SU1190987A3 - Method of producing cephalosporin derivatives or salts thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI(R<1> is H or carboxyl- protecting group; R<2> is aromatic hydrocarbon group, acylamino, etc.; R<3> is H or alkoxy; R<4> is H or halogen; R<5> is H or amino; A is -CH2-, etc.; Z is S,S O; one of dotted lines in the cephem ring is double bond) and its salt. EXAMPLE:7-[2-(2-Aminothiazole-4-yl)acetamido]-3-[2-(5-acetamido-1,2,3, 4-tetrazolyl) methyl]-DELTA<3>-cephem-4-carboxylic acid. USE:An antibacterial agent effective against Gram-positive and Gram-negative bacteria. Stable to beta-lactamse, having low toxicity. PROCESS:A compound shown by the formula II or its salt is reacted with an aromatic hydrocarbon, etc. in an organic solvent in the presence of an acid, etc., to give a compound shown by the formula III. This compound is reacted with a compound shown by the formula IV, to give shown by the formulaI.

Description

A-COOH BG

where Ra, R and A are as defined,

or with its reactive derivative of the carboxy group in a solvent at (-50) - (AO) C followed by the removal of a protecting group if necessary, or the free carboxy group is protected as an ester, or the desired compound is added as a salt or as a salt.

2. The method of claim 1, wherein the compounds of formula I are prepared, wherein A is methylene.

3. The method according to claim 1, characterized in that compounds of the formula T are prepared, where A is a group of the formula

-s1

OR5

where RC is a hydrogen atom or C -C-alkyl.

4. The method according to paragraphs. 2 and 3, about tl ich and Yu and C; in that compounds of formula 1 are prepared, where R is 1,2,4 triazolyl or 2- (1,2,3,4-tetrazolyl), optionally suitably substituted.

This invention relates to methods for producing new cephalosporin antibiotics, namely, cephalosporin derivatives of general formula I-K-vpA-CO H-r-r A.Lt. COORi where R. is a hydrogen atom or a protecting group forming an ester; x - - C2-C-acylamino, possibly substituted by chlorine; 15 benzoylamino group; 2-furoylamino group; phenyl; 1; i-hydroxyphenyl; 2-furyl or 2-thienyl, optionally substituted in position 5 with a carboxy or 20 carbomethoxy group; triazolyl, free or monosubstituted by methyl, chlorine, methylthio group, carbethoxy group or acetamido group or disubstituted by groups selected from the cyano group of carbomethoxy group and phenyl; or tetrazolyl, free or monosubstituted with 30 ny methyl, ethyl, phenyl, methylthio, carboethoxy, carbethoxymegde, or when mixed with microprotectyl, thiol, amino or acetamido, with the aforementioned triazolyl or tetrazolyl attached to the e-motilene-moiety to the isometra-mo mo ring to the isometra-moctanoic moiety is not a single moiety to which is not a traentone-motero group, an aromatic group or an acetamido moiety rings through a nitrogen-carbon bond; a vatrod or chlorine atom; a hydrogen atom or an amino group, free or protected by an acyl protecting group; A is methylene or a group of formulas f, Rj. - a hydrogen atom or C -C-alkyl, in the form of syn-isomer, their salts, which can be found as medicinal substances in medicine. It is known that cephalosporin biotics have a high protivoobnoe activity both in organisms and people, not only in willows of gram-positive and gram-like bacteria, but also against Gram-negative microorganisms that inhibit / 3-lactamase. However, due to the appearance of microbial and bacterial strains.

3 .1

resistant to known cephalosporin antibiotics, it is relevant to identify new cephalosporin derivatives that are active against microorganism strains resistant to known cephalosporins.

The aim of the invention is to obtain new cephalosporins, which have a broad antibacterial spectrum, are stable against beta-lactamase produced by bacteria, have low toxicity and are well absorbed by oral or parenteral administration.

This goal is achieved based on the reaction in the manufacture of 7-acylaminocephalosporins, which is known in the chemistry of cephalosporins, by acylation of 7-amino cephalosporic acids by the proposed method of preparing cephalosporin derivatives of general formula I or their salts, which consists in that

S

COORi

where R and R have the indicated meanings or a salt thereof, are reacted with a compound of the general formula III.

NA-COOH

IN-JT-R4 S,

where R ", RA and A have the indicated meanings, or with its reactive derivative at the carboxy group, in the solvent medium at. (-50) - (40) s, followed, if necessary, by deprotection, or the free carboxy group is protected as an ester, or the title compound is isolated in free form or as CO / 1I.

The target compounds are obtained with the value A - methylene, or the target compounds are obtained with the value A - a group of the formula

WITH

c

N

Oya

90987, 4

where R is a hydrogen atom or C -C-alkyl,. in the form of syn-isomer. . For both types of the target compounds, those most preferred are those where R 1,2,4-triazolyl or 2- (1,2,3,4-tetrazolyl), possibly suitably substituted. In Group

TS-IT

L A

 R3

formulas, 1 there are tautomeric forms when R is an amino group, which can optionally be protected by an amino group, as shown by the following equilibrium equation:

where R and R correspond to the specified

R. is an imino group which can optionally be protected. As salts of the compound represented by formulas 1 and P, salts with a basic or acidic group can be used, including salts of mineral acids such as hydrochloric, nitric or sulfuric acid; salts of organic carboxylic acids, such as oxalic, succinic, formic, trichloroacetic or

5 trifluoroacetic acid; and salts of sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzoyl sulfonic acid, toluene, 2-sulfonic acid, toluene-4-sulfonic acid, meticity; , benzene-1 3disulfonic acid, toluene-3,5-disul5 phonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene - 1, 2, 4-trisulfonic acid or

0 naphthalene-1,3,5-trisulfonic acid as salts in the main group; and alkali metal salts, for example sodium or potassium; alkaline earth metal salts like calcium

or magnes; ammonium salts; salts of nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl-beta-phenethylamine, 1-phenamine, N, N-dibenzylamine diamine, triethylamine, trimethylamine, tributylamine. pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine or dicyclohexylamine.

Acid halides can be used as reactive derivatives of compounds of formula III. Anhydrides of acids, mixed acid anhydrides, active amides of acids, active esters and active derivatives obtained by the reaction of the Vilsmeier reagent, and compounds of the formula Sh. Mixed acid anhydride. acid anhydrides with monoalkyl carbonates, such as monoethyl carbonate or monoisobutylcarbonate, .. mixed acid anhydrides with lower alkanoic acids, optionally substituted E halogen, such as pivalic acid or trichloroacetic. N-acylsaccharide, N-acyl-imidazole, H-acylbenzoyl amide, L, M-dicyclohexyl-N-acylurea or N-acylsulfonamide can be used as active acid amide. The cyanomethyl complex can be used as the active ester.

, ether, substituted phenyl esters, substitute {valuable benzyl esters or substituted thienyl esters.

As derivatives with vilsmeier reagent, active derivatives with can be used. reactive Vilsmeier produced by the reaction of an acylamide, such as dimethylformamide, or N, N-dimethylacetamide, with a halogenating agent such as

phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phoborr oxychloride, phosphorus oxybromide, phosphorus pentachloride, trichloromethyl chloroformate or

oxalylshoride. . I ...

When the compound of formula III is used in the form of a free acid or a salt, an appropriate condensing agent is used, as used are s-disubstituted carbodiimides, such as N, N -dicyclohexylcarbodiimide; an azolidine compound such as N, N-thionyl diimidazole; dehydrating agents, for example, L-eth6carbonyl-2-ethoxy-1, 2-deoxyquinoline, phosphorus oxychloride or alkoxyacetylene, 2-halopyridine salts, such as 2-chloropyridine methyl iodide or 2-fluoropyridine methyl iodide.

The acylation reaction is usually carried out in a solvent in the presence or absence of a base. Halogenated hydrocarbons, such as chloroform or methylene chloride, are used as such a solvent; ethers, such as tetrahydrofuran or; cyoxane; dimethylformamide, dimethylacetamide, acetone, water, or mixtures thereof. The bases used may be inorganic bases such as hydroxides, bicarbonates, alkali metal carbonates or acetates; tertiary amines, such as trimethylamine-n, triethylamine, tributylamine pyridine, N-methylpiperidine, N-methylmorpholium, lutidine or collidine, and secondary amines, such as dicyclohexylamine or diethylamine, and the like.

In an acylcrylation reaction, a compound of formula III or its reactive derivative is taken in an amount of from about 1 mole to several moles per mole of the compound of formula P or its salt. The reaction time is from 10 minutes to 48 hours.

In the case when the compound obtained by acylation is an compound of formula 1, where R is a protecting group forming an ester, it can be converted into the corresponding compound or its salt where RJ is a hydrogen atom. When a compound of Formula 1 is prepared, where it is a Kratom of hydrogen, it can be converted to the corresponding compound or its salt, where R is a carboxyl-protecting group. When a salt of a compound of formula 1 is prepared, it can be converted to the corresponding free compound. When in the acylation reaction there is an active group among the groups R, R2 and R, it can be protected at the time of the reaction or 5 is given after the reaction;

Tests of the pharmacological action of the proposed compounds give the following results.

Antibacterial activity.

In accordance with the standard method, the culture obtained by cultivating the bacteria in the heart broth broth at 37 ° C for 20 h.

sown on heart agar and cultured at 37 ° C for 20 hours, after which bacterial growth is visually inspected. The minimum inhibitory concentration (MIC, µg / ml) is the concentration at which growth is suppressed. The number of bacteria inoculated is 10 cells / plate (10 cells / ml).

The following compounds are tested. . A..Trifluoroacetic acid salt (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido | -3- (3-acetamido-1,2, 4-triazolyl) methyl-D-cephem-4-carboxylic acid ,

B. Trifluoroacetic acid salt of (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido-3- (furan-2-yl-carboximido) methyl 1-c-cephem-4-carboxylic acid

B. Trifluoroacetic acid salt of (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetate. Amino-3 acetamidomethyl-d cephem-4-carboxylic acid.

G. Trifluoroacetic acid salt of (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido3-3- (4-hydroxy 1 3m1) -L cephem-4-carboxylic acid.

D. Trifluoroacetic acid salt (2-aminothiazol-4-yl) -2- (syn) -oximino-acetamido-3-2- (5-methyl-1,2,3, 4-tetrazolyl) methyl-L-cefem-4-carbo new acid. . :

E. Trifluoroacetic acid salt of (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido (1,2,3,4-tetrazolyl) methyl | -L-cefem-4-carboxylic acid.

G. Trifluoroacetic acid, salt 7-G2- (2-aminothiazol-4-yl) -2- (syn) -

methoxyiminoacetamido-3-p- (1, 2,3,4-tetrazolyl) methyl 1-; -cepheme-4-car, bon6 acid.

3. Trifluoroacetic acid salt of (2-aminothiazol-4-Sh1) -2- (syn) methoxyiminoacetamido-3-C2- (5-amino-J ,, 4-tetrazolyl) methyl - &amp; cefem4 carboxylic acid.

I. Trifluoroacetic acid salt (2-aminothiazol-4-yl) -2- (ein) - methoxyiminoacetamido3-3-p- (5-acetamido-1, 2,3,4-tetrazolyl) methyl -t cephem-4-carboxylic acid .

,TO. Trifluoroacetic acid is a salt of (2-aminothiazol-4-yl) -2- (syn) methoxy-amino-acetamido-3-12- (5-methyl1, 2,3,4-tetrazolyl) mets-11-cefem-4 carboxylic acid.

L. Trifluoroacetic acid salt of 7- 2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido (5-ethyl1, 2,3,4-tetrazolyl) methylP-ft-cephem4-carboxylic acid.

M. Trifluoroacetic acid is a salt of (2-amino-3-sol-4-yl) -2- (syn) methoxyiminoacetamido-D-3-chloro, 2,3,4-triazolyl) methyl tercem-4 carboxylic acid.

H. Trifluoroacetic acid salt (2-aminothiazol-4-yl) -acetamide9 3- 2- (5-acetamido-1,2,3,4-tetra-zolyl methyl---cephem-4-carboxylic acid

O. Trifluoroacetic acid is a salt of 7- 2- (2-aminothiazol-4-yl) - acetamido 3- 2- (1, 2,3,4-tetrazoyl) methyl-L cephem-4-carboxylic acid. .

The position of the 1,2,4-triazolyl bond of the above compounds is not determined, since 1,2,4-triazolyl is attached to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond. It is also not indicated which of the nitrogen atoms of the 1,2,4-triazolyl group is attached to the exomethylene group in position 3 of the cephem core. The position of the substituent in the 1,2,4-triazolyl group is determined by indicating the position of the substituent in the parent compound. For example, compounds in which 3-methyl-1, 2,4-triazole-Z-methyl-thio-1,2,4 triazole, 3-acetamido-1,2,4-triazole, 3-chloro-1,2, 4-triazole, 3-atoxycarbonyl-1, 2,4-triazole, etc. the group is attached to the exomethylene group in position 3 of the cephem nucleus, referred to as -3- {(3-methyl-1., 2,4-triazolyl) methyl -; -3-С (3-m. Methylthio-1,2,4-triazole yl) methyl -; -3- (3-chloro-1,2,4-triazolyl) methylT- or -3-C (3-ethoxycarbonyl-1, 2,3-triazolyl) -methyl, respectively.

The results of the study of the antibacterial activity of the compounds are given in Table. 1. I

 Experiment with oral administration.

Each test compound is administered orally to mice (ICR, males, 4 weeks old) at a dosage of 2 mg per individual, and the excretion of the compound in urine is determined. The results are presented in table. 2. After absorption in vivo, all test compounds easily split off the ester group, giving appropriate. free carboxylic acids. For administration, the test compound is suspended in a 0.5% CMC solution and then administered orally. Quantitative analysis was performed using a paper disk method with the bacteria tested. Acute toxicity test. To determine the acute toxicity of the three test compounds, intramuscular injections were administered to the test compounds. ICR species, male animals, 4 weeks old are used as experimental animals. The results are summarized in table 3. The compounds of formula 1 and their salts can be administered to humans and animals in the form of free acid, netocic. Noah. salt or in the form of a physiologically acceptable ester. These compounds are used to treat and prevent bacterial infectious diseases. Preferably, the compounds are administered parenterally in the form of the free acid or non-toxic, salt or orally in the form of a physiologically acceptable ester. They can be prepared in formulations that are used,. like all cephalosporin drugs such as tablets, capsules, granules, syrup, injections (including drops), suppositories, etc. When preparing these dosage forms, diluents and / or additives, fillers such as starch, milk and cane sugar, calcium phosphate and carbonate, etc. can be used, if necessary. binders such as gum arabic, crystalline cellulose starch, carbroxymethylcellulose, hydroxypropylcellulose, and the like, lubricants such as talc, magnesium stearate, and the like. and pulverizer, such as carboxymethylcate, talc, and the like. With the introduction of the proposed cephalosporic forms to a human, the dosage and number of single doses are determined, based on the patient's condition and other factors. Usually, the dosage forms are administered either orally or parenterally in doses of about 505,000 mg of the proposed cephalosporin compound 1-4 times per day, per adult. 1 8710 Examples 1-11 describe the preparation of starting materials, examples 12-32 of the target products, and examples 33-39 of various dosage forms. Try (1). B15 ml of anhydrous acetonitrile is suspended with 2.75 g of 7-aminocephalosporanic acid 7-ACA), and 5.68 g of boron trifluoride and sulfuric ether are added to the resulting suspension, to form a solution. The solution is then reacted at room temperature for 5 hours. After completion of the reaction, the solvent is removed by distillation under reduced pressure, and the resulting residue is dissolved in 20 ml of aqueous acetone containing 50% by volume of water. The pH of the solution was adjusted to 3.5 by adding 28 wt.% aqueous ammonia solution while cooling with ice. The crystals captured are collected by filtration, washed successively with 5 ml of aqueous acetone (1: 1, vol.), 5 ml of acetone and then dried to obtain 2.14 g (yield 79%) of 7-amino-3-acetamidomethyl Dz cephem-4-carboxylic acid having T.PL. 155 C (with different). i. IR spectrum (KVg), 1795, 1640, 1610.1520, NMR spectrum (.CFgCOdu), ppm: 2.37 (ZN, s, -SNe), 3.82 (2H, s, Cg-H ), - 4, 60 (2H, s, bl (2H, broad with,, C-XH2). 2.71 g of 7-amino-3-acetamidomethyl-A cephem-4-carboxylic acid, obtained by in part (1), and 1.90 g of p-toluenesulfonic acid monohydrate is added to this suspension to form a solution. Then 4 g of diphenyl diazomethane is slowly added to the solution at room temperature, and the mixture is reacted at this temperature for 30 minutes After completion of the reaction, the solvent is distilled off at pressure, and the residue thus obtained is dissolved in a mixed solvent of 20 ml of water and 20 ml of ethyl acetate, the pH of the solution is adjusted to 7.0 by adding sodium bicarbonate. The precipitated crystals are collected by filtration, washed thoroughly with water and dried to give 2 , 84 g (65% yield) of 7-amino-3-acetamidomethyl-u-cepheme-4-carboxylic acid diphenyl ester, having so pl. 190-194 C (with diff. IR spectrum (KVg), cm: 1758 1720, 1647. NMR spectrum (SPSHz) ppm: 1.87 (ZN, s, -SN), 3.59 (2D , c ,,), 3.65, 4.27 (2H, AVquadruplet Hz, J),, 71 Qir (1H, g, Hz, Cg-H), 4.89 (1H, g, Hz,), 6 , 12 (1H, broad NHCO-), 6.90 (1H, s, -CHO, 7.36. EXAMPLE 2. The reaction and treatment are carried out in the same way as in process 1- (1 ), except that trifluoroacetic acid is used as the solvent. As a result, the products listed in Table 4 are obtained. EXAMPLE 3. The reaction and treatment are carried out in the same manner as in Example 1- (1), obtained compounds of table 5. EXAMPLE 4. (1). In 13 m l of sulfolane is suspended in 2.72 g of 7-ACA, and 14.2 g of boron trifluoride and sulfuric ether and 1.0 g of -5-methyl-1,2,3, tetrazole are added to the suspension, after which the reaction mixture is subjected reaction at room temperature for 17 hours. After completion of the reaction, the reaction mixture is introduced into 15 ml of ice-cold water. The pH of the mixture is adjusted to 3.5 by adding 28 wt% aqueous ammonia under ice cooling. Crystals precipitated were collected on a filter, washed successively with 5 ml of water and 5 ml of acetone and then dried to obtain 1.76 g of a mixture of 7-amino-3- 2- (5-mets, 2,3,4-tetrazolyl) methyl} -cepheme-4carboxylic acid and 7-amino-3- 1 (5-methyl-1,2,3,4-tetrazolyl) methyl AZ-cephem-4-carboxylic. acid in the form of crystals. (2). 1.76 g of the crystals obtained in part (1) were suspended in 18 ml of methanol, and 1.13 p-toluenesulfonic acid monohydrate was added to the suspension, to obtain a solution, and 4.6 g of diphenyldiazomethane were slowly added thereto. Conduct the reaction at. room temperature for 1 712 15 min. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in a mixed solvent of 30 ml of ethyl acetate and 30 ml of water, and the pH of the resulting solution was adjusted to 8 by the addition of sodium bicarbonate. The organic layer is then separated and dried over anhydrous magnesium sulphate. The solvent is distilled off under reduced pressure. The residue obtained is purified on a chromatographic column (C-200 silica gel Waco; the developing solvent benzene: ethyl acetate is 4: 1 by volume) to obtain 0.79 g of 7-amino-3- 2- (5-methyl1) diphenylmethyl ether , 2,3,4-tetrazole) -methyl-D-cephem-4carboxylic acid (mp. 157-160 ° C, decomposed) and 0.14 g of 7-amino-3- 1- (5- methyl 1,2,3,4 tetrazolyl) methyl - &amp; - cepheme-4-carboxylic acid (tp. 92 s, s decomp.). The following IR and NMR spectra of 7-amino-3 2- (5-methyl-1,2,3,4-tetrazolyl) methyl 1- &amp; -cepheme-4-carc &amp; onic acid. IR spectrum. (KBG),: 1770,. . NMR spectrum (CDCJj), ppm: 1.75 (2H, broad s, - NHj), 2.48 (3N, s, -CH), 3.20 (2H, s, Cj-H), 4 , 70 (1H, g, Hz, Sat-H), 4.87 (1H, g, Hz, C, -H), 5.30, 5.72. S), 6.92 (2H, ABk, Hz, I CH2 (1H, s, -CH), 7.30, (YUN, s, x2). Phenylmethyl ester 7-amino-C 1 - (5-methyl- 1,2,3,4-tetrazolyl) methyl. - 3-cephem-4-carboxylic acid. IR spectrum (KBr), cm: 9., 1770., 1725 .. NMR spectrum (CDCZ), ppm: 1.80 (2H, s, -Sh ,,), 2.1-5 (GH, s, -CH,), (2H, s, C2-H), 4.70 (1H, g , Hz, Sat-H), 4.85 (1H, g, Hz, C7-H) ,, 5.00, 5.38 (2H, ABc,, 6.90 (1H, s, Hz, sleep), 7.30 (YUN, s,

(3). In a mixed solvent consisting of 0.5 ml of anisole and 5 ml of trifluoroacetic acid, 0.462 g of 7-amino-3-2- (5-methyl 1-1, 2, 3, 4-tetrazolyl) diphenylmethyl ester is dissolved. methyl-D-cephem-4-carboxylic acid. The resulting solution was reacted at room temperature for 1 hour. After completion of the reaction, the solution of the distillate was distilled with H-Yu under reduced pressure, and 10 ml of water and 10 ml of ethyl acetate were added to the resulting residue. The pH of the mixture was adjusted to 8 by adding 28 wt.% aqueous ammonia under ice cooling. 15 Then, the aqueous layer was separated and the pH was adjusted to 3.5 by adding a blunt. hydrochloric acid under ice cooling. The crystals embedded in the precipitate are filtered off, successively washed with 20 ml of 5 ml of water and 5 ml of acetone and then dried. Obtain 0.26 g, 7-a 1ino-3- 2- (5-metsh1-1,2,3,4-tetrazolyl) methyl-D-cephem-4-carboxylic acid, with So. PL. (with different), 25

IR spectrum (KBG),, 1610, 1530.; .

NMR spectrum (CF-jCOOD), ppm: 2.70 (ZN, s, -SN), 3.73 (2H, s, C2-H), 5.40 (2H, s, Sb-NU, CZ-H), 30 5.80, 6.12, (2H, ABc, Hz,

one

CHj Repeatedly, the procedure, from 0.462 g of diphenylmethyl ester of 7 amino-3 l - (5-methyl-1,2,3,4-tetrazolyl) metric 3- | b-cefem-4-carboxylic acid, is obtained 0.25 g of 7- amino-3- 40 1 (5-metsh1-1,2,3,4ttetrazolyl) methylJ-Dz-cephem-4-carboxylic acid with m.p. (with different).

IR spectrum (KBG), sSi. 1795, 1615, 1530..45

 ; NMR spectrum (CFgCOGD), ppm: 2795 (EN, s, -CH,), 3.90 (2H, broad s, Cj-H), 5.45 (2H, s, Sat-.H ,, Cj-H), 5.57, 3.92 (2H, AVc: Hz,

 EXAMPLE 5 2.72 g of 55 7-ACA was dissolved in 19 ml of trifluoroacetic acid, and 7.1 g of roor trifluoride complex and sulfuric ether and 0.75 g of 1.2 were added to the resulting solution, 1.2 4 triazole. The reaction was carried out at room temperature for 7 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and 15 ml of water was added to the resulting residue. The pH of the resulting mixture was adjusted to 3.5 by adding 28 wt.% aqueous ammonia under ice cooling. The crystals that separated were collected by filtration, washed successively with 5 ml of water and 5 ml, and then dried to obtain 2.5 g of 7-amino-3-1- (1J2,4-triazolyl) methyl 3-L-cefem-4-carboxylic acid with m. square (with different).

IR spectrum. (KBG), cm-s 1610, 1530..

NMR spectrum (CFgCOOD), ppm, fractions: 4.00 (2H, broad s, Cr-H), 5.47

N (4H, broad s, Cg-H,, I

.

8.70 (1H, s,), 9.80 (1H, s,

Yu. .

EXAMPLE 6 Using tetrazoles, the reaction and treatment were carried out in accordance with Example 4- (1) or Example 5, resulting in the products listed in Table 6. Next, the products listed in Table 6, are esterified and then de-esterified in the manner described in Example 4- (2) and (3). The esters and carboxylic acids listed in Table 2 are obtained. 6,

PRI me R 7. Using these triazoles ,. the reaction and the treatment are carried out in accordance with Example 4- (1) or Example 5, to give the compounds listed in Table. 8. The carboxylic acids are esterified in a manner similar to that described in Example 4- (2) to give the compounds shown in Table. 9 (2.72 g of 7-ACA is used as the starting material).

Example The reaction is carried out in accordance with the method of example 4 under the conditions listed in table. 10, whereby the compounds listed in the same table are obtained.

PRI me R 9. Under the conditions listed in Table. 11, is carried out in the same manner as in Example 5 to give the compounds listed in the same table.

Example 10 The reaction and treatment according to Example 5 is repeated, except that instead of 7-ACA, the compounds listed in Table 12 are used as starting materials. The result is the products listed in the same table.

Example 11. In 20 ml of N, N-di (“1-methylformamide, 2.96 g of 7-amino-3-2- (5-methyl-1,2,3,4-tetrazolols) methyl 1 -D-cephem-4- carboxylic acid. The suspension is then converted into a solution by adding 1.1 g of triethylamine under ice cooling. 2.7 g of pivaloyl hydroxyiodide is added to the solution, and the mixture is reacted for 1 hour. After the reaction is completed, the reaction mixture is introduced into a mixed a solvent consisting of 250 ml of water and 200 ml of ethyl acetate and the pH adjusted to 7.0 tsatri bicarbonate. After removing the insoluble matter, the organic layer is separated After drying the residue with sulfuric ether, it is dissolved in 30 ml of ethyl acetate and a solution of .1 g of dry hydrogen chloride in 30 ml of sulfuric ether is added to the resulting solution with ice cooling and stirring. the crystals are collected by filtration, washed thoroughly with sulfuric ether, recrystallized from chloroform to obtain 2.72 g (yield 60.9%) of 7-amino 3-2- (5-methyl-1,2,3,4-tetrazolyl) pivaloyloxymethyl ester hydrochloride methyl} --cephem-4-carboxylic acid with so pl. 149-151.с (with decomp.). IR spectrum (KBG), cm- -. ; 1773 1741, 1730. .. NMR spectrum (dg-DMCO), ppm: .1.18 (9H, s, -C (CHj) 3, 2.44 (ZN, s, -SN, 3.60 (2H, s,), 5.23 (2H, s, Cg-H,), 5, &amp; 2 (2H, s.; (, 78-5.92 (2.H, m, -COOCHj, 0-) 7-Amino-3-2- (5-methyl-1,2,3,4-tetrazol1) methyl y-cephem-4-carboxylic acid or 7-amino-3 - {(3 -chloro-1,2,4-triazolyl) methyl -b-cephem-4-carboxylic acid, with the exception that K, L-dimethylformamide and triethylamide are replaced by acetone and 1,8-diazabicyclo (5,4.0) -indicant -7 (PBI)

respectively. The compounds listed in Table 2 are obtained. 13 - 15 with the release of 65 - 90%.

Example 12. (1) 2.72 g of 2- (2-tert-amyloxycarboxamidothiazol-4-yl) acetic acid is dissolved in 40 ml of anhydrous methylene chloride and 1.06 g of N-methylmorpholine is added to the solution, after which the reaction mixture is cooled to -35 ° C. Then 1.12 g of ethyl chlorocarbonate is added, and the reaction is carried out at (-35) - (-25) ° C for one and a half hours. 4.62 g of 7-amino-3-2- (5-methyl-1,2,3,4-tetrazol-1) methyl y-cephem-4-carboxylic acid diphenylmethyl ester was added to the reaction mixture and the reaction was carried out at (-30 ) - (-20) 0 for 1 hour and then at (-1-0) - (10) C for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residue is dissolved in a mixture of 40 ml of ethyl acetate and 30 ml of water. The organic layer is separated, mixed again with 30 ml of water, and the pH is adjusted to 1.5 by the addition of a normal hydrochloric acid with ice cooling. The organic layer is separated, mixed with 30 ml of water and adjusted to pH 7.0 by the addition of sodium bicarbonate while cooling with ice. The organic layer is separated and dried over anhydrous magnesium sulphate, then the solvent is distilled off under reduced pressure. Sulfuric ether is added to the residue, and the resulting crystals are collected by filtration. They are thoroughly washed with ether and dried to obtain 6.52 g (yield 91.1%) of the diphenylmethyl ester (2-tert.-amyloxycarboxamidothiazol-4-yl) acetamide aJ3- {2- (5-methyl-1,2, 3,4-tetrazolyl) methyl - &amp; cepheme-4-carboxylic acid with so pl. 103-105 ° C for decomp. IR spectrum (KVg). . ,, 1780, 1720, 1675. Nuclear Magnetic Resonance Spectrum (CDClj), ppm: 0.90 (3N, t, Hz, CH PN.-C-), 1.48 (6H, s, -CO-0- ), 1.92 (2P, к, Hz, СНдСН —С-), 2.44 (ЗН, s, МV “. J), 3.08 (2Н, broad с,),

N-T-CHo3, 62 (2H, s. D, 85, (1H,

S d: Hz, CfH), 5.50-5.90

H

(ZN, m, .Syu-H), 6.53 (1H, s, W2x), 6.88 (1H, s, CH-) ,; to

7.25 (YUN, s, / Oy X 2).

2.72 g of 2- (2-tert. TS amyloxycarbox & midothiazol-4-yl) acetic acid is suspended in 30 ml of anhydrous benzene, and 2.54 g of oxazolyl chloride is added to the suspension under ice cooling, after which reaction at the same temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 5 ml of anhydrous methylene chloride. The resulting mixture is added dropwise to a solution of 4.62 g of diphenylmethyl complex Fir 7-amino-3- 2- (5-methyl-1,2, 3,4, -tetrazolyl) methylT-cefem- 30 4-ka | ) of boic acid and 1.21 g of dimethylamiline in AO ml of anhydrous methylene chloride at (-50) - (-45) sec. After the addition of the mixture obtained is completed, the mixture is reacted for 30 minutes,

at (-20) - (for 30 minutes and then for 30 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure, and 40 the resulting residue is dissolved in 40 ml of ethyl acetate and 30 ml of water, after which the organic layer is separated 30 ml of water are again added to the organic layer, and the pH of the resulting mixture is adjusted to 45 to 1.5 by adding two normal hydrochloric acid while cooling with ice, then the organic layer is separated and 30 ml of water is added to it.

of which, the pH of the resulting mixture was adjusted to 50 to 7.0 by adding sodium bicarbonate while cooling with ice. The organic layer is separated, dried over anhydrous magnesium sulphate, after which the solvent is distilled off under reduced pressure. Sulfuric ether was added to the obtained residue, and the crystals that precipitated 3 precipitate were collected by filtration, washed thoroughly with ether and then dried to obtain 6.69 g (yield 93.5%) of diphenylmethyl ether (2-tert.-amyloxycarboxamidothiazole-4- yl) acetamido -3- 2- (5-methyl-1, 2,3,4-tetrazolyl) methyl - &amp; cephem-4-carboxylic acid with so pl. 103-105 ° C for decomp.

The physical properties of the obtained compound (IR and NMR spectra) are identical to those of the precursor compound.

(2). .6.52 g of (2-. Tert.-amyloxycarboxamidothiazol-4yl) diphenylmethyl ester (-2- (4-methyl-1,2,3,4-tetrazolyl) ) methyl-L-cephem-4-carboxylic acid, obtained in accordance with Example 12 (1). The reaction in the solution proceeds at room temperature for 2 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. Sulfur is added to the residue, and the resulting crystals are collected by filtration, washed thoroughly with sulfuric ether, and dried to obtain 4.61 g (yield. 92.1%) of 7-f2- (2-aminothiazol-4-yl) acetamido trifluoroacetic acid salt (5-metsh1-1,2,3,4-tetrazolyl) metal-D-cephem-4-carboxylic acid with so pl. 184-187C (with decomp.).

IR spectrum (KBG),) tZ, 1655, 1630.

NMR spectrum (d, DMCO), ppm:

ABOUT

sn.

.c, I

(ZN

3.45 (4H, broad N

N.

5.08 (1H, g.

cue c. Ss

 Hz, Cfi-H), 5.50-5.90 (ЗН, m,

   S n

8.96 (1H, g, Hz, -CONH-).

In a similar way, the trifluoroacetic acid salt of (2-aminothiazole 4-yl) acetamido-3-acemidomethyl-D-cephem-4-carboxylic acid, m.p. 153-154s (with diff.).

(3).  5.5 g of trifluoroacetic acid salt of (2-aminothiazol-4-yl) acetamido (5-methyl-1,2,3,4-tetrazolyl) methyl I-iv-cefem-A-carboxylic acid are suspended in 50 ml of water and to suspension while cooling with ice, slowly add 20 ml of one-normal aqueous sodium hydroxide.  The reaction mixture is purified on a chromatographic column with amberlite XAD-2 (solvent is water), and the ae is evaporated to dryness, yielding 4.1 g (code 88.4%) (2-aminothiazolyl) acetamido3-3-1 2- (5- Methyl-1,2,3, tetrazolyl) -methyl j-D-cefem-4-carb sodium silate with m. square  182-187 ° C (with decomp. ).  IR spectrum (KVg), see   1660.1610.      .  NMR spectrum (), mln.  share 2 ,. 41 (LC, s, -CH), 3.40 (2H, broad:,), 3.62 (2H, s, cue s, 5 4.93 (1H, g, Hz, Cg-H), 5, 25-6.02 (ЗН, and, Cr-H, rtg N-rr6, 09 (1H, s, A,), 8.80 (1H, g, S N Hz, -CONH-).  In a similar way receive.  (2-aminathiazol-4-yl) acetamido T 3-acetamidomethyl-b3. Cefem-4-carboxylate sodium.  T. square  product 155158С (with decomp. ).  IR spectrum, (KBG),: t) 175 1680, 1590.  NMR spectrum (VdO), million fractions: 1.98 (ZN, s, -COCHj), 3.16, 3.56 (2H, AVc, Hz, Cj-H), 3.52, (2H,) 3.84, 4.15 (2P , AVc: Hz, I) 5.02 (1H, g,.  .  C "-H), 5.57 (1H, g, Hz, Su-H), 6.40 (1H, s, L) S H Pri-me R 13.  (one).  2.72 g of 2- (2-tert.) is dissolved in 30 ml of anhydrous methylene chloride. -amyloxycarboxamidothiazol-4-yl) acetic acid and 1.06 g added.  N-methylmorpholine, after which the reaction mixture is cooled to -35 ° C.  Then 1.12 g of ethyl chlorocarbate is added, and the reaction is carried out at (-35) (-25) C for 1.5 h, after which the reaction mixture is cooled to (-40) ° C.  On the other hand, 2.96 g of 6-amino-3- 2- (5-methyl-1,2,3,4-tetrazolyl) -methyl j-L-cell-4-carboxyl acid is suspended in 30 ml of anhydrous methylene, and while cooling with ice, add 6.1 g of N, 0bis (trimethylsilyl) acetamide.  After the addition, the mixture is reacted at 5-10 ° C for 40 minutes to obtain a homogeneous solution.  The solution is added dropwise to the prepared reaction mixture while maintaining the temperature within (-40) - (-30) ° C.  After completion of the instillation in the reaction mixture, the reaction is carried out at (-30) (-20) ° C for 1 hour and then at (-10) - (10) C for 1 hour.  After completion of the reaction, the solvent was distilled off under reduced pressure, 40 ml of ethyl acetate and 40 ml of water were added to the residue to dissolve the residue.  The pH is adjusted to 7.5 with sodium bicarbonate under ice cooling.  The aqueous layer is separated, mixed with 4 ml of ethyl acetate and adjusted to pH 2.0.  by addition of hydrochloric acid with normal ice cooling.  Then the organic layer was separated, washed with 30 ml of water and dried over anhydrous magnesium sulphate, after which the solvent was distilled off under reduced pressure to obtain 5.07 g.  (yield 92.2%) (2-tert. -amyloxycarboxamide. Otazol-4-yl) acetamido | 3- 2- (5-methyl-1,2,3,4-tetrazol1) methyl-D-cephem-A-carboxylic acid with m. square  138-142 ° C.  (with ).  IR spectrum (KVg), 775 ,.  J720, 1675.  NMR spectrum (dg DMSO), ppm fractions: 0.88 (3N, t, Hz, CH, CH-6-), SI, 1.40 (6H, s, -C-), 1.79 (2H, k, Hz, CHjCHj-C-) , 2.45 (ЗН, с, N, -CH4, I1,3,46 (2Н, broad с, С ,, - Н), trsNо3, 54 (2Н, с, J 5.08 (1Н, g, й 1 Hz,), 5.61 (2H 5.77 (1H, g ,.  Hz, Cj-H), 6.76 (1 1G s, Jy.  ), 8.75 (1H, g, Hz, S AND -COONH-), (2).  In a mixture of solvents from 25 ml of trifluoroacetic acid and 8 m of anisole, 5.07 g are dissolved (2 rt. -Amsh1oxycarboxamidothiazol-4yl) -acetamido -3-2- (5-methyl-1,2,3, tetrazolyl) methyl1-D-cephem-4-carbonic acid obtained in part (1) The reaction in the resulting solution occurs at room temperature temperature for 30 min.  After the completion of the reaction, the solvent was distilled off under reduced pressure, sulfuric ether was added to the residue, and the resulting crystals were collected by filtration, washed thoroughly with ethyl ether and dried to obtain 4.72 g (yield 93.1 of trifluoroacetic acid salt (2 aminrythiazole-4- or yl) acetamido -3-f2- (5 methyl-1,2,3,4-tetrazolyl) methyl. - tsvfem-4-carboxylic acid with t. square  184-187 ° C (with decomp. ): The physical properties (IR and NMR spectra) of this compound are identical to the physical properties of the product obtained in Example 12 (2).  P r and m er14.  Using the compounds listed in Table 2 as starting materials.  16 and the reaction in accordance with Examples 12 or 1 are prepared by the compounds indicated in the same table.  P p i.  meper 15.  5.5 g are dissolved in 27 ml of K, H-dimethylformamide.  (2-thirds -amyloxycarboxamidothiazol-4-yl) acetamido2 (5-methyl 1,2, 3,4-tetrazol1) methyl -ft-cefem4-carboxylic acid obtained in Example 13- (1).  Then, while cooling with ice, it was added to the solution.  1 g of triethylamine and 2.9 g of the simethyl iodide pivolokyl, and the mixture obtained is subjected to reaction within the course of the preparation.  After completion of the reaction, the reaction mixture was introduced into a mixture of solvent, 250 ml of water and 250 ml of ethyl acetate, and the pH of the mixture was adjusted to 7.0 with sodium bicarbonate.  Organized The economic layer is separated, washed with water and dried over anhydrous magnesium sulphate.  The solvent is then distilled off under reduced pressure, to obtain 6.02 g of pivaloyloxymethyl ester of 7-2- (2-tert. -amyloxycarboxamidothiazol-4-pcs) acetamidoZ. -3-G2 (5-methyl-1,2,3,4-tetrazolyl) methyl JDs of cephem-4-carboxylic acid as a solid.  Without purification, it is dissolved in 30 ml of trifluoroacetic acid and reacted at room temperature for half an hour.  After completion of the reaction, the solvent was distilled off under reduced pressure, 80 ml of water and 80 ml were added to the residue. ethyl acetate, and pH. Bring to 7.0 with sodium bicarbonate while cooling with ice.  The organic layer is separated, dried over anhydrous magnesium sulphate, and a solution of 0.8 g of dry hydrogen chloride in 20 ml of sulfuric ether is added with stirring and ice-cooling, resulting in a white powder precipitating.  It is filtered off, washed thoroughly with ethyl ether and recrystallized from ethyl acetate. to give 3.82 g of (2-aminothiazol-4-yl) pyaloxymethyl ester hydrochloride (2-aminothiazol-4-yl) acetamido (5-methyl1, 2,3,4-tetrazolyl) methyl-citzhem-4carbonic acid with m. square  square  146148 ° C (with decomp. ).  IR spectrum (KBG), cm: 1782, 1750, 1670.     NMR spectrum (dg DMSO), ppm fractions: 1.15 (9H, s, -C (CH-) d, 2.46. (ZN, with N CHj), 3.51.  (2H, s,), 3.62 N.   N-ipCHo- (2H, s, and j | 5.15 (1H, g, Hz S С, -H), 5.26-5.79 (ЗН, m ,.  one : .   ), 5.87 (2H, s, -OSNO-), 6.62 T (1H, s,) 9.23 (1H, g, Hz, -CONH-).   .  Example 16, Exposure of the starting compounds listed in Table.  17 and 18, the same reaction as in Example 15 gave the compounds indicated in the same tables, Pr and meper17.  The acylation reaction wire in the same manner as in Example 13- (1) gives 7-f2 (2-chloroacetamidothiazol-4-sh1) acetamido-3- (3-chloro-1,2,4-triazolyl) methyl -cephem-A-carboxylic acid with t. square  120-122 ° C (with decomp. ).   IR spectrum (KBG), cm: 9cc 1775, 1710, 1680, 1650.  .   NMR spectrum (. d-DMCO ;, mln.  fractions: 3.43 (2H, s,), 3.60 (2H, s, T) 4.32 (2H, s, CfCH. , -), 5.09 b-.   , (1H, g, Hz-, Cft-H), 5.05 (2H,; -SN ABk,. 5 Hz, J.  ) 5.68 (1H, J 5 Hz, J 8 Hz, Cp-H), 6.97 (1H, s, /), 8.03 (1H, s, NS H –H), 8.95. (1H, g, Hz, -CONH-) EXAMPLE 18.  (one).  3.15 g of 2- (2-tert.) Is dissolved in 16 ml of N, Ndimethylacetamide. -amyloxycarboxamidothiazol-4 yl) -2- (syn) -methoxyiminoacetic acid, lio 1.69 g of phosphorus oxychloride are added dropwise with the resulting mixture stirred at this temperature for 1 h, and then dropwise into the solution add at. (-ZO) - (-. 20) ° C 3.16 g 7-amino-3-1 (3-chloro-. 1,2,4-triazolyl) methyl de cephem 4-carboxylic acid and 6.1. N, 0-bis (trimethylsilyl) acetamide in 32 ml of anhydrous methyl chloride on.  After adding dropwise, it is allowed to react at this temperature for 1 hour, then at-10 ° C for half an hour and then at room temperature for one hour. sa  After completion of the reaction, methylene chloride is distilled off under reduced pressure, and the resulting residue is introduced into a mixture of solvents from 80 ml of water and 100 ml of ethyl acetate.  The organic layer is separated, 80 ml of water are added and then the pH is adjusted to 7.0 with sodium bicarbonate.  The aqueous layer was separated and 80 ml of ethyl acetate was added, after which the pH was adjusted to 1.5 with hydrochloric acid with ice-cooling.  The organic layer is separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate.  The solvent is then removed by distillation under reduced pressure.  Sulfuric ether is added to the residue, and the resulting crystals are filtered off.  5.62 g are obtained (yield 91.8%) (2-tert. -amyloxycarboxamidothiazole 4-yl) -2- (syn) methoxyiminoacetamido-3- (3-chloro, 2,4-triazolyl) methyl -L-cephem-4carboxylic acid with m. square  198-200 C (with decomp. ).  IR spectrum (KBG), cm :-), 1720, 1670.  .  . NMR spectrum (d-DMCG), ppm fractions: 0.89 (3H, T, Hz,, CH3 1.44 (6 N, s, -C-), 1.78 (2H, q: Hz,,), 3.45 (2H, wide s, CjH), 3.87 (ZN, s, -OSNz), 4.96-5.40 (ZN, m, J Sb-N-), 5.82 (1H, gg, Hz, Hz, Su-N) , 7.24 (1H, S,. 1ГN / Ч), 8.02 (1Н, s, -Н), S Н Ь1 9.61 (1Н, g, Hz, -CONH-), 11.79 (1Н, broad with, -CONH-).  (2).  5.62 g (2-tert.) Is dissolved in 30 ml of trifluoroacetic acid. Amyloxycarbox1 Odothiazol-4-Sh1) -2 (syn) methoxyiminoacetamido-3- (3 chloro-1, 2,4-triazolyl) mets1-L-cefem-4-carboxylic acid, obtained in part (1), and the reaction is carried out at room temperature within 30 min.  After completion of the reaction, the solvent is distilled off under reduced pressure.  Sulfuric ether is added to the residue, the resulting crystals are filtered, washed thoroughly with ether and dried, resulting in 5.23 g (yield 93.1%) of a trifluoroacetic acid salt (2-aminothiazol-4-yl) -2- (syn ) -methoxyiminoacetamido3-3- (3-chloro-1,2,4-triazolyl) methyl-D-cephem-4-carboxylic acid with T. Ш1.   (with ).  IR spectrum (KBG): 1778, 1715, 1670, 1630.  NMC spectrum. (dg-DMCO) m. fractions: 3.48 (2H, broad s,), 3.93 (ZN, C, -OCH -), 4.98-5.42 (ZN, m, CH2C -H), 5.78 (1H.  gg, Hz, Hz,), 6.91 (1H, p.  x) | 3.02 (1H.  with,. , W, 9.74 OH 1 (1H, g, -CONH-).    Example 19 eleven).  3.15 g of 2- (2-tert.) Is dissolved in 40 ml of anhydrous methylene chloride. -amyloxycarboxamidothiazol-4-yl) -2- (syn) methoxy-iminoacetic acid and 1, Q6 g of N-methylmorpholine is added, followed by. the reaction mixture is cooled to -35 ° C. Then, 1.12 g of ethyl chlorocarbonate is added to the mixture, and the resulting mixture is reacted at (-35) (-25) ° C for 1.5 hours.  4.62 g of 7-amino-3- 2- (5-methyl-1, 2,3,4-tetrazolyl) methyl-D cephem-4-carboxylic acid 4.62 g of diphenylmethyl ester was added to the reaction mixture, and the reaction was carried out at ( -30) - (-20) C for 1 hour  Then the temperature is slowly raised and the reaction is additionally carried out at room temperature for 3 hours.  After completion of the reaction, the solvent was distilled off under reduced pressure.  50 ml of ethyl acetate and 40 ml of water are added to the residue.  dissolve it.  The organic layer is separated, 40 ml of water are added again and the pH is adjusted to 1.5 by the addition of two-normal hydrochloric acid and with ice-cooling.  Then organic.  the layer is separated and 40 ml of water is added, and the pH is adjusted to 7.0 with sodium bicarbonate with ice cooling.  The organic layer is separated and dried over anhydrous magnesium sulphate, after which the solvent is distilled off under reduced pressure.  Sulfuric ether is added to the residue, and the resulting crystals are filtered off, giving 7.06 g (yield 93.0%) of diphenyl methyl ether (2-tert.). -amyloxycarboxamidothiazol-4-yl) -2- (syn) methoxyiminoacetamido3 (5-methyl 1. , 2,3,4-tetrazolyl) methyl -D-cephem-4 carboxylic acid having m. square  94-99 0 (with decomp. ). .  -, IR spectrum (KBG).  CM j-Oc-o 790, 1725, 1685,.  NM1-spectrum (dg-DMCO), million  fractions: 0.87 (3N, t, Hz, -CH-SNL, 1.44; (6H, s, -C-), 1.75 (2H, q, Hz, -CH3, CH,), 2, 4 (ZN, s,) SNZ), 3, (2H, broad s, Cg-H), 3.81 (ZN, s, -IR,), 5.15 (1H, g, Hz,).  5.47 (2H, broad s, J), 5.87 v / rio (1H, gg, Hz, Hz,), 6.84 (1H, s, CH-), 6.93-7.52 (11H , m, gd 2, Ch.  ), 9.61 (1H, g, Hz, - LH-CONH-), 1-1.66 (. 1H, broad with, -CONH-).  (2).  The compound obtained in part (1) was reacted and treated in the same manner as in Example 12- (2) to give 5.07 g (91.9% of vodsod) trifluoroacetic acid salt (2-aminothiazol-4-yl) - 2 (syn) -methoxyiminoacetamido H-2 (5-methyl-1,2,3,4-tetraz olyl) methyl L-cephem-4-carboxylic acid with m. square  123-125 C (with diff. ).  IR spectrum (KBG) About. 1720, 1635.    NMR spectrum (CD ,, OD), million shares: —N-yCHj), 2.45 (AH ,. 3.44 (2H, broad s,), 3.99- (3N, s, -OCH), 5.10. (1H, g, Hz, Cg-H), 5.50, S-.   .  : 5.81 (2H, ABc, Hz,.   5.80 (1H, g, Hz,), 6.93 X (1K, s, D).  (3) The compound obtained above in part (2) is reacted and treated in the same manner as in Example 12- (3) to give (2-amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetamido-3- (2 - (5-methyl-1,2,3,4-tetrazolyl) methyl-D-cephem-4-sodium carboxylate with m. square  183-187 0 (with diff. ).   .  - IR spectrum (KBg), (, 1760, 665 1610.  JR spectrum (d -DMCO) -DgO), mln.  to 2, 50 (ZN, s, SNZ). 3.30 (2H, broad s,), 3.91 (ЗН, с, -ОСН. ), 5.12 (1H, g, J. -5 Hz, (Cg-H), 5.66 (2H, broad s, 1) 5.74 (1H, g, Hz.   , l) Su-H), -6.83 (1H, s). In a similar way, (2-aminothiazol-4-yl) -2- (syn) methoxy-imino-acetamido-3- (3-chloro-1,2) is obtained. 4-three azolyl) methyl-e-cephem-4-sodium carboxylate with m. square  168 ° C (with decomp. ).  .  IR spectrum (KBG), cm: S.   1670, 1605.  NMR spectrum (DjO), ppm  shares; 3.30 (2H, broad s,), 3.97 (ZN, s, -ISHI), 4.93-5.60 (ZN, m, SN, Sat-H), 5.77 (1H, g Hz -g.  C, -H), / 6.91.  (1H, s), 7.96 OH ,. c, /) - W example 20.  6.13 g of trifluoroacetic acid salt (2 aminothiazol-4yl) -2- (syn) methoxyiminoacetamido 3- (3-chloro-1,2,4-triazolyl) -methacem-4-carboxylic acid are suspended in 25 ml of water. , and sodium bicarbonate is added to the resulting suspension while cooling with ice, the pH of the suspension is adjusted to 8.0, turning the suspension into a solution.  The pH is then adjusted to 2.5 with concentrated hydrochloric acid at the same temperature with the indicated sample, as a result of which the crystals precipitate.  The crystals are filtered off, washed thoroughly with water, then with acetone, and dried. To obtain 4.71 g (yield, 94.9%) (2-aminothiazol-4-yl) -2- (syn) methoxy-imino-acetamido-3- (3-chloro) -1,2,4triazolyl) methyl -A-cephemcarboxylic acid with m. square  at least .  IR spectrum (KBG), cm:, 1660, 1625-.  NMR spectrum  (dg-DMCO) m. shares: 3.44 (2H, broad s, Cg-H), 3.85 (ZN, s, -OS%), 5.20 (2H, broad s, T), 5.20 (1H, g, Hz , C, -H) 5.78 (1K, gg, Hz, Hz, C, -H), ЖА7.16 (2H, broad6, 71 (1H, s, SH cue s, -NH,), 8, 04 (1H, -1S3: 9.60 (W, g, Hz, -CONH-).  In a similar way, (2-aminothiazol-4-yl) -2- (syn) -, g, methoxyiminoacetamido-3-2- (5-methyl1,. 2,3,4-tetrazolsh1) methyl-4z-cephem-carboxylic acid, with t. square  above 200 ° C.  .   765, IR spectrum (KBG), see 1660, 1625.  . , PRI me R 21.  Carried out the reaction and. In a similar manner as in Example 18- (1) or 19- (1), compounds obtained in Table 1 are obtained.  nineteen.  PRI me R 22.  By performing the reaction and treatment in the same manner as in Example 18 or 19, the compounds listed in Table 2 are obtained.  20 and table 21.  .  PRI me R 23.  (one).  3.70 g of 2-C2- (benzyloxycarboxamido) -5-chlorothiazol-4-yl -2- (syn) - is dissolved in 50 ml of anhydrous methylene chloride.  methoxyiminoacetic acid. ay, and.  1.06 g of N-methylmorpholine is added to the solution.  The reaction mixture is cooled to, then 1.12 g of ethyl chlorocarbonate is added, and the resulting mixture is reacted at (-30) (-20) C for 2 hours.  A solution of 4.37 g of 7-amino-3-acetamidomethyl-β-cephem-4-carboxylic acid diphenylmethyl ester in 50 ml of anhydrous chloroform is then added dropwise.  The resulting mixture is reacted at (-20) (-10) ° C for 1 hour and then at room temperature for 3 hours.  After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 50 ml of ethyl acetate and 40 ml of water, after which the organic layer was separated.  Again, 40 ml of water is added to the organic layer and the pH is adjusted to.  1.5 g of hydrochloric acid under ice cooling.  The organic layer is separated and dried over anhydrous magnesium sulphate.  The solvent was distilled off under reduced pressure, and sulfuric ether was added to the residue.  The resulting crystals are filtered.  The result is 6.50 g (yield 82.4%) of (2-benzyloxycarboxyamido) 5-chlorothiazol-4-yl) -2- (syn) methoxyiminoacetamido -3-acetamidomethyl-acetamidomethyl-diphenylmethyl ester (3-benzyloxycarboxyamido) ester). - cephem-4-carboxylic acid with t. square  132-136 ° C (with decomp. ).   . . .  IR Spectrum (KBG), cm: 1720, -1680-1640.   ; NMR spectrum (dg-DMCO), ppm fractions: 1.85 (ZN, s,,), 3.51 (2H, broad s,), 3.71-4.35 (2H, m, (, J3.89 (ZN, s, -IR, ), 5.14 (1H, g, Hz, Cg-H), 5.21 (2H, s, (.  dd, Hz,: CH-), 6.98-7.67 Su-H) 6.88 O) X 3), 7.78-8.21 (16 G,, -NHCO-), 9.69 ( 1H, g, Hz (1H, m-CONH-).   .  (2).  0.79 g of G2- (benzyloxycarboxamido) -5-chloro-diphenylmethyl ester is dissolved in 15 ml of anisole. azol-4-yl-2- (syn) methoxyimino-acetamido-T-3-acetamidomethyl-cepham 4-carb, onoic acid, and 1.33 g of aluminum chloride was added to the resulting solution under ice-cooling.  The mixture obtained reacts at 5–10 ° C for 2 h.  After completion of the reaction, the reaction mixture is added to 30 ml of ice water and the pH is adjusted to 7.5 by adding sodium bicarbonate.  The solution is separated by filtration.  The filtrate was washed with 30 ml of ethyl acetate and 50 ml of methyl ethyl ketone was added, after which the pH was adjusted to 2.0 with normal hydrochloric acid.  The organic layer is separated, washed with 30 ml of a saturated aqueous solution of NaCl chloride and dried over anhydrous magnesium fate.  The solvent was distilled off under reduced pressure, and sulfuric ether was added to the residue.  The resulting crystals are filtered, resulting in a gain of 0.37 g (yield 75, 7%) (2-amino-5-chloro-thiazole-4-yl) -2- (syn) methoxyiminoacetam-g to -3-acetamidomethyl -cepheme-4-carboxylic acid with t. square  148-152s (with decomp. ).  IR spectrum (KBG), cm: 1710, 1680-1620.  NMR spectrum (d-DMCO), ppm, fractions: 1.83 (3N, s, –COSNe), 3.42 (2H, broad).  cue c, Cj-H), 3.84 (MN, s, -OCH),.  .   , S, 3.70-4.22 (2H, m,. one , ),. 5.02.  (1H, g, Hz ,.  ), 5.67 (1H, g, Hz,), 7.85-8.21 (1H, m, -NHCO-), 9.46 (1H, g, Hz, -CONH-).  .  P p and I p24 (1).  Repeat the procedure of the reaction and treatment, similar to example 19- (1) and (2), except that be-.  Route 2- (thiazol-4-yl) -2- (syn) -methoxyiminoacetic acid instead of 2- (2 tert. -amyloxycarboxamidothiazol-4yl) -2- (syn) methoxyiminoacetic acid.  The result is the compounds listed in Table.  22 and 23.  Note eper 25.  (one).  In 30 ml of N, K-dimethylformamide, 6.13 g (2-tert. -amyloxycarboxamidothiazol-4-yl) -2- (syn) methoxyiminoacetamido-3- | (3-chloro, 2,4-triazolyl) methyl-L-cefem-4carbonic acid. acid, and 2.9 pivaloyloxymethyl iodide and 1 g of triethylamine are added to the resulting solution while cooling with ice.  The resulting mixture is reacted for 30 minutes.  After completion of the reaction, the reaction mixture was introduced into a mixed solvent of 300 ml of water and 300 ml of ethyl acetate, and the pH was adjusted to 7.0 by the addition of sodium bicarbonate.  Then the organic layer was separated by 1 {) t, washed successively with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate.  The solvent is then distilled off under reduced pressure.  Diisopropyl ether is added to the residue, and the resulting crystals are filtered, washed thoroughly with diisopropyl ether and dried.  6.6 g (yield 90.8%) of 7- 2- (2-tert4-amyloxycarboxamidothiaool-4-yl) -2 (syn) -methoxyiminoacetamido - (3-chloro-1, 2,4-triaolol) -methyl-1-u pivaloyloxymethyl ester are obtained. cepheme-4-carboxylic acid.  IR spectrum (KBG), cm, 1720, 1675.  NMR spectrum (MDCZj), ppm fractions: 0.96 (3N, t, Hz,), 1.30 31 s, -C (CH,),), 1.57 (6H, s, -C-), 1.91 (2H, k, Hz, -CHjCH (2H, broad-c, Cj-H), 4.02 4.89-5.34 (ЗН, m.  (ZN, s, -ASH,) SS SI RB, 70-6.2 7 | (ZN, N-JС-H), 7.14 (1H, s, VSJ, 7.90, 9.31 (1H, g, -CONH-).  (2).  In 33 ml of trifluoroacetic acid are dissolved 6.6 g of pivalos of simethyl ether (2-tert. amyloxycarboxamidothiazol-4-yl) -2 (syn) -metrxyiminoacetamido-3 (3-chloro-1,2,4-triazolyl) -methyl - &amp; cephem-4-carboxylic acid, and the resulting mixture is reacted at room temperature for half an hour.  After completion of the reaction, the solvent was distilled off under reduced pressure, and 80 ml of water and 80 ml of ethyl acetate were added to the residue, after which the pH of the resulting solution was adjusted.  to 7.0 with sodium bicarbonate under ice cooling.  The organic layer is separated, dried over anhydrous magnesium sulphate and a solution of dry hydrogen chloride in sulfuric ether is added under ice-cooling.  In the precipitate, laundry powder is precipitated.  The latter is filtered off, washed thoroughly with sulfuric ether and dried.  5.2 g are obtained (yield 88.2 pivoyloxymethyl ester hydrochloride 7-. 2- (2-aminothiazol-4-yl) -2 (syn) methoxyiminoacetamido -3t (3-chloro-1,2,4-triaz olyl) methyl - &amp; cephem-4-carboxylic acid with t. square  134-136 with (with decomp. ).  IR spectrum (KVg).  cm 1755, 1680.    NMR spectrum (dg-DMCO), ppm Shares of 1.17 (9H, s, -C (CH3),), 3.49 (2H, broad s, Cj-H), 3.93 (MN, s, -OCH,), 4.95-5, 40 (ЗН, m, I - ÑÑÑ-H), 5.60-6.02 (ЗН, m, -СООСН -, 1Н, s, сГЛт)), 6.91 (11 S Н 179 7 (1Н, s ,  8.83 (1H, g, -CONH-).  Example 26  3.7 g of phosphorus oxychloride are added to a mixed solvent consisting of 8 ml of anhydrous methylene chloride and 2.2 ml of N, N-dimethyl acetamide at 0-5 ° C, and then the mixture is subjected to reaction at the same temperature for 30 minutes .  The reaction mixture is then cooled to (-15) (-10) C and 2.4 g of 2- (2-aminothiazol-2-yl) -2- (syn) methoxyiminoacetic acid are added, and the resulting mixture is reacted with same temperature for 20 min.  A solution of 4.47 g of 7-amino-3-2- (5-methyl-1,2,3,4-tetrazolyl) methyl-L-cephaem-4 pivoyloxymethyl ester hydrochloride was added dropwise to the reaction mixture at -10 ° C. -carboxylic acid and 1.01 g of triethylamine in 20 ml of anhydrous methylene chloride.  After dripping, the mixture reacts for 30 minutes, for 30 minutes and then for 30 minutes at room temperature.  After completion of the reaction, the solvent was distilled off under reduced pressure, and 50 ml of water and 50 ml of ethyl acetate were added to the residue, after which the pH was adjusted to 7.0 with sodium bicarbonate.  The organic layer is separated, washed successively with 30 ml of water and 30 ml of total (aqueous sodium chloride solution and dried over anhydrous magnesium sulphate.  The solvent was distilled off under reduced pressure, and sulfuric ether was added to the residue.  The resulting crystals are collected by filtration.  The result of 5.1 g (yield 86%) pivaloxymethyl ether (2-aminothiazol-4-yl) -2 (syn) methoxyiminoacetamido 1-31 2- (5-methyl-1,2,3,4-tetrazolyl) methyl - cephaem-4-carboxylic acid with m. square 127-128 ° C (with decomp. ).  IR spectrum (KBG),, 17JO, 743, 16757.  .  PRI me R 27.  Carried out the reaction according to example 14 or 15 and using as starting compounds the compounds listed in table. . 24–27, the corresponding compounds are obtained, indicated in the same tables.  PRI me R 28.  The reaction and the treatment is carried out. in the same manner as in Example 25- (1), to give the compound indicated in Table.  28  Example 29  A solution of 2.5 g of mesitytylene sulfoxylate cytohydrate in 20 ml of ethyl acetate was added to a solution of 5.93 g of pivaloyloxymethyl ester (2-aminothiazol-4-yl) -2 (syn) methoxyiminoacetamido 1-3 2- (5-methyl-1,2 , 3,4-tetrazolyl) methi D-cepheme-4-carboxylic acid in 50 ethyl acetate.  The precipitated crystals are filtered off, washed with ethyl acetate and dried to obtain 7.39 (yield 93.2%) mesitylenesulfonic acid salts and pivaloyloxymethyl ester (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamide-3 2 ( 5-methyl-1,2,3,4-tetrazole) methyl 1 z-cephem-4-carboxylic acid with m.  218-2200s (with decomp. ).   - - 1782 IR spectrum (KBG), cm 1745, 1680.   .  NMR spectrum (), mln. the proportion of 1.15 (9H, s, -C (CH) s), 2.14 (GH, 2.43 (GH, s, /), 2, CH3 (6H, s, - (O), 52 (2H , broad C2-H), 3.93 (ZN, s, -OCH), 5.20 (1H, g, Hz,), 5.56 (2H, broad c ,. J -,). 5.78 (1H, gg, LH-i.   Hz, Hz, Su-N), 5 ,. 85 (2H, s, -COOCH, jO-), 6.50 (3N, broad s), 6.93 6.75 (2H, s,.      8 J o ti -CONH-).  PRI eri 30.  (one).  In 5 ml of N, N dimethylacetamide, dissolve 2.4 g of 2- (2-formamidothiazol-4-yl) -2- (syn) methoxyiminoacetic acid and in the obtained mixture at (-lO) - (-50) C 1.7 g of phosphorus oxychloride are added dropwise, after which the resulting 734.   the mixture reacts at (-5) - (0) C for 1 h.  On the other hand, 5 g of oxalic acid salt and 7-amino-3 2- (5-methyl-1,2,3,4-tetrazolyl) methyl-L-cephem-4-carboxylic acid pavaloyloxymethyl ester are suspended in 35 ml of ethyl acetate and 1.01 g of triethylamine are added to the resulting suspension at -30 °.  To the mixture is added.  .  drops of the previously obtained reaction mixture at - (- 30) - (-20) 0, and the mixture reacts at the same temperature for 1 hour.  After completion of the reaction, 12 nl of water was added to the reaction mixture and the organic layer was separated.  Then to it, 12 ml of water are added and the mixture is adjusted to pH 4.0 with sodium bicarbonate.  The organic layer is separated and dried over anhydrous magnesium sulphate, after which the solvent is distilled off under reduced pressure.  Sulfuric ether was added to the residue, the crystals were filtered off and 65 g (91% yield) of pivaloyloxymethyl ether (2-formamidothiazol-4-yl) -2- (syn) -methoxyimine hydrochloride D (5-methyl-1, 2,3,4) was obtained. -tetrazolyl) methyl -AZ-cephem-4-carboxylic acid with t. square  132-135 C.  IR spectrum (KBG) (.  P85, 1752, 1600. .    .   NMR spectrum (d-DMCO), million fractions: 1.20 (9H, s, -C (CH3) e), 2.51 (3N, s,), 3.61 (2H, broad with,), 3.97 (3N, s, -OCHj) , 5.38 (1H, d, J 5 Hz, Cg-H), 5.77 (2H, broad s, CH2-) 6.05 (2H, s, -OCH20-), 6.11 (1H, gg , Hz, Hz, Su-H), 7.60 hgH-1 (1H, s, A 8. 73 (1H, c, l | S H O 10.00 (1H, g, J-8 Hz, -CONH-), 12.63 (1H, broad s, C. ONH).  In the same way, the following compounds can be obtained: 1-Pivapoyloxyethyl ester (2-formamidothiazol-4-yl) -2- (syn) methoxyiminoacetamido3-3- (3-chloro, 2,4-triazolyl) methyl-L-cephem-4carboxylic acid (recrystallized from methanol).  T. square  151-154 p.  . IR spectrum (KBG), cm 1745, 1680.  NMR spectrum (dg-DMCO), ppm shares: 1. 17 (9H, s ,. -CCCH),), 1.53 (ZN, d -CH-) Hz, I), 3.50 (2H, Shkrokirs Shz S, -H), 3.90 (ZN, s, -OCHj), 4, 93-5,  sx.  .  .  (3N, m, Cg-H) I), 5.92 (1H, dd.   .  , Hz, Hz,), 6.83-7.08 TG h (1H, m, -CH-), 7.40 (1H, s.  CH, .  S H Nv.  8.04 (1H, s / V-H), 8.50 (. 1H, c) PM | : 9.75 (1I, d, Hz, -CONH-) О. . . .  .  .  ; -.  .   12.64 (1H, broad s, -CONH-).  1-Pivaloyloxyethyl, (2-formamidothiazol-4-yl) -2 (syn) -methoxyiminoacetamido-3-2 (5-methyl-1,2,3,4-tetrazolyl) methyl D-cephem-4-car ether. boned acids (recrystallized from methanol).  T. square  203-205 s (with decomp. ).  IR spectrum (KBG),:. . .  .  1750, 1680.   NMR spectrum (a, -PMSO) million shares: 1. 18 (9H, s, -C (SNrz), T, 53 (3N, d,. .  N.   Hz, - with Н -), 2, 50 (ЗН, с.  - ch sns.  .  N 3.71 (2H, broad singlet,), 4.00 (3N, s, –OCH3), - 5.35 (1H, d, Hz, Cg-H), 5.6. 8 (2H, broad with, :: -:. -: / I), 6.02. (1H, dd, Hz, J Hg - P2.  .  9 Hz, Su-H), 7.08 (in, m, -CH.  ), Nn,. SNE 7.58 (1H, s, 1), 8.70 (1H,. c, ng S H-.  .  V-y, 9.99 C1H, d, Hz, -CONH1270 (1H, broad s, -CONH-).  (2).  66 ml of methanol suspension.  are 6.55 I 1-pivaloyloxyethyl.  ether (2-formamidothiazol-4-yl 2- (syn. a) methoxyimino acetamido 1-3 (3-hl6p-1,2,4-triazolyl) methyl -A cephem-4-carboxy 6th acid and while cooling with ice, 4.2 ml of 12 N are added to the mixture  hydrochloric acid, after which the reaction mixture reacts n 5-10.  C for 2 hours  After the reaction was completed, the reaction mixture was introduced 736 in 660 ml of water.  The pH of the mixture is then adjusted to 5.0 with sodium bicarbonate, and the precipitated crystals are collected by filtration, and 5.73 g (91.4% codec) of 1-pivaloyloxyethyl ether (2-aminothiazol-4-yl) -2- (syn) methoxy -.  iminoacetamido-3- (3-chloro-1,2,4triazolyl) -methyl - &amp; -cepheme-4-carboxylic acid with T. square  145-147C.  Analogs. By the following method, the following compounds were prepared: (2-Aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido-3-2- (5-methyl-1, 4 tetrazolyl) methyl-L-cephem-4-carboxylated acid pivaloyloxymethyl ester .  T. square  127-128 С (with diff. ).  7-12 (2-aminothiazol-4-yl) -2- (syn) -methoxy 1-pivaloyloxyethyl ether. iminoacetamido-3- 2- (5-methyl-1,2, 3,4-tetrazolyl-L3-4-carboxylic acid.  T. square  127-130 ° C (with decomp. ).  The physical properties (IR and NMR) of these compounds are identical to those of the product obtained in Example 27.   Example 31.  (one).  In the same way as in example 14; or 15, 7- (2- (2-aminothiazol-4-yl) -2- (syn) ethoxyiminoacetamido-3-2- (5-methyl1, 2,3,4-tetrazole) methyl-U- cephem-4carboxylic acid.  T. square  99-102 0 (with diff. ).   .  .  IR spectrum (KBG) cm: - с-о 1-785, 1745, 1675,. 1615.  (2).  According to the method described in example 18 ,.  a salt of mesitylenesulfonic acid and pivaloyloxymethyl ester of (2-aminothiazol-4-yl) -2 (syn) -ethoxyiminoacetamido -3-2- (5-methyl-1,2,3,4- tetrazolyl) methyl - &amp; cephem-4-carboxylic acid.  T. square 190 ° C.  .  IR spectrum (KBG), about 1780, 174. 5, 1680.    .  Example 32  Under the same conditions as in the examples. 12-31, the following target compounds are obtained: Trifluoroacetic acid salt of (2-aminothiazol-4-yl) -2- (syn) -oximinoacetamido3-3- 2- (5-methyl-1,2,3, 4-tetrazolyl) methylZ y-cephem-4-carboxylic acid, T. square  175 C (with decomp. ).  IR spectrum (KBG), 1770 1680, 1630.  Trifluoroacetic acid salt 7- 2 (2-aminothiazol-4-yl) -2- (syn) -ok, syminoacetamido-3-benzyl-L-cephem-4carboxylic acid, t. square  139 ° C (with decomp. ).  IR spectrum (KBG), cm: -) с-о 1760 1710, 1660.  .  . The chlorophenol pivaloyloxymethyl ester of (2-aminothiazol-4-yl) -2 (syn) -oximoacetamido-3-L2 (5-methyl-1,2,3,4-tetrazolyl) methyl-1-cepheme-4-carboxylic acid, t. square  142-145 ° C (with decomp. ).  CC spectrum (KBG), - 1785 1750, 1675. .  ,; 7- 2- (2-Phenylaminothiazol-4-yl) acetamido-3-2- (5-methyl-1,2,3,4-tetrazolyl) methyl1. fem-4-carbono L wa acid, t. square  t65-169С.  (with ).   .  IR spectrum (KBG), cm, 1660, 1625.  .  PRI me R 33.  In accordance with the indicated recipe, the main component is pre-mixed and ground with milk sugar. An aqueous solution of hydroxypropylcellulose is added to the mixture.  The resulting mixture is kneaded j dried and powdered.  The powder is mixed with magnesium stearate pre-grinded with starch, and then the mixture is tableted.  The recipe contains the following components, mg:.  Pivaloyloxymethyl ester hydrochloride (2-aminothiazol-4-yl) -2 (snn) -methoxyiminoacetamido-3-2, - (5-methyl-1. 2,3,4 tetrazolyl) methyl-e3-cephem-carboxylic acid 1 30 Milk sugar. 20 Starch -44.  Hydroxypropylcellulose 5,4 Magnesium stearate 2 00 mg / tablet Similarly, tablets can be prepared by using other compounds instead of the active compound.  Example 34  In accordance with the above recipe, part of the starch and magnesium stearate are mixed and ground in a mortar, and the resulting powder is mixed with the residual amount of starch, hydroxypropyl cellulose, the main component.  The resultant mixture is formed into capsules using a standard dropping method.  The recipe has. The following composition, mg: (2-Aminothiazol-4-yl) pivaloyloxymethyl ester (2-aminothiazol-4-yl) -2 (syn) methoxyiminoacetamido-3- 2- (5-methyl-1,2,3,4-.  Tetrazrilyl) methyl- - &amp; C-cefem-4-carboxylic acid 136 Starch. 54 Hydroxypropylcellulose6 Magnesium stearate 4,200 mg / cap of sulfur Used instead of the indicated in.  Other compounds in a similar manner receive capsules.  Primer p. 35  In accordance with the given recipe, the main component is pre-mixed and ground in a mortar with milk sugars.  To the mixture is added an aqueous solution of hypropyzell oz.  The resulting mixture is kneaded, dried and powdered.  The powder is mixed with the magician stearate, pre-rubbed with the starch, and then the mixture is tabulated.    A formulation of the following composition is prepared, mg: Mesitylenesulfonic acid salt and pivaloyloxymethyl ester of 7-G2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido -Z2- (5-methyl-1,2,3, 4-tetrazolyl) methyl -U-cephem-4carboxylic acid 130 Milk sugar.  44 Oxypropylcellu poza 5.4 Magnesium stearate.  0.6 - 200 mg / tab. Instead of the indicated other compounds, tablets are obtained in a similar way.   PRI m 36.  Following this chain, a portion of the starch and rot stearate are mixed and ground to the mortar, and the resulting powder is then mixed with the remaining amount of ahmala, hydroxypropylcellulose and the main component.  The resulting mixture is molded in the form of capsules using a standard encapsulation method.  The following formulation is prepared, mg Mesitylenesulfonic-salt.  .  lots and pivaloyloxymethyl ester (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido-3 2- (5-methyl-1,2,3,4-tetrazolyl) methyl-D-cephem-4carboxylic acid 136 Starch 54

Hydroxypropylcellulose 6 Magnesium Stearate, 4

200 mg /

. /capsule

Using other compounds instead of this, in a similar manner, other encapsulated formulations are prepared. Example37. A mixture of sodium bicarbonate with (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido1-3 2- (5-methyl-1,2,3,4-tetrazolyl) metiJJ- 25

g 3-cephem-4-carboxylic acid is treated in a standard way, freeze-dried and sterilized sodium salt. 1 g (activity) of the sodium salt is dissolved in 20 ml of physiological saline solution, receiving an injection.

EXAMPLE 38 1 g (activity) of the freeze-dried product prepared in Example 37 was dissolved in 4 ml of a 0.5% (w / v) aqueous solution of lignocaine hydrochloride to give a diluted injection.

Example 39. 1 g (activity) of the freeze-dried product obtained in Preparation 5 is dissolved in 20 mp of 5% glucose solution, receiving an injection.

In addition, other proposed compounds (free carboxylic acids) of Formula 1 can also be molded into appropriate freeze-dried products (sodium salts) or injections by methods similar to those described in Examples 37-39.

43

-t-a-sot itg

ns1.click, R

 J

44

1190987. Table 2

COOR G.PPN

SNS

Test compound

N

H - VC-CONH,,,

Ty

 II1 N.j

Si

PG.N.SUN

OSSN

(SYN)

N

H.C-CO.H-j

S ,,,,

OSSEC. N C1

(SYN)

 0 -f CHzl HCOH

BF, -

Butyronitrile

2-Methylbutyronitrsht

3-Ethoxypropionitrile - Acrylonitrile

Cyanoacetic acid

Benzyl cyanide

 EtgO

Ethyl cyanoacetate

Chloroacetonitrile

Continuation of the table.Z LD ,, g / kg

oh oh

SNS

Table4

,ten

soon

1795, 1635,

168-170 (decomp.) 1610, 1520

1795.1635

170-172 (decomp.)

1620,1530

1800,1640,

CH 173-175 (times.)

1610.1530

1800, 1650

165-167

(decomp.) 1615, 1,525

192-195

 (different)

SNOW); 85-19

- / (decomp.)

SN СООСН СН 185-190

1785, 1730 (decomp.) 1610, 1530

1790, 1650

185-190 (decomp.) 1610, 1520

. - complex of boron trifluoride and sulfuric ether. The reaction is carried out in acetonitrile.

 S,

Table3

; zi-if7--

II Tt.

  AI

 ;

CO

W: b

ca

.

P1 uni -Y

zy., j i

y

2

Z r

00

"four

about

to p) y. "Well

W O

oh cr and

Yu

fe. about

cvl,

cm

about

N

tNl

about; n) well f- n)

X

there about

there about

82

about ON

about

O (P

to

fe o

Uj

and

in

r I-

vO

(S

33 O

tvl

to about about about about

um

F

about

r "4 33 o

Ij

PQ I

LO I

cm g

CSJ

Ni

g

-NSJA

her j 3 g m m I

Oh choa Oh (N

lv

ate l ate

ON.

cJ "h (h

t;

ffi yes 10

i

SC CN

Q

/ h

Oh oh

f

about t

  l um

f LO about with

with; with

LO P)

h) oh

00 s; G-- from I l sh and g -

t- Pq

1-i

f

- with u “l

I F

NI

and h and n

lh.h

from l ja

co oo oo

3: 3

Ш Ш CN cm

u 1L az

1st I

 . V p in o

t; with

LO ce 04 ft

and about

LO o 00

 "BUT

 -h

W

, ac o

W “

l Z I W I -h et-i ate

 -ffi CJ

az

 IЮ

Hc1

 N. II and

K CJ Cf | - cvj

Lt-, h

cho

.about

ate io tz about

t II (L

about

Ш «1-э. l "N SHOWER LO

-- cm -

 Tij l

about

1g

"-SP Yu S iU

 Well I

D) l tl l

GO - Yu O

t;

to

you te

CS

i v

I w- (PSS

X u "t) and-ch-n

 May 33 N

In M I I ON about P vo I I and 1L "

"" I "to"

jj a SL SL M

m vo

UGG IG AG u-

from cm CN CNI

R

year of day yes sh oo I

cr

"H A" h Pk Fv

"- n n in and

goch

00СП

CNIo

gy

oo nj

but

S

with; u p) n

with

:five

I

сГ5.

about

U

eight

:ABOUT

Th

If

fO

cho

t

hch

CN

sch

§ with s o,

I

g

S I O Yu R.

Cvl.

§

I

sc rt S R. E- I

about P5 V, S about about

,

t-o

0) with.

h "tsp

 gnjCN

AND

SP CVJ 1L

-

 I ""

 Io.

m - gCN

about

ate about go go

about about cm T-vO sch - s;

with

"about

 "O o -ft ft.

rvl co

I .d

Kc;

0) about. X o

0 P) o m

I "

Yu

ShS ft S

I ft

oh I

about G.

P1-3S. " "4f

tJsch o m CN | CTi

(.

t -

“- -

-e-

About .R

Ts soon

.79-82

1770, 1720 (decomp.)

96-101

1770, 1720 (decomp.)

Table 9

soonn- 0.

CH

(W, S, CHC), 7.30 (YUN, O 2), 7.85,

S,

N

, S, ..., 07 (1H, S,

1H

i

-n)

1.82 (2H, bS, -NHg), 3.10 (2H, S, C2-H), 4.55 (W, d, J 5 Hz, Cg-H), 4.72 (1H, d, Hz, St-H), 4.70, 5., 33 (2H, ABq, Hz, 8

J)

6.93 (1H, bS, -CH), 7.30 (YUN, S O / X 2), 7.70

)

N /

2.33 (2H, bS, -NHg), 2.78, 3.21 (211, ABq Hz, CZ-H); 4.71 (1H, d, Hz, Cg-H), 4.90 (1H, d, Hz,), 5.32, 5.92 (2H, ABq, Hz, SX

).

pui6.86 (2H, S, -sne

X 2), 7.20 (20H, S, LO X 4), 8.11 (1H, S, N

-n)

M

XT XT 90 1770, 1720 - (decomp.)

SNS

-fsj- | v | 167-1681770, 1720

-J COOCH CH lSS ZrN80-841770, 1720

(different)

2.32 (3N, S, -CH,), 3.42 (2H, S, Cr-H), 4.70 (W,; d, Hz, C, -H), 4.85 (1H, d , Hz, Su-H), 4.90 (2H,

S, X) 6.90 (1H, 5, SI-) |

, 30 (YUN, S, - {O / 2b

N

7.85 (1H, S,

-n

N

1.35 (3N, t,), 2.97, 3.30 (2H, ABq, Hz, Cg-H) ,. 4.30 (2H, q, - SNgSNe), 4.60

(1H, d, Hz, 4.80 (1H, d, Hz, C7-H), 5.30, 5.80 (2H, ABq, Hz,

one ).

S

i, 93 (1H, S,

.

with%

: Ck-), 7.30 (UN, S,

O / x.2), 7.88 (1H, S,

one-

11 1

-n)

1.90 (2H, bS, -NHg), 2.50 (3N, S, -SCHg), 3.40 (2H, S, Cr-H), 4.65 (1H, d, Hz, Cg-H ), 4.80 (1H, d, Hz,), 4.85 (2H, S,

P2-6,85 (W, S, CH-), 7.27 (UN, S,

 2), 7.90 (1H, S,

N

-n)

N The compound is obtained by using and treating 4-carboxy-1,2,4 triazole as the starting compound according to the procedure of examples 4- (1) and (2).

para-Nitrobenzyl-114-116 7-amino- ester es (with decomp.), 2,4-triazolyl) methyl-A-cephem-4carboxylic acid

Ethyl ether 7-68-72

amino-3- 1- (1,2,4- (with decomp.) triazole 1) methyl iv-cefem-4-carboxylic acid

7-amino-3-G1- (1,2, 149 4-triazolyl) methyl - (with decomp.) A. -cepheme-4-carboxylic acid

Table 12

1170, 1708

1770, 1720

1790.4610, 1530

GP

P)

S ch y

here N

about

CV).

TS

g cd - D,

R)

P}

about.

TO

(ft

ffi

CJ

and about

and gss

oo

CV

 and

91

-SNOSS (SNZ) s

136-138 (decomp.)

SN

-SNOSS SNS

Go1 °

—Shosh

BUT, oh

-snoso-chn I 11

SNZO

- by hand. with

0x alat

1190987

92 Table 14

1810, 1780, 17AO

. . 1790, 1720

1775, 1735

1780, 1752

1782, 1770

sh

(ABOUT

tr

s with; Yu

with H

1L

oo

"I

.

cho

x

WITH

/ BUT

one

tn

tr

t-

vO

II l

lA

"

.0

since g

TO

with about

Mr. I

about g

Xi

0) OK

X (U

OH

eo

koS

Swo

y:

oen "

1) (flS S

q IS

Ssh

Hock

with "0) S

ooMas

rt tfi

K -K-K

l cf s with; you are se

about

Go Oh

Oh g o

ABOUT

00

g

h

m

in nj "- D.

r 1Л

cl

about

g

cho

ABOUT

in r r

About about go go

h vO

-about "

with; - with

SP I with

ev f d)

oh so about

with

3 y

four

c

but

. “Jz; vXiZ:

pz.

about g

vO

ABOUT

but

cho

about oh so

Mr. VO

W, - s

Cvl "

- with;

I o

- with

see D,

about g

cho

about

cho. cho

about

CHO city

g

-with;

Iр)

ChGGO

mU

F °°

Sc

ABOUT

about

vO

About vD vn

W vO

r

OO / -N

about

tg

oa

f cr about

 h: o

W: I

z: i

1L 4D

about

about 1

oh oh

OO CHO t-vD

 h

G- .

t s

tn tfl

r p

g °

V

0

F: f

about p

cho

O vO cho

about

what g

about

CN1

Vd

Oh

W o GLPl

WITH

CHO I- CHO GW (O

LO oh,

P

P)

TO

t y p) H C-COWi II, - TSS0 OSH

 cHiCH c-ocom; CHs

-NHCOCHj, ClCHj CONH-

Mr 190987 126 Tab s CH2 (syn-isoper) COOR

1780, 1710, 1640 9

94-1011775, l720, 1670

(different)

156-157 1780, -1745, (decomp.) 1680, 1655

about

Ovi

 H

Yu

to

EngkTrifluoroacetic acid

LtrsiN

|

,

-N-.

SI COOCH SNC

1665,

1630 1-770,

1665,

1630 1770,

 l1730,

  .Q

1630

-Nrr-N 1775,

) -N 1740,

 670,

1630

-N -: N.

-tPA

T СООСН7, СНз

1660,

1630 N1775,

-N Ji

V- / 1730,

/ - sooSnz

COOCHa

1630.

1660, 1630

.1775. 1665,

1630 1775,

1670, 1630

1770

R

1710., 1620

.

h 1710

1620

1770

COOR

1710, 1620 138 Table2G. 1- - PG: 1, O M ((c if 30biep) soon

u-i

CN

P)

Cf

s E;

YU

rt

H

155

 Trifluoroacetic acid hydrochloride salt

156

1190987 T a b l and c a 26

Claims (4)

1. The method of obtaining derivatives of cephalosporin General formula T. where a hydrogen atom or an ester-forming protecting group; - C ₂ -C ₆ ~ acylamino, possibly substituted by chlorine; benzoylamino group .; 2-furoylamino group; phenyl; P-hydroxyphenyl; 2-furyl or 2-thienyl, optionally substituted in position 5 by a rarboxy or carbomethoxy group; triazolyl, free or monosubstitiated specified triazolyl or. tetrazolyl is attached to the exomethylene group in the position. 3 defume rings through nitrogen - carbon bond; ... - hydrogen atom or chlorine; . 1C - a hydrogen atom or an amino group, - free or protected by an acyl protective group; A is methylene or a group of the general formula -cII N ^X OK5 where is a hydrogen atom or C 1-6 alkyl, in the form of the syn isomer, or their salts, characterized in that the compound of general formula II 511, „, 1190987 where K-, and kx have the indicated meanings, or its salt is subjected to interaction with the compound of General formula 14 1190987 Ν —L-A-COOH Haguach where Ε ^, Ε ^ and A have the indicated values, or with its reactive derivative of the carboxy group in a solvent at (-50) - (40) C followed by, if necessary, removing the protective group or the free carboxy group is protected as an ester, or the target compound is isolated in free form or as a salt. 2. The method according to p. 1, characterized in that they obtain the compounds of formula 1, where A is methylene .. 3. The method according to π. 1, characterized in that they obtain compounds of formula T, where A is a group of formula -with- II . N l ^h he is ₅ where 85 · “is a hydrogen atom or C, -C ^ -alkyl. ' 4. The method according to paragraphs. 2 and 3, characterized in that they obtain compounds of formula 1, where K. ₂ - 1,2,4 triazolyl or 2- (1,2,3,4-tetrazolyl), possibly respectively substituted. one