J = 7 Hz); 6.90 (1H, singlet); 7.0-7.7 (19H, broad singlet); 9.97 (1H doublet, IJ 7 Hz),

Stage 2. Anisole (1.5 ml) and 3.0 m of trifluoroacetic acid are added to a solution of 7R-fD (-) - () ((3,4-diacetoxybenzoyl) -3-methyl-1 -ureido-ds-3 benzhydride ester Phenylacetamide-7L-methoxy-3-acetoxymethyl 3-cephem-4-carboxylic acid (0.40 g obtained (in stage 1), in dry dichloromethane (3 ml) while cooling with ice water. The mixture is stirred for 30 minutes and concentrated under reduced pressure. The residue is treated with diethyl ether to give 0.22 g of (-) L4.-C3- (3,4-diacetoxybenzoyl) -3-methyl25-1-ureido | -o6-phenylacetamido | -Tfiimethoxy-3-acetoxymethyl -3 tsefem-4carbo ovpo acid (compound E) in the form of a light yellow powder. TLC; Rf 0.60, developer 11IK-spectrum, KBr. 3700 2300, 1775, 1740-1680, 1505, NMR spectrum (acetone-60 MHz) 8 (ppm): 2.01 (ZN, singlet); 2.28 (6H, singlet); 3.17 (ZN, singlet); 3.2 (2H, schir.sletlet); 3.50 (ZN, singlet); 4.91 (2H, ABg); 5.09 (1H, singlet); 5.72 (1H, doublet, j = 7 Hz); 7.2-7.7 (8H, 1multiplet) 8.60 ( 1H, singlet); 9.85 (1H, doublet, 7 Hz). a) According to the procedure described in Example 5 (at stage 1), D (-) (3,4-diacetoxybenzoyl) 3-methyl-1-urethane-phenyl-acetic acid, prepared in Example 1 (at stage 2), obtained in Example 1 and 7p-amino-7O6-methoxy-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3 cefem-4-carboxylic acid benzhydryl ester to give (-) (3- (3,4-diacetoxybenzoyl) -3 -methyl-1-ureido} -o6-phenyl-acetamido5-7 (1C-methoxy-3- (1-methyl-1H tetrazole-5-sh1thiomethyl) -3-cephem-4carboxylic acid, benzhydryl ether; in the form of light yellow foaming crystals. IR spectrum,, 34001775, 1732-1690, 1510-1490. NMR spectrum (CDCC, 60 MHz), ((ppm): 2.38 (OH, singlet); 2.17 (MN, singlet); 3.50 (MN, singlet); 3.74 (MN, singlet); 3.8 (2H, bdsg); 4.3 (2H, 5.01 (1H, singlet), 5.67 (1H, doublet, 9 7 Hz), 6.89 (1H, singlet), 7.17, 7 (19H, wider singlet), 9 , 99 (1H, doublet, 7 Hz). The resulting b4nzgidrSh1y ether 7j) {D (-) -W-3-C3, 4-Diadetoxybenzos 3-methyl-1-ureidr-3-Phenylacetamido} 7y6-methoxy-3 - ( 1-methyl-1H-tetrazole 5-ylthiomersh1) -3-cephem-4-carboxylic acid 9 is treated as in Example 5 (in step 2) to give 7yifj) (-) (it-3- (3,4-diacetoxybenzoyl) -Z-methyl-1-ureido t "4-fench1 acetamido1 -1 methoxy-3- (-methyl-1H-tetrazole-5ylthiomethyl) -3-cephem-4-carboxylic acid Connections AA) as a light-s lo-yellow powder. TLC: Rf 0.54, Proponent II. IR spectrum, KBG, 3700-g 2300, 1775, 1720-1680, 1510. NMR spectrum (acetone-d 60 MHz) V (ppm); 2.28 (6H, singlet); 3.16 (ЗН,. Singlet); 3.48 (3N, Sin-gllet); 3, g (2H, br.singlet); 3.94 (SA, singlet); 4.36 (2H, AB); 5.03; (1H, singlet); 5.70 (1H, 7 Hz); 7.2-7.6 (8H, cartoon); 8.6 (1H, singlet); 9.82 (1H, doublet, 3 7 Hz). Minimum inhibitory concentrations for several species of bacteria have been determined for these compounds. These results are shown in Table. 1-3. Use sledzdapa bacteria. 1. Bacillus subtilis PSI-219, 2.Staphylococcus aureus 209P 3.Staphylococcus aureus ItJ-5 4. Sarcina lufea B 5.Escherichia coli NIHI 6.Shigella flexneri 26 7.Salmonella jparatypbi A 8.Klebsiella pneumoniae 15g. Proteus mlrabills 1287 10.Proteus moraahi IU-244, 11.Pseudomohas aerueinosa 1-272 12.Pseudomonas aeruginosa 1-169 13.Pseudomonas aeruginosa 1-169-Sh 222 14, Pseudomonas aeruginosa GNB-75 15.Pseudomonas aeruginosa GNB-75.B. M 57740 16.Pseudpraonas aetuginosa KAN-2 17.Pseudoinonas aeruginosa Pij-6 IS.Serratia marcescens ser-256 19.Serratia mafcescens FU-104 20.Enterobacter cloacae FU-250

27

28

t, 118289 Table 1

29

1118289

thirty; Table 2

31

1118289

32 Table3

Claims (2)

1. METHOD FOR PRODUCING CEPHALOSPORIN AQUEOUS PRODUCTS of Formula I where R | - a hydrogen atom or methyl; - a hydrogen atom or an oxy group; P- ₄ is an oxy or acetoxy group un = 2, moreover, both Rj groups are bonded to neighboring carbon atoms of the nucleus; R ^ is a hydrogen atom or a methoxy group; Rj is an acetoxy group or a group of the formula -SR ₆ , where Rg is 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 1,2,3-triazol-5-yl or 1-methyltetrazole -5-yl, characterized in that 7-aminocephalosporin of the general formula II where they have the indicated meanings; Y is a hydrogen atom or a group protecting a carboxy group or its reactive derivative is reacted with a substituted ureidophenylacetic acid of the general formula III hell; SOK- Conh- £ h- Coow "" БУ_ _Ш) 1118289 where jR ^ R and η have the values indicated by or with its reactive derivative in an inert organic C00Y solvent at a temperature from -30 to 35 ° С for 0, 5-48 hours, if necessary, remove the group protecting the carboxy group, and isolate the target product. 2. The method according to π. 1, it is important that the anhydride, ester or amide is used as the reactive derivative of the Substituted ureidophenylacetic acid of the general formula III. Featured priority! 06/22/78 at - methyl; Ri is a hydrogen atom or an oxy group; - oxy group and n = 2, oxy groups are in position 3.4; Rq is a hydrogen atom; Rg-1-methyltetrazole-5ylthiomethyl; 09/11/78 at - a hydrogen atom or methyl; - a hydrogen atom or an oxy group; R ^. - an oxy or acetoxy group and n = 2, both R, ₇ groups being bonded to adjacent carbon atoms of the nucleus; R ^ is a hydrogen atom or a methoxy group; Rg is an acetoxy group or a group of the formula -SR ₆ where Rg is 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 1,2,3triazol-5-yl or 1-methyltetrazole - 5 - silt