Derivatives dialkyldithiophosphoric or their pharmaceutically acceptable salts, antibacterial composition

 

(57) Abstract:

Usage: in medicine. The inventive product: derived dialkyldithiophosphoric f-crystals

< / BR>
where the acyl - lower allogenicity(lower)alkanoyl or group (II)

(II)

where R3Is H, OH, imino, or a group of f-crystals

< / BR>
where R4-H, a protective group, R5-H, lower alkylene, oxygen, NOR6; R6-H, a protective group, lower alkyl, lower alkenyl, lower cycloalkyl, carboxy(lower)alkyl or carboxy(lower)alkenyl; Het is pyridyl, thiadiazolyl, triazolyl or tetrazolyl; R1- simple bond or methylene; R2is methylene; X=S, Y=H. 2, S. p. f-crystals.

The present invention relates to new derivatives of cephalosporin, antibiotic compositions, which contain as an active ingredient the compound of the present invention, and methods for treating bacterial infections by introducing the subject of these compounds.

It is recognized that the cephalosporins are useful antibiotics of a wide antibacterial circle, and currently receive various derivatives of cyclosporine. However, due to the development of low-sensitivity or resistant bacteria necessary Sovershenstvovanie suitable antibiotics and synthesized many derivatives of cyclosporine, which in position 3 kernel cafema have a side chain of tirucalli, substituted heterocyclic group, and evaluated their antibacterial activity. The applicant has discovered that a certain class of such compounds has a strong bactericidal or antibacterial activity and shows a high blood level when administered orally.

Thus, the present invention provides a compound of formula I:

< / BR>
in which the acyl lower allogenicity(lower)alkanoyl, a group of the formula:

< / BR>
where R3hydrogen, hydroxy or perhaps a protected amino group, or a group of the formula:

< / BR>
where R4hydrogen or a protective group, R5two of hydrogen, lower alkylene, oxygen or the group NOR6(R6hydrogen, a protective group, lower alkyl, lower alkenyl, lower cycloalkyl, carboxy(lower)alkyl or carboxy(lower)alkenyl, and carboxypropyl may be protected),

Het pyridyl, thiadiazolyl, optionally substituted stands, triazolyl or tetrazolyl, R1simple bond or methylene, R2methylene, X is sulfur, and Y is hydrogen, or its pharmaceutically acceptable salt.

A method of obtaining a connection on p. 1, having formula II:

< / BR>
where the alphanumeric printer, characterized in that 1) the compound of formula III.

Although all of the compounds of formula I are suitable for the purposes of the present invention, there are several preferred compounds. Thus, particularly preferred are compounds in which R1denotes a single bond, Het represents 2-pyridyl, 1,2,3 - or 1,2,4-triazolyl, 1,2,3 - or 1,3,4-thiadiazolyl possibly replaced by stands.

For the purposes of the present invention such functional groups like carboxyl, and amino groups may be traditionally protected by appropriate protective groups commonly used in the field of cephalosporin antibiotics.

Carboxyamide group selected from those used in the art and which serve as locking carboxyl group when the reaction is carried out in other parts of the molecule. Such groups typically contain less than about 19 carbon atoms and bound to a carboxyl group reversible without affecting other parts of the molecule. Typical examples include the choice of substituted C1-C8-alkyl, for example methyl, methoxymethyl, ethyl, ethoxymethyl, iodomethyl, propyl, isopropyl, butyl, isobutyl, ethoxyethyl, methylthiophenyl, allyl, isoprenyl, hexenyl, phenylpropanal, dimethylhexane and so on; on the choice of substituted C7-C19- aralkyl, for example benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenylethyl, trityl, di-tert-butylhydroxyanisole, phthalidyl, phenacyl and so on; on the choice of substituted C6-C12- aryl, for example phenyl, toluyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl and so on; on the choice of substituted C1-C12- amino, which represents, for example, an ester with anatoxina, acetophenazine, acetaldoxime, N-hydroxysuccinimide, N-hydroxyphthalimide and so on; on the choice of substituted C3-C12-hydrocarbonization silyl, for example trimethylsilyl, dimethylsilane, dimethylethoxysilane, tert-butyldimethylsilyl and so on; on the choice of substituted C3-C12-hydrocarbonization of stannyl, such as tributylstannyl, and so on.

Other carboxyamide groups are pharmaceutically active astrobrowse group. Examples of such groups are 1-(kislorodozaschitny)-C2-C15is an alkyl group, for example remotemachine, branched, ring and oximeter, pivaloyloxymethyl, cyclohexaneacetic, cyclohexylcyclohexanes and so on;3-C15-alkoxycarbonylmethyl, such as ethoxycarbonylmethyl, isopropoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, tert-butoxycarbonylmethyl, isopentenyladenosine, cyclohexyloxycarbonyloxy, barilochekoristite and so on;2-C8-alkoxyalkyl, such as methoxymethyl, methoxyethyl and so on;4-C8-2-oxocyclohexyl, such as tetrahydropyranyl, tetrahydrofuranyl and so forth, substituted C8-C12-aralkyl, such as pencil, phthalidyl and so on;6-C12-aryl, for example phenyl, xylyl, indanyl and so on;2-C12alkenyl, for example allyl, isoprenyl, 2-oxo-1,3-dioxolan-4-yl-methyl and so on. Among the above compounds of the protective group to be used for blocking the carboxyl group while reactions are usually otscheplaut at the final stage of the reaction, and therefore, its structure is not essential. Therefore, as understood by the person skilled in the technical field, the protective group can be selected from a variety of equivalent groups, including amides, acid anhydrides, obrazovannym way.

Aminosidine group represents a1-C20-protective group conventional in the field of cephalosporin, which is being introduced and otscheplaut without exerting a negative impact on another part of the molecule. Typical examples of the group include1-C8-alkyl (tert-butyl, methoxymethyl, methoxyethoxymethyl, trichlorethyl, tetrahydropyranyl and so on), WITH7-C19-aralkyl (benzyl, methylbenzyl, benzhydryl, trityl, methoxybenzyl, nitrobenzyl and so on), WITH1-C8-alkylthio,6-C12-Uraltel (nitrophenylthio and so on), WITH5-C8-cycloalkylation,1-C8-acyl (for example, C1-C8-alkanoyl (formyl, acetyl, chloroacetyl, TRIFLUOROACETYL, etc.), WITH2-C12-alkoxycarbonyl (with the alkyl parts of methyl, ethyl, propyl, cyclopropylmethyl, cyclopropylethyl, isopropyl, butyl, isobutyl, pentyl, hexyl, trichlorethyl, pyridylmethyl, cyclopentyl, cyclohexyl, and so forth), WITH8-C19-arelaxation (having as aranceles part of the benzyl, benzhydryl, nitrobenzyl and so on), WITH7-C15-aroyl (benzoyl, nitrobenzoyl and so on), WITH3-C10-acyl dibasic acid (succinic, phthaloyl and so gave the 9-trialkylsilyl,3-C9-alkoxyalkyl and C1-C8-alkylidene or7-C14-aralkylated (benzyliden, methylbenzylidene, nitrobenzylidene and so on). Acid additive salt is also aminosidine connection. One or two of the above protective groups can be joined to amino.

Derivative of cephalosporin of formula I of the present invention can be obtained using any conventional method, which typically includes obtaining acid side chain, 3-Deputy kernel cafema, the introduction of the 7-acyl side chain and the 3-substituent, unlock and so on. However, the connection 1 may be conveniently obtained in accordance with any of the following methods 1,2 and 3 of the present invention.

Method 1.

In the first method, a cephalosporin derivative of the formula I can be obtained by the introduction of acyl groups in the amine of formula III:

< / BR>
where Het, X, Y, R1and R2have the above significance, and R denotes hydrogen or carboxyamide group, in which the compound of formula III or its reactive derivative is subjected to interaction with the acid of the formula: Acyl-HE, where Acyl, Het, X, Y, R, R1and R

Method 2.

In the second method, a cephalosporin derivative of the formula I can be obtained by reacting the compounds of formula IV:

< / BR>
where the Acyl denotes the selection of protected acyl, R3denotes alkyl or aryl, R, X and Y have the above significance, or its reactive derivative with the compound of the formula AcSR2SR1Het, where Ac denotes acyl, Het, R1and R2have the above values, obtaining the compounds of formula II, and exemption from protection of compound II. As stated above, sulfoxide the compounds of formula II preferably restore prior to release from protection.

Method 3:

In the third method, a cephalosporin derivative of the formula I can be obtained by reacting the compounds of formula V:

< / BR>
where the Acyl denotes the selection of protected acyl, R, X and Y have the above meanings and M denotes hydrogen or heavy metal, or its reactive derivative with the compound of the formula: Hal-R2SR1Het, where Hal denotes a halogen atom, Het, R1and R2have the above significance, or its reactive derivative, with obtaining the compounds of formula II, which frees mouth for what has been created starting materials for the above methods, that is the core of cafema acids with 7-side chain and 3-Deputy receive, for example, in accordance with the methods described in "Receiving" of this description. However, the present invention does not involve the limited use of the parent compounds, which are consistent with this description, and to obtain the compounds I can be used equivalent compounds obtained by the known methods.

The scheme of each method are described below.

The original substance of the way of 1.7-amine III and the acid can be obtained, for example, in accordance with the methods described in "Obtaining 6 and Get 1 and 2", respectively.

The amidation, which acyl group is introduced at position 7 kernel cafema can be carried out by reacting the carboxylic acid or its reactive derivative with a 7-amine or its reactive derivative. The amidation reaction can be performed in the mode of reaction, well known in this technical field. Thus, the amine is subjected to interaction with a slight excess of the acid in an appropriate solvent in the presence of the condensing substance at a temperature of from about -30 to 50oC, preferably when the rate is 2 o'clock

Examples of the condensing substances include carbodiimide, such as N, N'-diethylcarbamoyl, N, N'-dicyclohexylcarbodiimide and so on; a carbonyl compound such as carbonyldiimidazole and so on; isoxazolines salt; atilov compounds, such as 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline; galizana phosphoric acid; sulfonyl-halide; or aminirovanie enzyme, and so forth.

Preferably, the amine is subjected to interaction with 1-2 mol of carboxylic acid in the presence of 1-2 mol of the condensing substance in a solvent that does not contain active hydrogen, such as dichloromethane, chloroform, ethyl acetate, acetonitrile or the like.

Reactive derivatives of 7-amine represent the connection cafema, 7-amino group which is activated by various groups such as silyl groups such as trimethylsilyl, methoxydimethylsilyl, tert-butyldimethylsilyl and so on; Stanley group through which the amino group is associated with alkanols, acetone, acetylacetone, complex acetoacetate ether, acetoacetanilide, acetoacetanilide, cyclopentanedione, acetylbutyrate and so on, with the formation of enamine; alkylidene group, tako is Yong and so on; acid such as mineral acid, carboxylic acid, acid and so forth, with which the amino group forms a salt; acyl, which is easy to split, such as alkanoyl and so on; or other1-C10groups suitable for this purpose. Reactive amine derivatives include compounds in which a protected functional group other than the 7-amino group.

Examples of reactive derivatives of carboxylic acids (Acyl-HE) include symmetrical or mixed anhydride (mixed anhydride of the acid with a mineral acid (phosphoric acid, sulfuric acid, complex poluation carbonic acid, and so forth) organic acid (alanovoy acid, Aracinovo acid, acid, and so forth), and the like; galoyanized (mixed acid anhydride with halogenation); an active ester, for example, a complex analogy ether (vinyl ether, isopropanolamine ether and so on), complex arrowy ether (phenyl ether, galotanovy ether, nitrophenyloctyl ether and so on)complex heterocyclic ether (pyridyloxy ether, benzotriazolyl ether and so on), an ester of N-hydroxycodone, ester of diacylhydrazines (Sagnier (Uralkaliy ether, heterocyclic thiol ether and so on), active amide (aromatic amide formed by imidazole, triazole, 2-ethoxy-1,2-dihydroquinoline or Valladolid) and the like.

The above-mentioned reactive derivatives of amine and/or carboxylic acid is subjected to interaction in the presence of an acid-capturing reagents, for example inorganic bases, such as oxides, hydroxides, carbonates, bicarbonates of alkali metals or alkaline-earth metals; organic bases, such as tertiary amine, aromatic amine, and so forth; oxiranes, such as oxide alkylene, the oxide kalkilia and so on; pyridinium salts such as tripyridyltriazine trichloride and the like; adsorbents such as celite, and so forth. Preferably, the amine is subjected to interaction with 1-2 mol of a reactive derivative of carboxylic acid (Acyl-HE) and 0-2 mol acid exciting agent in an inert solvent containing no active hydrogen. The reaction between the enzyme complex air and halogentated carry even in an aqueous solvent.

After completion of the reaction, the reaction mixture is neutralized with acid, extracted with solvent and the concentration which result in obtaining secure product II, which is then released from the protection of the traditional way of obtaining the final product, a cephalosporin derivative of the formula I.

The original substance of method 2, compound IV can be obtained, for example, by amidation of the corresponding compounds having the amino group in position 7, using well-known techniques, commonly used for amidation as described in "Obtaining 7".

The other starting material, etiltiakarbotsianina (AU-SR2SR1Het) can be obtained by treatment of the appropriate heterocyclic thiol with sodium hydride at a temperature from about -30 to 30oC in a solvent such as dimethylformamide and so on, getting mercaptide alkali metal, which is then subjected to interaction with holomediterranean, getting etiltiakarbotsianina. Alternatively, the heterocyclic mercaptide alkali metal is subjected to interaction with, for example, bromchlormethane, receiving ClR2SR1Het, which is then treated thiacarbocyanine salt, receiving alltimetatiana AcSR2-SR1Het.

The reaction between compound IV and etiltiakarbotsianina carried out, preferably, put the it preferably 1-3 equivalents, acetyl - or benzyltrimethylammonium in an appropriate solvent in the presence of a base, such as sodium methylate, at a temperature of approximately -90 50oC, preferably from -80 to -10oC, approximately in the range of from 5 min to 20 h, preferably in the range from about 18 minutes before 7 o'clock

You can use any organic solvents, provided that they are not acidic. Examples of particularly preferred solvents are tetrahydrofuran, dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide, methanol, ethanol, propanol and the like.

Method 2 is also effective to carry out using dialkyldithiophosphates alkali metal, obtained by interaction of etiltiakarbotsianina with the alkoxide of an alkali metal.

After completion of the reaction, the reaction mixture is neutralized with acid, diluted with water, and extracted with a suitable solvent. Examples of suitable solvents include ethyl acetate, dichloromethane and the like. Then the extract is dried, concentrated under reduced pressure, if desired, and the residue is purified, for example, extraction, washing, recrystallization or column is Il, dichloromethane, methanol and the like. Suitable suenami for chromatography is a mixture of toluene and ethyl acetate. Exemption from protection leads to the obtaining of the desired derivative of cephalosporin of formula I.

Although the original substance method 3, compound V may be the salt of the metal or organic base, such as pyridine, it is preferable to use a salt of silver. The halogen atom of methyldiethylamine may be chlorine, bromine or iodine, preferably iodine.

Compound V can be obtained from the relevant source materials, such as compounds IV, as described below. Connection V after sulfoximine, if necessary, converted into 3-thiol, which is then subjected to interaction with the bottom, getting a salt, preferably a salt of silver.

Sulfoximine carried out by reacting the protected compound IV in an appropriate solvent with 1-2 mol oxidant, such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and so forth, at a temperature in the range of about -40 to 10oC, approximately during the time interval from 10 minutes to 5 hours, the Reaction mixture is then treated with an aqueous solution thiosul the Crude product is purified for example, column chromatography, on silica gel, elwira dichloromethane, chloroform and so on, if necessary.

3-Thiol is obtained from 3-sulfonylacetanilide, dissolving the latter in a suitable solvent, is added sodium hydrosulfide and the resulting mixture is subjected to interaction at a temperature in the range of about -40 to 0oC within approximately 30-60 minutes the Mixture is neutralized with acid, such as hydrochloric acid, extracted with an appropriate organic solvent, such as ethyl acetate. The extract is dried and concentrated to obtain a thiol. Examples of appropriate solvents include dimethylformamide, acetonitrile and the like.

Sol silver 3-thiol is obtained by interaction of the thiol with a slight excess of silver nitrate in a suitable solvent at a temperature in the range from approximately -30 to 20oC for about 10-30 minutes Examples of the solvent are tetrahydrofuran, dichloromethane and the like. Silver Sol receive, for example, by diluting the reaction mixture with water, extraction with a dilute solution of dichloromethane and concentration of the extract.

Alojamiento of alkylthiophenes is an in solvent, such as dimethylformamide, in the presence of a base such as sodium hydride. Received klimatisierung product then, if necessary, is subjected to the reaction of the iodine substitution of the iodide of sodium.

The reaction between compound V and 2-galoidzamyescyennykh methylthiopropionate carried out in a suitable solvent at a temperature in the range from approximately 0 to 30oC for about 2-20 hours Examples of suitable solvents are hexamethylphosphoramide, dimethylformamide and the like. The product is extracted with an organic solvent such as ethyl acetate, and the like, and the extract was concentrated. The residue is then purified, for example, column chromatography on silica gel.

Recovery sulfoxide II carried out using reducing agents commonly used in the field of cephalosporins, such as phosphorus trichloride, doghorse tin and the like.

As the final stage of product II is released from the protection of obtaining a cephalosporin derivative I of the present invention. Exemption from protection is carried out according to traditional methods.

Exemption from the protection of the carboxy-protective group can be performed is dstanley a reactive asteropaeus group, it can be split by treatment of the protected product in an inert solvent, acid, base buffer solution, ion exchange resins and the like. When carboxyterminal the group is not sufficiently reactive asteropaeus group, it can be activated by known methods prior to release from protection. The activation is carried out in dependence on the type of ester as follows: complex trichlorethylene esters are treated with metal and acid; complex p-nitrobenzoate ester is treated with a hydrogenation; salts ditionally acid or metal and acid; complex peacelove esters are treated with irradiation of light. Carboxyamide groups that represent aralkyl, you can split the catalytic hydrogenation on palladium, platinum, Nickel, and so forth. Carboxyamide groups that represent a tertiary alkyl, cyclopropylmethyl, 2-alkenyl, aralkyl, sulfonylated, can be split by treating the product with acid in the presence of a cation acceptor, such as anisole, sensation and so on, if necessary. Examples of acids include mineral acid, a Lewis acid such as aluminum chloride, tin tetrachloride, camerasurveillance and so forth, a strong carboxylic acid, such as triperoxonane acid and so on. When carboxyamide group is a 2-alkenyl, it can be split by treatment of the product chelate compound triarylphosphine-palladium. When carboxyamide group represents phenacyl, 2-alkenyl, hydroxyalkyl or the like, it can be split by treatment of the product with alkali or nucleophilic reagent. As you can see, for exemption from protection use other equivalent methods known in the art.

Protected hydroxy can be exempt from the protection of the traditional way, for example the influence of a strong carboxylic acid, acid about it (for example, aluminium chloride, bis-(alkylsilanes)oxide) and so on, if necessary, in the presence of a cation acceptor, with the aim of splitting the essential communications, under the action of acid or base to hydrolysis group of ester, and so forth. This reaction is usually carried out in a solvent at a temperature in the range of about -10 to 50oC during the period of time from 30 min to 10 h, obtaining the desired gidroksosoedinenii.

Protected amino can traditionally be exempt from protection, for example, seeduwa: the influence of strong acids (triperoxonane acid, triftoratsetata and so on), Lewis acid (aluminum chloride, tin tetrachloride, chloride, titanium, zinc chloride, and so forth) and other acids, if necessary, in the presence of a cation acceptor (anisole, bentolila and so on);

(b) arelaxation (carbobenzoxy, methylcarbamate, diphenylmethylene and so forth) or similar aminosidine group: the influence of the mentioned Lewis acid and a cation acceptor or hydrogen (catalytic hydrogenation using palladium or Nickel catalyst and so on);

(c) the lowest alkanoyl (formyl, acetyl, chloroacetyl, etc.), group, forming a Schiff base (the group of divalent carbon, for example, ethylidene, propylidene, benzylidene, replaced benzyliden and so on), aralkyl (trityl, replaced trityl and so on), arieti (phenylsulfonyl and so on), tetrahydropyranyl, silyl or stannyl (tributylstannyl and so on), or similar group: the influence of acid (hydrochloric acid, sulfuric acid, methanesulfonate and so on);

(d) other: methods specific to each protective group (for example, thiourea for haloacetic or N-alkyldiethanolamine; hydrazine for dibasic who ranks exemption from protection are provided, for example, in J. F. W. McOmie Ed, "Protective groups in organic chemistry", page 183 (1973) PLEUM Press, new York; S. Patai Ed, "the Chemistry of functional groups" (1969), Intersales of Publ. John Willy & sons Ltd., London; Fl UPP Ed. "Cephalosporins and penicillins", Academic Press, new York (1972), and so on.

The present invention also provides a method for obtaining compounds stated in paragraph 1 of the formula, which includes the introduction of the 3-substituent, 4-carboxylate complex ester, 4-carboxylate salt or 7-alala, recovery sulfoxide or exemption from protection. Structural variants can be obtained by modification of the nuclei cafema, for example, in position 7, if desired.

The obtained free acid 1 then transformed into a pharmaceutically acceptable salt, if desired, by conventional methods, described below. Such salts can be formed by the respective base used for medical purposes in the field of cephalosporin antibiotics, such as salts of light metals, such as lithium salt, sodium, potassium, magnesium, calcium or aluminum, which can lead to physiologically acceptable ion. Other preferred salts are those formed WITH1-C12-alkylammonium, their bases, such as pyridine, collidine, picoline, chinoline, dimethylaniline and the like. In addition, a cephalosporin derivative of the formula I may be protected by any of the above C2-C15-pharmaceutically active astrobrowse groups with the production of esters which exhibit bactericidal activity after oral or parentelem introduction, especially when administered orally.

Carboxylate salt of the free acid 1 can be obtained traditionally by interaction of the acid with 1 base or the salt of a weak carboxylic acid of the base. For example, the acid neutralized with 1 base (hydroxide, carbonate or bicarbonate light metal) or subjected to metabolic degradation salt of a lower carboxylic acid (sodium acetate, sodium lactate, sodium 2-ethylhexanoate and so on). The obtained salt can be selected by diluting the reaction mixture with appropriate solvent in which the salt is hard or slightly soluble, or by lyophilization.

The reaction is usually completed within an approximate range from 1 to 10 min at a temperature lower than approximately the 50oC. When there are no side reactions, the reaction may continue during the Yu acid, allow to obtain the compound of formula I. Accordingly, the present invention further proposes a method of obtaining the compounds of formula I by treating the salt of compound I with an acid.

When the connection I has a basic group such as amino, it can be subjected to interaction with acid, for example hydrochloric acid, acetic acid, to obtain the acid additive salt using traditional in the field of cephalosporins method, for example, treating the compound I is approximately 1-2 mol acid at a temperature of from about 0 to 50oC for about 10-90 minutes

Although the above mentioned methods 1, 2 and 3 are preferred to obtain the compound I, the present invention is not limited to the compounds obtained by these methods, and scope of the present invention includes any compound I obtained by any of the means well known to specialists in this field of technology.

The above reaction is carried out at a temperature in the range of approximately from -80 to 100oC, preferably in the range of approximately -40 to 50oC, within the approximate range from 10 minutes to 20 hours When the product is stable, the time reaktsionny solvent, anhydrous conditions, the introduction of inert gas, mixing and so on.

Examples of reaction solvents for the above-mentioned methods are hydrocarbons, such as pentane, hexane, octane, benzene, toluene, xylene and the like; golozhabernyi hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene and the like; ethers such as diethyl ether, methylisobutyl ether, dioxane, tetrahydrofuran and the like; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and the like; esters such as ethyl acetate, isobutyl acetate, methylbenzoate and the like; nitrophenolate, such as nitromethane, nitrobenzene and the like; NITRILES, such as acetonitrile, benzonitrile and the like; amides, such as formamide, ndimethylacetamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide and the like; sulfoxidov, such as dimethyl sulfoxide and the like; carboxylic acids such as formic acid, acetic acid, propionic acid and the like; organic bases, such as diethylamine, triethylamine, pyridine, picoline, kallidin, quinoline and the like; alcohols such as methanol, atanua, or mixtures thereof.

The desired product is recovered from the reaction medium by removing impurities, such as unreacted educt, by-products or solvents, using traditional methods, such as extraction, evaporation, washing, concentration, precipitation, filtration, drying and the like. The isolated product is subjected to conventional processing, such as adsorption, elution, distillation, precipitation, recrystallization, chromatography and the like.

Although the above methods 1 and 2, 3 are preferred to obtain the compound I, the present invention is not limited to the compounds obtained by these methods, and within the scope of the present invention assumes all compound I obtained by any means known to specialists in this field of technology.

The compound of the present invention is subjected to in vitro experiments and in vivo to determine potency as antibiotic funds. When tested in vitro connection I proved extremely effective against gram-positive bacteria, such as Staphylococcus aureus and Streptococcus pyogenes and gram-negative bacteria, for example Escherichia coli Entero present invention provides a method of combating bacteria by the interaction of bacteria with an effective amount of the compounds of formula I.

The absorption rate in vivo of compound I after oral administration is determined by the introduction of the compounds of the present invention to mice and measuring blood levels. The result shows that compound I results in a good level of blood by oral administration, which shows excellent absorption rate.

Therefore, the compound of formula I is an effective antibiotic in oral and parenteral administration and are suitable for the treatment of infections caused by a wide range of bacteria that are sensitive to the compound of formula I.

In another embodiment, the invention features a method of treating and controlling bacterial infections in humans, animals, perishable materials, or as a disinfectant, which envisages making effective amount of the compounds of formula I.

The present invention also provides pharmaceutical compositions containing as an active ingredient an effective amount of the compounds of formula I, its pharmaceutically acceptable salt or hydroxy and/or aminosidine derived.

For oral administration the compound I can be prepared in a standard costly, diluents or fillers. For parenteral administration, the compound I is prepared, for example, subcutaneously, intramuscularly, intravenously or intraperitoneally injected solutions or suspensions. In addition, the compound of the present invention can be prepared in the form of ointment, suppository, liniment, and the like. Suitable daily dose of injected compound I may be from about 10 mg to 4000 mg, preferably about 100 to 2000 mg, by oral administration, and about 10 to 400 mg, preferably about 50 to 2000 mg, when administered parenterally.

The following techniques are intended to further illustrate the present invention and should not limit its scope.

In the examples the following abbreviations are used: Ac is acetyl; At - 2-aminothiazol-4-yl; Bh diphenylmethyl; Boc tert-butoxycarbonyl; Et is ethyl; Me is methyl; Ph is phenyl; PMB p-methoxybenzyl; Tr, trityl.

Getting 1: alltimer

NaSHet __ AcSCH2Het

1) Het 1,2,3-triazole (1P1).

To a suspension of sodium salt of 1,2,3-triazole-4-thiol (38 g, 309 mmol) in dimethylformamide (150 ml) at -20oC added dropwise chloromethylthiazole time (37.4 g, 300 mmol) for 10 min, and the mixture was stirred at the same temperature is ract washed with water, aqueous solution of acid sodium carbonate and water, and dried in the presence of sodium sulfate and concentrate under reduced pressure. The crystalline residue is washed with hexane, dried and recrystallized from simple ether to obtain 4-acetylthiourea-1,2,3-triazole (38,9 g), yield 69%, the melting point of 88-89oC. NMR (CDCl3) ppm: 2,36 (c, 3H) 4,37 (c, 2H), 6,3 (Shir. s, 1H), 7,73 (s, 1H). IR n (CHCl3cm-1: 3430, 3152, 1693, 1131.

2) Het 1,2,4-triazole (R).

To a solution of 1,2,4-triazole-3-thiol (2,23 g, 22,1 mmol) in dimethylformamide (30 ml) was added sodium hydride (60% in oil, 840 mg, 21 mmol) and the mixture was stirred at room temperature for 10 minutes To this solution at a temperature of from -50 to -60oC was added a solution of chloromethylthiazole (2.50 g, 20,1 mmol) in dimethylformamide (5 ml), and the mixture is stirred at the same temperature for 20 min, mixed with different number of Fritillaria (6,70 g, 24 mmol) and pyridine (1,94 ml of 24.0 mmol), stirred under cooling on ice with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 20:1) and crystallized from simple ether with 124-125oC.

NMR d (CDCl3) ppm: 2,32 (c, 3H), 4,50 (c, 2H), 7,1-7,2 (m, 6N), 7.3 to 7.4 (m, N), s, 1H), IR n (CHCl3) cm-1: 1690, 1490, 1472, 1444, 1383, 1352, 1271, 1228, 1131.

3) Het 5-tetrazolyl (RAS).

To a solution of tetrazole-5-thiol (3.00 g, 29,41 mmol) in dimethylformamide (50 ml) cooled on ice was added sodium hydride (60% suspension in oil, 2,59 g, 64,75 mmol), and the mixture is stirred while cooling on ice for 5-6 minutes To the mixture was added a solution of chloromethylthiazole (4,39 g, 35,26 mmol) in dimethylformamide (10 ml) and the mixture is stirred at room temperature for 2 hours, the Reaction mixture was diluted with 10% hydrochloric acid (11 ml) with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate, filter and concentrate. The residue is purified column chromatography on silica gel (toluene: ethyl acetate 1: 1), and the obtained residue was washed with a mixture of n-hexane and simple ether to obtain 5-acetylcholinesterase (2,49 g) as colorless crystals. Exit 45% melting point 90oC. NMR d (CDCl3ppm: 2,42 (c, 3H), 4,68 (c, 2H), 8-9 (Shir. s, 1H), IR n (CHCl3) cm-1: 3072 Shir. 1692, 1500, 1356, 1131.

4) Het is 2-pyridyl (RAS).

To a solution of 2-mercaptopyridine (1,11 g, 9,98 mmol) howl temperature for 2-3 minutes To this mixture at a temperature of -30oC was added a solution of chloromethylthiazole (1.12 g, 9,00 mmol) in dimethylformamide (2 ml), and the mixture is stirred at a temperature of -20 to -30oC for one hour. The reaction mixture was diluted with ethyl acetate, washed with water and saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate 20: 1) obtaining 2-acetylhomocysteine (1,43 g) as a yellow oil, yield 72% NMR d (CDCl3) ppm: 2,35 (c, 3H) and 4.65 (c, 2H), 7,03 (DDD, J=7,4 Hz, J=4.9 Hz, J=1.0 Hz, 1H), 7,18 (DDD, J=8.0 Hz, J=1.0 Hz, J=1.0 Hz, 1H), 7,51 (DDD, J=8.0 Hz, J=7,4 Hz, J=1.8 Hz, 1H), of 8.47 (DDD, J=4.9 Hz, J= 1.8 Hz, J= 1.0 Hz, 1H). IR n (CHCl3cm-1: 1686, 1576, 1556, 1452, 1414, 1353, 1123 and 956.

5) Het 1,2,3-triazole-4-yl: using benzoyl-derived (R).

1. To a suspension of 1,2,3-triazole-4-itiola in the form of sodium salt (10.0 g, 81,3 mmol) in dimethylformamide (100 ml) cooled on ice was added bromochloromethane (100 ml), and the mixture is stirred for one hour at the same temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrated to obtain 4-chlorotri-1,2,3-triazole (of 10.21 g) in the form of the. What, 1H). IR n (nujol) cm-1: 3140, 1499, 1393, 1246, 1230, 1117, 1002.

To a solution of thiobenzoic acid (470 mg, 3.4 mmol) in dimethylformamide (1 ml) cooled on ice was added sodium hydride (136 mg, 3.4 mmol, 60% dispersion in oil) and then after 10 minutes 4-chloromethyl-thio-1,2,3-triazole (449 mg, 3 mmol), and the mixture is stirred while cooling on ice for 10 min and at room temperature for 4 h, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with aqueous 5% solution of acid sodium carbonate, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 5:1) to obtain 4-benzoylthiourea-1,2,3-triazole (417 mg). Yield 55% Recrystallization of this product from a mixture of hexane:ether allows to obtain colorless needle-like crystals with a melting point of 72.5-73,5oC. NMR d (CDCl3) ppm: 4,57 (c, 2H), 7,4-the 7.65 (m, 3H), of 7.75 (s, 1H), 7,9-of 7.96 (m, 1H); IR n (CHCl3cm-1: 3425, 3146, 1667, 1206, 1175, 911.

Getting 2: chloromethyl:

NaSHet __ ClCH2SHet.

1) Het, trityl-1,2,4-triazole-3-yl (R).

To a solution of 1,2,4-triazole-3-itiola (10.0 g, 99 mmol) in dimethylformamide (100 ml) cooled on ice was added sodium hydride (60% dispersion in oil, 3 is mercaptide, mixed with bromchlormethane (100 ml) and stirred at the same temperature for 14 hours, the Reaction mixture was diluted with ethyl acetate, washed with saline, dried in the presence of sodium sulfate and concentrate. To a solution of the residue 3-chlorotri-1,2,4-triazole in dimethylformamide (100 ml) was added while cooling on ice trailhead (27,6 g, 99 mmol) and triethylamine (13,8 ml) and the mixture stirred for 30 minutes under cooling on ice. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is crystallized from a simple broadcast receiving trityl-3-chlorotri-1,2,4-triazole (20.2 g) in the form of white crystals, yield 52% melting point 121-122oC. NMR (CDCl3) ppm: 5,18 (c, 2H), 7,1-7,2 (m, 6N), 7.03 is to 7.4 (m, N), 7,95 (s, 1H), IR n (CDCl3) cm-1: 1599, 1492, 1472, 1445, 1389, 1365, 1353, 1325.

2) Het is 1-methyl-1,2,4-triazole-3-yl and 2 - methyl-1,2,4-triazole-3-yl (R).

1. To a mixture of 1,2,4-triazole-3-itiola (10.1 g, 0.10 mol) and p-methoxybenzylamine (17,2 g, 0.11 mol) in dichloromethane (50 ml) was added a mixture of aqueous 1 n sodium hydroxide solution (105 ml) and Tetra-butylammonium (750 mg, 2.3 mmol) and the mixture stirred at room temperature tectia sodium sulfate and concentrated. The residue is crystallized from toluene to obtain 3-p-methoxybenzylthio-1,2,4-triazole (16,71 g) as colorless crystals. The output 76% melting point 100-101oC. NMR d (CDCl3) ppm; of 3.77 (s, 3H), 4,32 (s, 2H), 6,79-6,83, 7,23-7,27 (A2B2, 4H), 7,00-7,8 (Shir. s, 1H), 8,13 (C. 1H). IR n (CHCl3cm-1: 3400, 3120 Shir. 1611, 1512, 1485, 1465, 1441, 1302.

2. To a solution of 3-p-methoxybenzylthio-1,2,4-triazole (10.0 g, 45,2 mmol) in methanol (100 ml) was added while cooling on ice, the solution diazomethane simple ether (obtained from 15 g 11-nitrosomethylamino), and the mixture is stirred for one hour. The reaction mixture was concentrated and purified column chromatography of Lobar (toluene:ethyl acetate 1:2-1:3) to give 3-p-methoxybenzylthio-2-methyl-1,2,4-triazole) of 5.17 g; NMR d (CDCl3) ppm: 3,63 (c, 3H), 3,79 (c, 3H), 4,34 (c, 2H), 6,80-6,84, 7,19-7,24 (A2B2, 4H), 7,88 (c, 1H); IR n (CHCl3) cm-1: 1611, 1511, 1476, 1464, 1440, 1360, 1302. Exit 49% (and 3-p-methoxybenzylthio-1-methyl-1,2,4-triazole) of 3.60 g; NMR d (CDCl3) ppm: 3,78 (c, 3H), a 3.87 (c, 3H), or 4.31 (c, 2H), 6,80-6,85, 7,30-7,34 (A2B2, 4H), 7,99 (c, 1H); IR n (CDCl3) cm-1: 1612, 1512, 1465, 1440, 1421, 1356, 1302. Exit 34%

3. To a solution of 3-p-methoxybenzylthio-2-methyl-1,2,4-triazole (5,09 g, and 21.7 mmol) in a mixture of dichloromethane (40 ml) and methanol (40 ml) was added horocycle silver (690 g of 25.9 mmol) and the mixture was stirred at room T2 methyl-1,2,4-triazole collected by filtration, washed with methanol and dried. To a suspension of this product in dimethylformamide (40 ml) was added bronchosoothe (40 ml) and lithium chloride (2,82 g, to 65.2 mmol) and the mixture stirred for 22 h at room temperature. The reaction mixture is mixed with saturated salt solution and ethyl acetate and filtered to remove nerastvorimogo substances. The organic layer is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 4:1) to obtain 3-chlorotri-2-methyl-1,2,4-triazole (of 1.62 g) as a colourless oil, yield 46% NMR d (CDCl3) ppm: a 3.87 (c, 3H), 5,19 (c, 2H), of 7.96 (c, 1H). IR n (CHCl3) cm-1: 1479, 1395, 1360.

4. To a solution of 3-p-methoxybenzylthio-1-methyl-1,2,4-triazole (3.55 g, 15.1 mmol) in a mixture of dichloromethane (30 ml) and methanol (30 ml) was added horocycle silver (4.11 g, to 18.1 mmol), and the mixture is stirred at room temperature for 1.5 hours, the Reaction mixture was diluted with methanol (100 ml) and the obtained crystals 3 Argentinia-1-methyl-1,2,4-triazole collected by filtration, washed with methanol and dried. To a solution of this product in dimethylformamide (30 ml) was added bromochloromethane (30 ml) and lithium chloride (1,96 g of 45.3 mmol) and the mixture stirred pererastajushhaja substances. The organic layer is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) to obtain 3-chlorotri-1-methyl-1,2,4-triazole (of 1.05 g) as a colourless oil. Exit 43% NMR d (CDCl3) ppm: 3,93 (c, 3H), to 5.21 (c, 2H), 8,06 (c, 1H). IR n (CHCl3), cm-1: 1509, 1471, 1424, 1392, 1359.

3) Het 1,2,3-thiadiazolyl (RA-1).

To a solution of 1,2,3-thiadiazole-5-thiol in the form of a sodium salt dihydrate (purity 70,9% 2.50 g, 10,07 mmol) in dimethylformamide (20 ml) was added while cooling on ice bromochloromethane (20 ml), and the mixture is stirred while cooling on ice for 1.5 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate, filter and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate 20:1) to obtain 5-chloro-methylthio-1,2,3-thiadiazole (1.60 g) as a colourless oil. Exit 95% NMR d (CDCl3) ppm: 4,93 (c, 2H), 8,69 (c, 1H). IR n (CHCl3) cm-1: 1419, 1395, 1256, 1102.

4) Het 1,3,4-thiadiazole-2-yl (R-1).

To a solution of 1,3,4-thiadiazole-2-thiol (4.72 in g, 40 mmol) in dimethylformamide (80 ml) was added while cooling on ice hydride on the military solution is added bromochloromethane (80 ml), and the mixture is stirred at the same temperature for 2 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 20:1) to obtain 2-chlorotri-11,3,4-thiadiazole (6,05 g) as a colourless oil, yield 91% NMR d (CDCl3)ppm: 5,32 (c, 2H), 9,16 (c, 1H), IR n (CHCl3) cm-1: 1389, 1232, 1061.

5) Het 2-methyl-1,3,4-thiadiazole-5-yl (RA-2).

To a solution of 2-methyl-1,3,4-thiadiazole-5-thiol (2.64 g, 20 mmol) in dimethylformamide (40 ml) was added while cooling on ice, sodium hydride (880 mg, 60% dispersion in oil, 1.1 equivalent, 22 mmol) in portions and the mixture is stirred for 10 minutes To the resulting solution was added bromochloromethane (40 ml), and the mixture is stirred at the same temperature for 1 hour and 30 minutes, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and purified by chromatography on silica gel (toluene:ethyl acetate 10:1) to obtain 5-chlorotri-2-methyl-1,3,4-thiadiazole (3.3 grams) as a colourless oil. Exit 91% NMR d (CDCl3) ppm: 2,79 (c, 3H), 5,24 (c, 2H). IR n (CHCl3) cm-1: 1430, 1392, 138 is (2.00 g, 14.5 mmol) in dimethylformamide (20 ml) cooled on ice was added bromochloromethane (20 ml) in one portion and the mixture is stirred for 1.5 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate, filter and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate(20:1)-(10:1)) obtaining 5-chlorotri-1-methyltetrazole in the form of colorless crystals (1.73 g). Yield 72% melting point 55-56oC. NMR d (CDCl3) ppm: 4,03 (c, 3H), from 5.29 (c, 2H). IR n (CHCl3) cm-1: 1467, 1408, 1384, 1278, 1235, 1171.

7) Het 2-methyltetrazol-5-yl (R).

1. To a solution of 5-p-methoxybenzimidazole (7,00 g of 31.5 mmol) in methanol (150 ml) was added while cooling on ice, the solution diazomethane simple ether (obtained from 14 g of N-nitrosomethylamino), and the mixture is stirred for 1 h, and then concentrated. The residue is purified column chromatography of Lobar (toluene: ethyl acetate=5:1) to obtain 5-p-methoxybenzylthio-2-methyltetrazole (a 4.86 g; NMR d (CDCl3) ppm: 3,78 (c, 3H), 4,29 (c, 3H), of 4.38 (c, 2H), 6,81-6,85, 7,30-7,34 (A2B2), 4H); IR n (CHCl3) cm-1: 1611, 1512, 1390, 1324, 1303; colorless oil, yield 65%) and 5-p-methoxybenzylthio-1-methyltetrazole (2,71 g; NMR d (C is of Tallaght, yield 36%).

2. To a solution of 5-p-methoxybenzylthio-2-methyltetrazole (a 4.86 g, 20,59 mmol) in a mixture of dichloromethane (40 ml) and methanol (40 ml) was added silver perchlorate (6,17 g, 26,78 mmol) and the mixture was stirred at room temperature for 2 hours, the Reaction mixture was diluted with methanol (100 ml) and the obtained crystals 5-argentite-2-methyltetrazole collected by filtration, washed with methanol and dried. To a solution of this product in dimethylformamide (40 ml) was added bromochloromethane (40 ml) and lithium chloride (2.67 g, of 61.7 mmol) and the mixture was stirred at room temperature for 20 hours, the Reaction mixture is mixed with saturated salt solution and ethyl acetate and filtered to remove nerastvorimogo substances. The organic layer is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 20:1) to obtain 5-chlorotri-2-methyltetrazole (1,91 g) as a colourless oil. The output 56% NMR d (CDCl3) ppm: 4,37 (c, 3H), 5,23 (c, 2H). IR n (CHCl3) cm-1: 1440, 1422, 1410, 1395, 1325.

Getting 3: Substitution of iodine

< / BR>
1) Het is 1-methyl-1,2,4-triazole-3-yl (R).

To a solution of 3-chlorotri-1-methyl-1,2,4-triazole (981 mg, 6.0 mmol) in acetone (10 ml) th mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrated to obtain 3-iodo-methylthio-1-methyl-1,2,4-triazole (1.50 g) as a yellow oil. NMR (CDCl3) ppm: 3,94 (c, 3H), 4.75 in (c, 2H), 8,07 (c, 1H).

2) Het-2-methyl-1,2,4-triazole-3-yl (R).

To a solution of 3-chlorotri-2-methyl-1,2,4-triazole (981 mg, 6.0 mmol) in acetone (10 ml) was added sodium iodide (1.78 g, 12,0 mmol), and the mixture is stirred at a temperature of 50oC for 3 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrated to obtain 3-iodo-methylthio-2-methyl-1,2,4-triazole (1.47 g) as a yellow oil. NMR d (CDCl3) ppm:3,84 (c, 3H), 4,71 (c, 2H), 7,98 (c, 1H).

3) Het 1,2,3-dideaza-5-yl (3PA2-1).

To a solution of 5-chlorotri-1,2,3-thiadiazole (999 mg, 6,00 mmol) in acetone (10 ml) was added sodium iodide (1.78 g, 12,00 mmol), and the mixture is stirred at a temperature of 50oC for 2 hours After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed once with water, dried in the presence of sodium sulfate, filtered and concentrated to obtain 5-iodometry-1,2,3-thiadiazole in the form of a brown oil (1.55 g). NMR d (CDCl3) ppm: 4,53 (c, 2H), 8,62 (c, 1H).

ml) was added sodium iodide (1.5 g, 2.0 equivalent, 10 mmol), the mixture is stirred at a temperature of 50oC for 3 hours After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrated to obtain 2-iodometry-1,3,4-thiadiazole (1.2 g, contains approximately 10% of the original chlormethiazole connection) as a yellow oil. NMR d (CDCl3) ppm: 4,85 (c, 2H), 9,14 (c, 1H).

5) Het 2-methyl-1,3,4-thiadiazole-5-yl (RA-2).

To a solution of 5-chlorotri-2-methyl-1,3,4-thiadiazole (730 mg, 4 mmol) in acetone (6 ml) was added sodium iodide (1.2 g, 2.0 equivalent, 8 mmol), and the mixture is stirred at a temperature of 55oC for 2 h, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrated to obtain 5-iodometry-2-methyl-1,3,4-thiadiazole (of 1.05 g) as a yellow oil. NMR d (CDCl3) ppm: 2,79 (c, 3H), 4,78 (c, 2H).

6) Het 1-methyltetrazol-5-yl (RA-2).

To a solution of 5-chlorotri-1-methyltetrazole (987 mg, 6.0 mmol) in acetone (10 ml) was added sodium iodide (1.78 g, 12,0 mmol), and the mixture is stirred at a temperature of 50oC for 3 hours After cooling, the reaction mixture is diluted with water, and ek is irout obtaining 5-iodometry-1-methyltetrazole in the form of a yellow oil (1,33 g, contains about 20 mol. chloride). NMR d (CDCl3) ppm: 3,98 (c, 3H), 4,76 (c, 2H).

7) Het 2-methyltetrazol-5-yl (R, part 3).

To a solution of 5-chlorotri-2-methyltetrazole (987 mg, 6.0 mmol) in acetone (10 ml) was added sodium iodide (1.78 g, 12,00 mmol), and the mixture is stirred at a temperature of 50oC for 3 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrated to obtain 5-iodometry-2-methyltetrazole (1,43 g) as a yellow oil. NMR d (CDCl3) ppm: to 4.38 (c, 3H), 4,74 (c, 2H).

Getting 4: Modification of the Het.

1) Introduction of trityl with getting trityl-1,2,3-triazole-4-yl (R).

To a suspension of 1,2,3-triazole-4-thiol in the form of sodium salt (109 g, 870 mmol) in dimethylformamide (300 ml) was added dropwise at a temperature of -20 to -30oC chloromethylated (109 g, 870 mmol) and the mixture was stirred at room temperature for 2 hours To the reaction mixture was added while cooling on ice trailhead (292 g, 1.05 mol) and pyridine (84,5 ml, 1.05 mol), and the mixture is stirred at room temperature for 18 h, diluted with dichloromethane, washed with saline, dried in the presence of sodium sulfate and concentrate in the ash (183 g), exit 49% melting point 115-116oC, colorless crystals, NMR d (DCl3) ppm: 2,29 (c, 3H), 4,34 (c, 2H), 7,05-to 7.15 (m, 6N), 7.3 to 7.4 (and N), 7,47 (s, 1H). IR n (CHCl3) cm-1: 1688, 1488, 1199, 1128, 1072, 1033, 954.

2) Introduction of bromide to obtain (1/2)-methyl-1,2,3-triazole-4-yl (R).

To a solution of 4-acetylthiourea-1,2,3-triazole (6 g, 31,75 mmol) in tetrahydrofuran (30 ml) was added dropwise at a temperature of -78oC a solution of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (35 ml, 35 mmol), and the mixture is stirred at the same temperature for 5 minutes, then add methyl triftorbyenzola (4,0 ml, 35 mmol). After stirring at the same temperature for 2 h, the reaction mixture was diluted with 10% hydrochloric acid (26 ml) and water then extracted with ethyl acetate. The extract was washed with aqueous solution of acid sodium carbonate and brine, is dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (n-hexane:ethyl acetate 1:2) to give 4-acetylthiourea-3-methyl-1,2,3-triazole (2,22 g, NMR d (CDCl3) ppm: 2,32 (s, 3H), of 4.13 (s, 5H), to 7.77 (s, 1H). IR n (CHCl3) cm-1: 1698, 1429, 1355, 1263, 1226, 1205, 1127, 1100, 957, the melting temperature of 37-38oC, yield 34% ), 4-acetylamino-1-m is 1285, 1131, 1106, 1058, 1031, 956, the melting point of 71-72oC, yield 14% ), and 4-acetylthiourea-2-methyl-1,2,3-triazole (175 mg, NMR d (CDCl3) ppm: 2,35 (c, 3H), 4,20 (c, 3H), 4,30 (c, 2H), 7,56 (c, 1H). IR n (CHCl3) cm-1: 1691, 1446, 1369, 1130, 1006, 990, 956; oil; yield 3%).

Getting 5: Introduction 7-acyl

< / BR>
1) Acyl (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pentenol (R-1).

To a suspension of the hydrochloride complex diphenylmethylene ester of 7-amino-3-methanesulfonate-3-cefem-4-carboxylic acid (1,49 g, 3 mmol) and (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pentenol acid (1,03 g of 3.45 mmol) in dichloromethane (30 ml) was added at a temperature of -30oC N-methyl-morpholine (1.1 ml, 10 mmol) and 2 min phenyl dichlorophosphate (0,49 ml of 3.27 mmol), and the mixture is stirred at the same temperature for one hour and 20 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (6 ml) and extracted with ethyl acetate. The extract is washed with water, aqueous 5% solution of acid sodium carbonate and brine, is dried in the presence of sodium sulfate and concentrate. The residue (2.6 g) is dissolved in hot isopropanol (100 ml), cooled and dedicated pale yellow powder is collected by filtration to obtain complex diphenylmethylene the th acid (2,01 g). Exit 91% NMR d (CDCl3) ppm: 1,12 (t, J=7,6 Hz, 3H), and 1.54 (s, N), to 2.5-2.7 (m, 2H), 2,85 (s, 3H), 3,55, 3,80 (Avcv, J=18 Hz, 2H), 5,09 (d, J=5 Hz, 1H), 5,95 (DD, J=5 Hz, J=8 Hz, 1H), 6,45 (so J=7,4 Hz, 1H), 6,74 (s, 1H), 6,86 (s, 1H), 7,2-7,5 (m, 10H), 7,80 (d, J=8 Hz, 1H). IR n (CHCl3) cm-1: 3400, 1786, 1725, 1669, 1545, 1367, 1287, 1220, 1156.

2) Acyl (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane-acetyl (R).

To a suspension of (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-tricalciumphosphate acid and 41.7 g of 78.8 mmol) in dichloromethane (600 ml) was added at a temperature of -30oC N-methylmorpholin (7,575 g, 75 mmol) and the mixture stirred for 10 min, mixed with hydrochloride complex diphenylmethylene ester of 7-amino-3-methanesulfonate-3-cefem-4-carboxylic acid (37,27 g, 75 mmol), stirred at the same temperature for 50 min, mixed with the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (14,38 g, 75 mmol), stirred while cooling on ice for 3 h, diluted with water, extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (toluene containing 0.5% acetic acid:ethyl acetate 10:1) and the eluate is treated with ether-hexane to obtain complex diphenylmethylene ester of 7-[new acid (57,42 g). Colorless powder. Yield 79% This product contains approximately 5% of the isomer 2-cafema. NMR d (CDCl3) ppm: 1,48 (c, 9H), 2,78 (c, 3H), 3,45, 3,76 (Avcv J=19.6 Hz, 2H), 5,13 (d, J=5 Hz, 1H), the 6.06 (DD, J=5 Hz, J=8,8 Hz, 1H), of 6.96 (s, 1H), 7,02 (s, 1H), 7,2-7,5 (m, N). IR n (CHCl3) cm-1: 3400, 1793, 1724, 1690, 1543, 1513, 1493, 1445, 1368, 1285, 1222, 1157.

3) Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath (R).

To a suspension of the hydrochloride complex diphenylmethylene ester of 7-amino-3-methanesulfonate-3-cefem-4-carboxylic acid (37,27 g, 75 mmol) and (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-tricalciumphosphate acid (45,63 g, 86 mmol) in dichloromethane (600 ml) was added at a temperature of -30oC N-methylmorpholin to 27.2 ml, 0.25 mol) for 3 minutes After 4 minutes and to the mixture was added phenyl dichlorophosphate (12.3 ml, 82 mmol). After stirring for 3 h the mixture was diluted with 10% hydrochloric acid (40 ml) and water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of acid sodium carbonate, dilute hydrochloric acid and water, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is dissolved in isopropanol (2 l) by heating and cooled to obtain a complex diphenylmethyl the et'hem-4-carboxylic acid (67 g); colorless powder, yield 92%

4) Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-methoxyaminomethyl (RW-1).

To a suspension of the hydrochloride complex diphenylmethylene ester of 7-amino-3-methanesulfonate-3-cefem-4-carboxylic acid (994 mg, 2 mmol) and (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-methoxyethoxy acid (662 mg, 2.2 mmol) in dichloromethane (16 ml) was added at a temperature of -30oC N-methylmorpholin, (to 0.72 ml, 6.6 mmol) and phenyl dichlorophosphate (0.33 ml, 2.2 mmol), and the mixture is stirred at the same temperature for 2.5 hours, the Reaction mixture was cooled by adding 10% hydrochloric acid (5 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous solution of acid sodium carbonate and water, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate 2: 1, containing 0.5% acetic acid) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-methoxyimino - Tyl] amino-3-methanesulfonyl-hydroxy-3-cefem-4-carboxylic acid (1.07 g), yield 72% NMR d (CDCl3) ppm: 1,53 (c, 9H), 2,83 (c, 3H), 3,63, 3,88 (Avcv, J= 19 Hz, 2H), 4.09 to (s, 3H), 5,18 (d, J=5 Hz, 1H), 6,04 (DD, J=5 Hz, J=9 Hz, 1H), 6,95 (s, 1H), 7,2-7,5 (m, 13H).

5) Aleocharine complex diphenylmethylene ester of 7-amino-3-methanesulfonate-3-cefem-4-carboxylic acid (1,49 g, 3 mmol) and (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-cyclopentyloxy- -acetic acid (1.23 g, 3.5 mmol) in dichloromethane (30 ml) at a temperature of -30oC was added N-methylmorpholine (1.1 ml, 10 mmol) and after 1 min phenyl dichlorophosphate (0,49 ml, 3.3 mmol) and the mixture was stirred at the same temperature for 2 hours, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (6 ml) and water (50 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous solution of acid sodium carbonate and water, dried in the presence of sodium sulfate and purified by chromatography on silica gel (toluene: ethyl acetate 5:1, containing 0.5% acetic acid) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-cyclopentyloxy - aminoacetate] -3-methanesulfonate-3-cefem-4-carboxylic acid (1,86 mg) as a white foam, entrance 78% NMR d (CDCl3) ppm: 1,53 (c, 9H), 1,3-2,0 (m, 8H), 2,80 (s, 3H), 3,61, 3,88 (Avcv, J=19 Hz, 2H), 4,9-5,0 (m, 1H), 5,17 (d, J=5 Hz, 1H), 6,04 (DD, J=5 Hz, J=9 Hz, 1H), of 6.96 (s, 1H), and 7.3-7.5 (m, N), or 8.6 (Shir. s, 1H). IR n (CHCl3) cm-1: 3400, 1792, 1724, 1685, 1543, 1367, 1226, 1220, 1158.

6) Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(2-propenyloxy)acetyl (R-2).

To a suspension of the hydrochloride complex diphenylethylamine-4-yl)-2-(2-propenyloxy )acetic acid, 1.13 g, (3.46 mmol) in dichloromethane (30 ml) at a temperature of -30oC was added N-methylmorpholine (1.1 ml, 10 mmol) and after 1 min phenyl dichlorophosphate (0,49 ml of 3.27 mmol), and the mixture was stirred at the same temperature for 2 hours, the Reaction mixture was stirred for 1 H. a solution of hydrochloric acid (6 ml) and water (30 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous solution of acid sodium carbonate and water, dried in the presence of sodium sulfate and purified by chromatography on silica gel (toluene: ethyl acetate 5:1, containing 0.5% acetic acid) to obtain the complex diphenyl ether 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl-2-(2-propenyloxy - Mino)acetamido]-3-methanesulfonate-3-cefem-4-carboxylic acid (1,83 g) as a pale yellow foam, yield 79% NMR d (CDCl3) ppm: 1,53 (c, 9H), 2,82 (c, 3H); 3,61, 3,86 (Avcv, J=20 Hz, 2H), 4,80 (d, J=6 Hz, 2H), 5,17 (d, J=5 Hz, 1H), 5,23-of 5.40 (m, 2H), 5,94-6,13 (m, 2H), 6,95 (s, 1H), 7,2-7,5 (m, N), or 8.6 (Shir. s, 1H). IR n (CHCl3cm-1: 3400, 1792, 1725, 1686, 1544, 1367, 1286, 1223, 1219, 1160.

Getting 6: Acid with 7-side chain.

1) (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-tricalciumphosphate acid (R:BocATtr).

< / BR>
1. To a suspension of complex ethyl ester (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyimino the t-BUTYLCARBAMATE (240 ml 1.04 mol) dropwise at room temperature, and the mixture is stirred for 19 hours, the Reaction mixture is mixed with 0.5 N. the solution of hydrochloric acid (500 ml), and take the dichloromethane layer. The organic layer is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is diluted with ethanol (200 ml) and again concentrated. To a solution of this residue in ethanol (300 ml) under cooling on ice, was added dropwise a solution of sodium hydroxide (64 g, 1.6 mol) in water (300 ml), and the mixture is stirred while cooling on ice for 30 min and at room temperature for 19 hours, the Reaction mixture is mixed with concentrated hydrochloric acid (140 ml) and ice water (1000 ml) and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrate. The resulting crystalline residue was washed with water, dried and washed with simple ether to obtain (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-hydroxylaminoxymes acid (86,3 g) as colorless crystals, melting point 170-173oC (decomposition). NMR (CDCl3SOCD3) ppm: 1.55V (c,9H), 7,38 (c, 1H). IR n (Nujol) cm-1: 3640, 3510, 3125, 2520 Shir. 1730, 1635, 1600, 1530, 1295, 1165, 1000.

2 To a solution of (Z)-2-(2-tribalat potassium carbonate (92 g, 0.67 mol) and triphenylmethylchloride (100 g, 0.36 mol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into a mixture of concentrated hydrochloric acid (111 ml) and ice water (1500 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous solution of acid sodium carbonate, 2% hydrochloric acid and brine, then dried in the presence of sodium sulfate and concentrate. The remainder kristallisera from dichloromethane to obtain (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-tricalciumphosphate acid (144 g) as colorless crystals, yield 91% melting point 157-158oC. NMR d (CDCl3CD3SOOD3) ppm: 1.50 in (c, 9H),? 7.04 baby mortality (c, 1H), 7,2-7,4 (m, 15 NM). IR n (Nujol) cm-1: 3200, 1726, 1697, 1563, 1281, 1243, 1155.

2) (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pontenova acid (S 1108)

< / BR>
1. To a solution of complex methyl ester 4-chloroacetoacetic acid (700 mg and 4.65 mmol), Propionaldehyde (405 mg, 6,97 mmol) and acetic acid (28 mg, 0.47 mmol) in dichloromethane (3 ml) was added a solution of piperidine (24 mg, 0.28 mmol) in dichloromethane (0.5 ml), and the mixture is stirred at a temperature of -27oC for 120 minutes, the Reaction mixture was washed with dilute chlorotoluron-2-propylenecarbonate acid in the form of its complex with methyl ether (818 mg), the output is 92% NMR (CDCl3) ppm: 1,08 (t, J=7.5 Hz, 3H), of 1.55 (t, J=7.5 Hz, 3H), about 2.2-2.8 (m, 2H), of 3.78 (s, 3H), 3,82 (s, 3H), 4,35 (s, 2H), and 4.40 (s, 2H), 7,0-7,4 (m, 1H).

To a solution of complex methyl ether 4-chloro-2-propylenecarbonate acid (818 mg, the 4.29 mmol) in dimethylformamide (2.1 ml) was added sodium bromide (957 mg, 9.3 mmol), and the mixture is stirred at a temperature of 22oC for 2 h to obtain a complex solution of methyl ester 4-bromo-2-propylenecarbonate acid. NMR d (CDCl3) ppm: to 1.15 (t, J=7.5 Hz, 3H), 2,50 (kV, J= 7.5 Hz, 3H), 2,53 (kV, J=7.5 Hz, 2H), 3,82 (s, 3H), 3,90 (s, 3H), 4,15 (s, 2H), 4,22 (s, 2H), 7,10 (t, J=7.5 Hz, 1H), 7,12 (t, J=7.5 Hz, 1H). This solution was diluted with dichloromethane (0.7 ml), mixed with a solution of thiourea (354 mg and 4.65 mmol) in dimethylformamide (1.4 ml) and stirred at a temperature of from 15oC to 30oC for 25 minutes, the Reaction mixture was washed with aqueous solution of sodium hydroxide and saline concentrate at a temperature of less than 15oC under reduced pressure mixed with acetone (1.8 ml) and neutralized with 35% hydrochloric acid. Selected crystals are washed with acetone and dried in the presence of sodium sulfate with obtaining hydrochloride difficult methyl ester (Z)-2-(2-aminothiazol-4-yl)-2-pentenol acid (452 mg), output is adequate C9H12N2O2HClH2O. NMR d (CO3OD) ppm: 1,14) (t, J=8 Hz, 3H), 2,61, (arc, J=7,6 Hz, 2H), 3,84 (s, 2H), of 6.71 (t, J=7,6 Hz, 1H), 6,83 (s, 1H). IR n (CHCl3) cm-1cm-1: 3360, 3095, 1721, 1635, 1592, 1235.

3. A solution of the hydrochloride difficult methyl ester (Z)-2-(2-aminothiazol-4-yl)-2-pentenol acid (550 mg, 2.2 mmol) in dichloromethane (3 ml) is shaken with a 7% aqueous solution of acid sodium carbonate (3.8 ml). Take the organic layer and concentrate to 1.7 ml of the resulting solution is mixed with a solution of di-tert-BUTYLCARBAMATE (of 0.53 ml, 2.3 mmol, 1.05 equivalent) and pyridine (57 μl, to 0.72 mmol) or dimethylaminopyridine (27 mg, 0.22 mmol) in dichloromethane (0.8 ml) and stirred at a temperature of 25oC for 6 hours, the Reaction mixture was mixed with 1.6% hydrochloric acid (1,72 ml) and stirred. Take the organic layer, washed with aqueous solution of acid sodium carbonate, dried and concentrated under reduced pressure. The residue is purified column chromatography on silica gel with getting complicated methyl ester (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pentenol acid (528 mg) in the form of oil, 71% yield NMR d (CDCl3) ppm: 1,10 (t, J=7,6 Hz, 3H), 1,52 (c, 9H), 2,42 (DQC, J=7,6 Hz, 2H), 3,85 (s, 3H), 6,76 (t, J= 7,6 Hz, 1H), 6.89 in (s, 1H). IR n (CHCl3) cm-1oC for 90 min, the Reaction mixture was adjusted to a pH of 4.7 with the use of 35% hydrochloric acid and maintained for 1 h at a temperature of 20oC. the crystals formed are collected by filtration, washed with isopropanol and dried to obtain (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pentenol acid (325 mg), yield 86% of the melting point 187oC (decomposition). NMR d (CDCl3), ppm of 1.09 (t, J= 7,6 Hz, 3H), of 1.55 (s, N), 2,64 (arcs, J=7,6 Hz, 2H), 6,69 (t, J=7,6 Hz, 1H), of 6.96 (C. 1H). IR n (CHCl3) cm-1: 3160, 2548 Shir. 1721, 1685, 1556, 1252, 1156.

Getting 7: other modifications of the rings cafema.

1). Getting 7-amine: Het 1,2,3-triazole-4-yl (R).

To a solution of complex diphenylmethylene ether 7 phenylacetamido-3-(1,2,3-triazole-4-yl)thiomethyl-thio-3-cefem-4-carboxylic acid (629 mg, 1 mmol) in dichloromethane (7 ml) cooled on ice was added pyridine (162 μl, 2 mmol) and Piatigorsky phosphorus (380 mg, 1.8 mmol) and the mixture was stirred at room temperature for 40 minutes the Solution is added dropwise to a solution of 1,3-butanediol (and 0.46 ml) in dichloromethane (2 ml) at a temperature of -30oC. After PE is ETANA. The extract is dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue yields a powder (518 mg) containing hydrochloride complex diphenylmethylene ester of 7-amino-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid from ethyl acetate dichloromethane. This powder (100 mg) is suspended in dichloro methane, shaken with 5 aqueous solution of acid sodium carbonate, then dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel with getting complicated diphenylmethylene ester of 7-amino-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (10 mg). Output 10% NMR d (CDCl3)-CD3OD3) ppm: 3,61, to 3.73 (Avcv, J=17 Hz, 2H), 4,07 b 4,14 (Avcv, J=14 Hz, 2H), 4,74 (d, J=5 Hz, 1H), 4.95 points (d, J=5 Hz), 1H), of 6.96 (s, 1H), 7,2-7,5 (m, J=5 Hz, 10H), 7,56 (s, 1H), IR n (CHCl3) cm-1: 1776, 1726.

2) Getting 7-amine: Het, trityl-1,2,3-triazole-4-yl (R).

1) To a solution of complex diphenylmethylene ether 7 phenylacetamido-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (10.0 g, 15.9 mmol) in dichloromethane (100 ml) cooled on ice was added pyridine (1,54 ml, 19.1 ml) and Fritillaria (5.32 g, of 19.1 mmol) and the mixture was stirred at room temperature for the comfort with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrate. To a solution of the residue in dichloromethane (50 ml) cooled on ice was added pyridine (2.57 m) ml of 31.8 mmol) and Piatigorsky phosphorus (5,96 g, 28.6 mmol) and the mixture stirred for 30 minutes, the Reaction mixture was added dropwise to a solution of 91.3-butanediol (8.6 ml, with 95.9 mmol) in dichloromethane (25 ml) at a temperature of -30oC, and the mixture is stirred at a temperature of -20 to -30oC for 10 min and cooled on ice for 40 minutes, the Reaction mixture is mixed with water, diluted with dichloromethane, washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is sprayed with simple ether, washed with simple ether, dissolved in dichloromethane, washed with 5% aqueous solution of acid sodium carbonate, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) to obtain the complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimately-3-cefem-4-carboxylic acid (6,70 g, pale yellow foam, yield 56% NMR d (CDCl3) ppm: 3,62, 3,82 (Avcv, J=17.6 Hz, 2H), 4,05, 4,16 (Avcv, J=a 13.4 Hz, 2H), of 4.66 (d, J=5.0 Hz, 1H), 4,87 (d, J=5.0 Hz, 1H), 6.90 to (s, 1H), 7,05-7.5 (m, 25H), 7,45 (c, 1H). IR n (CHCl3) cm3) ppm: to 3.58, to 3.73 (Avcv, J=17.5 Hz, 2H), 4,05, 4,14, (Avcv, J=13,7 Hz, 2H), 4,73 (d, J=5.0 Hz, 1H), 4,94 (d, J= 5.0 Hz, 1H), 6,97 (s, 1H), of 7.25-7.5 (m, 10H), 7,56 (s, 1H). IR n (CHCl3) cm-1: 3430, 1780, 1730, 1602, 1495, 1451, 1388, 1362; melting point 112-115oC).

3) Oxidation of the sulfoxide (RV).

To a solution of complex diphenylmethylene ester 7-(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - cetamide)-3-methanesulfonate-3-cefem-4-carboxylic acid (30.0 g, of 30.9 mmol) in dichloromethane (300 ml) at a temperature of -30oC add m-chloroperbenzoic acid (7,33 g, the degree of acid 80% to 1.1 equivalent 34,0 mmol), and the mixture is stirred at a temperature of -20 to -30oC for 20 minutes After 20 min, the reaction mixture is mixed with aqueous 5% sodium thiosulfate solution (15 ml), diluted with dichloromethane, washed with aqueous 5% solution of acid sodium carbonate and brine, is dried in the presence of sodium sulfate and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate 5:1-3:1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino]-3-methanesulfonate-3-cefem-4-carboxylic it is Avkv, J=18.6 Hz, 2H), 4,55 (d, J=5.0 Hz, 1H), of 6.31 (DD, J=5.0 Hz, J= 10.1 Hz, 1H), 7,00 (s, 2H), 7,15-to 7.50 (m, 25N), 7,88 (d, J=10.1 Hz, 1H), 8,33 (Shir. s, 1H). IR n (CHCl3) cm-1: 3430, 1806, 1725, 1687, 1543, 1510, 1493, 1368, 1282, 1227, 1188, 1154.

4) Substitution of obtaining thiol (RV).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-methanesulfonate-3-cefem-4-carboxylic acid (25,0 g, to 25.3 mmol) in dimethylformamide (200 ml) at a temperature of -30oC add the hydrate of sodium hydrosulfide (70% 5,07 g, 2.5 equivalents, and 63.4 mmol), and the mixture is stirred at a temperature of from -20 to 30oC for one hour. The reaction mixture is mixed with 10% hydrochloric acid (20 ml), diluted with water, extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is dissolved in toluene and concentrated to dryness to obtain 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - ndimethylacetamide]-3-mercapto-3-cefem-4-carboxylic acid (23.3 g, contains 8 wt. toluene) as a yellow foam. Exit 91% NMR d (CDCl3) ppm: 1,49 (c, 9H), 3,27, 3,67 (Avcv, J=18,4 Hz, 2H), 4,50 (d, J=4,8 Hz, 1H), 5,12 (Shir. s, 1H), and 6.25 (DD, J=4,8 Hz, J=10,0 what measures 1: 3-Substitution dilacerata

< / BR>
1). The acyl phenylacetyl; Het 1,2,3-triazole-4-yl (R).

To a solution of 4-acetylthiourea-1,2,3-triazole (920 mg, to 4.87 mmol) in dimethylformamide (24 ml) at a temperature of -60oC was added dropwise a solution of sodium methylate in methanol (1,28 ad 7.5 ml). After stirring at the same temperature for 30 min was added dropwise a solution of complex diphenylmethylene ether 7 phenylacetamido-3-methanesulfonyl-hydroxy-3-cefem-4-carboxylic acid (2,32 g, 4 mmol) in dimethylformamide (8 ml). After 30 min the reaction mixture was neutralized with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and purified by chromatography on silica gel. The fraction crystallized from ethyl acetate to obtain complex diphenylmethylene ether 7 phenylacetamido-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (1,14 g). Exit 45% melting point 169-171oC (decomposition), NMR d (CDCl3CD3OD) ppm: 3,52, 3,62 (Avcv, J=14 Hz, 2H), 4.95 points (d, J=5 Hz, 1H), 5,74 (d, J= 5 Hz, 1H), 6,92 (s, 1H), 7,2-7,5 (m, 15 NM), EUR 7.57 (s, 1H), IR n (KV) cm-1: 3400, 3300, 1784, 1700, 1650, 1520, 1375, 1220, 1170.

2). Acyl (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pentanol; Het 1,2,3-triazole-4-yl (E-1).

To a solution of 4-aceta sodium in methanol (1.9 ml) at a temperature of -60oC, and the mixture is stirred for 20 min, mixed with a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-pentanoyl-amino-3-methanesulfonate-3-cefem-4-carboxylic acid (740 mg, 1 mmol) in dimethylformamide (3 ml) and stirred at the same temperature for 40 minutes, the Reaction mixture was diluted with 10% hydrochloric acid (2 ml) and water (30 ml) and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and purified by chromatography on silica gel (toluene:ethyl acetate 2:1) obtaining a complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-phenteramine] - -3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (553 mg) as colorless foam. The output is 70% NMR d (CDCl3) ppm: 1.14 in (t, J=7,6 Hz, 3H), and 1.54 (s, N), 2,55 is 2.75 (m, 2H), 2,9-3,3 (Shir. 2H), 3,91, 4,07 (Avcv, J=12 Hz, 2H), to 4.98 (d, J=4.4 Hz, 1H), 6,83 (s, 1H), 7,2-7,5 (m, 10H), a 7.62 (s, 1H), 8,11 (d, J= 8 Hz, 1H). IR n (CHCl3) cm-1: 3420, 3330, 3150, 1758, 1712, 1665, 1551, 1218, 1155.

3). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-cyclopentylacetyl.

Het 1,2,3-triazole-4-yl (E-3).

To a solution of 4-acetylthiourea-1,2,3-triazole (374 mg, to 1.98 mmol) in dimethylformamide (9 ml) was added to cap the minutes To this mixture was added dropwise a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-cyclopentyloxy - aminoacetate] -3-methanesulfonate-3-cefem-4-carboxylic acid (1.20 g, 1.5 mmol) in dimethylformamide (4.5 ml), and the mixture is stirred at the same temperature for 40 min, mixed with acetic acid (0.3 ml), diluted with water and extracted with ethyl acetate. The extract is washed with water, 5% aqueous solution of acid sodium carbonate and purified by chromatography on silica gel (toluene:ethyl acetate(3:1)-(2:1)). Eluting the substance crystallized from toluene and recrystallized from ethyl acetate to obtain complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-cyclopentyloxy- -aminoacetate]-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (274 mg). Output is 22% melting point 198oC (decomposition). NMR d (DCl3CD3OD) ppm: 1.55V (c, 9H), 1,3-2,0 (m, 8H), 3,56, and 3.72 (Avcv, J= 17 Hz, 2H), 4,9-5,0 (m, 1H), is 5.06 (d, J=4,8 Hz, 1H), 5,86 (d, J=4,8 Hz, 1H), 6,97 (s, 1H), and 7.3-7.5 (m, 11N), 7,60 (s, 1H). IR n (KBR) cm-1: 3330, 3200, 1785, 1725, 1698, 1660, 1570, 1525, 1370, 1241, 1220, 1160.

4). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(2-propenyloxy- )acetyl.

Het 1,2,3-triazole-4-yl (E-2).< drops of 1.26 N. a solution of sodium methylate in methanol (1.9 ml) and the temperature of -60oC, and the mixture is stirred at the same temperature for 25 min and cooled to a temperature of -78oC. To the reaction mixture was added dropwise a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonyl-aminothiazol-4-yl)-2-(2-propenyloxy - iamino)acetamido] -3-methanesulfonate-3-cefem-4-carboxylic acid (770 mg, 1 mmol) in dimethylformamide (3 ml) and the mixture is stirred at the same temperature for 40 minutes, the Reaction mixture was diluted with 1 N. a solution of hydrochloric acid (2 ml) and water (50 ml) and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and purified by chromatography on silica gel (toluene:ethyl acetate 2:1). Erwerbende substance crystallized from toluene to obtain complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylmethyl-4-yl)-2-(2-propenyloxy - imino)acetamido]-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (415 mg) as colorless crystals. The output is 51% melting point 167-170oC (decomposition). NMR d (CDCl3CD3OD) ppm: 1.55V (c, 9H), 3,54, 3,69 (Avcv, J=17 Hz, 2H), 4.16 the (s, 2H), 4,82 (d, J=5.8 Hz, 2H), 5,07 (d, J= 4,6 Hz, 1H), 5,26 (DD, J=1.4 Hz, J=a 10.6 Hz, 1H), lower than the 5.37 (DD, J=1.4 Hz, J=17,4 Hz, 1H),200, 1782, 1717, 1696, 1658, 1534, 1370, 1281, 1240, 1221, 1154=

5). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,2,3-triazole-4-yl (EE).

To a solution of 4-acetylthiourea-1,2,3-triazole (11,50 g, 61 mmol) and dimethylformamide (300 ml) was added dropwise a solution of sodium methylate (1,28 N. 94 ml) in methanol at a temperature of from -60 to -50oC. After stirring for 20 min to the mixture for 7 min at the same temperature was added a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-methanesulfonate-3-cefem-4-carboxylic acid (48,55 g, 50 mmol) in dimethylformamide (190 ml). After 50 min the reaction mixture is diluted with acetic acid (10 ml) and water (2 l) and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is crystallized from toluene and recrystallized from a mixture of ethyl acetate toluene with getting complicated diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2-trisiloxane - acetamido]-3-(1,2,3-triazolyl-4-yl)tomatillo-3-cefem-4-carboxylic acid as colorless crystals (29,14 g). The output is 57% temperature plvl who 2H) 5,08 (d, J=5 Hz, 1H), 5,88 (d, J=5 Hz, 1H), 6,98 (s, 1H), was 7.08 (s, 1H), 7,2-7,5 (m, 25N), 7,60 (s, 1H). IR n (KBR) cm-1: 3390, 3210, 1800, 1725, 1688, 1555, 1495, 1449, 1375, 1275, 1245, 1225, 1155.

6). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,2,3-triazole-4-yl (Tolentino) (E-4).

To a solution of 4-benzoylthiourea-1,2,3-triazole (150 mg, of 0.60 mmol) in dimethylformamide (3 ml) at a temperature of -60oC was added a solution of sodium methylate in methanol (1,26 N. of 0.95 ml), and the mixture is stirred for 80 minutes at a temperature of from -50 to -60oC. To the mixture at -70oC was added a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-methanesulfonate-3-cefem-4-carboxylic acid (485 mg, 0.5 mmol) in dimethylformamide (2 ml), and the mixture is stirred at -70oC for 20 min, the Reaction mixture is mixed with acetic acid (0.1 ml), diluted with water, extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is crystallized from toluene to obtain complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(1,2,3-triazole-4-ultimatelty)-3-the 5, 3,63 (Avcv, J=and 17.2 Hz, 2H), 4,12, 4,15 (Avcv, J= 14,2 Hz, 2H), 5,08 (d, J=5 Hz, 1H), 5,88 (d, J=5 Hz, 1H), 6,98 (s, 1H), was 7.08 (s, 1H), 7,2-7,5 (m 25N), 7,60 (s, 1H). IR n (KBr) cm-1; 3390, 3210, 1800, 1725, 1688, 1555, 1495, 1449, 1375, 1275, 1245, 1225, 1155.

7). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 1 trityl-1,2,3-triazole-4-yl (E).

To a solution of 4-acetylthiourea-1 trityl-1,2,3-triazole (25,0 g, 58 mmol) in a mixture of dimethylformamide (300 ml) and tetrahydrofuran (100 ml) at a temperature of -78oC was added dropwise a solution of sodium methylate in methanol (1,35 N. of 37.8 ml, 51 mmol). After stirring for 15 min to the mixture at a temperature of -78oC for 5 min was added a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - ndimethylacetamide] -3-methanesulfonate-3-cefem-4-carboxylic acid (45,0 g, to 48.3 mmol) in a mixture of dimethylformamide (120 ml) and tetrahydrofuran (45 ml). After stirring for 1 h at a temperature of 78oC, the reaction mixture was diluted with 10% hydrochloric acid (19 ml) and water (1.5 l) and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (toluene: the 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trityloxy - acetamido] -3-(1-trityl-1,2,3-triazole-4-yl)-2-trityloxy-aminoacetate - up]-3-(1-trityl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid as a white powder (49,1 g). The output 84% NMR d (CDCl3) ppm: 1.50 in (c, 9H), 3,31, 3,56 (Avcv, J=17 Hz, 2H), of 4.05 (s, 2H), equal to 4.97 (d, J=4,8 Hz, 1H), of 5.84 (DD, J=4,8 Hz, J=8.7 Hz, 1H), 6,86 (s, 1H), 7,02 (s, 1H), 7,05 to 7.4 (m, 14N), was 7.45 (s, 1H), 8,4-8,7 (Shir.s, 1H). IR n (CHCl3) cm-1: 3400, 1783, 1718, 1685, 1541, 1490, 1443, 1368, 1154.

8). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-methoxyaminomethyl; Het - 1 trityl-1,2,3-triazole-4-yl (3E1-2-2).

To a solution of 4-acetylthiourea-1 trityl-1,2,3-triazole (414 mg, 0.96 mmol) in a mixture of dimethylformamide (5 ml) and tetrahydrofuran 2.5 ml) was added 1,28 n solution of sodium methylate (0,69 ml, 0.88 mmol) at a temperature of -78oC, and the mixture is stirred for 12 minutes To this mixture was added dropwise a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-methoxyimino - ethyl] amino-3-methanesulfonate-3-cefem-4-carboxylic acid (594 mg, 0.8 mmol) in dimethylformamide (2.5 ml) for 2 min, and the mixture is stirred at the same temperature for one hour. To the mixture was added 10% hydrochloric acid (1 ml) for cooling the reaction and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) to obtain the complex diphenylmethyl)tomatillo-3-cefem-4-carboxylic acid as a white foam (579 mg). The output is 70% NMR d (CDCl3) ppm: 1.52m (c, 9H), 3,65, 3,81 (Avcv, J=18 Hz, 2H), 4,10, 4,19 (Avcv, J= 12 Hz, 2H), 5,02 (d, J=4,8 Hz, 1H), 5,90 (DD, J=4,8 Hz, J=8,8 Hz, 1H), 6.87 in (s, 1H), 7,0-7,5 (m, N), 8,8 (Shir. s, 1H), IR n (CHCl3cm-1: 3400, 1780, 1720, 1680, 1540, 1370.

9). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath. Het is 1-methyl-1,2,3-triazole-4-yl (E-1).

To a solution of 4-acetylthiourea-1-methyl-1,2,3-triazole (392 mg, of 1.93 mmol) in a mixture of dimethylformamide (6 ml) and tetrahydrofuran (2 ml) at a temperature of -78oC was added dropwise a solution of 1.28 N. of sodium methylate (1,33 ml, 1.70 mmol) in methanol. After stirring for 15 min, to the mixture was added a solution of dimethyl ether complex 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-methanesulfonate-3-cefem-4-carboxylic acid (1.50 g, 1.54 mmol) in dimethylformamide (5 ml). After stirring for one hour at the same temperature, the reaction mixture is neutralized with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 3:2) obtaining konop-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (1,43 g). The yield is 90% Colorless foam. NMR d (CDCl3) ppm: 1,49 (c, 9H), 3,35, 3,51 (Avcv, J=16,8 Hz, 2H), 3,92 (s, 3H), 4,08 (s, 2H), is 5.06 (d, J=4,7 Hz, 1H), 5,91 (DD, J=8.6 Hz, J=4,7 Hz, 1H), 6,93 (s, 1H), 6,99 (s, 1H), 7,15-to 7.50 (m, N), 7,66 (d, J= 8.6 Hz, 1H), 8,83 (Shir. C. 1H); IR n (CHCl3cm-1: 3390, 1781, 1714, 1684, 1540, 1490, 1443, 1366, 1281, 1218, 1153, 970.

10). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 2-methyl-1,2,3-triazole-4-yl (E-2).

To a solution of 4-acetylthiourea-2-methyl-1,2,3-triazole (392 mg, of 1.93 mmol) in a mixture of dimethylformamide (8 ml) and tetrahydrofuran (4 ml) was added dropwise a solution of 1.28 N. of sodium methylate (1,33 ml, 1.70 mmol) in methanol at a temperature of -78oC, and the mixture is stirred for 15 minutes To the mixture was added a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-methanesulfonate-3-cefem-4-carboxylic acid (1.50 g, 1.54 mmol) in dimethylformamide (5 ml). After mixing, the mixture is neutralized with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (n-hexane:ethyl acetate 1:1) with Poluchenie]-3-(2-methyl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid 91,45 mg) as colorless foam. The output is 91% NMR d (CDCl3) ppm: 1.50 in (c, 9H), 3,32, 3,43 (Avcv, J= 16,8 Hz, 2H), 3,98 (s, 2H), 4,10 (s, 3H) 5,07 (d, J=4.9 Hz, 1H), 586 (DD, J=8,3 Hz, J=4.9 Hz, 1H), 6.90 to (s, 1H), 6,99 (s, 1H), 7,15 was 7.45 (m, 25N), 7,49 (s, 1H), to 7.61 (d, J=8,3 Hz, 1H), cent to 8.85 (Shir. s, 1H). IR n (CHCl3) cm-1: 3402, 1785, 1717, 1686, 1563; 1493, 1445, 1369, 1280, 1155, 1115, 1079, 972, 910.

11). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Her - 1 trityl-1,2,4-triazole-3-yl (E).

To a solution of 3-acetylthiourea-1 trityl-1,2,4-triazole (1,17 g, a 2.71 mmol) in a mixture of dimethylformamide (10 ml) and tetrahydrofuran (5 ml) was added dropwise a solution of sodium methylate in methanol (1,28 n, 2.0 ml, 2.56 mmol) at a temperature of 78oC, and the mixture is stirred for 15 minutes To this mixture was added dropwise a solution of complex diphenylmethylene ether 7-/(Z)-2-(2-tert-butoxycarbonylamino-4-yl) 2-trailokyanath/-3-methanesulfonate-3-cefem-4-carboxylic acid (2,40 g, 2,47 mmol) in dimethylformamide (5 ml). After stirring for 50 min at the same temperature, the reaction mixture is cooled to 10 hydrochloric acid (0.95 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified et-butoxycarbonylamino-4-yl)-2-trailokyanath]-3 -(1-trityl-1,2,4-triazole-3-yl)tomatillo-3-cefem-4-carboxylic acid as a colourless foam (1,93 g). NMR (DCl3) of 1.50 ppm (c, 9H), 3,30, 3,41 (Avcv, J is 17.4 Hz, 2H), 4,17 (s, 2H), 4.95 points (d, J 4.9 Hz, 1H), 5,90 (DD, J 4.9 Hz, J 8.5 Hz, 1H), 6,94 (s, 1H), 7,05-of 7.55 (m, N): 7,89 (s, 1H), 8,4-8,6 (Shir.s, 1H). IR n (CHCl3) cm-13398, 1981. 1715, 1683, 1540, 1442, 1367, 1270, 1154.

12). Acyl (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2 - trailokyanath; Het is 5-tetrazolyl (3E1-2-1).

To a solution of 5-acetylcholinesterase (478 mg, 2,52 mmol) in dimethylformamide (30 ml), cooled at -70oC, was added dropwise a solution of 1.26 N. of sodium methylate in methanol (3.9 ml), and the mixture is stirred at a temperature of from -60 to -65oC for 25 minutes To the reaction mixture, cooled at -70oC, was added dropwise a solution of complex diphenylmethylene ester 7-(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - cetyl]amino-3-methanesulfonate-3-cefem-4-carboxylic acid (2.00 g, of 2.06 mmol) in dimethylformamide (7 ml), and the mixture is stirred at a temperature of from -65 to -70oC for 40 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (0.5 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate, filter and concentrate. The residue is purified column chromatography is mportant diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-(tetrazol-5-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow foam (968 mg), containing an unidentified side product (approximately 10%). NMR d (CDCl3CD3OD) ppm: 1.52m (c, 9H), to 3.58, 3,71 (Avcv, J=17.6 Hz, 2H), 4,46 (s, 2H), 5,10 (d, J=4,8 Hz, 1H), of 5.99 (d, J= 4,8 NC, 1H), 6,95 (s, 1H), 7,06 (s, 1H), 7,15-to 7.50 (m, 25N). IR n (l3) cm-1: 3402, 3200 Shir. 1786, 1717, 1672, 1544, 1492, 1446, 1369, 1280, 1154.

13). Acyl - 2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 2-pyridyl (2E1-3).

To a solution of 2-acetylthiophene (249 mg, 1.25 mmol) in a mixture of dimethylformamide (4.0 ml) and tetrahydrofuran (2.0 ml), cooled at a temperature of -78oC, are added dropwise 1,26 n solution of sodium methylate in methanol (0,87 ml, 1.10 mmol), and the mixture is stirred at a temperature of -78oC for 15 minutes To this reaction mixture was added a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-methanesulfonate-3-cefem-4-carboxylic acid (971 mg, 1.00 mmol) in diphenylformamidine (2 ml), and the mixture is stirred at a temperature of -78oC for one hour. The reaction mixture is mixed with 10% hydrochloric acid to stop the reaction, diluted with water and extracted with ethyl acetate. The extract is washed with diluted aqueous solution of carbonic acid sodium iilegal (toluene: ethyl acetate 4:1) and rechromatography on silica gel (toluene:ethyl acetate 7: 1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(pyrid-2-ultimatelty)-3-cefem-4-carboxylic acid as a colourless foam (753 mg). The output is 73% NMR d (CDCl3) ppm: 1,51 (c, 9H), 3,42, 3,56 (Avcv, J= and 17.2 Hz, 2H), of 4.45 (s, 2H), 5,04 (d, J=4.9 Hz, 1H), by 5.87 (DD, J=4.9 Hz, J= 8.6 Hz, 1H), 7,01 (DDD, J=7,4 Hz, J=4.9 Hz, J=1.0 Hz, 1H), 7,03 (s, 1H), 7,11-7,53 (m, 28N), to 2.41 (DD, J=4.9 Hz, J=1.8 Hz, J=1.0 Hz, 1H), 8,55 (Shir. s, 1H), IR n (CHCl3) cm-1: 3402, 1784, 1717, 1686, 1574, 1543, 1514, 1493, 1450, 1369, 1282, 1154.

Example 2: 3-substitution of the iodide

< / BR>
1). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - trityl-1,2,4-triazole-3-yl (E-4).

To a suspension of trityl-3-chlorotri-1,2,4-triazole (11,75 g, 30.0 mmol) in acetone (150 ml) was added sodium iodide (9.00 g, 60,0 mmol), and the mixture is stirred at a temperature of 50oC for 3 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate to obtain trityl-3-iodometry-1,2,4-triazole in the form of yellow crystals (NMR (CDCl3) ppm: 4,70 (c, 2H), 7,1-7,2 (m, 6N), 7.3 to 7.4 (m, N), of 7.96 (s, 1H); 13,0 g). To a solution of 1-oxide complex diphenylmethylene ether 7[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - tetramino]-3-argentite-3-cefem-4-carboxylic acid (16,8 g, 15 mmol) in hexamethylphosphoramide (90 ml) was added, trityl-3-iodometry-1,2,4-triazole (13 g) and the mixture peremeshivaniem saline and filtered through celite. The organic layer is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate 5:1-3:1) to obtain 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(trityl-1,2,4-triazole-3-ultimatelty(-3-cefem-4-carboxylic acid 11,29 g in the form of a pale brown foam. The output is 59% NMR d (CDCl3) ppm: 1,49 (c, 9H), 3,19, 3,82 (Avcv, J=18.5 Hz, 2H), 4,19 (d, J= 4,6 Hz, 1H), 4,16, 4,22 (Avcv, J=13,7 Hz, 2H), to 6.19 (DD, J=4,6 Hz, J=10.1 Hz, 1H), 6,97 (s, 1H), 7,05-7.5 (m, N), of 7.90 (s, 1H), 8,04 (d, J= 10.1 Hz, 1H), 8,30 (Shir. s, 1H), IR n (CHCl3) cm-1: 3400, 1804, 1725, 1689, 1543, 1496, 1449, 1371, 1040.

2). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 1-methyl-1,2,4-triazole-3-yl (E-2).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-argentite-3-cefem-4-carboxylic acid (3,37 g, 3 mmol) in hexamethylphosphoramide (20 ml) was added 3-iodometry-1-methyl-1,2,4-triazole (1.50 g), and the mixture is stirred at room temperature for 3 hours, the Reaction mixture was diluted with saturated brine and ethyl acetate and filtered with the aim of BPM is sodium and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 1:1) to give 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino]-3-(1-methyl-1,2,4-triazole(3-ultimatelty)-3-cefem-4-carboxylic acid (1,82 g) as a yellow-brown foam. The output 58% NMR d (CDCl3) ppm: 1,46. (c, 9H), 3,76 (c, 3H), 3,49, 4,12 (Avcv, J=18,4 Hz, 2H), 4,28 (s, 2H), 4,46 (d, J=4,8 Hz, 1H), 6,24 (DD, J=4,8 Hz, J= 9.8 Hz, 1H), 6,93 (s, 1H), 6,98 (s, 1H), 7,2-of 7.55 (m, 25N), to $ 7.91 (s, 1H), 8,02 (d, J=9.8 Hz, 1H), 8,66 (Shir. s, 1H). IR n (CHCl3) cm-1: 3410, 1803, 1724, 1689, 1545, 1510, 1497, 1450, 1372, 1042.

3). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 2-methyl-1,2,4-triazole-3-yl (E-1).

To a solution of 1-oxide complex diphenylmethylene ester 7b-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trityloxy - acetylamino] -3-argentite-3-cefem-4-carboxylic acid (3,37 g, 3 mmol) in hexamethylmelamine (20 ml) was added a solution of 3-iodometry-2-methyl-1,2,4-triazole (1.47 g) in hexamethylphosphoramide (3 ml), and the mixture is stirred at room temperature for 3 hours, the Reaction mixture was diluted with saturated brine and ethyl acetate and filtered to remove insoluble substances. The organic layer was washed with solely the Le (toluene:ethyl acetate 1: 1) to give 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(2-methyl-1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (1,76 g) as a brown foam. The output 56% NMR d (CDCl3) ppm: 1,47 (c, 9H), 3,66 (c, 3H), 3,47, 3,97 (Avcv, J=18,8 Hz, 2H), to 4.38 (d, J=4,8 Hz, 1H), 4,22, 4,48 (Avcv, J= 13,7 Hz, 2H), and 6.25 (DD, J=4,8 Hz, J=10.0 Hz, 1H), of 6.96 (s, 1H), 6,97 (s, 1H), 7,2-7,5 (m, 25N), 7,79 (s, 1H), 8,02 (d, J=10.0 Hz, 1H), 9,59 (Shir. s, 1H). IR n (CDCl3) cm-1: 3400, 1805, 1722, 1688, 1542, 1509, 1496, 1449, 1371, 1041.

4). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,2,3-thiadiazole-5-yl (3E1-1-1).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-mercapto-3-cefem-4-carboxylic acid (purity 92% 3.0 g, 3.0 mmol) in tetrahydrofuran (20 ml) was added a solution of silver nitrate (560 mg, 3.3 mmol) in water (3 ml), and the mixture is stirred while cooling on ice for 20 min, the Reaction mixture was diluted with water and extracted with dichloromethane. The extract is washed once with water, dried in the presence of sodium sulfate, filtered and concentrated to obtain 1-oxide complex diphenyl-methyl ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-Argentia-3-cefem-4-carboxylic acid (3,37 g) as a yellow-brown foam.

To a solution of this salt of silver in hexamethylphosphoramide (20 ml) was added a solution of 5-iodomethyl is of 3 hours The reaction mixture is mixed with saline and extracted with ethyl acetate. After filtration to remove insoluble substances, the extract washed with water, dried in the presence of sodium sulfate, filter and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate(3:1)-(2: 1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amino-3-(1,2,3-thiadiazole-5-yl)tomatillo-3-cefem-4-carboxylic acid (1,49 g) in powder form is not quite white. The output is 47% NMR d (CDCl3) ppm: 1,48 (c, 9H), 3,23, 3,91 (Avcv, J=17.6 Hz, 2H), 3,91, 4.09 to (Avcv, J=14.1 Hz, 2H), 4,49 (d, J=4,8 Hz, 1H), of 6.31 (DD, J=4,8 Hz, J=10.0 Hz, 1H), 6,98 (s, 1H), 7,15-7.5 (m, 25N), of 7.96 (d, J=10.0 Hz, 1H), 8,45 (Shir. s, 1H), for 9.47 (s, 1H). IR n (CHCl3) cm-1: 3400, 1804, 1718, 1690, 1543, 1510, 1493, 1446, 1369, 1226, 1154, 1031.

5). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,3,4-thiadiazole-2-yl (2E1-1).

1. To a solution of 1-oxide diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl-(2-trisiloxane - acetamido]-3-mercapto-3-cefem-4-carboxylic acid (2,78 g, 3 mmol) in tetrahydrofuran (20 ml) was added a solution of silver nitrate (560 ml) 1.1 equivalent, 3.3 mmol) in water (3 Mactan washed with water, dried in the presence of sodium sulfate and concentrated to obtain the residue (3.4 g) as a brown foam. To a suspension of this salt of silver in hexamethylphosphoramide (20 ml) was added 2-iodometry-1,3,4-thiadiazole (1.2 g) at room temperature and the mixture is stirred for 17 hours, the Reaction mixture was diluted with brine and extracted with ethyl acetate. The extract is filtered to remove solids, washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate(3: 1)-(2: 1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(1,3,4-thiadiazole-2-ultimatelty)-3-cefem-4-carboxylic acid (776 mg) as a pale brown foam. The output 25% NMR d (CDCl3) ppm: 1,49 (c, 9H), 3,74, 3,98 (Avcv, J=18 Hz, 2H), 4,29, 4,84 (Avcv, J=14 Hz, 2H), 4,55 (d, J=4,8 Hz, 1H), 6,27 (DD, J=4,8 Hz, J=10 Hz, 1H), 6,98 (s, 1H), 7,00 (s, 1H), 7,2-7,5 (m, 25N), 7,86 (d, J=10 Hz, 1H), 8,45 (Shir. s, 1H), 9,00 (s, 1H), IR n (CHCl3) cm-1: 3400, 1802, 1718, 1688, 1544, 1369, 1154.

2. A solution of a silver salt of 11-complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-mercapto-3-cefem-4-carboxylic acid (0.2 g) in hexa is th add 2 brometalia-1,3,4-thiadiazole (0.05 g). After sedimentation at room temperature for 10 h, thin layer chromatography (toluene:ethyl acetate 2:1) each portion allows to obtain the value of Rfsame as for the product, described in section 1 (Rf=0,2).

3. 1-Oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-mercapto-3-cefem-4-carboxylic acid (1.85 g, 2 mmol) was added to a solution of 2-iodometry-1,3,4-thiadiazole (675 mg, 2.6 mmol) in dimethylformamide (10 ml) at a temperature of -50oC. To the mixture was added dropwise a solution of pyridine (of 0.21 ml, 2.6 mmol), and the mixture is stirred at a temperature of -50oC for one hour. The reaction mixture is mixed with 1 N. a solution of hydrochloric acid (3 ml), diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate(3:1)-(2:1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(1,3,4-thiadiazole-2-ultimatelty)-3-cefem-4-carboxylic acid as pale brown foam (305 mg). Output 15%

6). Acyl - (Z)-2-(2-tert-butoxycarbonyl the aqueous diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-mercapto-3-cefem-4-carboxylic acid (1,85 mg, 2 mmol) in tetrahydrofuran (12 ml) was added solution of silver nitrate (373 mg, 1.1 equivalent, 2.2 mmol) in water (2 ml) under cooling on ice, and the mixture is stirred for 10 minutes, the Reaction mixture was diluted with water and extracted with dichloromethane. The extract is washed with water, dried in the presence of sodium sulfate and concentrate to obtain a silver salt in the form of a brown foam (2.1 mg). To a suspension of this salt in hexamethylphosphorotriamide (10 ml) was added 5-iodometry-2-methyl-1,3,4-thiadiazole (1,05 g), and the mixture is stirred at room temperature for 4 h, the Reaction mixture was diluted with brine and extracted with ethyl acetate. The extract is filtered to remove solid, washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate(3:1)-(2:1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amido]-3-(2-methyl-1,3,4-thiadiazole-5-ultimatelty)-3-cefem-4-to - arbonboy acid pale yellow foam (382 mg). Output is 18% d (CDCl3) ppm: 1,49 (s, N), 2,68 (s, 3H), 3,76, 3,97 (Avcv, J=19 Hz, 2H), 4,23, 4,75 (Avcv, J=14 Hz, 2H), 4,60 (d, J=4,6 Hz, 1H), 6,28 (DD, J=4,6 Hz, J=10 Hz, 1H) 6,97 LASS="ptx2">

7). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl-(2-trailokyanath; Het - 1-methyl-5-tetrazolyl (3E1-1-2).

1. To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amino-3-mercapto-3-cefem-4-carboxylic acid (purity 92% 3.0 g, 3.0 mmol) in tetrahydrofuran (20 ml) was added a solution of silver nitrate (560 mg, 3.3 mmol) in water (3 ml) under cooling on ice, and the mixture is stirred for 20 minutes, the Reaction mixture was diluted with water and extracted with dichloromethane. The extract is washed with water, dried in the presence of sodium sulfate, filtered and concentrated to obtain 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-argentite-3-cefem-4-carboxylic acid as pale brown foam (3,37 g).

2. To this solution of the silver salt in hexamethylphosphoramide (20 ml) was added a solution of 5-iodometry-1-methyltetrazole (1,33 g) in hexamethylphosphoramide (3 ml) and the mixture stirred for 16 h at room temperature. The reaction mixture was diluted with brine and extracted with ethyl acetate. After you filter out the insoluble substances extract promotoria on silica gel (toluene:ethyl acetate(3:1)-(2:1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-(1-methyl-5-tetrazolyl)tomatillo-3-cefem-4-carboxylic acid in the form of a brown foam (773 mg), exit 24% NMR d (CDCl3) ppm: 1,48 (c, 9H), 3,75 (c, 3H), of 3.73, 3,89 (Avcv, J=17.6 Hz, 2H), 4,22, 4,76 (Avcv, J=14,2 Hz, 2H), 4,50 (d, J=4,6 Hz, 1H), 6,27 (DD, J=4,6 Hz, J=10,2 Hz, 1H), 6,97 (s, 1H), 7,00 (s, 1H), 7,10-to 7.50 (m, 25N), 7,73 (d, J=10,2 Hz, 1H), 8,48 (Shir. s, 1H), IR n (CHCl3) cm-1: 3400, 1802, 1718, 1686, 1543, 1510, 1493, 1446, 1369, 1275, 1227, 1154, 1031.

8). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 2-methyltetrazol-5-yl (E-3).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-argentite-3-cefem-4-carboxylic acid (3,37 g, 3 mmol in hexamethylphosphoramide (20 ml) was added a solution of 5-iodometry-2-methyltetrazole (1,43 g) in hexamethylphosphoramide (3 ml) and the mixture is stirred at room temperature for 3 hours, the Reaction mixture was diluted with saturated brine and ethyl acetate and filtered. The organic layer of the filtrate is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate(4:1)-(3:1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino]-3-(2-methyltetrazol-5-ultimatelty)-3-cefem-4-carbon 3H), 4,24, to 4.41 (Avcv, J=a 13.9 Hz, 2H), 4,22 (s, 3H), 4,24, to 4.41(Avcv, J=a 13.9 Hz, 2H), (d, J=4,8 Hz, 1H), 6,27 (DD, J=4,8 Hz, J=10.0 Hz, 1H), 6,95 (s, 1H), 6,99 (s, 1H), 7,2-7,5 (m, 25N), to $ 7.91 (d, J=10.0 Hz, 1H), 8,45 (Shir. s, 1H). IR n (CHCl3) cm-1: 3410, 1806, 1725, 1690, 1543, 1510, 1496, 1382, 1372, 1320, 1044.

Example 3: modifying the Het.

1). Cleavage of trityl from ring trityl-1,2,4-triazole (E).

To a solution of 1-oxide complex diphenylmethylene ether 7[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - tetramino] -3-(trityl-1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (11.3 g) in acetone (60 ml) under cooling on ice, add monohydrate toluene-p-sulfonic acids (1.68 g, 8,83 mmol) and the mixture stirred for 4 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with aqueous 5% solution of acid sodium carbonate and brine, is dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate(1:1)-(1:2)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino]-3-(1,2,4-triazole-3-ylthio-methylthio)-3-cefem-4-carboxylic acid 2,84 g), in the form of a brown foam. Exit 31% NMR d (CDCl3CD3OD) ppm: 1,51 (c, 9H), to 3.58, 4 ) cm-1: 3380, 3200 Shir. 1803, 1720, 1690, 1547, 1510, 1497, 1450, 1372, 1040.

2). Methylation of the rings 1,2,3-triazole in positions 1, 2, and 3 (E).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-tert-butoxycarbonylamino-4-yl)-2-trailokyamohana - tamido] -3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (6,00 g, by 5.87 mmol) in a mixture of dichloromethane (60 ml) and tetrahydrofuran (30 ml) was added at a temperature of -50oC diisopropylethylamine (1.12 g, to 6.43 mmol). After 3 min stirring at a temperature of -40 to -50oC to the mixture was added methyl ester of triftoratsetata (2.4 ml) was diluted with water and extracted with ethyl acetate. The extract is washed with water and saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 3:2) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(3-methyl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (1.84 g, yield 30%), NMR d (CDCl3CD3OD) ppm: 1.52m (c, 9H), 3,43, 3,55 (Avcv, J=17.3 Hz, 2H), a 3.87, 3,94 (Avcv, J=13,7 Hz, 2H), 3,95 (s, 3H), 5,12 (d, J=4,8 Hz, 1H), of 5.99 (d, J=4,8 Hz, 1H), of 6.96 (s, 1H), 7,06 (s, 1H), 7,15-to 7.50 (m, 25N), 7,73 (s, 1H); IR n (CHCl3) cm

3). Methylation of the ring, 1,2,4-triazole (E).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino]-3-(1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (2,71 g, 2,61 mmol) in tetrahydrofuran (50 ml) at a temperature of -78oC was added a solution of lithium bis (trimethylsilyl)amide in tetrahydrofuran (1M, 2,9 ml), and the mixture is stirred at a temperature of -78oC for 10 min, mixed with a complex methyl ether of triftoratsetata (0.33 ml, of 2.92 mmol) and stirred at a temperature of -78oC for 30 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (2.1 ml), diluted with water and extracted with ethyl acetate. The extract was washed with aqueous solution of acid sodium carbonate and brine, is dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (ethyl acetate) to obtain the I-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonyl the (0.73 g) as a pale brown foam. Exit 27% NMR d (CDCl3CD3OD) ppm: 1,51 (c, 9H), 3,31 (c, 3H), 3,85 (c, 2H), 4,12, 4,70 (Avcv, J=14.6 Hz, 2H), 4,74 (d, J=4,8 Hz, 1H), of 6.26 (d, J=4,8 Hz, 1H), of 6.96 (s, 1H), 7,01 (s, 1H), 7,2-7,5 (m, 25N), 8,11 (Shir. s, 1H), IR n (CHCl3) cm-1: 3400, 1805, 1722, 1690, 1545, 1507, 1497, 1450, 1372, 1040.

Example 4: sulfoxide

< / BR>
1). Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Her - 1-methyl-1,2,4-triazole-3-yl (E-2).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(1-methyl-1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (1.78 g, 1,69 mmol in dimethylformamide (15.0 ml) at -20oC add trichloride phosphorus (0,42 ml, 4,18 mmol), and the mixture is stirred at the same temperature for 20 minutes, the Reaction mixture was poured in two layers of cold aqueous solution of acid sodium carbonate and ethyl acetate. The organic layer is washed with water and saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(1-methyl-1,2,4-triazole-3-altimeter, 2H), 3,76 (s, 3H), 4,25 (s, 2H), of 5.05 (d, J=4,6 Hz, 1H), to 5.85 (DD, J=4,6 Hz, J=8,2 Hz, 1H), 6.89 in (s, 1H), 7,00 (s, 1H), 7,2-7,5 (m, 25N), to 7.77 (d, J= 8,2 Hz, 1H), 7,89 (s, 1H), from 9.0 to 9.3 (Shir. s, 1H). IR n (CHCl3) cm-1: 3400, 1790, 1725, 1590, 1542, 1509, 1496, 1449, 1372.

2). Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 2-methyl-1,2,4-triazole-3-yl (E-1).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(2-methyl-1,2,4-triazole-3-ultimately-3-cefem-4-carboxylic acid (1.73 g, of 1.64 mmol) in dimethylformamide (15 ml) at -20oC add trichloride phosphorus (0,41 ml, 4,08 mmol), and the mixture is stirred at the same temperature for 20 minutes, the Reaction mixture was poured in two layers of cold solution of acid sodium carbonate and ethyl acetate and stirred. The organic layer is washed with water and saline, dried in the presence of sulfonate sodium and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) obtaining a complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(2-methyl-1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (1.60 g) as a dark-b is, N), 5,91 (DD, J=4,6 Hz, J=8.6 Hz, 1H), 6,93 (s, 1H), 6,95 (s, 1H), 7,2-7,5 (m, 25N), 7,83 (d, J=8.6 Hz, 1H), (s, 1H), 9,15-9,3 (Shir. s, 1H). IR n (CHCl3) cm-1: 3420, 1790, 1724, 1690, 1542, 1497, 1450, 1372.

3) Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het 4-methyl-1,2,4-triazole-3-yl (E-4).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(4-methyl-1,2,4-triazole-3-ultimately-3-cefem-4-carboxylic acid 706 mg, 0,671 mmol) in dimethylformamide (8 ml) was added to trichloride phosphorus (0.17 ml, was 1.69 mmol), and the mixture is stirred at -20oC for 30 minutes, the Reaction mixture was poured into chilled on ice two layers of aqueous 5% solution of acid sodium carbonate and ethyl acetate. The organic layer is washed with water and saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (ethyl acetate) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino]-3-(4-methyl-1,2,4-triazole-3-ylthio)-methylthio-3-cefem-4-carboxylic acid (404 mg) as a pale brown foam. The output 58% NMR d(CDCl3) ppm: 1,46 (c, 9H), 3,31 (c, 3H), 3,43, 3,56, (Avcv, J=17,2 J=8,5 Hz, 1H), a 9.7 to 10.1 (Shir. s, 1H). IR n (CHCl3) cm-1: 3410, 1789, 1723, 1689, 1542, 1507, 1495, 1448, 1370.

4) Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,2,3-thiadiazole-5-yl (E-1).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl-amino-3-(1,2,3-thiadiazol-5-yl]tomatillo-3-cefem-4-carboxylic acid (1,46, 1.38 mmol) in dimethylformamide (12 ml), cooled to -20oC, add trichloride phosphorus (0.35 ml, of 3.48 mmol), and the mixture is stirred at -20oC for 20 min, the Reaction mixture was poured into 2 layers of 5% aqueous solution of acidic sodium carbonate (35 ml) and ethyl acetate while cooling on ice. The organic layer is washed with water and saline, dried in the presence of sodium sulfate, filtered and concentrated, after which the resulting residue is purified column chromatography on silica gel (toluene:ethyl acetate 5: 1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-(1,2,3-thiadiazole-5-yl)tomatillo-3-cefem-4-carboxylic acid as a yellow foam (1.24 g). Yield 86% NMR d (CDCl3CD3OD) ppm: 1.52m (c, 9H), 3,51, 3,67 TO n (CHCl3) cm-1: 3400, 1789, 1718, 1686, 1543, 1492, 1445, 1369, 1277, 1225, 1154.

5) Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,3,4-thiadiazole-2-yl (E-1).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxanes - tamido] -3-(1,3,4-thiadiazole-2-ultimatelty)-3-cefem-4-carboxylic acid (760 mg, to 0.72 mmol) in dimethylformamide (7 ml) was added to trichloride phosphorus (180 μl, 2.5 equivalent to 1.79 mmol) at a temperature of -30oC, and the mixture is stirred for 30 minutes, the Reaction mixture was poured into aqueous 5% solution of acid sodium carbonate (70 ml) and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sulfonate sodium and concentrate. Satok purify by chromatography on silica gel (toluene:ethyl acetate 4:1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-triisocyanate - tamido] -3-(1,3,4-thiadiazole-2-ultimatelty)-3-cefem-4-carboxylic acid as pale yellow foam (544 mg). The yield was 73% NMR d (CDCl3) ppm: 1.50 in )c, 9H), 3,51, 3,67 (Avcv, J=17 Hz, 2H), 4,53, 4,58 (Avcv, J= 14 Hz, 2H), 5,07 (d, J=4,8 Hz, 1H), 5,98 (DD, J=4,8 Hz, J=9 Hz, 1H), 6,97 (s, 1H), 7,03 (s, 1H), 7,2-7,5 (m, 25N), 7,58 (d, J=9 Hz, 1H), 8,6 (Shir. s, 1H), 8,98 (s, 1H). IR is delamination-4-yl)-2-trailokyanath; Het is 2-methyl-1,3,4-thiadiazole-5-yl (E-2).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxanes - tamido] -3-(2-methyl-1,3,4-thiadiazole-5-ultimatelty)-3-cefem-4-carboxylic acid (363 mg, 0,339 mmol) in dimethylformamide (3 ml) was added to trichloride phosphorus (85 μl, 2.5 equivalent, 0.85 mmol) at a temperature of -30oC, and the mixture is stirred for 30 minutes, the Reaction mixture was poured into 5% solution of acid sodium carbonate (25 ml) and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 4:1) obtaining a complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2-trisiloxane-and - cetamide] -3-(2-methyl-1,3,4-thiadiazole-5-ultimately-3-cefem-4-carboxylic acid as pale yellow foam (246 mg). Exit 69% NMR d (CDCl3) ppm: 1.50 in (c, 9H), 2,69 (c, 3H), 3,53, 3,68 (Avcv, J=18 Hz, 2H), 4,50 (s, 2H), 5,07 (d, J=5 Hz, 1H), 6,00 (DD, J=5 Hz, J=9 Hz, 1H), 6,97 (s, 1H), 7,03 (s, 1H), 7,2-7,5 (m, 25N), of 7.69 (d, J=9 Hz, 1H), cent to 8.85 (Shir. s, 1H). IR n (CHCl3) cm-1: 3400, 1787, 1720, 1690, 1543, 1369, 1219, 1155.

7). Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het - 1 ebonyline-thiazol-4-yl)-2-trisiloxane - acetyl]amino-3-(1-methyl-5-tetrazolyl)tomatillo-3-cefem-4-carboxylic acid (745 mg, 0,708 mmol) in dimethylformamide (7 ml) at -20oC add trichloride phosphorus (0,18 ml, to 1.79 mmol) and the mixture is stirred at this temperature for 20 minutes, the Reaction mixture was poured into 2 layers of 5% aqueous solution of acidic sodium carbonate (20 ml) and ethyl acetate while cooling on ice. The organic layer is washed with water and saline, dried in the presence of sodium sulfate, filter and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate 3:1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl]amino-3-(1-methyl-5-tetrazolyl)tomatillo-3-cefem-4-carboxylic acid in the form of a brown foam (608 mg). Exit 83% NMR d (CDCl3CD3OD) ppm: 1.52m (c, 9H), 3,57, to 3.73 (Avcv, J=17.6 Hz, 2H), 3,81 (s, 3H), 4,56 (s, 2H), 5,09 (d, J=5,0 1H), 6,02 (d, J=5.0 Hz, 1H), 6,94 (s, 1H), 7,05 (s, 1H), 7,15-to 7.50 (m, 25N). IR n (CHCl3) cm-1: 3400, 1788, 1717, 1686, 1543, 1492, 1446, 1369, 1279, 1227, 1154.

8). Recovery: Acyl - (Z)-2-(2-tert-butoxycarbonyl-aminothiazol-4-yl)-2-trailokyanath; Het - 2-methyltetrazol-5-yl (E-3).

To a solution of 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(2-methyltetrazol-5C add to trichloride phosphorus (0.33 ml, of 3.28 mmol), and the mixture is stirred at the same temperature for 20 minutes the Reaction mixture is poured into two cold layer of an aqueous solution of acid sodium carbonate and ethyl acetate and stirred. The organic layer is washed with water and saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate 5: 1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(2-methyltetrazol-5-ultimatelty)-3-cefem-4-carboxylic acid (1.20 g) as a yellow foam, yield 88% NMR d (CDCl3ppm: 1.50 in (c, 9H), 3,40 (Shir. s, 2H), 4,25 (s, 3H), 4,28 (s, 2H), 5,07 (d, J=4,8 Hz, 1H), to 5.85 (DD, J=4,88 Hz, J 8.2 Hz, 1H), 6.89 in (s, 1H), 6,98 (s, 1H), 7,2-7,5 (m, 25N), EUR 7.57 (d, J= 8,2 Hz, 1H), 8,7-8,9 (Shir. s, 1H). IR n (CHCl3) cm-1: 3420, 1792, 1725, 1690, 1542, 1497, 1450, 1392, 1372, 1323.

9). Oxidation: Acyl - 2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,2,3-triazole-4-yl.

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(1,2,3-triazole-4-ultimately-3-cefem-4-carboxylic acid (511 mg, 0.5 mmol) in a mixture of dichloromethane (10 ml) and methanol (10 ml) was added m-chloroperbenzoic misreaction the mixture is poured into 5% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with aqueous solution of acid sodium carbonate, dilute hydrochloric acid and brine, then dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (toluene:ethyl acetate(2:1)-(1:1)) obtaining 1-oxide complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (232 mg). Exit 45% Extract part of the original substance (236 mg, 48% ), NMR d (CDCl3) ppm: 1,42 (c, 9H), 3,45, 3,94 (Avcv, J=18 Hz, 2H), 3,93, 4.09 to (Avcv, J=14 Hz, 2H), 4,54 (d, J=4,8 Hz, 1H), 6,18 (DD, J=4,8 Hz, J= 9 Hz, 1H), 6,94 (s, 1H), of 6.96 (s, 1H), 7,2-7,6 (m, N), 8,02 (d, J=9 Hz, 1H), IR n (CHCl3) cm-1: 3380, 3200, 1799, 1716, 1690, 1545, 1370, 1155.

Example 5: Amidation

< / BR>
1). The acyl deformalities; Het 1,2,3-triazole-4-yl (E-5).

To a solution of complex diphenylmethylene ester of 7-amino-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (550 mg, of 1.08 mmol) and deformationally acid (160 mg, 1.13 mmol) in dichloromethane (8 ml), cooled to a temperature of -30oC, was added N-methylmorpholine (0,27 ml of 2.46 mmol) and phenyldichlorophosphine (0,19 ml of 1.27 mmol), and the mixture is stirred at a temperature of -30oC xtraceroute with ethyl acetate. The extract was washed with an aqueous solution of salt, dried in the presence of sodium sulfate and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate 1:1) to obtain the complex diphenylmethylene ether 7 differetiated-3-(1,2,3-triazole-4-ultimatelty)-3-cefem- -4-carboxylic acid (475 mg) as a pale yellow foam. Exit 69% NMR d (CDCl3) ppm: 3,56 (c, 2H), 3,59 (c, 2H), 4,05 (c, 2H), 4,99 (d, J=4,8 Hz, 1H), 5,79 (DD, J=8.7 Hz, J=4,8 Hz, 1H), 6.90 to (s, 1H), 6,91 (t, J=56,2 Hz, 1H), and 7.1-7.5 (m, 10H), to 7.59 (s, 1H), 7,68 (d, J=8.7 Hz, 1H). IR n (CHCl3) cm-1: 3430, 3300 Shir, 1785, 1690, 1512, 1496, 1454, 1378, 1333.

2). Acyl N-tert-butoxycarbonyl-2-phenylglycine; Het - trityl-1,2,3-triazole-4-yl (E/2).

To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (914 mg, to 1.21 mmol) and D-N-tert-butoxycarbonyl-2-phenylglycine (320 mg, of 1.27 mmol) in dichloromethane (9 ml), cooled to a temperature of -30oC, was added N-methylmorpholine (0,31 ml, 2.82 mmol) and phenyldichlorophosphine (0,22 ml of 1.47 mmol), and the mixture is stirred at this temperature for 50 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water and extracted with ethyl acetate. The extract was washed with brine, suezette 10: 1) to obtain the complex diphenylmethylene ester 7-(D-N-tert-butoxycarbonyl-2-phenylglycylamino)-3-(trityl-1,2,3-tri - azole-4-ultimatelty)-3-cefem-4-carboxylic acid (501 mg) as colorless foam. Exit 42% NMR d (CDCl3) ppm: 1,42 (c, 9H), 3,22: 3,44 (Avcv, J=17.5 Hz, 2H), 3,93, 3,98 (Avcv, J=13.3 Hz, 2H), to 4.81 (d, J=4,8 Hz, 1H), 5,20 (d, J= 6.0 Hz, 1H), 5,62 (d, J=6.0 Hz, 1H), USD 5.76 (DD, J=4,8 Hz, J=9.1 Hz, 1H), 6,50 (d, J=9.1 Hz, 1H), 6,91 (s, 1H), 7,05-to 7.15 (m, 6N), 7,25 was 7.45 (m, 24N), to 7.59 (s, 1H), IR n (CHCl3) cm-1: 3430, 1788, 1710, 1697, 1495, 1455, 1448, 1370.

3). Acyl D-Mandalay; Het, trityl-1,2,3-triazole-4-yl (E-3).

To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (800 mg, 1.06 mmol) and D(-)-almond acid (242 mg, of 1.59 mmol) in dichloromethane (4 ml) was added dicyclohexylcarbodiimide (328 mg, of 1.59 mmol) and the mixture is stirred while cooling on ice for one hour. The reaction mixture was concentrated, diluted with ethyl acetate and filtered to remove solids. The filtrate is washed with saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is purified column chromatography of Lobar (toluene: ethyl acetate 2:1) obtaining a complex diphenylmethylene ether 7-D-mandelamide-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-- carboxylic acid (466 mg) as a yellow foam. Output 50% NMR d (CDCl3) ppm: to 3.41 (d, J=3.3 Hz, 1H), 3,57, 3,78 (Avcv, J=17,4 Hz, 2H), 4,06, 4,16 (Avcv, J=a 13.4 Hz, 2H), 4,91 (d, J=4,8 Hz, 1H), 5,15 (d, -1: 3600, 3400, 1788, 1725, 1692, 1602, 1509, 1495, 1450, 1375, 1315.

4). Acyl (Z)-2-(2-tert-butoxycarbonylamino-4-yl)acetyl; Het - trityl-1,2,3-triazole-4-yl (E-1).

To a solution of complex diphenylmethylene ester of 7-amino-3-trityl-1,2,3-triazole-4-ultimatelty))-3-cefem-4-carboxylic acid (800 mg, 1.06 mmol) and 2-(2-tert-butoxycarbonylamino-4-yl)acetic acid (287 mg, 1.11 mmol) in dichloromethane (8 ml) at a temperature of -30oC was added N-methylmorpholine (0,27 ml of 2.46 mmol) and phenyldichlorophosphine (0,19 ml of 1.27 mmol), and the mixture is stirred at this temperature for 40 minutes. The reaction mixture is cooled to 10% hydrochloric acid, 11 ml), diluted with water, extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate 3:1) obtaining a complex diphenylmethylene ester of 7-[2-(2-tert-butoxycarbonylamino-4-yl)acetamido]-3-(trityl-1, 2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (812 mg) as a pale yellow foam. Exit 77% NMR d (CDCl3) ppm: 1.57 in (c, 9H), to 3.41 (s, 2H), 3.72 points, to 3.75 (Avcv, J=17,8 Hz, 2H), was 4.02, 4,06 (Avcv, J=13,6 Hz, 2H), 4,79 (d, J= 4,6 Hz, 1H), 5,54 (DD, J=8.0 Hz, J=4.6 Hz, 1H), to 6.57 (s, 1H), 6,76 (s, 1H), 7,05-to 7.15 (m, 6N), of 7.25-7.5 (m, N), 7,44 (s, 1H), 7,76 (d, J=8.0 bonlinecasin-4-yl)-glyoxal (E-4); et trityl-1,2,3-triazole-4-yl.

To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (800 mg, 1.06 mmol) and 2-(2-tert-butoxycarbonylamino-4-yl)Glyoxylic acid (303 mg, 1.11 mmol) in dichloromethane (8 ml) under cooling to a temperature of -30oC was added N-methylmorpholine (0,27 ml of 2.46 mmol) and phenyldichlorophosphine (0,19 ml of 1.27 mmol), and the mixture is stirred at a temperature of -30oC for one hour. The reaction mixture is mixed with 10% hydrochloric acid 1 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) to obtain the complex diphenylmethylene ether 7[2-(2-tert-butoxycarbonylamino-4-yl)glycosylamine]-3-(tre - Teal-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (679 mg) as a yellow foam. The output 64% NMR d (CFCl3) ppm: 1.55V (c, 9H), 3,67, 3,85 (Avcv, J=17,1 Hz, 2H), 4,10, 4,21 (Avcv, J=13.3 Hz, 2H), 5,00 (d, J= 4,7 Hz, 1H), 5,70 (DD, J=9,2 Hz, J=4,7 Hz, 1H), 6,91 (s, 1H), 6,05-to 7.15 (m, 6N), 7,2 was 7.45 (m, N), 7,47 (s, 1H), 8,19 (d, J=9,2 Hz, 1H), and 8.5 and 8.6 (Shir. s, 1H), 8,86 (s, 1H). IR n (CHCl3) cm-1: 3400, 1788, 1725, 1702, 1672, 1565, 1512, 1495, 1480, 1448, 1372,

6). Is the suspension of the hydrochloride complex diphenylmethylene ester of 7-amino-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (110 MK, 0.2 mmol) and (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-tricalciumphosphate acid (122 mg, 0.23 mmol) in dichloromethane, (3 ml) was added N-methylmorpholine (72 μl, 0.66 mmol) and phenyldichlorophosphine (33 μl, 0.22 mmol) at a temperature of -30oC. After 2 h stirring, the reaction mixture was diluted with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, purified by chromatography on silica gel and kristallisera from toluene to obtain complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (11 mg), melting point 190-200oC (decomposition), NMR d (CDCl3CD3OD( ppm: 1,53 (c, 9H), 3,45, 3,63 (Avcv, J=and 17.2 Hz, 2H), 4,12, 4,15 (Avcv, J=14,2 Hz, 2H), 5,08 (d, J= 5 Hz, 1H), 5,88 (d, J=5 Hz, 1H), 6,98 (s, 1H), was 7.08 (s, 1H), 7,2-7,5 (m, 25N), 7,60 (c, 1H). IR n (KBr) cm-1: 3390, 3210, 1800, 1725, 1688, 1555, 1495, 1449, 1375, 1275, 1245, 1225, 1155.

7). Acyl - (Z)-2-(2-tritylimidazole-4-yl)-2-(diphenylethylenediamine)acetyl; Het, trityl-1,2,3-triazole-4-yl (E-6).

To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (800 mg, 1.06 mmol) and (Z)-2-(2-tritylimidazole-4-yl)-2-(diftime the 0oC was added N-methylmorpholine (0,27 ml of 2.46 mmol, phenyl dichlorophosphate (0,19 ml of 1.27 mmol) and the mixture is stirred at a temperature of -30oC for 30 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 10: 1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-trityl-aminothiazol-4-yl)-2-(diphenylmethanediisocyanate - diimino)-acetamido] -3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-- 4-carboxylic acid (1.07 g) as a yellow foam. The yield was 73% NMR d (CDCl3) ppm: (Avcv, J=17,1 Hz, 2H), 4,07, 4,12 (Avcv, J=13,2 Hz, 2H), 4,90 (d, J=5.0 Hz, 1H), 4,93, 5,03 (Avcv, J= 17,0 Hz, 2H), 5,80 (DD, J=9.1 Hz, J=5.0 Hz, 1H), for 6.81 (s, 1H), 6.87 in (s, 1H), 6,93 (s, 1H), 7,0-7,4 (m, N)that was 7.45 (s, 1H), 8,11 (d, J=9.1 Hz, 1H). IR n (CHCl3) cm-1: 3400, 1790, 1740, 1688, 1526, 1498, 1451, 1380.

8). Acyl - (Z)-2-(2-tritylimidazole-4-yl)-2-[(Z)-1-diphenylmethanediisocyanate - Himeno]acetyl; Het, trityl-1,2,3-triazole-4-yl (E-7).

To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (800 mg, 1.06 mmol) and (Z)-2-(2-tritylimidazole-4-yl)-2-[(Z)-1-divinatory -30oC was added N-methylmorpholine (0,27 ml of 2.46 mmol) and phenyldichlorophosphine (0,19 ml of 1.27 mmol), and the mixture is stirred at a temperature of -30oC for 1 h, the Reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, extracted with ethyl acetate. The extract was washed with aqueous saline solution, dried in the presence of sodium sulfate and concentrate. The residue by chromatography on silica gel (toluene:ethyl acetate 10:1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tritylimidazole-4-yl)-2-] (Z)-1-diphenylmethylene - amoxiillin(acetamido)-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-ceph em-4-carboxylic acid (1,05 g) as a yellow foam. Yield 70% NMR d (CDCl3) ppm: 1,65 (d, J=7,1 Hz, 3H), 3,41, 3,66 (Avcv, J=16,8 Hz, 2H), 4,12, 4,16 (Avcv, J=a 13.4 Hz, 2H), 4,91 (d, J= 4,6 Hz, 1H), 5,20 (kV, J=7.2 Hz, 1H), of 5.82 (DD, J=8.7 Hz, J=4.6 Hz, 1H), 6,77 (s, 1H), 6,85 (s, 1H), 6,87 (s, 1H), 7,0-7,4 (m, N), 7,45 (c, 1H), they were 8.22 (d, J= 8.7 Hz, 1H). IR n (CHCl3) cm-1: 3400, 1787, 1730, 1685, 1523, 1493, 1447, 1375.

9). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(1-diphenylmethoxy - anilinomethylene)acetyl; Het, trityl-1,2,3-triazole-4-yl (E-9).

To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (800 mg, 1.06 mmol) and (Z)-2-(2-tert-bainova salt, 786 mg, 1.12 mmol) in dichloromethane (8 ml) under cooling to a temperature of -30oC was added N-methylmorpholine (0.15 ml, of 1.36 mmol) and phenyldichlorophosphine (0,19 ml of 1.27 mmol), and the mixture is stirred at a temperature of -30oC for 40 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified column chromatography on silica gel (toluene:ethyl acetate 5:1) to obtain the complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(1-diphenylmethoxy - dicarbonylnickel)acetamido] -3-(trityl-1,2,3-triazole-4-ultime - tilty)-3-cefem-4-carboxylic acid (936 mg) as a yellow foam. Yield 70% NMR d (CDCl3) ppm: 1,53 (s, N), 3,33, 3,51 (Avcv, J= 18,0 Hz, 2H), 4,07 (s, 2H), 4,80 (d, J=4,8 Hz, 1H), to 5.66 (s, 1H), 5,73 (DD, J=4,8 Hz, J=9.0 Hz, 1H), of 5.89 (s, 1H), 6,84 (s, 1H), 6,93 (s, 1H), 7,0-7,4 (m, 36N), was 7.45 (s, 1H), 7,68 (d, J=9.0 Hz, 1H), 8,7-9,1 (Shir. s, 1H). IR n (CHCl3) cm-1: 3400, 1786, 1724, 1696, 1545, 1494, 1445, 1370.

10). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(1-tert-butoxycarbonyl - delamination-4-yl)-2-(1-tert-butoxycarbonyl-1 methylethoxy)acetyl; Het, trityl-1,2,3-triazole-4-yl (E-8).

To a solution of SL is 1.06 mmol) and (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(1-tert-butoxycarbonyl - Neil-1 methylethoxy)acetic acid (479 mg, 1.12 mmol) in dichloromethane (8 ml) under cooling to a temperature of -30oC was added N-methylmorpholine (0,27 ml of 2.46 mmol) and phenyldichlorophosphine (0,19 ml of 1.27 mmol) and the mixture is stirred at a temperature of -30oC for 50 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified column chromatography on silica gel (toluene: ethyl acetate(10:1)-(5:1)) obtaining complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(1-tert-butoxy - carbonyl-1-methylethanamine-acetamido]-2-(trimethyl-1,2,3-triazole-4-yl - tomatillo)-3-cefem-4-carboxylic acid (855 mg) as a yellow foam. Exit 69% NMR d (CDCl3) ppm: 1.39 in (c, 9H), 1,53 (c, 9H), 1.61 of (c, 3H), 1,63 (c, 3H), 3,63, 3,84 (Avcv, J=17.3 Hz, 2H), 4.09 to, 4,20 (Avcv, J=a 13.4 Hz, 2H), free 5.01 (d, J= 4,9 Hz, 5,94 (DD, J=9.0 Hz, J=4.9 Hz, 1H), to 6.88 (s, 1H), 7,05 to 7.4 (m, N), 7,46 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,1-8,4 (Shir. s, 1H). IR n (CHCl3) cm-1: 3420, 1788, 1725, 1687, 1545, 1495, 1445, 1371.

Example 6: Structural variants.

1). R2methylene (R) (E-4) (E-17).

1. To a suspension of sodium azide (19,0 g, 0,283 mol) in diphenylacetamide (130 ml) was added trailhead (76,0 g, 0,extracted with simple ether. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate to obtain trailside. To a solution of this azide in acetone (300 ml), add methylpropionate (24 ml, 0.27 mol) and the mixture heated under reflux for 6 days. The reaction mixture is cooled to room temperature and diluted with simple ether. The crystals formed are collected by filtration to obtain 1-trityl-1,2,3-triazole-4-incorporationg difficult methyl ester (62,0 g) as colorless crystals. The output 62% melting point 189-190oC. NMR d (CDCl3) ppm: 3,93 (c, 3H), 7,05-to 7.15 (m, 6N), 7.3 to 7.4 (m, N), 8,02 (s, 1H). IR n (CHCl3) cm-1: 1722, 1544, 1492, 1444, 1338.

2. To a suspension of lithium aluminum hydride (6,17 g, 0,163 mol) in tetrahydrofuran (600 ml) while cooling on ice, add methyl ester 1-trityl-1,2,3-triazole-4-icarbonell acid (40,0 g, to 0.108 mol) and the mixture was stirred at room temperature for 1 h To the reaction mixture are added dropwise aqueous tetrahydrofuran while cooling on ice. The mixture is neutralized with 10% hydrochloric acid, filtered to remove insoluble substances, diluted with ethyl acetate, washed with saline, dried in the presence of sodium sulfate and the,4 g) as white crystals. Exit 91% melting point 200-201oC. NMR d (CDCl3) ppm: 2,4-2,9 (Shir, C. 1H), amounts to 4.76 (s, 2H), 7,05-to 7.15 (m, 6N), 7.3 to 7.4 (m, N), the 7.43 (s, 1H). IR n (CHCl3) cm-1: 3600, 3600-3200 cm. 1600, 1490, 1443.

3. To a solution of 1-trityl-1,2,3-triazole-4-ylmethanol (8.00 g, 23.5 mmol) in a mixture of dichloromethane (150 ml) and dimethylformamide (15 ml) at -40oC added triethylamine (3.9 ml, 28 mmol) and methanesulfonamide (2.2 ml, 28.4 mmol), and the mixture is stirred at a temperature of from -30 to -40oC for 25 minutes, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. To a solution of the residue in acetone (150 ml) was added thioacetic potassium (as 4.02 g of 35.2 mmol) and sodium iodide (7,03 g, 46,9 mmol) and the mixture was stirred at room temperature for hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water and saline, dried in the presence of sodium sulfate and concentrate. The resulting crystals are washed with simple ether to obtain 4-acetylthiazole-1 trityl-1,2,3-triazole (8,01 g) as white crystals. Yield 86% melting point 172-173oC. NMR d (CDCl3) ppm: 2,32 (c, 3H), 4,19 (c, 2H), 7,05-to 7.15 (m, 6N), 7.3 to 7.4 (m, nourani (100 ml) cooled on ice was added 4-acetyltributyl-1 trityl-1,2,3-triazole (7.50 g, for 18.8 mmol) and the mixture is stirred at room temperature for 40 minutes To the reaction mixture are added dropwise aqueous tetrahydrofuran and the mixture is neutralized with 10% hydrochloric acid. The solution is filtered and the filtrate diluted with ethyl acetate, washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is crystallized from a simple ether and washed with simple ether to obtain 1-trityl-1,2,3-triazole-3-iletilmeyen (5,14 g) as white crystals. Exit 77% melting point 140-141oC. NMR d (CDCl3) ppm: 1,99 (t, J=7.8 Hz, 1H), 3,84 (d, J=7.8 Hz, 2H), 7,1-7,2 (m, 6N), 7.3 to 7.4 (m, 10H). IR n (CHCl3) cm-1: 1491, 1444.

5. To a solution of 1-trityl-1,2,3-triazole-4-iletilmeyen (3.00 g, of 8.40 mmol) in dimethylformamide (10 ml) was added sodium hydride (60% dispersion in oil, 370 mg, a 9.25 mmol) and the mixture stirred for 5 min at room temperature. The reaction mixture is diluted with a solution of bremgarten (15 ml) in dimethylformamide (15 ml) at a temperature of -30oC, and the mixture is stirred at a temperature of -20 to -30oC for 30 minutes, the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate, concentration and room temperature for 1 h The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on a column of silica gel (toluene:ethyl acetate 10:1) and crystallized from simple ether to obtain 4-acetylthiocholine-1 trityl-1,2,3-triazole (2.65 g) as colorless crystals, yield 71% melting point 106oC. NMR d (CDCl3) ppm: 2,32 (c, 3H), 3,89 (c, 2H), 4.04 the (c, 2H), 7,1-7,2 (m, 6N), 7.3 to 7.4 (m, N), to 7.93 (s, 1H). IR n (CHCl3) cm-1: 1690, 1491, 1440.

6. 3-Substitution allatom. To a solution of 4-acetylethylenediamine-1 trityl-2,3-triazole (756 mg, 1.70 mmol in a mixture of dimethylformamide (8 ml) and tetrahydrofuran (4 ml) under cooling to a temperature of -78oC add 1,28 n solution of sodium methylate in methanol (1,24 ml of 1.59 mmol) and the mixture stirred for 15 minutes at a temperature of -78oC. To the reaction mixture was added a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-methanesulfonate-3-cefem-4-carboxylic acid (1.50 g, 1.54 mmol) in dimethylformamide (5 ml), and the mixture is stirred at a temperature of -78oC for 50 minutes, the Reaction mixture is mixed with 10% hydrochloric colorstay sodium sulfate and concentrated. The residue is purified double-column chromatography of Lobar (toluene:ethyl acetate 3:1) and once by chromatography on silica gel (toluene:ethyl acetate(10:1)-(5:1)) obtaining complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido)-3-(1-trityl-1,2,3-triazole-4-ilmmilieilmi)-3-cefem-4-- carboxylic acid (1.18 g) in the form of a colorless foam. Yield 60% NMR d (CDCl3) ppm: 1.50 in (c, 9H), 3,35, 3,51 (Avqwb J=17,0 Hz, 2H), of 3.77 (s, 4H), 5,04 (d, J=4,6 Hz, 1H), of 5.89 (DD, J=4,6 Hz, J=8,4 Hz, 1H), 6.89 in (C. 1H), 7,02 (s, 1H), 7,05-of 7.60 (m, 2H), 8,65 (Shir. s, 1H). IR n (CHCl3cm-1: 3400, 1784, 1717, 1686, 1542, 1492, 1445, 1369.

7. Exemption from protection. To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(1-trityl-1,2,3-triazole-4-ilmmilieilmi)-3-cefem-4-- carboxylic acid (1.13 mg, 0,884 mmol) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40oC was added a solution of aluminium chloride (0,94 mg, 7,07 mmol) in anisole (3 ml), and the mixture is stirred at a temperature of from -30 to 40oC for 1 h, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (7.5 ml) and diluted with water. The aqueous solution washed with ethyl acetate. The aqueous layer was concentrated under reduced damera of styrene and divinylbenzene (methanol:water 4:1). The resulting powder was washed with ethyl acetate to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(1,2,3-Tr - eazol-4-ilmmilieilmi)-3-cefem-4-carboxylic acid (318 mg) as pale-yellow-white powder. Exit 68% NMR d (D2O-NaHCO3) ppm: 3,53, 3,79 (Avcv, J=17,4 Hz, 2H), of 3.77, a 3.87, (Avcv, J= 13,8 Hz, 2H), 4,00, 4,03 (Avcv, J=14,8 Hz, 2H), 5,26, (d, J=4,6 Hz, 1H), of 5.83 (d, J=4,6 Hz, 1H), 6,99 (s, 1H), 7,88 (s, 1H). IR n (KV cm-1: 3100 Shir. 1760, 1655, 1600, 1525, 1385, 1345. This compound is a strong antibacterial agent against Morgania morganii SR9 (0.1 ág/ml) and Enterobacter cloacae SR233 (0.8 µg/ml) and shows a high level in the blood by oral administration (12,1 mg/ml, 15 min, mouse).

2). R1METROTILE (R) (E).

1. To a solution of sodium salt of 1,2,3-triazole-4-itiola (2.00 g, 16.3 mmol) in dimethylformamide (8 ml) at a temperature of -30oC add 1-chloromethylthiazole (2,4, g, 94% 16.3 mmol) in dimethylformamide (3 ml), and the mixture is stirred at room temperature for one hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 2:1) to obtain 4-(1-acetylthiourea)-1,2,3-t (s, 1H), 9,5-10,5 (Shir. s, 1H). IR n (CHCl3) cm-1: 3440, 3160 Shir. 1692, 1487, 1445, 1378, 1358.

2. To a solution of 1x-(1,2,3-triazole-4-ylthio-ethylthiourea (127 mg, 0,626 mmol) in dimethylformamide (4 ml) at -70oC was added a solution of lithium acetate in methanol (1,8-called solution of 0.67 ml of 1.21 mmol), and the mixture is stirred for one hour at temperatures from -55 to -60oC. To the solution at a temperature of -78oc was added a solution of complex diphenylmethylene ether 7 phenylacetylamino-3-tripterocalyx-3-cefem-4-carboxylic acid (316 mg, 0.5 mmol) in dimethylformamide (3 ml) and the mixture is stirred at a temperature of -78oC for 10 minutes, the Reaction mixture is mixed with 10% hydrochloric acid (1.0 ml), diluted with water and extracted with ethyl acetate. The extract is washed with saline, dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene: ethyl acetate 1:1) to obtain a mixture of complex diphenylmethylene ether 7 phenylacetylamino-3-[1-(1,2,3-triazole-4-ylthio)ethyl]thio-3-cefem-- 4-carboxylic acid and 2-cefem-isomer (100 mg). By re-chromatography can be distinguished difficult diphenylmethylene ether 7 phenylacetylamino-3-[1-(1,2,3-triazole-4-ylthio)ethyl] thio-3-cefem-4 J=4,8 Hz, 1H), 5,78 (DD, J=4,8 Hz, J=8,8 Hz, 1H), 6,95 (s, 1H), and 7.1 to 7.4 (m, N), to 7.50 (s, 1H).

3). 7-methoxy (R) (E).

1. To a solution of complex diphenylmethylene ester of 7-amino-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (8,02 g of 10.7 mmol) in benzene (200 ml) was added 3,5-di-tert-butyl-4-hydroxybenzaldehyde (3.00 g, 12.8 mmol) and the mixture is heated for 1.5 h with azeotropic distillation, and then concentrated. To a solution of the residue in a mixture of benzene (100 ml) and dichloromethane (70 ml) at a temperature of -30oC add magnesium sulfate (5.3g) and Nickel peroxide (10.7 g), and the mixture is stirred at room temperature for one hour. The reaction mixture was filtered to remove solids. To the filtrate at a temperature of -40oC add methanol (180 ml), dried in the presence of molecular sieves 4A, and the mixture is stirred at room temperature for 1 hour, after which the reaction mixture is concentrated. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 20:1) to obtain the complex diphenylmethylene ester 7-(3,5-di-tert-butyl-4-hydroxybenzylidene)amino-77-(3,5-di-tert-butyl-4-hydroxybenzylidene)amino-7-amino-7-methoxy-3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cafe - m-4-carboxylic acid (5.10 g) as pale-yellow). IR n (CHCl3) cm-1: 1777, 1705, 1602, 1495, 1446, 1378.

3. To a solution of complex diphenylmethylene ester of 7-amino-7-methoxy-3-(trityl-1,2,3-triazole-4-ultimately-3-cefem- -4-carboxylic acid (1.50 g, 1.92 mmol) in dichloromethane (10 ml) at -40oC was added N-methylmorpholine (of 0.48 ml, 4,37 mmol), deformations acid (299 mg, 2,11 mmol) and then phenyldichlorophosphine (0,34 ml of 2.27 mmol), and the mixture is stirred at a temperature of from -30 to -40oC for one hour. The reaction mixture is mixed with 10% hydrochloric acid (2.0 ml), diluted with water and extracted with ethyl acetate. The extract is washed with diluted hydrochloric acid, aqueous 5% solution of acid sodium carbonate and brine, is dried in the presence of sodium sulfate and concentrate. The residue is purified by chromatography on silica gel (toluene:ethyl acetate 3:1) to obtain the complex diphenylmethylene ether 7 deformalisation-7-methoxy-3-(trityl-1,2,3-triazole-4-yl - tomatillo-3-cefem-4-carboxylic acid (1.55 g) as a pale yellow foam. The output is 89% NMR d (CDCl3) ppm: 3,47, 3,54 (Avcv, J=15,0 Hz, 2H), 3,60 (s, 5H), 4,05, 4,13 (Avcv, J=13,6 Hz, 2H), to 4.98 (s, 1H), 6,84 (s, 1H), 6,94 (t, J=55,8 Hz, 1H), 7,05-7.5 (m, N), 7,49 (s, 1H). IR n (CHCl3) cm-1: 3380, 1778, 1696, 1600, 1495,Teal-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (1.51 g, of 1.66 mmol) in a mixture of anisole (2.4 ml) and dichloromethane (6 ml) under cooling on ice, add triperoxonane acid (6 ml), and the mixture is stirred while cooling on ice for 50 min and at room temperature for 20 minutes the Reaction mixture is cooled with ice, mixed with water (2 ml) and ethyl acetate, washed with water, dried in the presence of sodium sulfate and concentrate. The residue is dissolved in ethyl acetate and extracted with 5% aqueous solution of acid sodium carbonate. The aqueous extract was adjusted to pH 2.0 to 3.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried in the presence of sodium sulfate and concentrate. The residue is sprayed by a simple mixture of ether and hexane to obtain 7-deformalisation-7-methoxy-3-(1,2,3-triazole-4-altimet - ylthio-3-cefem-4-carboxylic acid (195 mg) as a pale yellow foam. The output is 24% NMR d (D2O-NaHCO3) ppm: 3,55 (c, 3H), 3,36, 3,65 (Avcv, J=17,0 Hz, 2H), 3,74 (s, 2H), 4,11, 4,19 (Avcv, J=13,8 Hz, 2H), 5,15 (s, 1H), 7,11 (t, J=55,4 Hz, 1H), 7,98 (s, 1H). IR n (KBR) cm-1: 3240 Shir. 1770, 1680, 1520, 1365.

Example 7. Exemption from protection.

< / BR>
1). The acyl deformalities; Het 1,2,3-triazole-4-yl (E-5).

To a solution of complex diphenylmethylene ether 7 diformitatii and anisole (1.2 ml) under cooling on ice, add triperoxonane acid (3 ml), and the mixture is stirred while cooling on ice for 1 h, the Reaction mixture was concentrated to dryness and the residue is sprayed simple ether, washed and dried to obtain 7-differetiated-3-(1,2,3-triazole-4-ultimatelty)-3-cefem- -4-carboxylic acid (257 g) as white powder. Exit 77% NMR d (D2O-NaHCO3) ppm: 3,47, 3,67 (Avcv, J=17,4 Hz, 2H), 3,68 (s, 2H), 4,12, 4,24 (Avcv, J=a 13.4 Hz, 2H), 5,11 (d, J=4,6 Hz, 1H), to 5.66 (d, J=4,6 Hz, 1H), 7,09 (t, JHF= 55,4 Hz, 1H), 8,01 (s, 1H). IR n (KBr) cm-1: 3400 Shir, 3260, 1765, 1662, 1545, 1360, 1333.

This compound is a strong antibacterial agent against Staphilococcus aureus smith (0.1 ág/ml) and shows a high level in the blood by oral administration (28 μg/ml, 15 min, mouse).

2). The acyl phenylacetyl; Het 1,2,3-triazole-4-yl (E-1).

To a suspension of complex diphenylmethylene ether 7 phenylacetylamino-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (186 mg, 0,296 mmol) in dichloromethane (3 ml) under cooling on ice, added anisole (0.45 ml) and triperoxonane acid (0.45 ml), and the mixture is stirred for 1 hour and 40 minutes, the Reaction mixture was concentrated, proscout hexane and washed with ethyl acetate to obtain 7-phenylacetylamino-3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid in wigs, 2H), 3,07, 4,20 (Avcv, J=14 Hz, 2H), to 5.03 (d, J= 5 Hz, 1H), 5,61 (d, J=5 Hz, 1H), and 7.3-7.5 (m, 5H), of 7.90 (s, 1H). IR n (KBr) cm-1: 3440, 1775, 1660, 1540, 1353, 1238.

This compound shows a strong antibacterial activity against Staphilococcus aureus smith (0.05 mg/ml) and 209 PJC-1 (0.05 mg/ml) and has a high level in the blood by oral administration (15 mg/ml, 15 min, mouse).

3). Acyl D-Mandalay; Het (trail to N)-1,2,3-triazole-4-yl (E-3).

To a solution of complex diphenylmethylene ether 7-D-mandelamide; -3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4- -carboxylic acid (445 mg, 0,502 mmol in a mixture of anisole (0.8 ml) and dichloromethane (2 ml) under cooling on ice, add triperoxonane acid (2 ml), and the mixture is stirred while cooling on ice for 30 min and at room temperature for 20 minutes, the Reaction mixture is diluted with a dilute aqueous solution of acid sodium carbonate, washed with ethyl acetate, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried in the presence of sodium sulfate and concentrate. The residue is sprayed with simple ether to obtain 7-D-mandelamide-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (59,2 mg) as a yellowish-white powder. The output 25% NMR d (D2O-NaHCO3)(KBr) cm-1: 3360 Shir. 1770, 1673, 1520, 1452, 1365.

This compound exhibits a high level in the blood by oral administration (18,5 mg/ml, 15 min, mouse).

4). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl]-2-pentanol; Het 1,2,3-triazole-4-yl (E-6).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-phenteramine] - -3-(1,2,3-triazole-4-ultimately-3-cefem-4-carboxylic acid (537 mg, of 0.68 mmol) in a mixture of anisole (2 ml) and nitromethane (8 ml) at a temperature of -30oC was added a solution of aluminium chloride (0.54 g, 4 mmol) in anisole (2 ml), and the mixture is stirred for one hour. The reaction mixture was diluted with ethanol (3 ml), stirred for 5 min, mixed with 1 N. a solution of hydrochloric acid (8 ml) and water (200 ml), washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organic solvents. The resulting aqueous solution is subjected to chromatography in the presence of a copolymer of styrene and divinylbenzene (methanol:water 4:1) to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-phenteramine]-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (156 mg) as a white solid. Exit 44% NMR d (D2-NaHCO3) ppm: 1,07 (t is C, 1H), 6,50 (s, 1H), 8,03 (s, 1H). IR n (KBr) cm-1: 3400 Shir. 1763, 1655, 1530, 1388, 1348.

5). Acyl - (Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trailokyanath; Het is 1,2,3-triazole-4-yl (EE).

To a suspension of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (9,2 g, 9 mmol) in a mixture of anisole (18 ml) and nitromethane (72 ml) was added dropwise a solution of aluminium chloride (9.6 g, 72 mmol) in anisole (31 ml) at a temperature of -30oC. After stirring for one hour at the same temperature, the reaction mixture was cooled, ethanol (25 ml), stirred for several minutes, diluted with 1 N. a solution of hydrochloric acid (75 ml) and water (500 ml), and washed with ethyl acetate. The aqueous layer is separated, concentrated to remove organic solvents, and passed through a column of adsorbent based on styrene-divinylbenzene copolymer. Product elute with a mixture of methanol and water (4:1) to obtain 7-(Z)-2-(2-aminothiazol-4-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow powder (4,19 g). Output 90% NMR d (D2O-NaHCO3) ppm: 3,51, 3,75 (Avcv, J=and 17.2 Hz, 2H), 4,14, 4,25 (Avcv, J= a 13.9 Hz, 2H), total of 5.21 (d, J=4,7 Hz, 1H), of 5.84 (d, inim antibacterial agent against Escherichia coli. 7437 (0.02 μg/ml) and Enterobacter cloacae SR233 (0.8 µg/ml) and shows a high level in the blood by oral administration (29.6 ág/ml, 15 min, mouse).

6). Acyl (Z)-2-[2-tert-butoxycarbonylamino to amino)-thiazol-4-yl]-2-methoxyaminomethyl; Het 1-(trityl to N)-1,2,3-triazole-4-yl (E-5).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-methoxyimino-AC - ethyl]amino-3-(1-trityl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (570 ml, 0.55 mmol) in a mixture of anisole (1.7 ml) and nitromethane (5 ml) at a temperature of -30oC was added a solution of aluminium chloride (0.51 g, a 3.83 mmol) in anisole (1.8 ml) and the mixture stirred for 30 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (4 ml) and ethyl acetate 10 ml), stirred at room temperature for 5 min, poured into a solution of acid sodium carbonate (3.2 g) in water (100 ml) and stirred for several minutes. After you filter out the insoluble matter, the reaction mixture is washed with ethyl acetate, concentrated in vacuo to remove organic solvents. The resulting aqueous layer is purified by chromatography on stiroldivinilbenzol copolymer (water: methanol 10: 1), obtaining the sodium salt of 7-[(Z)-2-(2-aminot the ENES (194 mg). The output 64% NMR d (D2O) ppm: 3,48, 3,67 (Avcv, J=17 Hz, 2H), 3,99 (s, 3H), 4,11, 4,23 (Avcv, J= 14 Hz, 2H), 5,17 (d, J=5 Hz, 1H), 5,80 (d, J=5 Hz, 1H), 7,02 (s, 1H), of 7.97 (s, 1H). IR n (KBr) cm-1: 3400, 1753, 1660, 1605, 1390, 1040.

This compound shows a strong antibacterial activity against Proteus vilgaris CN329 (0.02 μg/ml) and Morgania morganii SR9 (0.1 ág/ml) and high blood levels of 15 μg/ml, 15 min, mouse) by oral administration.

7). Acyl (Z)-2-[(2-tert-butoxycarbonylamino to amino)-thiazol-4-yl]-2-cyclopentylacetyl; Het 1,2,3-triazole-4-yl (E-11).

To a suspension of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-cyclopentyloxy - aminoacetate]-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid 258 mg, 0,304 mmol) in a mixture of anisole (1 ml) and nitromethane (4 ml) at a temperature of -30oC was added a solution of aluminium chloride (0.25 mg, 1.88 mmol) in anisole (1 ml) and the mixture stirred for 50 minutes, the Reaction mixture was diluted with ethanol (2 ml), stirred at the same temperature for 5 min, mixed with 1 N. a solution of hydrochloric acid (4.0 ml) and water (200 ml) and stirred at room temperature for 5 minutes the Aqueous layer was washed with ethyl acetate, concentrated under reduced pressure to adalenycoree (methanol:water 4:1) to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-cyclopentylacetic] -3 - (1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (93 mg) as a white solid. Exit 53% NMR d (D2O-NaHCO3) ppm: 1,4-2,0 (m, 8H), 3,50, 3,70 (Avcv, J= 17 Hz, 2H), 4,13, 4,23, (Avcv, J=14 Hz, 2H), 5,17 (d, J=4,8 Hz, 1H), 5,77 (d, J=4,8 Hz, 1H), 6,98 (s, 1H), 8,03 (C. 1H). IR n (KBr) cm-1: 3300 Shir, 1675, 1665, 1526, 1385, 1343.

This compound is a potent antibacterial agent against Escherichia coli EC-14 (0.8 µg/ml) and Pseudomonas aeruginosa A25619 (0.8 µg/ml).

8). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl]-2-(2-propenyloxy)acetyl; Het 1,2,3-triazole-4-yl (E-10).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(2-propenyloxy - imino)acetamido]-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (376 mg, 0.46 mmol) in a mixture of anisole (1.5 ml) and nitromethane (6,0 ml) at a temperature of -30oC was added a solution of aluminum chloride and 0.37 g, 2.8 mmol) in anisole (1.5 ml) and the mixture stirred for 50 minutes, the Reaction mixture was mixed with ethanol (2 ml) and stirred at the same temperature for 5 min and mixed with 1 N. a solution of hydrochloric acid (5 ml) and water (200 ml). The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organovo copolymer (methanol: water 4:1). Larousse substance is washed with ethyl acetate to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propenyloxy)acetamido] -3- (1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (127 mg) as a white solid. Output 50% NMR d (D2O-NaHCO3) ppm: 3,48, 3,67 (Avcv, J=17 Hz, 2H), 4,11, 4,24 (Avcv, J=14 Hz, 2H), 4.72 in (d, J=5.6 Hz, 2H), 5,18 (d, J=4,6 Hz, 1H), and 5.30 (DD, J=1.6 Hz, J=a 10.6 Hz, 1H), lower than the 5.37 (DD, J=1.6 Hz, J=17,4 Hz, 1H), of 5.82 (d, J=4,6 Hz, 1H), 6,07 (DDT, J=5.6 Hz, J=a 10.6 Hz, J= 17,4 Hz, 1H), 7,03 (s, 1H), to 7.99 (s, 1H). IR n (KBr) cm-1: 3450, 3270, 1753, 1618, 1653, 1545, 1532, 1384, 1357, 1021, 1000. This compound is a strong antibacterial agent type Escherichia coli EC-14 (0.4 µ g/ml) and Enterobacter cloacae SR233 (0.8 µg/ml).

9). Acyl N-(tert-butoxycarbonyl BC)-2-phenylglycyl; Het-(trityl to N)-1,2,3-triazole-4-yl (E-2).

To a solution of complex diphenylmethylene ester 7-(N)-tert-butoxycarbonyl-2-phenylglycylamino)-3-(trityl-1,2,3-Tria - Zol-4-ultimatelty)-3-cefem-4-carboxylic acid (480 mg, 0,487 mmol) in a mixture of anisole (1.2 ml) and dichloromethane (3 ml) under cooling on ice, add triperoxonane acid (3 ml), and the mixture is stirred while cooling on ice for 30 min and at room temperature for 50 minutes, the Reaction mixture is shaken with ice water and ethyl acetate while cooling on ice. The aqueous layer concertography in the presence stiroldivinilbenzol copolymer (methanol: water 4:1). The spray residue from ethyl acetate to obtain 7-(2-phenylglycylamino)-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-- carboxylic acid (157 mg) as a white powder. Exit 67% NMR d (D2O) ppm: 3.46 in, 3,67 (Avcv, J=17,1 Hz, 2H), 4.25 IN, OR 4.31, J=14,2 Hz, 2H), 5,13 (d, J=4.4 Hz, 1H), 5,27 (s, 1H), to 5.66 (d, J=4.4 Hz, 1H), 7,54 (s, 5H), 8,07 (s, 1H). IR n (KBr) cm-1: 3400, 3060 Shir, 1763, 1690, 1595, 1458, 1388, 1345.

10). Acyl-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl]acetyl; Het (trail to N)-1,2,3-triazole-4-yl (E-1).

To a solution of complex diphenylmethylene ester of 7-[2-(2-tert-butoxycarbonylamino-4-yl)acetamido] -3-(trityl-- 1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (779 mg, 0,784 mmol) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40oC was added a solution of aluminum chloride (0,83 g, 6,24 mmol) in anisole (3 ml), and the mixture is stirred at a temperature of from -30 to -40oC for 50 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (6.3 ml), diluted with water, washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organic solvents. The residual solution is subjected to chromatography in the presence of stiroldivinilbenzol copolymer (methanol:water 4: 1), and the resulting powder was promoveu acid (225 mg) as a white powder. Exit 59% NMR d (D2O CD3OD-NaHCO3) ppm: 3,57 (c, 2H), 3,43, 3,60 (Avcv, J=17,4 Hz, 2H), 4,08, 4,20, (Avcv, J=13,8 Hz, 2H), is 5.06 (d, J=4,7 Hz, 1H), 5,65 (d, J=4,7 Hz, 1H), of 6.49 (s, 1H), 7,92 (s, 1H). IR n (KBr) cm-1: 3510, 3260 Shir, 1759, 1664, 1579, 1401, 1551, 1352, 1326. This compound is a potent antibacterial agent against Staphilococcus aureus smith (0.1 ág/ml). Escherichia coli EC-14 (0.8 µg/ml) and Proyeus vulgaris CN-329 (0.8 µg/ml) and shows a high level in the blood by oral administration (17,1 μg/ml, 15 min, mouse).

11). Acyl-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl]Glyoxylic; Het (trail to N)-1,2,3-triazole-4-yl (E-4).

To a solution of complex diphenylmethylene ester of 7-[2-(2-tert-butoxycarbonylamino-4-yl)glycosylamine] -3-(Tr - ITIL-1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (649 mg, 0,644 mmol) in a mixture of anisole (2.5 ml) and nitromethane (10 ml) at -40oC was added a solution of aluminum chloride (0,69 g, 5,19 mol) in anisole (2.5 ml), and the mixture is stirred at a temperature of from -30 to -40oC for 50 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (5.2 ml), diluted with water, washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organic solvents. The residual solution undervienna powder is washed with ethyl acetate to obtain 7-[2-(2-aminothiazol-4-yl)glycosylamide]-3-(1,2,3-triazole-4-illiam - ethylthio)-3-cefem-4-carboxylic acid (130 mg) as a yellow powder. Exit 40% NMR d (CD3SOCD3) ppm: 3,83 (c, 2H), of 4.44 (c, 2H), 5,19 (d, J=4,6 Hz, 1H), of 5.68 (DD, J=8,2 Hz, J=4.6 Hz, 1H), 7,40 (s, 2H), 7,87 (s, 1H), 7,9-8,1 (Shir. s, 1H), 9,81 (d, J=8,2 Hz, 1H). IR n (KBr) cm-1: 3300 Shir. 3120, 1764, 1660, 1620, 1519, 1480, 1355. This compound is a potent antibacterial agent against Escherichia coli EC-14 (0.4 µ g/ml).

12). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)thiazol-4-yl]-2-(trityl to N)oksiminomyetil; Het (trityl - N)-1,2,3-triazole-4-yl (EE).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(1-trityl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (29 g, is 22.9 mmol) in a mixture of anisole (50 ml) and nitromethane (200 ml) was added dropwise a solution of aluminum chloride (20.7 g, 156 mmol) in anisole (50 ml) at a temperature of from -30 to -40oC, and the mixture is stirred for one hour at the same temperature. The reaction mixture is diluted with 1 N. a solution of hydrochloric acid (200 ml) and water and washed with ethyl acetate. The aqueous layer was concentrated to remove the organic solvent under reduced pressure and passed through a column of adsorbent on the basis of stiroldivinilbenzol copolymer. The product water elute with methanol (4:1) to obtain 7-[(Z)-2V as pale-yellow powder. Exit 68% NMR d (D2O-NaHCO3) ppm: 3,51, 3,75 (Avcv, J=and 17.2 Hz, 2H), 4,14, 4,25 (Avcv, J= a 13.9 Hz, 2H), total of 5.21 (d, J=4,7 Hz, 1H), of 5.84 (d, J=4,7 Hz, 1H), 6,99 (s, 1H), 8,07 (s, 1H). IR n (KBr) cm-1: 3280, 3100, 1760, 1760, 1660, 1590, 1525, 1345, 1385, 1175, 995.

This compound is a potent antibacterial agent against Escherichia coli 7437 (0.02 μg/ml) and Enterobacter cloacae SR233 (0.8 µg/ml) and shows a high level in the blood by oral administration 29.6 ág/ml, 15 min, mouse).

13). (Selected as disodium salt) Acyl (Z)-2-[2-(trailmen to amino)thiazol-4-yl]-2-(diphenylmethylene to carboxy)methoxyaminomethyl; Het (trail to N)-1,2,3-triazole-4-yl (E-12).

The solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tritylimidazole-4-yl)-2-(diphenylmethanediisocyanate - iamino)acetamido] -3-(trityl-1,2,3-triazole-4-ultimatelty)-3-cefem-4-- carboxylic acid (1.04 g, 0,749 mmol) in a mixture of 98% formic acid (16 ml) and water 0.8 ml) was stirred at room temperature for 3 hours, the Reaction mixture was concentrated. The residue was washed with simple ether, filtered and dried. To a solution of this residue in a mixture of anisole (2 ml) and nitromethane (8 ml) at -40oC was added a solution of aluminum chloride. (0.50 g, 3,76 mmol) in anisole (2 ml), and the mixture is stirred at a temperature of from -3,8 ml) and water washed with ethyl acetate and concentrated under reduced pressure to remove organic solvents. The residual aqueous solution is subjected to chromatography in the presence of styrene-divinylbenzene copolymer (methanol: water 4: 1). The residue is washed with ethyl acetate and the resulting powder was dissolved in a dilute aqueous solution of acid sodium carbonate and purified by chromatography in the presence of analytical stiroldivinilbenzol (water). The eluate lyophilizer and sprayed with ethyl acetate, obtaining the sodium salt of 7-[(Z)-2-(2-amino-thiazol-4-yl)-2-(Sociocybernetics)ACE - tamido] -3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (121 mg) as pale-yellow-white powder. Exit 26% NMR d (D2O) ppm: 3,49, 3,70 (Avcv, J=17,4 Hz, 2H), 4,12, 4,24 (Avcv, J=13,8 Hz, 2H), 4,57 (s, 2H), 5,18 (d, J=4,8 Hz, 1H), of 5.82 (d, J=4,8 Hz, 1H),? 7.04 baby mortality (s, 1H), 8,02 (s, 1H). IR n (KBr) cm-1: 3600-2400 Shir, 1760, 1655, 1595, 1530, 1390, 1350, 1320. This compound is a potent antibacterial agent against Proteus mirabilis PR-4 (0,006 mg/ml) and Proteus vulgaris CN-329 (0,006 mg/ml).

14). (Selected as disodium salt) Acyl (Z)-2-[2-(trailmen to amino)-triazole-4-yl]-2-/(S)-1-(diphenylmethylene to carboxy)toksienosti; Het (trail to N)-1,2,3-triazole-4-yl (E-13).

A solution of the difficulty is to} -3-(trityl-1,2,3-triazole-4-ultimatelty)-3-ceph em-4-carboxylic acid (1.01 g, determined as 0.720 mmol) in a mixture of 98% formic acid (16 ml) and water (0.8 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was washed with simple ether, filtered and dried. The product is dissolved in a mixture of anisole (2.0 ml) and nitromethane (8.0 ml), cooled at -40oC, mixed with a solution of aluminum chloride (0,48 mg, 3.61 mmol) in anisole 2.0 ml) and stirred at a temperature of from -30 to -40oC for 1.5 h, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (3.6 ml), diluted with water, washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organic solvents. The resulting aqueous solution is subjected to chromatography in the presence of styrene-divinylbenzene copolymer (methanol:water 4:1). The resulting powder was washed with ethyl acetate, dissolved in a dilute aqueous solution of acid sodium carbonate and purified by chromatography (analytical) on stiroldivinilbenzol copolymer water and lyophilizers. The lyophilisate is washed with ethyl acetate and sprayed with obtaining the sodium salt of 7-{(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-Sociocybernetics-acetamido}-3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid, 4,11, to 4.23 (Avcv, J=13,8 Hz, 2H) and 4.65 (q, J= 7,0 Hz, 1H), 5,18 (d, J=4,8 Hz, 1H), of 5.84 (d, J=4,8 Hz, 1H), 7,02 (s, 1H), 7,98 (s, 1H). IR n (KBr) cm-1: 3600-2400, Shir, 1760, 1655, 1590, 1528, 1388, 1350. This compound is a potent antibacterial agent against Proteus mirabilis PR4 (0,01 µg/ml). Proteus vulfaris CN-329 (0,006 mg/ml) and Escherichia coli EC-14 (0.2 ág/ml).

15). Acyl (Z)-2-[2-(tert-butoxycarbonylamino - up amino) thiazol-4-yl]-2-[1-diphenylcarbinol to carboxy)-vinylacetylene]acetyl; Het (trail to N)-1,2,3-triazole-4-yl (E-15).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-tert-butoxycarbonylamino-4-yl)-2-(1-diphenylmethoxy - harmonicgeneration)acetamido]-3-(trityl-1,2,3-triazole-4-yl-Timati - ltio)-3-cefem-4-carboxylic acid (910 mg, 0,723 mmol) in a mixture of anisole (3.0 ml) and nitromethane (12.0 ml) at -40oC was added a solution of aluminum chloride (0,77 g, 5,79 mmol) in anisole (3.0 ml), and the mixture is stirred at a temperature of from -30 to -40oC for 50 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (5.8 ml), diluted with water, washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organic solvents. The resulting aqueous solution is subjected to chromatography in the presence of stradivariuses-3-yl)-2-(1-carboxymethyloxime)acetamido- -3-(1,2,3-triazole-4-ultimately-3-cefem-4-carboxylic acid (326 mg) as pale-yellow-white powder. Exit 77% NMR d (D2O-NaHCO3) ppm: 3,48, 3,68 (Avcv, J=17,4 Hz, 2H), 4,11, 4,23 (Avcv, J=a 13.9 Hz, 2H), 5,16 (d, J=1.7 Hz, 1H), 5,171 (d, J=4,8 Hz, 1H), 5,32 (d, J=1.7 Hz, 1H), by 5.87 (d, J=4,8 Hz, 1H), 7,21 (s, 1H), 8,00 (s, 1H). IR n (KBr) cm-1: 3600-2400 Shir, 1766, 1660, 1630, 1580, 1530, 1390, 1360. This compound is a potent antibacterial agent against Proteus mirabilis PR4 (less than 0,003 mg/ml) and Serratia marcescens SR1005 (0.8 µg/ml).

16). Acyl (Z)-2-[2-tert-butoxycarbonylamino to amino)-thiazol-4-yl]-2-[(1-tert-butoxycarbonyl to carboxy)-1-methylethoxy]acetyl; Het (trail to N)-1,2,3-triazole-4-yl (E-14).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-(1-tert-butoxy - carbonyl-1-methylethoxy)acetamido] -3-(trityl-1,2,3-triazole-4-ilti - methylthio)-3-cefem-4-carboxylic acid (822 mg, 0,706 mmol) in a mixture of anisole (3.0 ml) and nitromethane (12 ml) at -40oC was added a solution of aluminum chloride (0.75 g, 5,64 mmol) in anisole (3 ml), and the mixture is stirred at a temperature of from -30 to 40oC for one hour. The reaction mixture is mixed with 1 N. a solution of hydrochloric acid (5.7 ml), diluted with water, washed with ethyl acetate and concentrated under reduced pressure to remove the remaining organic solvents. Residual Rast is the first powder is washed with ethyl acetate to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxy)ACET - amido] -3-(1,2,3-triazole-4-ultimatelty)-3-cefem-4-carboxylic acid (299 mg) as pale yellowish white powder. The 71% yield NMR d (D2O-NaHCO3) ppm: 1,48 (c, 3H), 1.50 in (c, 3H), 3,50, 3,69 (Avcv, J=17,4 Hz, 2H), 4,12, 4,24 (Avcv, J=a 13.9 Hz, 2H), 5,19 (d, J=4.9 Hz, 1H), of 5.82 (d, J= 4.9 Hz, 1H), 6,99 (s, 1H), 8,01 (s, 1H). IR n (KBr) cm-1: 3600-2400 Shir, 1768, 1670, 1635, 1580, 1535, 1385, 1360. This compound is a potent antibacterial agent against Proteus mirabilis PR4 (0,01 µg/ml), Serratia marcescens A13880 (0.8 µg/ml) and Pseudomonas aerufinosa A25619 (1.6 ĩg/ml).

17). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl)]-2-(trityl-N) oksiminomyetil; Het - 1-methyl-1,2,3-triazole-4-yl (E-1).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(1-methyl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (708 mg, 0,683 mmol) in a mixture of anisole (2.0 ml) and nitromethane (8.0 ml) was added dropwise a solution of aluminum chloride (727 mg, vs. 5.47 mmol) in anisole (2.0 ml) at -40oC, and the mixture is stirred for one hour at a temperature of from -30 to -40oC. the Reaction mixture is diluted with 1 N. a solution of hydrochloric acid (5.5 ml) and water and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to remove organic solvent and passed through a column of adsorbent on the basis of strategyrelated] -3-(1-methyl-- 1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow powder (96,3 mg). The output is 27% NMR d (D2O-NaHCO3) ppm: 3,50, 3,81 (Avcv, J= 17,4 Hz, 2H), 4,11 (s, 3H), 4,12, 4,22 (Avcv, J=14,0 Hz, 2H), 5,24 (d, J=4,6 Hz, 1H), of 5.83 (d, J= 4,6 Hz, 1H), 6,99 (s, 1H), of 8.09 (s, 1H). IR n (KBr) cm-1: 3252, 2928, 1770, 1650, 1620, 1523, 1404, 1348, 1181, 1019. This compound is a potent antibacterial agent against Escherichia coli 7437 (0.02 μg/ml). Enterobacter cloacae SR233 (0.8 µg/ml) and Haemophil influenzae and SR3508 (0.1 ág/ml).

18). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)triazole-4-yl)-2-(trityl to N) oksiminomyetil; Het - 2-methyl-1,2,3-triazole-4-yl (E-2).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(2-methyl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid (1.39 g, of 1.34 mmol) in a mixture of anisole (5.0 ml) and nitromethane (20 ml) was added dropwise a solution of aluminum chloride (1,43 g to 10.8 mmol) in anisole (5 ml) at -40oC. After stirring at -30 to -40oC for one hour the mixture is diluted with 1 N. a solution of hydrochloric acid (11,0 ml) and water, washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to remove organic solvents, and passed through a column of adsorbent based on styrene-divinylbenzene saparamadu] -3-(2-methyl - 1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow powder (534 mg). The yield is 75% NMR d (D2O-NaHCO3) ppm: 3,52, 3,80 (Avcv, J= 17.3 Hz, 2H), 4,17 (s, 3H), 4,18, 4,25 (Avcv, J=13,7 Hz, 2H), 5,23 (d, J=4,8 Hz, 1H), of 5.82 (d, J= 4,8 Hz, 1H), 6,99 (s, 1H), to 7.84 (s, 1H). IR n (KBr) cm-1: 3288, 1768, 1663, 1606, 1530, 1365, 1255, 1177, 1005. This compound is a potent antibacterial agent against Escherichia coli 7437 (0.02 μg/ml).

19). Acyl (Z)-2-[2-(tert-butoxycarbonylamino - up amino)thiazol-4-yl]-2-(trityl to N)oksiminomyetil; Het - 3-methyl-1,2,3-triazole-4-yl (E-3).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(3-methyl-1,2,3-triazole-4-yl)tomatillo-3-cefem-4-carboxylic acid 900 mg, 0,869 mmol) in a mixture of anisole (4.0 ml) and nitromethane (16 ml) was added a solution of aluminum chloride (924 mg, 6.95 mmol) in anisole (2.0 ml) at -40oC, and the mixture is stirred for one hour at a temperature of from -30 to -40oC. the Reaction mixture is diluted with 1 N. a solution of hydrochloric acid (7.0 ml) and water and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to remove organic solvent and passed through a column of adsorbent n is eat 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(3-methyl-- 1,2,3-aminothiazol-4-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow powder (366 mg). The yield is 80% NMR d (D2O-NaHCO3) ppm: 3,53, 3,78 (Avcv, J= 17,4 Hz, 2H), 4,08 (s, 3H), 4,14, 4,27 (Avcv, J=14,1, 2H), 5,23 (d, J=4.5 Hz, 1H), of 5.84 (d, J= 4.5 Hz, 1H), 6,98 (s, 1H), 7,95 (s, 1H). IR n (KBr) cm-1: 3204, 2984, 1768, 1664, 1610, 1529, 1382, 1347, 1262, 1176, 1127, 996. This compound is a potent antibacterial agent against Escherichia coli 7437 (0.02 μg/ml) and Enterobacter cloacae SR233 (0.4 µ g/ml).

20). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino) triazole-4-yl]-2-(trityl to N)oksiminomyetil; Het 1-(trityl - N)-1,2,4-triazole-4-yl (1E11).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-(1-trityl-1,2,4-triazole-3-yl)tomatillo-3-cefem-4-carboxylic acid (1.89 g, 1.50 mmol) in a mixture of anisole (7,0 ml) and nitromethane (28,0 ml) was added dropwise a solution of aluminum chloride (1,99 g, 15 mmol) in anisole (7 ml) at temperatures from -40 to -30oC, and the mixture is stirred at the same temperature for one hour. The reaction mixture is diluted with 1 N. a solution of hydrochloric acid (15 ml) and water and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to remove organic solvents, and passed through a column of adsorbent on the basis of stiroldivinilbenzol copolymer. Prodo] -3-(1,2,4-Tr - eazol-3-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow powder (418 mg). The total yield of 34% NMR d (D2O-NaHCO3) ppm: 3,54; 3,79 (Avcv, J= 17,4 Hz, 2H), 4,42 (s, 2H), total of 5.21 (d, J=4.3 Hz, 1H), of 5.83 (d, J=4.3 Hz, 1H), 6,98 (s, 1H), 8,40 (s, 1H). IR n (KBr) cm-1: 3280, 3132, 1768, 1665, 1605, 1530, 1390, 1349, 1273, 1178, 1004. This compound is a potent antibacterial agent against Escherichia coli 7437 (0.02 μg/ml), Enterobacter cloacae SR233 (0.8 µg/ml) and Klebsiella pneumoniae SR1 (0.05 µl/ml).

21). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl)]-2-(trityl to N) oksiminomyetil; Het - 1-methyl-1,2,4-triazole-3-yl (E-7).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(1-methyl-1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (1.52 g, of 1.47 mmol) in a mixture of anisole (5.0 ml) and nitromethane 20 ml) at -40oC was added a solution of aluminum chloride (1.56 g, 11.7 mmol) in anisole (5.0 ml), and the mixture is stirred at a temperature of from -40 to -30oC for one hour. The reaction mixture is mixed with 1 N. a solution of hydrochloric acid (12 ml), diluted with water, washed with ethyl acetate, concentrated to remove the remaining organic solvents, and passed through a column of adsorbent based on styrene-divinylbenzene copolymer. The adsorbed product AluI is getting 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(1-me - til-1,2,4-triazole-3-ultimatelty)-3-cefem-4-carboxylic acid (628 mg) as a yellow powder. The output is 81% NMR d (D2O-NaHCO3) ppm: 3,55, 3,83 (Avcv, J=and 17.2 Hz, 2H), with 3.89 (s, 3H), and 4.40 (s, 2H), 5,24 (d, J=4,7 Hz, 1H), of 5.82 (d, J=4,7 Hz, 1H), 6,99 (s, 1H), at 8.36 (s, 1H). IR n (KBr) cm-1: 3200 Shir, 1765, 1660, 1630, 1600, 1520, 1380, 1348.

22). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino) thiazol-4-yl]-2-trityl to N)oksiminomyetil; et 2-methyl-1,2,4-triazole-3-yl (E-8).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(2-methyl-1,2,4-triazole-4-3-ultimatelty)-3-cefem-4-carboxylic acid (1.54 g, 1,49 mmol) in a mixture of anisole (5.0 ml) and nitromethane (20 ml) at -40oC was added a solution of aluminum chloride (1,58 g, to 11.9 mmol) in anisole (5.0 ml), and the mixture is stirred at a temperature of from -40 to -30oC for 50 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (12 ml), diluted with water, washed with ethyl acetate, concentrated to remove the remaining organic solvents, and passed through a column of adsorbent on the basis of stiroldivinilbenzol copolymer. The adsorbed product elute using water and methanol (1:4). The eluate concentrated to obtain a powder, which is washed with ethyl acetate, obtaining 7-[(Z)-2-(2-aminothiazol-4-screens 83% NMR d (D2O-NaHCO3) ppm: 3,54, 3,81 (Avcv, J=17,4 Hz, 2H), 3,85 (s, 3H), of 4.44, 4,50 (Avcv, J=14.1 Hz, 2H), total of 5.21 (d, J=4,8 Hz, 1H), of 5.83 (d, J=4,8 Hz, 1H), 6,98 (s, 1H), 8,03 (s, 1H). IR n (KBr) cm-1: 3200 Shir. 1765, 1655, 1600, 1525, 1473, 1382, 1345.

23). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl]-2-(trityl to N)oksiminomyetil; Het - 4-methyl-1,2,4-triazole-3-yl (E-16).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetylamino] -3-(4-methyl-1,2,4-triazole-3-ultimately-3-cefem-4-carboxylic acid (378 ml, 0,365 mmol) in a mixture of anisole (1.0 ml) and nitromethane (4,0 ml) at -40oC was added a solution of aluminum chloride (388 mg, of 2.92 mmol) in anisole (1.0 ml), and the mixture is stirred at a temperature of from -40 to -30oCC for 50 minutes, the Reaction mixture was mixed with 1 N. a solution of hydrochloric acid (3.0 ml), diluted with water, washed with ethyl acetate, concentrated under reduced pressure to remove the remaining organic solvent and purify by chromatography in the presence of stiroldivinilbenzol copolymer (methanol: water 4: 1). The resulting powder was washed with ethyl acetate to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(4-me - til-1,2,4-triazole-3-ultimatelty)-3-cefem-4-,80 (Avcv, J=17.5 Hz, 2H), 4,35, 4,50 (Avcv, J=a 13.4 Hz, 2H), 5,19 (d, J=4.9 Hz, 1H), of 5.83 (d, J= 4.9 Hz, 1H), 7,00 (s, 1H), and 8.50 (s, 1H). IR n (KBr) cm-1: 3200 Shir, 1767, 1655, 1630, 1605, 1520, 1377, 1340. This compound is a potent antibacterial agent against Escherichia coli EC-14 (0.05 mg/ml) and Morhauia morganii SR9 (0.1 ág/ml).

24). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)-thiazol-4-yl-2-(trityl-N)oksiminomyetil; Het 1,2,3-triadica-5-yl (E-2).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amino-3-(1,2,3-thiadiazol-5-yl)tomatillo-3-cefem-4-carboxylic acid (1,21 g of 1.16 mmol) in a mixture of anisole (4 ml) and nitromethane (16 ml) and cooled to -40 to -30oC was added a solution of aluminum chloride (1.23 g, a 9.25 mmol) in anisole (4.0 ml), and the mixture is stirred at a temperature of from -40 to -30oC for 50 minutes To the reaction mixture was added 1 n hydrochloric acid (10 ml), diluted with water and washed with ethyl acetate. The aqueous layer was concentrated to remove organic solvents, purified by chromatography on stiroldivinilbenzol copolymer (methanol:water 4:1), and the resulting powder was washed with ethyl acetate to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyindolacetic] aminase 71% NMR d (D2O-NaHCO3) ppm: to 3.58, 3,88 (Avcv, J=17,4 Hz, 2H), 4,37, 4,48 (Avcv, J=14.1 Hz, 2H), 5.25-inch, (d, J=4,7 Hz, 1H), of 5.83 (d, J=4,7 Hz, 1H), 6,97 (s, 1H), 8,76 (s, 1H. IR n (KBr) cm-1: 3200 Shir, 1760, 1655, 1600, 1520, 1380, 1340, 1200, 1170. This compound shows a strong antibacterial activity against Escherichia coli 7437 (0,01 µg/ml), Escherichia coli SR377 (0.4 µ g/ml), Magtape morganii SR9 (0.05 mg/ml) and Enterobacter Cloacae SR233 (0.4 µ g/ml).

25). Acyl (Z)-2-[-2-(tert-butoxycarbonylamino - up amino)-thiazol-4-yl-2-(trityl to N)oksiminomyetil; Het 1,3,4-thiadiazole-2-yl (E-1).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido]-3-91,3,4-thiadiazol-2-ultimatelty)-3-cefem-4-carboxylic acid (535 mg, 0.51 mmol) in a mixture of anisole (1.0 ml) and nitromethane (4 ml) was added a solution of aluminum chloride (0,61 mg, 4.6 mmol) in anisole (2 ml) at a temperature of -30oC, and the mixture is stirred for 40 minutes, the Reaction mixture was mixed with ethanol (2 ml), stirred for 5 min at the same temperature, diluted with 1 N. a solution of hydrochloric acid (6 ml) and water (200 ml) and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to remove organic solvents, and passed through a column stiroldivinilbenzol copolyme is 2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(1,3,4-t - diazol-2-ultimatelty)-3-cefem-4-carboxylic acid as pale yellow solid (201 mg). The output is 74% NMR d (D2-NaHCO3) ppm: 3,60, 3,89 (Avcv, J=17 Hz, 2H), 4,57, with 4.64 (Avcv, J=14 Hz, 2H), 5,24 (d, J=5 Hz, 1H), of 5.83 (d, J=5 Hz, 1H), 6,98 (s, 1H), 9,41 (s, 1H). IR n (KBr) cm-1: 3300, 1765, 1665, 1600, 1370. This compound is a potent antibacterial agent against Escherichia coli SR377 (0.4 µ g/ml) Enterobacter cloacae SR233 (0.4 µ g/ml) and Morgania morganii SR9 (0.1 ág/ml).

26). Acyl (Z)-2-(2-tert-butoxycarbonylamino to amino)-thiazol-4-yl)-2-(trityl to N) oksiminomyetil; Het - 2-methyl-1,3,4-thiadiazole-5-yl (E-2).

To a solution of complex diphenylmethylene ester (388 mg, 0,368 mmol) of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(2-methyl-1,3,4-thiadiazole-5-ultimatelty)-3-cefem-4-carboxylic acid in a mixture of anisole (1.0 ml) and nitromethane (4,0 ml) at a temperature of -30oC was added a solution of aluminum chloride (0.45 g, 9,2 equivalent, 3.4 mmol) in anisole (1.5 ml), and the mixture is stirred at this temperature for 40 minutes, the Reaction mixture was mixed with ethanol (2.0 ml), stirred for 5 min at the same temperature and diluted with 1 N. a solution of hydrochloric acid (6.0 ml) and water (200 ml). The aqueous layer was washed with ethyl acetate, concentrated under reduced pressure to remove the remaining organic solvents and miss shape with obtaining 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine]-3-(2-methyl-- 1,3,4-thiadiazole-5-ultimatelty)-3 cefem-4-carboxylic acid (149 mg). The yield is 75% NMR d (D2O-NaHCO3) ppm: 2,72 (c, 3H), to 3.58, a 3.87 (Avcv, J=17,0 Hz, 2H), 4,51, 4,57 (Avcv, J=14,0 Hz, 2H), 5,23 (d, J= 5.0 Hz, 1H), of 5.83 (d, J=5.0 Hz, 1H), 6,97 (s, 1H). IR n (KBr) cm-1: 3200, 1772, 1668, 1605, 1515, 1390, 1340. This compound is a potent antibacterial agent against Escherichia coli 7437 (0.02 μg/ml), Enterobacter cloacae SR233 (0.8 µg/ml), Escherichia coli SR377 (0.8 µg/ml) and Morgania morganii SR9 (0.05 mg/ml).

7). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)thiazol-4-yl]-2-(trityl up to 4 oksiminomyetil; Het tetrazol-5-yl (E-3).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amino-3-(5-tetrazolyl)tomatillo-3-cefem-4-carboxylic acid (942 mg, contains approximately 10% of the product) in a mixture of anisole (3.0 ml) and nitromethane (12 ml) and cooled to -40 to -30oC was added a solution of aluminum chloride (980 mg, 7,37 mmol) in anisole (3.0 ml), and the mixture is stirred at a temperature of from -40 to -30oC for one hour. The reaction mixture is diluted with 1 N. a solution of hydrochloric acid (7.5 ml) and water, washed with ethyl acetate, concentrated under reduced pressure to remove the remaining organic solvents and subjected to chromatography in prisutstvie 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyindolacetic/amino-3-(Tetris - ol-5-yl)tomatillo-3-cefem-4-carboxylic acid as pale yellow powder (289 mg). Output is 28% (from complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amino-3 - methanesulfonate-3-cefem-4-carboxylic acid). NMR d (D2O-NaHCO3) ppm: 3,47, 3,65 (Avcv, J=17,4 Hz, 2H), to 4.38, 4,43 (Avcv, J=13,7 Hz, 2H), 5,18 (d, J=4,6 Hz, 1H), of 5.83 (d, J= 4,6 Hz, 1H), 6,99 (s, 1H). IR n (KBr) cm-1: 3200 Shir, 1765, 1650, 1600, 1525, 1385, 1345, 1175. This compound is a potent antibacterial agent against Escherichia coli 7437 (0,01 µg/ml).

28). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)thiazol-4-yl]-2-(trityl to N)oksiminomyetil; Het=1-methyl-5-tetrazolyl (E-4).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetyl] amino-3-(1-methyl-5-tetrazolyl)tomatillo-3-cefem-4-carboxylic acid (576 mg, 0,555 mmol) in a mixture of anisole (2.0 ml) and nitromethane (8.0 ml) under cooling to a temperature of from -40 to -30oC was added a solution of aluminum chloride (591 mg, of 4.44 mmol) in anisole (2.0 ml) and the mixture is stirred at a temperature of from -40 to -30oC for one hour. The reaction mixture is diluted with 1 N. a solution of hydrochloric acid (5.0 ml) and water and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to galopolimer (methanol:water 4:1). The resulting powder was washed with ethyl acetate to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyindolacetic]amino-3-(1-me - til-5-tetrazolyl)tomatillo-3-cefem-4-carboxylic acid as a yellow powder (200 mg). The output is 68% NMR d (D2O-NaHCO3) ppm: 3,59, 3,90 (Avcv, J=17,4 Hz, 2H), 4.00 points (s, 3H), 4,58, 4,63 (Avcv, J=13,8 Hz, 2H), 5,24 (d, J= 4.9 Hz, 1H), of 5.83 (d, J=4.9 Hz, 1H), 6,98 (c, 1H). IR n (KBr) cm-1: 3300 Shir, 1765, 1660, 1605, 1525, 1385, 1345, 1170. This compound shows a strong antibacterial activity against Escherichia coli 7437 (0.02 μg/ml), Escherichia coli SR377 (0.4 µ g/ml), Morgania morganii SR9 (0.1 ág/ml) and Enterobacter cloacae SR233 (0.8 µg/ml).

29). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino)thiazol-4-yl]-2-(trityl to N)oksiminomyetil; Het 2-methyltetrazol-5-yl (E-09).

To a solution of complex diphenylmethylene ester of 7-[Z-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - tetramino]-3-(2-methyltetrazol-5-ultimatelty)-3-cefem-4-carboxylic acid (1,16 g, 1.12 mmol) in a mixture of anisole (4.0 ml) and nitromethane (16 ml) at -40oC was added a solution of aluminum chloride (1.19 g, of 8.95 mmol) in anisole (4.0 ml) and the mixture is stirred at a temperature of from -40 to -30oC for one hour. The reaction mixture is mixed with 1 N. a hydrochloric acid solution of 9.0 ml), rasburicase solvent and passed through a column of adsorbent on the basis of stiroldivinilbenzol copolymer. The adsorbed substance elute with a mixture of water-methanol (1:4) and concentrate to obtain a powder, which is washed with ethyl acetate, obtaining 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyimino-acetamido] -3- (2-methyltetrazol-5-ultimatelty)-3-cefem-4-carboxylic acid (466 mg) as yellow powder. The output is 79% NMR d (D2O-NaHCO3) ppm: 3,48, 3,88 (Avcv, J=17.3 Hz, 2H), 4,36, (s, 3H), 4,50 (s, 2H), 5,26 (d, J=4,7 Hz, 1H), of 5.82 (d, J=4,7 Hz, 1H), 6,98 (s, 1H). IR n (KBr) cm-1: 3300 Shir, 1767, 1660, 1630, 1600, 1528, 1387, 1340, 1321.

30). Acyl (Z)-2-[2-(tert-butoxycarbonylamino to amino) thiazol-4-yl]-2-(trityl to N) oksiminomyetil; Het is 2-pyridyl (E-3).

To a solution of complex diphenylmethylene ester of 7-[(Z)-2-(2-tert-butoxycarbonylamino-4-yl)-2-trisiloxane - acetamido] -3-(2-pyridylamino)-3-cefem-4-carboxylic acid (722 mg, 0.70 mmol) in a mixture of anisole (2.0 ml) and nitromethane (8.0 ml) under cooling to a temperature of -40oC was added a solution of aluminum chloride (744 mg, 5,59 mmol) in anisole (2.0 ml), and the mixture is stirred at a temperature of from -40 to -30oC for one hour. The reaction mixture is diluted with 1 N. a solution of hydrochloric acid (6.0 ml) and water, washed with ethyl acetate, concentrated under reduced pressure to remove the remaining armamento elute with a mixture of methanol-water (4:1). The eluate concentrate. The residue is washed with ethyl acetate and dried to obtain 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(2-Piri - gitimately)-3-cefem-4-carboxylic acid (289 ml). The output is 79% NMR d (D2O-NaHCO3) ppm: 3,55, 3,78 (Avcv, J=and 17.2 Hz, 2H), 4,43, 4,49 (Avcv, J=14,0 Hz, 3H), 5,16 (d, J=4,6 Hz, 1H), of 6.96 (s, 1H), 7.23 percent (DDD, J=7.5 Hz, J=4.9 Hz, J=0.8 Hz, 1H), 7,46 (Shir. d, J=8.0 Hz, 1H), 7,74 (DDD, J=8.0 Hz, J-7.5 Hz, J=1.6 Hz, 1H), 8,39 (width, d, J=4.9 Hz, 1H). IR n (KBr) cm-1: 3320, 2976, 1764, 1665, 1619, 1575, 1530, 1415, 1353, 1120. This compound is a potent antibacterial agent against Escherichia coli 7437 (0,01 µg/ml) and shows a high level in the blood by oral administration (18,7 μg/ml, 15 min, mouse).

The analysis of each connection is as follows.

Antibacterial activity in vitro. The solution of the test compounds at 0.01 N. aqueous solution of acid sodium carbonate applied to the Cup with agar medium by the method of two-fold dilutions, and the minimum inhibiting concentrations against gram-negative and gram-positive bacteria measured in accordance with the standard method proposed by the Japanese society of chemotherapy.

The level in the blood 15 min after oral administration. The test compound (40 mg/kg) is selected blood in the cavity of the heart and the concentration of the test compounds was measured by the method of coloured culture using Escherichia coli 7437.

Example 8. Medical preparations.

1). Granules, mg:

7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxykynurenine] -3-(1,2,3 - triazole-4-ultimatelty)-3-cefem-4-carboxylic acid 100

Lactose 600

Corn starch 290

Hydroxypropylcellulose 10 mg

The above materials granularit traditional wet method and 1 g of each substance is Packed in the form of granules and is prescribed three times a day to a patient suffering from an infection caused by susceptible bacteria.

2). Tablets mg

7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxykynuramine] -3-(1,2,3 - triazole-4-ultimatelty)-3-cefem-4-carboxylic acid 100

Lactose 65

Corn starch 32

Hydroxypropylcellulose 2

Magnesium stearate 1

The above materials granularit traditional wet method and formulated in tablet press machine to obtain tablets with a diameter of 7.5 mm, and then appoint two times a day to a patient suffering from an infection caused by susceptible bacteria.

3). Hard capsule, mg:

7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxykynuramine-[3-(1,2,4 - triazole-3-ultimatelty)-3-cefem-4-carboxylic acid 100

Cornstarch 47

Magnesium stearate 1, irout in the form of hard gelatin capsules (size # 4), then appoint three times a day to a patient suffering from an infection caused by susceptible bacteria.

1. Derivatives dialkyldithiophosphoric General formula

where the acyl lower allogenicity(lower)alkanoyl or a group of the formula

< / BR>
where R3hydrogen, hydroxy or perhaps a protected amino group,

or a group of the formula

< / BR>
where R4hydrogen or a protective group;

R5two of hydrogen, lower alkylene, oxygen or the group NOR6;

R6hydrogen, a protective group, lower alkyl, lower alkenyl, lower cycloalkyl, carboxy (lower)alkyl or carboxy(lower)alkenyl, and carboxypropyl can be protected;

Het pyridyl, thiadiazolyl, optionally substituted stands, triazolyl or tetrazolyl; R1simple bond or methylene;

R2methylene;

X is sulfur;

Y is hydrogen,

or their pharmaceutically acceptable salts.

2. Antibacterial composition comprising a cephalosporin derivative and a pharmaceutically acceptable carrier or diluent, characterized in that as a cephalosporin derivative it contains a connection on p. 1 in an effective amount.

Priority signs:

19.07. the rmula

< / BR>
Het pyridyl, thiadiazolyl;

21.11.90 R3a group of the formula

;

Het thiadiazolyl, triazolyl, tetrazolyl;

19.06.91 allgraph formula

< / BR>
Het tetrazolyl.

 

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