Derivatives of 3-trifluoromethyl-1-carb-1 detia-3-cefem-4 - carboxylic acid and intermediate product to obtain

 

(57) Abstract:

Derivatives of 3-trifluoromethyl-1-carb-1 Detia-3-cefem-4-carboxylic acid and intermediate product to obtain them. The inventive offered as antibiotics 7--acylamino-1-carb(1 detya)-3-trifluoromethyl-3-cefem-4-carboxylic acids and their derivatives. Also provides pharmaceutical compositions including antibiotics, intermediate compounds and method for their preparation. 3 S. and 8 C.p. f-crystals, 1 table.

The invention relates to 1-carb(1 detya)-cephalosporin antibiotics, intermediate compounds for their production, pharmaceutical compositions including antibiotics, and to a method of treatment of infectious diseases in humans and other animals.

1-carb(1 detya)- cephalosporin antibiotics have a bicyclic ring system, represented by the following formula, in which the numbering system is consistent with accepted at an arbitrary system item cafema.

< / BR>
1-carb(1 detya)-cephalosporins are referred to for convenience in this description as a 1-carbazepine or as 1-carb-(1-zetia)-3-cefem-4-carboxylic acids or their derivatives.

Getting 1-carbazepine and C-3 - substituted mnt UK N 2041923 disclose a method of obtaining a 3-H and 3-halo-1-carbazepine, while it is quite natural and other Tetrahedron letters 24, No. 44, page 4837-4838 (1983), suggest a way to get 3-hydroxy-()-1-carbazaepine.

Although many safe and potent antibiotics class-lactams are known and used clinically, studies in this class continue in attempts to find antibiotics with improved efficiency, in particular against microorganisms, insensitive or resistant against known antibiotics.

The invention offers antibiotics on the basis of 7-b-acylamino-1-carb(detya)-3-cefem-4-carboxylic acid, substituted in position 3 by trifluoromethyl. Position 7 of these antibiotics is replaced by acylamino part, such as D-arylpyrimidine, or geterotsiklicheskikh replaced by oxyiminocephalosporins. Also offering pharmaceutical compounds, including antibiotics, intermediate compounds and methods for their preparation. Examples of such antibiotics include

7-b-D-phenylglycylamino-1-carb(1 detya)-3-trifluoromethyl-3-cefem-4-carboxylic acid,

7-b-D-p-hydroxyphenylglycine-1-carb(1 detya)-3-trifluoromethyl-3-cefem-4-carboxylic acid,

7-b-D-m-methylsulfonylmethane-1-carb(1 detya)-3-trifluoromethyl-3-cefem-4 - carboxylic what-carboxylic acid.

The invention provides compounds of formula (I):

< / BR>
where

R2means hydrogen or carboxyamide group;

R is a substituted methyl group of the formula:

where Q NH2;

R4phenyl or substituted phenyl of the formula:

< / BR>
where

a and a' denote hydrogen, halogen, hydroxy or (C1-C4) alkylsulfonamides; or

R4means thiazolyl, substituted amino group; or

R is a group of the formula ,

where

R5means thiazolyl, substituted amino group,

R6hydrogen or (C1-C4) alkyl, or

when R2represents hydrogen, and their pharmaceutically acceptable salts.

1-carb(1 detya)caremy represented by the above formula (I), where R2denotes hydrogen, or their pharmaceutically acceptable salts inhibit the growth of microorganisms pathogenic to man and animals, and can be used to combat infectious diseases. Compounds of the invention obtain in this way in the same stoichiometric form, in which the semi-synthetic cephalosporin antibiotics.

The term "carboxyamide group" used VLA blocking or protecting carbonisation group, while the reaction is carried out in relation to other functional groups on the compound. Examples of such protective groups are carboxylic acids are 4-nitrobenzyl, 4-methylbenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzyl, 2,2', 4,4'-tetramethoxybenzene, tert-butyl, tert-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4', 4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, tert-butylmethylether, phenacyl, 2,2,2-trichlorethyl, -(di(n-butyl)methylsilyl)ethyl, p-toluensulfonate, 4-nitrobenzenesulfonate, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-EN-3-yl, etc. used carboxyamide group is not crucial, while derivational carboxylic acid is stable to the conditions of subsequent reaction with other provisions of the ring system and can be split at the appropriate time without breaking the rest of the molecule. Preferred protective group of carboxylic acid is an allyl group. Similar carboxyamide groups used in the cephalosporin, penicillin and peptide, can also be used to protect the carboxyl substituents gruau chemistry", J. G. U. Mcomie, as amended Plenum Press, new York, 1973, Chapter 5; T. C. Greene "Protective groups in organic synthesis", John Willy & sons, new York, 1981, Chapter 5. Related term "protective carboxy" means that the carboxyl group is replaced by one of the above carboxyamide groups.

In the above definition of the compounds represented by formula (I), (C1-C4)alkyl refers to remotemachine and branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl.

When in formula (I) R is a substituted phenyl group in which the substituent(s) present(s) in the form of a and a', examples of such groups are halophenol, such as 4-chlorophenyl, 3-bromophenyl, 2-forfinal, 2,2-dichlorophenyl and 3,5-dichlorophenyl; hydroxyphenyl, for example 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl and 3,4-dihydroxyphenyl; alkylsulfonate, for example 3-methylsulfonylamino, 4-methylsulfonylamino, 3,5-(dimethylsulfonium)phenyl, 4-n-butylmethylamine and 3-metilsulfonilmetane.

Examples of the compounds represented by formula (I), when R denotes acetiminophen group represented by the formula:

< / BR>
represent the property is to be obtained in accordance with that given in the end of the description schemes.

3 Tripterocalyx (triplet" or "TF") carbacephem starting material of scheme 1 can be obtained by the method of Evans and others, U.S. patent N 4673737, which was put into this description by reference. This 3-triplet - starting material is first subjected to interaction with thiophenols in nitrogen atmosphere in the presence of an amine, preferably a tertiary amine such as triethylamine or diisopropylethylamine, obtaining benzhydryl 7--phenoxyacetamide-1-carb(1 detya)-3-phenylthio-3-cefem-4-carboxylate. The intermediate 3-phenylthio then subjected to interaction with anti-hydride under nitrogen atmosphere in the presence of free-radical inhibitor, such as 2,2'-azo(bis)isobutyronitrile (AIBN), and heated, preferably to a temperature of about 120oC, to obtain the intermediate 3-(tri-n - butyl)stannane, as shown in figure 1. This is an intermediate compound of tin combined with positive halogenation agent, and preferably bromine, to obtain benzhydryl-7 b-phenoxyacetamide-1-carb(1 detya)-3-bromo-3-cefem-4 - carboxylate. The intermediate 3-bromoaniline then heated (preferably to a temperature of about 70oC) and combine with the mixture of cadmium, chloride, copper, dibromodifluoromethane is and the fact that DMF is preferred other suitable connection, including the connection group of the formula:

< / BR>
in which

R' denotes hydrogen or (C1-C4) alkyl;

R" and R"' independently represent (C1-C4)alkyl, or together with the nitrogen atom form a saturated ring, such as pyrrolidine or piperidine.

This intermediate compound is then acelerou using di-tert-BUTYLCARBAMATE ((tert-BOC)2O) followed by treatment with a base, such as LiOH, receiving 7-(tert-butyloxycarbonyl) intermediate connection (not shown). (For more details on this interchange tert-butoxycarbonyl protective group on phenoxyacetyl-protective group can be found in the application Europatent N 8836996.5, publ. N 0301877 Docket N X-6913).

Group, tert-butoxycarbonyl (tert-BOC) and complex benzhydryl ether can be split using known methods, for example using triperoxonane acid (TFA) in the presence of anisole. The obtained nuclear intermediate compound 7-amino-3-trifluoromethyl then N-acelerou activated form of the desired 7-acyl group. In scheme 1 D-phenylglycinol group introduced by reacting 7-amino-nuclear intermediate compound with tert-is butylchloroformate, as shown below.

< / BR>
Any remaining tert-butoxycarbonyl protective group can then be split by processing triperoxonane acid. Although phenoxyacetate and tert-butoxycarbonyl (tert-BOC) group is used as aminosidine groups, and benzhydryl group as carboxyamide group, a specialist in this field of technology related to chemistry-lactams, will understand that other carboxyl and aminosidine groups serve as functional equivalents.

The method of scheme 1 is carried out in a largely anhydrous conditions, which are conditions of the reaction, free from the presence of water. In accordance with this, the solvent is dried before using them in the way. Suitable organic solvents include methylene chloride, chloroform, methyl alcohol, di - or trichloroethane, tetrahydrofuran (THF), dimethylpropylene-urea (DMPU), hexamethylphosphoric triamide (NMRA), dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, simple diethyl ether, dimethylacetamide, dimethylsulfoxide, dimethoxyethane and mixtures thereof.

Free-radial inhibitors described in article lard and Jorgensen Radial chain the links. Suitable free radical inhibitors include AIBN, Bu3SnH, Cl3CBr, benzoyl peroxide, etc. given in the above article on page 19 under the table VI. Other inhibitors include photolysis X2where X is Cl, Br and I (Slicer, Henkel, Seebach. Chem.Ber. 110, 2880 (1977)), O2(Russell, Kaup y.A.C.S. 91, 3851 (1967)), metal salts (Tung, Held. J. Chem, Soc. Chem.Commun, 205 (1978)) and esters digitoxigenin acids (Barton, Creech, Kretschman, Tetra, Letters, 25, 1955 (1984)).

Defined above, the term "positive halogenation agent" refers to a compound having an electrophilic halogen, or, in other words, the connection leading to the halogen with a positive charge. Examples of such agents are, for example, SbF5F2IF5, BrF3, SF4, Cl2, HOCl, (CH2CO)2NCl, N-chlorosuccinimide, Me3COCl, NO2Cl, SO2Cl2, Br21,3-debromination, N,N-dibromobenzophenone, HOBr, N-bromosuccinimide, C4H8O2Br2, ICl, IBr, I2N-iodosuccinimide and 1,3-diiodo-5,5-dimethylhydantoin.

Scheme 2 depicts the synthesis of compounds of formula (I) using the method of scheme 1 using p-nitrobenzenesulfonamide group instead of benzhydryl.

benjamina)-3-florfenicol acid (N Ntry-BOC-FPAA) and 1-chloro-3,5 - dimethoxytoluene (CDMT) to obtain tert-BOC-protected intermediate. This intermediate compound is then treated with zinc and HCl followed by treatment triperoxonane acid.

Alternative 3-cryptomaterial formula (I) can be obtained in accordance with scheme 3.

In scheme 3 3 triflate intermediate compound in an anhydrous organic solvent is transformed into 3-bromo-intermediate connection using a substitution reaction using brainstream salt, pre-LiBr, in the presence of difficult amine-base. Brainstrain salts include the alkali metal bromide, tetraalkylammonium bromide and tetraalkylammonium bromide. Preferred difficulty amine is 2,6-lutidine. This 3-bromopropionate connection then turn directly in 3-cryptomelane intermediate compound by treatment with a mixture of zinc and dibromodifluoromethane in the presence of copper bromide and DMF. Intermediate p-nitrobenzyl 7 phenoxyacetamide-1-carb(1 detya)-3-trifluoromethyl-3-cefem-4-carboxylate is treated with a mixture of Zn/HCl, removing groups of ester p-nitrobenzyl and then re-etherification allylbromide. Phenoxyacetyl group otscheplaut using well-known methods, i.e. using PCl5/pyridine. This intermediate compound can then be treated with the activated form of the desired carboxylic acid to obtain 7-asialingo Deputy, mainly in accordance with the invention in figure 1. 4-Allyl carboxyamide group can then be split using known methods for the exemption from protection, i.e. applying tetracationic-hasfinally(0), with subsequent cleavage of the tert-BOC-protected groups triperoxonane acid, obtaining the compounds of formula (I). As in scheme 1, the amino acid used carboxyamide groups are illustrative, and expert in the field of b-lactam will understand that it is possible to use other protective groups.

In schemes 1 and 3 3-bromopropionate connection is subjected to interaction with a mixture of copper halide (Br, Cl, I) dialogicality, or cadmium, or zinc, and DMF or a group of the formula:

< / BR>
where R', R" and R"' have the above values.

I believe that this mixture results in situ triptoreline, which interacts with 3-bromopropionyl connection with the formation of 3-formativos intermediate compounds. Preferably at least one molar equivalent of triptoreline or triforma the th equivalent tricornered.

The substitution reaction in which the 3-triflate turn 3-bromopropionate connection more fully presented in figure 4.

Scheme 4 R1means hydrogen and R2has the above value, then ka And indicates a protected amino or acylamino formula:

< / BR>
where R has the above meaning.

The reaction is carried out in an aprotic solvent such as, for example, presented above in the description. 3 Triplet combine with lithium bromide and preferably 2,6-lutidine. The mixture is heated to a temperature of about 60-70oC, preferably about 65oC, and retain for a period of time sufficient to obtain 3-bromoguanine. The heating time is preferably about 16 hours, and more preferably about 48 hours Usually obtained products include a mixture of 2/3 of the isomers. 2-Isomer can then be isomerizate 3-isomer by reacting 2-isomer with a strong base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0]non-5-ene (DBN). As disclosed, 3-bromoguanine is suitable intermediate compound for producing compounds represented by formula (I). It should be understood, however, that by themselves 3-bromoguanine alleuropean 1-carb(1 detya)-3-cefem-3-bromo-4-carboxylic acids or their pharmaceutically acceptable salts. For example, in figure 3 the stage of conversion of 3-bromo 3-trifluoromethyl can be omitted with formation of (3-bromo)cafemom.

The term "difficulty aminosilane" includes both aromatic and aliphatic amines employed. Aromatic amines employed include amines with alkyl Deputy related to aromatic carbon atom adjacent to the nitrogen atom. Preferred substituents can be larger than methyl, such as ethyl, isopropyl, tert-butyl, and aryl. More preferred aromatic amines can be employed amines with at least two aromatic carbon atoms adjacent to the nitrogen Deputy, with such substituents as (C1-C6)alkali and (C1-C4)alkoxy. In addition, bicyclic and polycyclic amines can be used if at least one carbon atom adjacent to the nitrogen atom, contains a suitable Deputy. Aliphatic amines employed may also be used, and they include tertiary amines, such as diisopropylethylamine, ethyldiethanolamine etc.

In one aspect the invention provides 7-amino-1-karbotitanosianirovanie compounds and their salts and SL is Loy (I). These intermediate compounds represented by formula (II):

< / BR>
where R2denotes hydrogen or carboxyamide group, or an acid additive salt.

7-amino compounds of the formula (II) form salts with conventional acids such as mineral acids, for example hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid, and selforganizes acid, such as methanesulfonate, n-butanesulfonate, benzosulfimide, p-toluensulfonate and naphthalenesulfonate. Such salts are used for isolation and purification of 7-amino-acids and their esters. The compound of formula (II) can also form salts with hydroxides, carbonates and bicarbonates of alkali or alkaline-earth metals. Examples of such salts are sodium, potassium, calcium and magnesium salts. Salts can be formed with amines such as dibenzylamine, cyclohexylamine, triethylamine, ethanolamine, diethanolamine etc.

The compound 7-amino-1-carb-3-cafema formula (II) N-acelerou carboxylic acid RCOOH or its reactive derivative to obtain the compounds of formula (I). N-acylation can be carried out using General methods ACI is t with an acid RCOOH in the presence of a desiccant, such as carbodiimide, such as dicyclohexylcarbodiimide. Alternative carboxylic acid can be converted into a reactive derivative of carboxyl group and a reactive derivative used in the N-acylation. Reactive derivatives of the carboxylic groups are halides, azides acids and anhydrides of the acids, such as active esters formed using ethylchloride and isobutylphthalate; phenylcarbamate; N-hydroxyamide, such as formed using N-hydroxysuccinimide and N-hydroxyphthalimide; well educated with hydroxybenzotriazole (HBT); and similar active carboxyprimaquine. During the N-acylation of any free amino - or carboxypropyl present in the carboxylic acid RCOOH, it is desirable to protect.

In another aspect of the invention features the preferred compounds of formula:

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where R4has the above values.

In another aspect of the invention proposes a method of obtaining compounds of the formula:

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which lies in the interaction of the compounds of formula:

< / BR>
with a mixture of a halide of copper, cadmium or zinc, disastermanagement, essentially, in an anhydrous inert organic solvent, where X denotes a halogen. R2has the above meanings and R9R10N indicates a protected amino group, or R9denotes hydrogen and R10denotes an acyl group having carbonisation the origin of the Method may occur at a temperature in the range of about 10-90oC, preferably about 60oC.

Compounds of the invention are for the treatment of infectious diseases in humans and other animals and to pharmaceutical compositions suitable for the treatment. Therapeutic method consists of introducing a person or an animal is antibiotic effective non-toxic dose of the compounds represented by formula (I) or its pharmaceutically acceptable salt, when R2means hydrogen.

1-Carbazepine proposed by the invention form salts with suitable bases, in particular pharmaceutically acceptable non-toxic salts. The carboxyl group is 1-carbazepine can form salts with hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals. Examples of such pharmaceutically acceptable salts is nucleiclosely, the triethylamine, ethanolamine, diethanolamine and similar amines. Similarly, when 1-carbacephem substituted by two or more carboxyl groups, di - and tri-salts get traditional salt-forming methods.

Connection 1-carbazepine submitted in accordance with the invention with the Deputy of the amino group in position 7 of the side chain, form salts with suitable acids to produce antibiotics as pharmaceutically acceptable salts. Examples of suitable acids are hydrochloric, Hydrobromic, sulfuric and phosphoric acids.

1-Carbazepine submitted in accordance with the invention, in the case when R2denotes hydrogen, can form zwitterions (lotrisonebuy) form a connection when the substituent in position 7 includes free amino.

Is antibiotic effective amount is the amount of between 25 mg and 2 g approximately. The compound, salt or ester can be entered in a single dose or in multiple doses during the day. Processing (treatment), you may continue during the period of time from one week to ten days, or more long-term, depending on the duration infect patient, the status of a specific organism, the severity of infection, General health of the patient and the tolerance of the patient to the antibiotic.

1-carb(1 detya)cefem you can enter parenterally, orally, subcutaneously, or rectally. As with other antibiotics on the basis of the lactam, the method of the invention can be used prophylactically to prevent infection after exposure or before a potential exposure, such as preoperative. Antibiotic 1-carb(1 detya)cefem may be introduced by conventional methods, for example in capsules, tablets, suppositories, syringe, or by intravenous drip infusion.

The pharmaceutical compositions of the invention include is antibiotic non-toxic amount of 1-carb(1 detya)-3-cafema represented by the formula (I) or formula (III), where R2denotes hydrogen, or its pharmaceutically acceptable salt, and a pharmaceutical carrier.

Pharmaceutically acceptable salts are useful antibiotics for receiving antibiotic compounds. Compositions for oral administration include capsules, tablets, pellet and liquid slurry. The antibiotic or salt or ester in the form of su with filler, for example, a stabilizer, prior to filling. Capsules can contain about 100-5000 mg for obtaining compositions uniform dose.

Tablets containing about 100-500 mg of antibiotic or salt or complex ester receive traditional means, and they may contain in addition a binder, a disintegrator, a stabilizer, an antioxidant, etc.

Liquid preparations of antibiotic can be obtained for infant and geriatric use. The pediatric suspension form with oral antibiotic fillers, such as suspendresume tools, flavors, stabilizers, etc. Solutions of antibiotics in a similar way can be formulated with solubilization, flavorings, sugar, water, etc.

Parenteral formulations of antibiotics for injection formulated with water for injection, ringer's solution, physiological saline or glucose solution. The antibiotic can also be entered as an intravenous fluid drip method.

For parenteral use the antibiotic or its derivative gain is preferably in the form of a dry crystalline powder or in the form of lyophilized powder and injected into the vial. have these values:

tert-BOC tert-butoxycarbonyl or tert-butyloxycarbonyl,

GHUR liquid chromatography high resolution

THF tetrahydrofuran,

Y constant interactions for NMR spectra in Hz,

DMF N,N-dimethylformamide,

DMPU dimethylpropyleneurea,

BSU bis(trimethylsilyl)urea,

BSA bis(trimethylsilyl)acetamide", she

DMAP dimethylaminopyridine,

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene,

AIBN azo(bis)isobutyronitrile,

DCC dicyclohexylcarbodiimide,

TFA triperoxonane acid,

HMPA hexamethylphosphoric triamide,

DMSO dimethyl sulfoxide.

The experimental part.

Preparation 1. Dimenisonal (7S,6R)-7 - phenoxyacetamide-3-phenylthio-1-carb-(1-zetia)-3-cefem-4-carboxylate.

A solution of dimethyl [7S, 6R]-7-phenoxyacetamide-3 - tripterocalyx-1-carb(1 detya)-3-cefem-4-carboxylate (40,0 g, 63,00 mmol) in 180 ml of anhydrous acetonitrile is treated under the N2diisopropylethylamine (15,4 ml, 88,0 mmol) and thiophenols (7,1 ml of 69.0 mmol). The reaction mixture was stirred over night at ambient temperature. The solvent is removed in vacuo and the residue purified by chromatography on silica gel (elution with 35:65 ethyl acetate/hexane) to give ), 6.90 (d, Y, 8 Hz, 2 H), 5.44 (m, 1 H), 4.54 (s, 2H), 3.81 (dt, Y, 5, 12 Hz, 1 H), 2.0-2.3 (m, 2 H), 1.7-1.8 (m, 1 H), 1.3-1.5 (m, 1 H).

The drug 2. Diphenylmethyl (7S, 6R)-7 - phenoxyacetamide-3-bromo-1-carb(1 detya)-3-cefem-4-carboxylate.

Diphenylmethyl [7S, 6R]-7-phenoxyacetamide-3 - tripterocalyx-1-carb (1 detya)-3-cefem-4-carboxylate (150 g, 0.238 mol) is dissolved in 1600 ml of anhydrous DMF and treated with 2,6-lutidine (63,8 g, 0,595 mol) and literotica (121, 1million g of 1.43 mol). The reaction mixture is heated to 65oC for 30 min and maintained at this temperature for 64 hours, the Reaction mixture was cooled to room temperature and 75% of the solvent is removed under reduced pressure at a temperature of 50oC., the Suspension is diluted with ethyl acetate/simple ether, washed with a solution of NaHCO3(3 times), 1 N. HCl solution (3 times) and brine, then dried in the presence of magnesium sulfate, filtered through silica gel with 10% ethyl acetate/CH2Cl2and evaporated under reduced pressure until precipitation of a solid body. Solid beige color (34.4 g) collect and after further evaporation mother solutions raise an additional 10.6 g of a solid body. These two parties solids are combined because they both represent a desirable D3-isomers (Yasin-isomers balance as follows. Dissolution of the mixture, or 64.7 g, 0,115 mol) in 675 ml of anhydrous CH2Cl2carried out by treatment with DBU (4.7 g, 0,031 mol). After 3 h at room temperature, the reaction mixture was filtered through silica gel with 10% ethyl acetate/CH2Cl2and evaporated. The residue is dissolved with a small amount of ethyl acetate, diluted with hexane and cooled to 0oC. This results in a 17.6 g of pure 3-isomer, and the other to 39.4 g (from stock solution) chromatographic on silica gel (elwira gradient of toluene to 30/70 ethyl acetate in toluene). Get to 31.5 g of a mixture of 2/3-isomers, which is dissolved in ethyl acetate, diluted with hexane, tatrallyay product and cooled to 0oC. Gain of 18.2 g of 3-isomer, leaving 14.2 g of a mixture of 2/3-isomers. The total number equal to 80.8 g, specified in the header of the product emit at exit 61%

Preparation 3. Allyl [7S, 6R]-7-phenoxyacetyl-amino-3-bromo-1-carb(1 detya)-3-cefem-4 - carboxylate.

(a) Allyl [7S, 6R]-7-phenoxyacetamide-3 - tripterocalyx-1-carb(1 detya)-3-cefem-4-carboxylate (1.0 g, 1,9826 mmol) and dried nitebreed (0,689 g, 7,9302 mmol) are combined in DMF (3.0 ml). The mixture after dissolution of all solids slowly heated to approximately 67oC and stirred wny NaHCO3. Organic matter is separated and washed with 50 ml of 1 n HCl solution, dried in the presence of sodium sulfate, filtered and concentrated to a reddish-brown oil. Flash chromatography with elution with 7% EtOAc/CH2Cl2leads to obtain 87 g of product with a yield of about 10%

(b) 3-Triflate from stage (a) above (200 mg, 0,3965 mmol) are combined with dried lithium bromide (138 mg, 1,586 mmol) and DMPU (2 ml) and the mixture is heated up to 65-67oC for 6 hours To the mixture was added 2,6-lutidine (0,4362 mmol) and the mixture is stirred at a temperature of 67oC over night (14 h). The mixture is poured into 50 ml EtOAc and 20 ml of a saturated solution of NaHCO3. Organic matter washed with 25 ml of 1 n HCl solution, separated and dried in the presence of sodium sulfate, filter and concentrate to a brown-yellow oil. Flash chromatography with elution with 7% EtOAc/CH2Cl2allows to obtain 45 mg (26%) 60/40 mixture of 2/3-isomers.

(c) Repeating the method described in stage (b), except that 2,6-lutidine placed in the mixture at the beginning of the method, and not after the start of heating. Use the following number:

Starting material 3-triphala 200 mg, 0,3965 mmol

2,6-Lutidine 0,793 mmol, 92 ál

Lithium bromide 138 mg, 1,586 mmol

DMPU 2 ml

Yes the built in stage (c) method except that DMF is used instead of DMPU. Use the following number:

Starting material 3-triflate 145 mg, 0,2875 mmol

2,6-Lutidine 0,5749 mmol, 67 ál

Lithium bromide 100 mg, 1.15 mmol

DMF, 1.5 ml

This methodology leads to getting to 61.2 mg (49%) of a mixture of 2/3-isomers in a ratio of 70/30.

(e) Repeating the method described in stage (d), except that the mixture is heated to approximately 2.5 times more long-term, or 48 hours Using the following quantities:

Starting material 3-triflate 11 g, 21,808 mmol

2,6-Lutidine 43,616 mmol, 5,08 ml

Lithium bromide 7.6 g, 87,232 mmol

DMF 120 ml

This drug allows to obtain 4.6 g specified in the connection header, or 48.5% yield of a mixture of 2/3-isomers at a ratio of more than 95/5, respectively. Data on the 2-isomer:

1H-NMR (300 MHz, CDCl3): 7.32 (t, J 1 Hz, 2 H), 7.10 (d, J 9 Hz, 1 H), 7.05 (t, J 6 Hz, 1 H), 6.92 (d, J 8 Hz, 2 H), 6.50 (m, 1 H), 5.95 (m, 1 H), 5.35 (m, 3 H), 4.90 (s, 1 H), 4.63 (m, 2 H), 4.55 (s, 2 H), 4.15 (m, 1 H), 2.35 (m, 1 H), 2.15 (m, 1 H); IR (CHCl3): 3019, 1771, 1747, 1691, 1517, 1495, 1236 and 1182 cm-1.

Mass spectrum, m/e 434 (M+), 436 (M++ 2).

Analysis for C19H17N2O5Br:

Calculated, C, 52.43, H 4.40, N 6.44

Found, C, 52.23, H 4.36, N 6.37

Example 1. Diphenylmethyl [7S, 6R]-7 - phenoxyacetamide-3-phenylthio-1-carb(1 detya)-3-cefem-carboxylate (37,0 g, 62,7 mmol) in 32 ml of anhydrous diglyme process under N2the anti-hydride (42,1 ml, 157,0 mmol) and azo (bis) isobutyronitrile (AIBN) (12,4 ml, 75.2 mmol). The reaction mixture is heated to 120oC for 45 min and then cooled to ambient temperature. The residue is purified by chromatography on silica gel (elwira 40:60 ethyl acetate/hexane). Get 37,1 g light viscous oil (77%).

1H-NMR (CDCl3): d 7.55 (d,J=Hz, 2H), 7.44 (d, J=Hz, 2H), 7.2-7.4 (m, 7H), 7.0-7.1 (m, 2H), 6.9 (m, 3H), 5.48 (m,1H), 4.56 (s,2H), 3.87 (m, 1H), 2.6-2.7 (m, 1H), 2.3-2.45 (m,1H), 1.9-2.0 (m,1H), 1.2-1.4 (m,12H), 0.8-0.85 (m, 15H).

IR (CHCl3): 2958.2, 2923.7, 1766.2, 1689.9, 1523.0, 1496.2, 1374.4 and 1239.5 cm-1.

Mass spectrum (FAB): m/e (M+) 771.

UV (EtOH): lmax275 nm (9960).

Analysis for C41H52N2O5Sn: C, H, N,

Example 2. Diphenylmethyl [7S, 6R]-7 - phenoxyacetamide-3-bromo-1-carb(1 detya)-3-cefem-4-carboxylate.

Standan example 1 (8,58 g, 11,13 mmol) in 400 ml of anhydrous THF cooled in a bath containing a mixture of acetone with dry ice and treated dropwise with a solution of Br2(1.78 g, 11,13 mmol) in 100 ml of THF for 30 minutes the Solvent is removed under reduced pressure and chromatographie the DCl3): 7.2-7.5 (m, 12H), 7.0-7.1 (m, 2H), 6.98 (s,1H), 6.9 (d, J= 8gts, 2H), 5.40 (m,1H), 4.54(s, 2H), 3.95 (m, 1H), 2.7-2.8 (m, 2H), 1.9-2.0 (m,1H), 1.5-1.7 (m,1H), 1.3-1.4 (m, 1H).

IR (CHCl3): 3025.2, 1787.0, 1742.2, 169.7, 1600.6, 1518.9, 1496.0, 1302.3 1242.7 cm-1.

Mass spectrum (FAB) m/e(M+) 561.

UV (EtOH): lmax275 nm (4870).

Analysis: C29H25BrN2O5: C,H,n

Example 3. Diphenylmethyl [7S, 6R]-7 - phenoxyacetamide-3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4-carboxylate.

Suspension of cadmium (20,0 g, 178 mmol) in 100 ml anhydrous DMF is cooled in a bath of ice water under N2and treated dropwise with a solution of CF2Br2. Periodic removal of the ice bath is necessary for maintaining a smooth continuation of the reaction. After addition of compounds bath removed and the reaction mixture stirred at ambient temperature for 1 h In a separate flask the source of the intermediate compound 3-bromide (10.0 g, 17.8 mmol) was dissolved in 18 ml of anhydrous DMPU and heated to a temperature of 70oC. a Solution of cadmium reagent is treated with a solution of CuCl2(17.6 g, 178 mmol) and the resulting reddish-brown solution was added to 3-bromo-intermediate connection via cannula over 1 h After cooling to room temperature the mixture again and magnesium sulfate and reduced to a brown oil in vacuum. This oil chromatographic on silica gel with 40:60 ethyl acetate/ hexane, gaining 4.7 g (49%) specified in the header of the product in the form of foam.

1H-NMR (CDCl3) 7.3-7.4 (m, 12H), 7.0-7.2 (M, 3H), 6.9(d, J=8gts, 2H), 5.49 (m, 1H), 4.58 (s,2H), 3.96 (m, 1H), 2.3-2.5 (m, 2H), 2.0-2.1(m,1H), 1.4-1.5(m, 1H).

IR (CHCl3): 1787.0, 1742.2, 1692.7, 1600.6, 1518.9, 1496.0, 1302.3 and 1242.7 cm-1.

Mass spectrum (FAB) m/e (M++1) 517.

UV (EtOH): lmax264 nm (8946).

Analysis: C30H25F3N2O5. (C, H, n

Example 4. Diphenylmethyl [7S,6R]-7-tert, butoxycarbonylamino-3-trifluoromethyl-1-carb (1 detya)-3-caramcambodia.

Diphenylmethyl [7S, 6R]-7-phenoxyacetamide-3 - trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylate (4.7 g, 8.5 mmol) is dissolved in 85 ml of anhydrous CH2Cl2under the N2, cooled in a bath of ice water, and treated with di-tert-BUTYLCARBAMATE (2,04 g, 9,35 mmol) and dimethylaminopyridine (DMAP) (0.52 g, 4.3 mmol). After 45 min the reaction mixture is heated to ambient temperature 4 hours the Solution is filtered through silica with 20:80 ethyl acetate/CH2Cl2. After removal of solvent in vacuo, the residue taken in 85 ml of anhydrous THF and cooled in an ice bath. Added dropwise LiOH (9.7 ml of 1 M solution) and the solution heated to the m HCl, a saturated solution of NaHCO3, saline solution, dried in the presence of anhydrous magnesium sulfate and evaporated in vacuum to dryness. Gain of 4.2 g of the crude foam orange.

1H-NMR (CDCl3) 7.3-7.4 (m, 10H), 6.95 (s,1H), 5.98 (Shir.d, J=11 Hz, 1H), 5.22 (m, 1H), 3.87 (m, 1H), 2.3-2.5(m, 2H), 2.0-.1 (m, 1H) and 1.6-1.7 (m, 1H), 1.23 (s, 9H).

IR (CHCl3): 1785.3, 1740.0, 1718.5, 1497.3, 1301.7 and 1243.3 cm-1.

Mass spectrum (FAB):m/e (M++1) 517.

UV (Eton) lmax264 nm (8946).

Analysis of C27H27F3N 2O5. (C, H, n

Example 5. Trifurcata salt [7S, 6R]-7 - amino-3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4 - carboxylic acid.

The product from example 4 (2,99 g, a 3.87 mmol) was dissolved in cold triperoxonane acid (TFA) (40 ml) and triethylsilane (13 ml) under N2at 0oC. the Reaction support at 0oC for 30 min in the ice bath, after which the bath is removed and the mixture is stirred for 20 minutes was Added anhydrous CH3CN and toluene, and the volume reduced in vacuo. This process is repeated flask and concentrated to dryness. The residue is then suspended in CH3CN and filtered. Solid is washed with a mixture of CH3/simple diethyl ether and then twice simple diethyl ether, receiving 925 mg (66%) is 0-8.2 (Shir.with, 1H), 4.92 in (d, J=Hz, 1H), 3.97 (m, 1H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 2H).

Example 6. [7S, 6R]-7-[D-alpha-(tert-butoxy-carbylamine)phenylacetylamino] -3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Trifenatate salt from example 5 (0,90 g, 2,47 mmol) is suspended in 25 ml of ethyl acetate under N2and treat silistralocation (1,51 ml, 8,15 mmol) and then heated at 35oC up until all solids are in solution. In a separate flask trust-VOS-phenylglycine dissolved in 25 ml of ethyl acetate under N2, cooled to -45oC and treated sequentially with isobutylphthalate (of 0.21 ml, 2,47 mmol) and N-methylmorpholine (0,326 ml, 2,96 mmol). After 30 min, the amine solution is cooled to 0oC, and then added via cannula over 5 min and stirred for 30 min at a temperature of dew from -45 to -35 oC for 1.5 h at a temperature of dew to 0oC. At this time, add 2.0 ml of methanol, the ice bath removed and the solution stirred for 10 min before heating to room temperature, evaporation and chromatography on silica using 3% acetic acid in ethyl acetate to obtain specified in the header of the product in the form of semifinished foam beige (1,03 g, 87%).

1H-Amha-(amino)phenylacetyl-amino]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4 - carboxylic acid.

Tert-BOC-protected acid from example 6 is placed in a flask at 0oC and treated with a mixture of cold triperoxonane acid (TFA) (20 ml) and triethylsilane (7 ml). After stirring for 15 min at 0oC the ice bath removed and the reaction mixture stirred for 10 min at ambient temperature, diluted with a solution of CH3CN and reduce in volume. Further dilution with a solution of CH3CN accompany the process of evaporation to dryness, suspendirovanie balance EtO2and filtering. The obtained solid is washed repeatedly with a solution EtO2and dried in vacuum to obtain 0.74 g of the crude product with a purity of about 85% by Reversed-phase chromatography on a column of C-18 with a step gradient of 10% CH3CN/H2O 30% of CH3CN/H2O leads to obtain 0.39 g (50%) specified in title product as a white solid.

1H-NMR (D1O)d 7.5-7.6 (m,5H), 5.44 (d, J=7 Hz, 1H), 5.21 (s,1H), 3.95 (m,1H), 2.25 (Shir.m, 2H), 1.7-1.8 (m,1H), 1.0-1.1 (m,1H).

IR (CHCl3): 1776.7, 1740.0, 1693.7, 1561.6, 1300.2 and 1166.1 cm-1.

Mass spectrum (FAB): m/e (M++1) 384.

UV (EtOH): lmax257 nm (9190).

Example 8. [7S, 6R] -7-{ [2-(tert-butoxy - carbonyl)amino-4-thiazolyl] (methoxyimino)azeti the Ino-3 - trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid (0.10 g, 0,275 mmol)is treated under the N2bis(trimethylsilyl)urea (0,281 g, 1.38 mmol) and 1.4 ml of anhydrous DMF. Solids, dissolved after heating the suspension to a temperature of 45oC, remain in solution at this temperature for 1 hour In a separate flask [2-(tert-butoxycarbonyl)-amino-4-thiazolyl] -(methoxyimino)acetic acid (0.083 g, 0,275 mmol) was dissolved in 1.4 ml of DMF, cooled to -5oC, treated with oxalylamino (0.035 g, 0,275 mmol) and heated to ambient temperature 30 minutes a Solution of germ cooled to a temperature of the cooling medium, treated with pyridine (0,067 g, 0,825 mmol) and then a solution of the carboxylic acid. After stirring for 2 h the solution is cooled in an ice bath and treated with 2 ml of water, diluted with ethyl acetate and distribute faction. The organic layer is washed with two times 1 N. HCl solution, water and saline, dried in the presence of magnesium sulfate, filtered and evaporated to dryness. The crude solid (0,101 g) flash chromatographic on silica using 4% of the SPLA in ethyl acetate, getting 0,087 g (59%) specified in the header of the product.

Example 9. [7S, 6R] -7-([2-amino-4-thiazolyl (methoxyimino)acetyl]amino)-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carbom and EtOH under N2and process diphenylmethyl [7S, 6R]-7-{ [2-(tert-butoxycarbonyl)-amino-4-thiazolyl] (methoxyimino)acetyl} amido-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylate. After 30 min the reaction mixture was treated with a solution of CH3CH and evaporated to dryness. This crude residue (by 0.055 g) chromatographic preparative GHUR on a reversed-phase column using a stepwise gradient of CH3CN:H2O:HOAc 15:84:1 to 20:79:1, receiving 0,021 g of the final product.

1H-NMR (DMSO-d6) a 9.25 (d, J=11 Hz, 1H), 7,18 (Shir.s, 2H), 6,70 (s, 1H), 5,48 (m, 1H), 3,9 (m, 1H), 3,80 (s, 3H), 2,37 (Shir.m, 2H), 1,95 (m, 1H), 1,6 (m, 1H).

Example 10. [7S, 6R]-7-[D-alpha-(tert-butoxycarbonylamino)-4-hydroxyphenylethylamine] -3-trifluoromethyl-1 - carb-(1-zetia)-3-cefem-4-carboxylic acid.

A solution of D-alpha-(tert-butoxycarbonylamino) -4 - hydroxyphenylarsonic acid (0,214 g, 0,799 mm) in 2.4 ml of anhydrous THF is treated with 1-hydroxybenzotriazole (to 0.108 g, 0,799 mm) and DCC (0,198 g, 0,959 mm) at 0oC. the Precipitate formed after 5 min, and the suspension is heated to ambient temperature and stirred for 2 h, after which the solution is filtered and cooled to 0oC. Zwitterion (amphoteric ion) carbacephem suspended in 2.4 ml of anhydrous THF and obrabecim the t 0.8 ml TFG, cooled to 0oC and treated with a cold solution of ester. After 30 min the bath removed and the reaction mixture was stirred over night. The solvent is evaporated and the residue distributed between ethyl acetate and aqueous solution of NaHCO3. The organic layer is extracted again in an aqueous solution of NaHCO3and the combined organic layers separated by ethyl acetate and reduce pH to 2.5 with 1 n HCl solution. The aqueous layer was washed with ethyl acetate and the combined organic layers are dried in the presence of magnesium sulfate, filter and concentrate to obtain 0,371 g (67%) specified in the header of the product, which is not subjected to further purification.

Example 11. [6R, 7S] -7-[D-a-(amino) -4-hydroxyphenylethylamine]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

The product from example 10 was placed in the flask at a temperature of 0oC and treated with a mixture of cold triperoxonane acid (TFA) (2.2 ml) and triethylsilane (0.5 ml). The flask was immediately placed in a rotary evaporator and concentrated to an oil, which is ground to powder using diethyl ether, receiving solid, which is collected by filtration and washed with a solution EtO2. This solid is dried in vacuum for the a W a stepped gradient from 99/1:H2O/HOActo 5/94/1:CH2CN/H2O/ acetic acid after lyophilization allows you to get to 0.055 g (25%) specified in the header of the product in the form of a solid white color.

1H-NMR (D2O) d7,35 (m, 2H), 6,97 (m, 2H), of 5.40 (d, J=7 Hz, 1H), 5,13 (s, 1H), 3,90 (s, 1H), 2,1-2,3 (Shir.m, 2H), 1,73 (m, 1H) and 1,10 (m, 1H).

IR (KBr):1768,0, 1688,9, 1613,6, 1519,1 1300,2 cm-1.

Mass spectrum (FAB):m/e (M++1 to 400.

UV (ethanol): lmax234,257 nm ( 1280, 9030).

Analysis:

Calculated C 51,13, H of 4.04, N 10,52

Found, C 51,25, H is 4.21, N 10,29

Example 12. [6R, 7S]-7-b-[D-a-(amino)-4 - perforazione]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

A solution of racemic tert-BOC-protected 4-florfenicol (0,216 g, 0.80 mm) 8.0 ml of ethyl acetate cooled to a temperature of -45oC, treated with isobutylacetate (0.104 g ml, 0.80 mm) and N-methylmorpholine (0,097 ml, 0,88 mm), and then stirred for 30 minutes 7-Amino-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4 - carboxylic acid (0,200 g, 0.80 mm) was dissolved in 8.0 ml of ethyl acetate after the addition of monociliated (0,341 ml of 1.84 mm) and added to the mixed anhydride at -45oC. After 30 min the solution was heated to 0oC for 1 h and then treated with 0.5 ml MeOH, on the oC. the Product chromatographic on silica gel, using 3:87:10 SPLA/ethyl acetate/ hexane. Both diastereoisomer visible when1H-NMR together with minor impurities. The crude product (0,228 g) is treated with a cold solution of TFA (1.8 ml) and Et3SiH (0.6 ml), concentrated, proscout using EtO2, collected by filtration and washed with EtO2. Salt of the crude TFA (0,209 g) chromatographic on column C18two stepped gradient from 15% CH3/H2O up to 20% of CH3/H2O, getting clean after lyophilizate 0,030 g (10%) of the product of L-amino acids and 0.046 g (14%) of the product obtained from D-amino acids. Retention time when GHUR: C181/20/79: SPLA/CH3CN/H2O, 2 ml/min, L=4,11 min, D=5,38 minutes L-diastereoisomer:

1H-NMR(CDCl) d to 9.1 (m, 1H), 7,50 (m, 2H), 7,22 (t, J=10 Hz, 2 H), 5,17 (Shir.s, 1H), 4,89 (Shir.s, 1H), 3,76 (m, 1H), 2,17 (m, 2H),1,73 (m, 1H), 1,60 (m, 1H).

IR (CHCl3):cm-1.

Mass spectrum (FAB):m/e (M+).

UV (EtOH): lmax257 nm ()

Example 13. [7S, 6R]-7-{[2-(trifluoromethyl)- amino-4-thiazolin] (triphenylarsine)acetyl} amido-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

7-Amino-3-trifluoromethyl-1 - carb(1 detya)-3-cefem-4-carboxylic acid (0,300 g, 1.20 mm) (zwitterion karbuz the h and then at room temperature for 30 minutes In a separate flask [2-trailmen-4 - thiazolyl](trisiloxane)uksnow acid (0,806 g, 1.20 mm) dissolved in 6.0 ml of dry DMF and cooled to 0oC, treated dropwise with oxalylamino (0,105 ml, 1.20 mm) and heated to ambient temperature. The core was then cooled to 0oC, treated with pyridine (0,194 ml, 2.4 mm) and the acid chloride acid, heated to ambient temperature and stirred for 2 hours After addition of 2.0 ml of water the reaction mixture is treated with 1 N. HCl solution and extracted with ethyl acetate. Ethylacetate layer washed with water, 1 N. HCl solution, water, saline, dried in the presence of magnesium sulfate and concentrated. The crude product (1.12 g) chromatographic by filtration through silica gel using 3% of the SPLA/ethyl acetate, receiving 0.95 g (88%) indicated in the title product as a white powder.

Example 14. [7S, 6R]-7-([2-amino-4-thiazolyl(oxyimino)acetyl]amido)-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

A solution of bis-trailrunner carbacephem from example 13 in 4.5 ml of THF is treated with 7.6 ml of 75% aqueous solution of formic acid and slowly heated to 40oC under nitrogen for 2 hours After cooling, add 20 ml of CH2CN with the following concentration is>/CH3CN and solid allocate by centrifugation. After additional washes with the use of EtO2solid chromatographic on a column of HP-20ss using 1% HOAc/H2O after boot CH3CN.

The obtained solid chromatographic on column C18using 1/10/89:HOAc/CH3CN/H2O getting 0,027 g solid cream color.

1H-NMR (DMSO-d6) 9.13 (d, J=9 Hz, 1H), 7.07 (s, 2H), 6.64 (s, 1H), 5.50 (m, 1H), 3.89 (m, 1H), 2.25 (m, 2H), 1.95 (m, 1H), 1.60 (m, 1H).

IR (CHCl3) cm-1.

Mass spectrum (FAB): m/e (M+)

UV (EtOH): lmax257 nm.

Example 15. Diphenylmethyl [7S, 6R]-7-phenoxy-acetamido-3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4-carboxylate.

The suspension is washed with acid zinc with (58.2 g, 0.89 mol) in 1780 ml of anhydrous DMF under nitrogen is treated dropwise 205,4 (0.98 mmol) of CF2Br2CF2Br2added in order to maintain the temperature at the level of 45-50oC. After completion of addition, the reaction mixture was stirred at ambient temperature for 1.5 h, and during this time the mixture is returned to room temperature. The solution of the zinc reagent is cooled to a temperature of -30oC and treated with DM is the forehead diphenylmethyl(6R, 7S)-7 - phenoxyacetamide-3-bromo-1-carb(1 detya)-3 - cefem-4-carboxylate (50.0 g, 0,089 mmol) dissolved in anhydrous DMPU (100 ml) and 100 ml of DMF under nitrogen and heated to 65oC. Add the copper solution to the bromide via cannula over 1 h, maintaining the temperature at 65oC. After 1 h, the reaction mixture is cooled to 50oC and stirred for 16 hours, the Reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, poured into a saturated solution of NaHCO3that filtered through brownmillerite, washed twice NaHCO3, water, 1 N. HCl solution (twice), water and brine, then dried in the presence of magnesium sulfate and reduced to a brown oil in vacuum. This oil is filtered through silica gel using a 60-40 ethyl acetate/hexane and recrystallized from ethyl acetate/hexane, getting 28.4 g (58%) solids not quite white.

Example 16. Allyl [7S, 6R]-7 - phenoxyacetamide-3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4 - carboxylate.

After dissolution of the product from example 15 (26,00 g 0,050 mol) in 375 ml of N,N - dimethylformamide and 750 ml of tetrahydrofuran under nitrogen was added 375 ml of 1 n HCl solution, followed by addition of zinc powder (19,61 g, 0.30 mmol). The solution is what I ethyl acetate perform four flush 1 N. HCl solution, water, saline, dried in the presence of sodium sulphate and evaporated under reduced pressure to a crude solid orange color. The solid is dissolved in ethyl acetate, was added 50% aqueous sodium bicarbonate solution and two-phase solution is treated with sulfuric acid tetrabutylammonium salt (17,83 g, 0,052 mol). After stirring for 15 min, the layers separated, and an ethyl acetate layer is dried in the presence of sodium sulphate, filtered and evaporated under reduced pressure to a viscous oil. The oil is dissolved in 110 ml of chloroform and treated with allylbromide (7,26 g to 0.060 mol), dissolved in 35 ml of chloroform, via an addition funnel over 30 minutes the Solution was stirred at ambient temperature overnight, restore to a rigid body and chromatographic on silica gel using 70% hexane/30% ethyl acetate, getting after evaporation under reduced pressure 14,35 g specified in the title compound (68%).

1H-NMR (CDCl3) 7.45 (d, J=8 Hz, 1H), 7.30 (t, J=7 Hz, 2H), 7.00 (t, J= 7 Hz, 1H), 6.87 (d, J=10 Hz, 2H), 2.0-6.58 (m, J= Hz, 1H), 5.45 (DD, J=9 Hz, 1H), 5.4-5.2 (m, 2H), 5.72 (t, J=6 Hz, 2H), 5.43 (s, 2H), 3.95-3.85 (m, 1H), 2.55-2.4 (m, 1H), 2.4-2.25 (m, 1H), 2.1-1.95 (m, 1H), 1.6-1.4 (m, 1H).

Example 17. Diphenylmethyl [7S, 6R]-Togo acid zinc powder with (58.2 g, 0.89 mol) is suspended in 1780 ml of anhydrous DMF in a three-liter three-neck flask equipped with a septum, thermometer, tubing for nitrogen, addition funnel and condenser with dry ice. Approximately 20% chilled on ice dibromodifluoromethane (205,4 g, 0.98 mol) are added dropwise at a fast pace through the addition funnel, and after 15 min the beginning of the exothermic reaction causes the temperature rise of up to 50oC. Rest dibromodifluoromethane added at a rate that maintains the internal temperature of the reaction at the level of 45-50oC, then dibromodifluoromethane stirred for 90 min after the addition of all connections. After cooling the solution to a temperature of -30oC add 150 ml of DMPU, followed by the addition of CuCl (88,1 g, 0.89 mol), stirred for 20 min, then bath replace the ice bath and stirring is continued for 20 minutes In a separate flask the original vinylboronic (50.0 g, 0,089 mol) is dissolved in 100 ml of anhydrous DMPU and 100 ml of anhydrous DMF and heated to a temperature of 65-70oC. the bromide is added a cold copper reagent via cannula over approximately 1 h, maintaining the temperature at 65-70oC during the addition and then stirred for 1 h but poured into 50% aqueous solution of bicarbonate, is separated, washed twice with 50% aqueous bicarbonate, water, two times 1 N. HCl solution, water, saline, dried in the presence of magnesium sulfate and reduced to a brown oil. Oil chromatographic on silica gel using 60:40 hexanitrate, and then crystallized from ethyl acetate/hexane to obtain 28.4 g of a solid substance beige (58%).

Example 18. p-Nitrobenzyl[7S, 6R]-7 - phenoxyacetamide-3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4-carboxylate.

Specified in the header connection receive in accordance with the method of example 17 (except that CuBr used instead of CuCl), getting a solid beige color with a yield of 64%

1H-NMR (CDCl3) d 8.19 (d, J=9 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 7.30 (t, J= 6 Hz, 3H), 7.03 (t, J=8 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 5.45 (t, J=5 Hz, 1H), 5.37 (Quartet, J=15 Hz, 2H), 4.57 (s, 2H), 4.0-3.9 (m, 1H), 2.6-2.35 (m, 1H), 2.4-2.3 (m, 1H), 2.1-2.0 (m, 1H), 2.6-2.4 (m, 1H).

Example 19. Hydrochloric mixture of allyl-[7S - 6R]-7-amino-3-trifluoromethyl-1-carb(1 detya)-3-cefem-carboxylate.

The product from example 16 (10,53 g, 0,0246 mol) is dissolved in 83 ml of dry methylene chloride under nitrogen and cooled to 0oC. the Solution is treated with pyridine (2,41 g, 0,0305 mol) via syringe, after which the portions within 20 MIA during this time the solution preobladayut to the temperature of the ice bath and treated with isobutyl alcohol (18,4 g, 0,248 mol), dissolved in 20 ml of diethyl ether are added via syringe over 5 min After 20 min, the ice bath removed and the reaction mixture was stirred 1 h is Formed thick, fleecy solid white color, which is cooled to 0oC, collected by filtration, washed twice 50/50 mixture of methylene chloride/plain diethyl ether and once with diethyl ether. This solid is dried in vacuum for 3 h, the gain of 6.49 g is specified in the header of the product in the form of chapeaurouge solid white (77%).

1H-NMR (DMCO-d6d 9,20 (c, 3H), from 6.0 to 5.8 (m, 1H), 5,35 (d, J 1 Hz, 1H), 5,24 (d, J 1 Hz, 1H), 4,90 (d, J 1 Hz, 1H), 4.75 V (t, 2H), 4,1 to - 3.9 (m, 1H), 3,5-3,2 (m, 2H), 2,2-2,1 (m, 1H), 1,9-1,7 (m, 1H).

Example 20. Allyl (7S, 6R)-7-[D-a- (tertbutoxycarbonyl)-3-forgenerating]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylate.

A solution of (tert-butoxycarbonylamino)-3-florfenicol acid (1.05 by 0,00321 mol ) in 21 ml of anhydrous methylene chloride is treated with N-methylmorpholine (0.35 g, 0,00343 mol) and 1-chloro-3,5-dimethoxytrityl (0,58 g, 0,00321 mol) at a temperature of 0oC under nitrogen and stirred for 45 minutes, the Product from example 16 (1,00 g, 0,00306 mol) are suspended in 8 ml of methylene chloride, treated with N-methylmorpholine (0.35 g, 0,00343 mol) of ether. After 20 min at 0oC bath removed and the solution stirred for 90 minutes After evaporation of the solvent in vacuo the residue is dissolved in ethyl acetate, insoluble materials are removed by filtration through brownmillerite and evaporated to an oil, after which the crude product chromatographic on silica gel using 75:25 hexane/ethyl acetate, then 65: 45 hexane/ethyl acetate, receiving 1.45 g (88%) indicated in the title product as a beige foam.

1H-NMR (CDCl3d between 7.4 and 7.3 (m, 2H), a 7.2 to 7.0 (m, 2H), 6.75 in (d, 1H), 6,0-to 5.85 (m, 1H), 5,7-5,5 (m, 1H), 5,4-5,2 (m, 2H), 5,2 to 5.1 (m, 1H), 4,8 - 4,7 (m, 1H), 3.95 to to 3.8 (m, 1H), 2,6-2 2,2 (M, 2H), of 2.0 to 1.7 (m, 1H), of 1.40 (s, 9H), 1.3-1,1 (m, 1H).

Example 21. (7S, 6R)-7[D, L-α-(tert-butoxycarbonylamino)-3 - forgenerating]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

The product from example 20 (1.45 g, 0,00268 mol) is dissolved in 4.5 ml of ethyl acetate and 1 ml of methylene chloride under nitrogen and toxigenic by bubbling nitrogen into the flask for 5 minutes the Solution is cooled in an ice bath and treated 0,070 g tetranitroaniline, 0,070 g tetraphenylporphine and 6.4 ml (0,00322 mol) 0.5 M solution of 2-ethylhexanoate sodium acetate. After 5 min the bath removed and the solution stirred for 30 minutes, pouring in 30 ml of a mixture of 50/50 of Dyatlovo is the number of methylene chloride, washed with 1 N. HCl solution, dried in the presence of magnesium sulfate and evaporated to obtain 1.20 g (89%) indicated in the title compound, which is not subjected to further purification.

Example 22. (6R, 7S)-7-b-[D-a-(amino)-3-perforazione]-3-trifluoromethyl-1-carb (1 detya)-3-cefem-4-carboxylic acid.

The product from example 21 (1,15 g, 0,00229 mol) was added in one portion to a cooled on ice to a solution of TFA (11.5 ml) and anisole (0.75 ml, 0,00687 mol) under nitrogen and stirred for 30 minutes, the Reaction mixture was diluted with acetonitrile and restore the vacuum, again diluted with acetonitrile and evaporated at a temperature of 30oC to dryness. The remainder proscout simple diethyl ether and the resulting solid collected by filtration and washed repeatedly simple diethyl ether. The crude solid is dried in vacuum, obtaining 0,89 g of a mixture of diastereoisomers; 0.20 g of product chromatographic reversed-phase chromatography on a column of C-18 portions (0,020 g) using 10% acetonitrile/1% AcOH/H2O getting after lyophilization to 0.032 g of the desired product.

Example 23. Allyl (7S, 6R)-7-a-(tert-butoxycarbonylamino)-3-atlantomediterranean]-3-trifluoromethyl-1-carb (1 detya)-3-cefem-4-carboxylate.

1H-NMR (CDCl3d to 7.50 (s, 1H), 7,35 to 7.1 (m, 6H), 6,0-of 5.75 (m, 2H), 5,4-5,1 (m, 4H), 5,8-5,7 (m, 2H), 3.95 to to 3.8 (m, 1H), 3,10 (Quartet, J 8 Hz, 2H), 2,6-2,0 (m, 3H), of 1.40 (s, 9H), of 1.30 (m, 1H).

Example 24. (7S, 6R)-7-[D, L-α-(tertbutoxycarbonyl)-3-atlantomediterranean] -3-trifluoromethyl-1-carb (1 detya)-3-cefem-4-carboxylic acid.

The crude compound indicated in the heading is obtained from the product of example 23 in accordance with the method of example 21 (96%) and not subjected to further purification.

Example 25. (6R, 7S)-7-b-[D-a-(amino)-3-ethylsulfonylimidazo-amino]-3-trifluoromethyl-carba-(1-zetia)-3-cefem-4-carboxylic acid.

Specified in the header of the product is obtained from the crude product of example 24 in accordance with the method of example 22 and chromatographic on a column of C-18 using 20% acetonitrile/1% ammonium acetate/ H2O, receiving 14% of the product after lyophilization.

1H-NMR (DMCO-d6d 9,85 (Shir.s, 1H), and 9.3 and 9.1 (m, 1H), 7.3 to a 7.0 (m, 4H), 5,3-5,2 (m, 1H), 4.72 in (s, 1H), 3,7-3,6 (m, 1H), 3,1 and 2.9 (m, 1H), 2,2-1,9 (m, 2H), 1,4-1,3 (m, 1H), 1,25-of 0.95 (m, 4H).

Example 26. Allyl (7S, 6R)-7-[a-(tertbutoxycarbonyl)-3-bromophenylacetate]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylate.

Specified in the header connection receive in accordance with methodolgy foam (91%).

1H-NMR (CDCl3d of 7.5 to 7.2 (m, 5H), from 6.0 to 5.7 (m, 2H), 5,5-5,2 (m, 3H), of 5.0 to 4.7 (m, 1H), 3.95 to to 3.8 (m, 1H), 2,6-2,2 (m, 2H), 2,1 to 1.7 (m, 1H), and 1.4 (s, 9H), of 1.1-1.3 (m, 1H).

Example 27. (7S, 6R)-7-[D, L-α- (tertbutoxycarbonyl)-3-bromophenylacetate]-3-trifluoromethyl-1-carb (1 detya)-3-cefem-4-carboxylic acid.

Specified in the header of the product with the release of more than 100% release in a reaction similar to the reaction of example 21. The starting material is product of example 26.

Example 28. [6R, 7S]-7-b-[D-a-(amino)-3 - bromophenylacetate]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Specified in the header connection receive in accordance with the method of example 26 and chromatographic using 15% acetonitrile /1% AcOH/H2O getting the product with output 10%

1H-NMR (DMSO-d6d 9.20 (Shir.s, 1H), 7.65 (s, 1H), 7.65 (s, 1H), 7.50 (d, J 5 HZ, 1 H), 7.40 (d, J= 5 Hz, 1H), 7.30 (t, J 5 Hz, 1H), 5.3-5.2 (m, 1H), 4.75 (s, 1H), 3.7-3.6 (m, 1H), 2.20-2.0 (m, 2H), 1.4-1.2 (m, 2H).

Example 29. Allyl [7S, 6R]-7-[a-tert - butoxycarbonylamino)-3-triftormetilfullerenov]-3-trifluoromethyl-1 - carb(1 detya)-3-cefem-4-carboxylate.

Specified in the header connection receive in accordance with example 20 as a white foam (91%).

1H-NMR (CDCl3) d 7.4-7.2 (m, 4H), 6.9-6.8 (m, 1H), 6.. 7S, 6R)-7-(D, L-α-(tert - butoxycarbonylamino)-3-trifluromethanesulfonate] -3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Specified in the header connection receive in accordance with the method of example 21, receiving more than 100% of the crude solid light yellow color. The starting material is product of example 29.

Example 31. [6R, 7S]-7-b-[D-a-(amino)-3-triftormetilfullerenov]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Specified in the header connection receive in accordance with the method of example 22, using the product of example 30 as a starting substance, and chromatographic on C18 column portions (0,020 g) using 15% acetonitrile /1% AcOH/H2O, obtaining a product having a yield of 12%

1NMR (DMSO-d6d 9.5-9.3 (m, 1H), 8.6 (Shir.s, 3H), 7.9-7.6 (m, 4H), 5.56-5.35 (m, 1H), 5.16 (s, 1H), 3.85-3.75 (m, 1H), 2.3-2.1 (m, 2H), 1.35-1.25 (m, 1H), 1.25-1.1 (m, 1H).

Example 32. [6R, 7S)-7-b-[D-a-(amino)-3,4-dichlorophenylamino]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Racemic solution of tert-BOC-protected 3,4-dichloraniline (0,550 g, 0,00173 mol) in 21 N,N-dimethylformamide is cooled to -45oC under nitrogen, add isobutylparaben 80,22 ml, 0,00173 mo is so Monoisostearate (1,53 g, 0,00824 mol) was added to a stirred suspension of 7-amino-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid (0,600 g, 0,00165 mol) in 15 ml of N,N - dimethylformamide and the solution is heated to 40oC for 30 minutes the Solution similarvideo kernel Hledat and add to the mixed anhydride at a rate that maintains the internal temperature of the reaction at the level of -40oC. the Solution is slowly heated to 0oC after 2 h, add 1, 2 ml MeOH, and the ice bath removed. After reaching ambient temperature the solution is diluted with ethyl acetate, filtered through brownmillerite, washed four times 1 N. HCl solution, water, saline, dried in the presence of magnesium sulfate and concentrated under reduced pressure. The remainder chromatographic on silica gel using 2/80/ 18:HOAc/ethyl acetate/hexane. The crude product was added to a mixed solution of TFA (4.0 ml) and Et3SiH (1.2 ml) in an ice bath and after 30 minutes the solution is concentrated and proscout simple diethyl ether, collected by filtration and washed with simple diethyl ether. Chromatography of the crude TFA salt (0,114 ) on a C18 column with a gradient to 25% CH3CN/H2O allows you to get after l is 1H-NMR (DMSO d6d 9.15 (Shir.s, 1H), 7.7-7.6 (m, 2H), 7.38 (d, J 8 Hz, 1H), 5.3-5.25 (m, 1H), 4.75 (s, 1H), 3.8-3.7 (m, 1H), 2.2-2.1 (m, 2H), 1.4-1.2 (m, 2H).

Example 33. [6R, 7S]-7b-[D-a-(amino)-3-chloro-4-hydroxyphenylethylamine] -3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4-carboxylic acid.

Specified in the header of the product is obtained in accordance with the reaction conditions of example 32, except that the pure tert-BOC-protected D-3-chloro-4-hydroxyphenylglycine used for acylation, receiving 41% yield solid white.

1H-NMR (DMSO-d6) d 7.40 (s, 1H), 7.15 (d, J 9 Hz, 1H), 6.95 (d, J 10 Hz, 1H), 5.17 (d, J 5 Hz, 1H), 4.75 (s, 1H), 3.7-3.6 (m, 1H), 2.2 1.9 (m, 2H), 1.45-1.3 (m, 1H), 1.15-1.0 (m, 1H).

Example 34. Allyl [7S, 6R] -7-[[2- (triphenylmethyl)amino-4-thiazolyl] (tributoxy-carbonyloxy) -acetyl] amido-3 - trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylate.

Specified in the header connection receive in accordance with the method of example 20 to yield 41% solid white.

1H-NMR (CDCl3) d 8.68 (d, 1H), 7.34 (c, 16H), 7.02 (s, 1H), 6.80 (s, 1H), 6.0-5.9 (m, 1H), 5.57 (d, 1H), 5.4-5.2 (m, 2H), 4.8-4.7 (m, 4H), 4.0-3.9 (m, 1H), 2.5-2.4 (m, 1H), 2.4-2.3 (m, 1H), 2.2-2.1 (m, 1H), 1.65-1.5 (m, 1H), 1.44 (s, 9H).

Example 35. [7S, 6R]-7-[2-amino-4 - thiazolyl(carboxymethoxy)acetyl] -3-triptime treated with 2.5 ml of cold triperoxonane acid and 0.8 ml of cold triethylsilane under nitrogen in an ice bath for 1 h Then the bath is removed and the solution warmed to room temperature and pereshivayut during the night. The solution was diluted with acetonitrile and evaporated to small volume in vacuo at 30oC, then diluted with a further 2 times with acetonitrile and evaporated to dryness. The remainder proscout simple diethyl ether and 73 mg of the crude solid beige collected by filtration with suction (57% yield).

65 mg (0,126 mmol) of the above crude product is dissolved in 3 ml of anhydrous acetonitrile under nitrogen, followed by addition of 3 mg (0,0126 mmol) of triphenylphosphine and 1 mg (0,00252 mmol) of palladium acetate. The solution is cooled in an ice bath while adding via syringe 0.036 ml (0,132 mmol) of anti-hydride. After 1 h the solution process of 0.014 ml (0,252 mmol) of acetic acid and stirred for 30 minutes the Precipitate is collected and washed with simple diethyl ether and then recrystallized from methanol/ethyl acetate/diethyl ether to obtain 21 mg of a light yellow solid (yield 35%).

1H-NMR (DMSO-d6d 9,45 is 9.3 (m, 1H) 7,14 (c, 2H), 6,76 (c, 1H), 5,5-5,4 (m, 1H), 4,56 (c, 2H), from 3.9 to 3.8 (m, 1H), 2,4-2,2 (m, 2H), 1,95-of 1.85 (m, 1H), 1,6-of 1.45 (m, 1H)

Example 36. Allyl (7S, 6R)-7-[D,L-α- (tertbutoxycarbonyl)-3-titilation in accordance with the method of example 20, looks solids not quite white (91%).

Example 37. [7S, 6R]-7-[D,L-α- (tertbutoxycarbonyl)-3-trilateration]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Specified in the title compound is obtained from the product of example 36 in accordance with the method of example 21 without further purification.

Example 38. [6R,7S]-7-b-[D-a-(amino)-3-trilateration]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Specified in the header of the product is obtained from the crude product of example 37 in accordance with the methodology described for example 22, and chromatographic on C18 column using methanol/acetic acid, water, receiving an 18% yield lyophilization.

1H-NMR (DMSO-d6d of 9.3 to 9.2 (m, 1H), and 7.6-7.5 (m, 2H), 7,15 (d, 1H), 5,3-5,2 (m, 1H), 4,90 (s, 1H), 3,85-3,6 (m, 1H), 2,2-2,0 (m, 2H), 1,45-1,2 (m, 2H).

Example 39. Allyl [7S, 6R]-7-b-[D-a-(tertbutoxycarbonyl)-3-benzeneacetate]-3-trifluoromethyl-1-carb-(1-zetia)-3-cefem-4-carboxylate.

Specified in the title compound, obtained according to the method of example 20 has the form of a white foam (yield 60%).

Example 40. [7S, 6R]-7-b-[D-a-(tertbutoxycarbonyl)-3-bensiinipoletamine]-3-trifluoromethyl-1 - camera 39 in accordance with the method of example 21, and not purified.

Example 41. [6R, 7S)-7-b-[D-a-(amino)-3-bensiinipoletamine]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

Specified in the procurement connection receive in accordance with the method of example 22 from the crude product of example 40 and chromatographic the button C18 using methanol/acetic acid/water, then lyophilized obtaining solid white with a yield of 32%

1H-NMR (DMSO-d6d a 9.35 (d, 1H), 9,1-8,5 (Shir.s, 3H), 8,1-7,9 (m, 2H), and 7.9 (s, 1H), 7.5 to to 7.3 (m, 2H), 5,5-to 5.3 (m, 2H), from 3.9 to 3.7 (m, 1H), 2,2-2,1 (m, 2H), 1,4-1,3 (m, 1H), 1,2-1,1 (m, 1H).

Example 42. Allyl 7-[(N-tert - butyloxycarbonyl-N-phenoxyacetyl)-amino] -3-bromo-1-carb(1 detya)-2,3-cefem-4-carboxylate

A mixture of 60/40 D2/3 compound 3-bromo from preparation 3 (100 mg, 0,2297 mmol) are combined with DMAR (29 mg, 0,2343 mmol) and di-tert-BUTYLCARBAMATE (0,2412 mmol, 84 μl). The mixture is stirred for approximately 1 h at room temperature. The mixture directly chromatographic on silica gel with elution with 20% EtOAc/CH2Cl2getting 104 mg (85% yield) specified in the title compounds as a mixture of 60/40 2/3 isomers, respectively. Data on the 2-isomer.

1H-NMR (300 MHz, CDCl3) 7,30 (t, J=8 Hz, 2H), 7,0 (t, J 6 Hz, 1H)Example 43. Allyl-7-[(N-tert-butoxycarbonyl-N-phenoxyacetyl)amino]-3-bromo-1-carb(1 detya)-2-cefem-4-carboxylate.

Pure D2-isomer 3-bromoguanine from preparation 3 (4.6 g, 10,57 mmol) are combined with di-tert-BUTYLCARBAMATE (2,54 g, 11,6241 mmol, 2.65 ml) and DMA (1,33 g, 10,88 mmol), then stirred. The mixture is treated as in example 34, receiving 5.3g (93,6% yield) specified in the header of the product.

Example 44. Allyl [7S, 6R]-7-tert-butyloxycarbonyl-3-bromo-1-carb-(1-zetia)-2-cefem-4-carboxylate.

The product from example 42 (104 mg, 0,1947 mmol) are combined with THF (2 ml), and the first portion of LiOH (0,1652 ml) and stirred for 40 minutes Then add the second portion of LiOH (0,0295 ml) and the mixture is stirred for 1 h the Mixture was poured into 40 ml of EtOAc and then mixed with 10 ml of water and 10 ml of a saturated solution of NaHCO3. Organic matter is separated, is dried in the presence of sodium sulfate, filter and concentrate to obtain 79 mg (yield more than 100%) of the crude product. Data on the 2-isomer:

1H-NMR (300 MHz, CDCl 3) 6,35 (m, 1H), 5,95 (m, 1H), 5,35 (m, 2H), 5,15 (m, 2H), 4,88 (s, 1H), and 4.68 (m, 2H), of 4.05 (m, 1H), 2,35 (m, 2H) and of 1.42 (s, 9H).

Example 45. Allyl [7S, 6R]-7 - butyloxycarbonyl-3-bromo-1-carb(1 detya)-2-cefem-4-carboxylate.

The product from example 43 (which are second portion of LiOH (1,55 ml) and the mixture stirred for 1 h The mixture is treated in accordance with example 36, receiving as 4.02 g (yield more than 100%) specified in the header of the product.

Example 46. Allyl [7S, 6R]-7 - butyloxycarbonyl-3-bromo-1-carb(1 detya)-3-cefem-4-carboxylate.

The product from example 44 (16 mg, 0,0399 mmol) are combined with 0.3 ml of CH2Cl2and DBU (0,0064 mmol, and 1.0 µl). The mixture is stirred for 60 min at room temperature. The mixture measure the pipette after 1 h of silica and then elute with 10% EtOAc/CH 2Cl2. Specified in the header of the product passed through DBU on the silica. The mixture is concentrated to a foam, receiving of 15.1 ml of product with a ratio of 15/85D2/3 - isomers that predstavljaet 94,9% recovery on the basis of theoretical minimum of 16 year

Example 47. Allyl [7S, 6R]-7 - butyloxycarbonyl-3-bromo-1-carb-(1-zetia)-3-cefem-4-carboxylate.

The product from example 45 (4.0 g, 9.97 mmol) is treated according to example 46 except that 6% etAOc/CH2Cl2use instead of 10% solution, getting clean 3-isomer. Use the following reaction conditions:

DBU 2.5 mmol, 0,373 ml

CH2Cl270 ml

The crude mixture contribute directly to the chromatographic column to a depth of 8 inches (20.32 cm) and ø is a and 610 mg of a mixture of 2/3 of isomers, re chromatographic, as described above with an additional 250 ml of pure 3-isomer and 360 mg of pure 2-isomer. Pure 3-isomer was added to obtain the total number of 2.23 g (66% yield) of pure 3 - isomer.

1H-NMR (300 MHz, CHCl3) 5,95 (m, 1H), 5,35 (m, 3H), of 5.15 (m, 1H), 4.75 in (m, 2H), 3,85 (m, 1H), 2,75 (m, 2H), 2.0 (m, 1H), 1,70 (m, 1H) and of 1.42 (s, 9H).

IR (CHCl3): 3019, 1775, 1718, 1504, 1369, 1206 1055 cm-1.

Macc-spectrum: m/e 400 (M+).

Analysis for C16H21N2O2Br:

Calculated C 47,89, H 5,28, N Is 6.78, Br of 19.91

Found, C 47,85, H of 5.05, N 6,77, Br 19,76

Example 48. [7S, 6R]-7-(aminophenylacetic)-amino-3-bromo-1-carb(1 detya)-3-cefem-4 - carboxylic acid.

A) a 25-ml flask is added at a temperature of 30oC 78 mg (0,1944 mmol) allyl [7S, 6R)-7 - butyloxycarbonyl-3-bromo-1-carb(1 detya)-3-cefem-4-carboxylic acid in 4 ml of EtOH and 37 mg (0,1944 mmol) of the monohydrate of n-toluenesulfonic acid, after which the mixture is concentrated to dryness. Added EtOH (4 ml) and the mixture is again concentrated to dryness. In a separate flask 46 mg (0,1944 mmol) (2-propenyloxy)carbylamine-D-phenylglycine and 34 mg (0,1944 mmol) chlorodimethylsilane 1.5 ml of CH2Cl2combined and cooled to 0oC. was Added N-methylmorpholine (NMM) and the mixture paramacharyal to room temperature ture 2-5 PM The mixture is concentrated almost to dryness, then add 1 ml of CH2Cl2and 1 ml of a 50/50 mixture of EtOAc/hexane. The mixture is then loaded up to 15 g (silica) chromatography column and elute with 10% MeOH/EtOAc, receiving 74 mg allyl-7-(phenyl(2-propenyloxy)carbylamine)acetylamino-3-bromo-1-carb(1 detya)-3-cefem-4-carboxylate, the physical data is given below.

1H-NMR (300 MHz, CDCl3) 7,30 d (s, 5H), was 7.08 (m, 1H), 5,95 (m, 3H), 5.25 in (m, 6H), 4.72 in (d, J 6 Hz, 2H), to 4.52 (m, 2H), 3,82 (m, 1H), 2,62 (m, 2H), 1,58 (m, 1H), 1,25 (m, 1H).

IR (CHCl3): 3019, 1775, 1727, 1689, 1496, 1241 and 1052 cm-1.

Mass spectrum: m/e 517.

Analysis for C23H24N3O6Br:

Calculated C 53,29 H 4,67, N 8,11, Br 15,4

Found, C 53,51, H 4,46, N 7,93, Br 15,4

B) a 25-ml flask combine 73 mg (0,1408 mmol) of product from part (A) in 2.0 ml of CH3CH and 1.0 ml Et2O, 7.4 mg (0,0282 mmol) of triphenylphosphine and 1,4 mg (0,0056 mmol) of palladium acetate. The mixture is cooled to 0oC after 5 min and after microspec add 76 μl of solution Bu3SnH. The mixture is heated to room temperature and stirred for 45 minutes To the mixture was added 4 μl Bu3SnH and 2 ml of Et2O and stirred for an additional 30 minutes Added concentrated HCl solution (23,5 μl, 12 M), and at this time ablaut 20 ml Et2O and the mixture centrifuging. The solid is decanted and washed (2x10 ml of CH3CN/10 ml Et2O), then washed with twice 15 ml of Et2O. the Mixture is dried in vacuum, obtaining 51,5 mg solid brown color, which is dissolved in 1.2 ml of CH3CN and 0.13 ml of 1 n HCl, centrifuged, and decanted into 15 ml centrifuge tube, forming a twist, add a bit higher than 1 equivalent, 1.5 M solution of NH4OH, in order to set the pH at around 4.0, and at this time, the precipitated solid white color, which is then centrifuged and decanted, rinsing once with 8 ml Et2O and 8 ml twice 1/1 Et2O/hexane, then dried to obtain 46,5 kg specified in the header of the product. Physical data this product is shown below.

1H-NMR (300 MHz, D2O) d 7.55 (m, 5H), 5.40 (d, J=12hz, 1H), 5.20 (s, 1H), 3.85 (m,1H), 2.50 (m, 2H), 1.55 (m, 1H), 1.25 (m, 1H).

IR(KV) 3150, 3050, 1770, 1750, 1625, 1550, 145 and 1325 cm-1.

Mass spectrum: m/e 394(M++1).

Example 49. 7-(((2-Amino-4-thiazolyl)-methoxyaminomethyl)amino)-3-bromo-1-carb(1 dia)-3-cefem-4-carboxylic acid.

A) In a 50 ml flask unite 240 mg (0,5981 mmol) allyl-7-butoxyaniline-3-bromo-1-carb(1 detya)-3-cefem-4-carboxylate in 8 ml EtOH and 114 mg (0.5 rdih substances. The mixture is concentrated to dryness, add 8 ml EtOH and the mixture is again concentrated to dryness. In the second flask of 50 ml volume unite 181 mg (0,5891 mmol)[2-(tert-butoxycarbonyl)amino-4-thiazolyl](methoxyimino)-acetic acid and 105 mg (0,5891 mmol) chlorodimethylsilane 4.5 ml of CH2Cl2and cooled to 0oC. In a second flask was added N-methylmorpholine (NMM) (69 μl, 0,628 mmol) and the contents stirred for 45 minutes After mixing add another equivalent of NMM and the contents of the first flask in CH2Cl2through the pipette. The temperature in the second flask is brought to room temperature and the contents stirred for 2.5 hours the Mixture is concentrated almost to dryness, then add 2.5 ml of CH2Cl2/EtOAc. The mixture is then loaded into the flask chromatography column (50 g silica) and elute with 80/20 CH2Cl2/EtOAc. The desired substance concentrate to obtain 270 mg specified in the header of the product.

1H= NMR (300 MHz, CDCl3d to 9.45 (s, 1H), 8.25 (d, J=8 Hz, 1H), 6.98 (s, 1H), 5.95 (m, 1H), 5.68 (m, 1H), 5.35 (m, 2H), 4.75 (m, 1H), 4.0 (m, 1H), 3.95 (s, 3H), 2.80 (m, 2H), 2.10 (m,1H), 1.90 (m, 1H) and 1.52 (s, 9H).

Mass spectrum: m/e 583 (M++1).

Analysis for C22H25N5O7SBr:

Calculated C 45.29, H 4.32, N 12.00

Found, C, 45.09, H 4.52, N 11.76

hexanoate of sodium in 3 ml EtOAs. The flask 3.1 mg (0,0116 mmol) of triphenylphosphine and 13.4 mg (0,0116 mmol) tetranitroaniline (0), and the mixture is stirred for 1.5 hours To precipitate solid was added 30 ml of Et2O and the mixture is stirred for 20 min, then poured into 200 ml of CH2Cl2and 75 ml of 1 n HCl solution. Solid produce, dried in the presence of sodium sulfate, filtered and concentrated to dryness to obtain 250 mg

(C) In a flask with a capacity of 50 ml was placed 251 mg (0,4591 mmol) of product from part (C) above and 3 ml of CH2Cl2and the mixture is cooled to 0oC. To the flask was added to 0.22 ml (1,36 mmol) Et3SiH and 3 ml triperoxonane acid, and the mixture is heated to room temperature and stirred for 35-40 minutes the Mixture is diluted with 25 ml of CH3CN and concentrate to 1 ml Three times was added 10 ml of CH3CN and 10 ml of toluene and the mixture is concentrated to dryness to obtain a yellowish brown solid. Solid chromatographic on 75 g silica) and elute using a 0.5% AcOH/a 4.5% isopropanol/20% CH3CN/75% EtOAc to yield only the desired solid. The desired fractions are concentrated to 1/2 ml and precipitious with Et2O. the Mixture is centrifuged and dried to obtain 60 mg specified in the header of the product. The solid body is.

1H-NMR(300 MHz, D2O) d 7.08 (C. 1H), 5.46 (d, J=12hz, 1H), 4.10 (m, 1H), 4.05 (s, 3H), 2.78 (m, 2H),05 (m, 1H) and 1.80 (m, 1H).

Mass spectrum: m/e 444 (M++1).

The compounds of formula (I) inhibit the growth of some pathogenic organisms, as demonstrated by the method of cultivation in agar, in which the compound is diluted to an appropriate concentration range in 0.1 M phosphate-buffered solution, pH 7.0, is introduced into the agar Mueller-Hinton (Difco), supplemented with 1% Bacto-Supplementum With (Difco), at the 50oC and utverjdayut in Petri dishes. Fresh night culture of the studied bacteria were diluted to approximately 1 x (10)4cells/μl and applied in a volume of 1 μl on the surface of agar plates. Inokulirovanny plates incubated overnight at a temperature of 35oC in ambient air. The final values of the minimum inhibitory concentration (MIC) recorded as the lowest concentration of antibiotic in micrograms per milliliter, which inhibit the development of visible growth on the plates. Below are summarized the results of such tests with compounds of the above examples. The following number of connections assigned to the compounds mentioned in the table:

1. 7b-[D-a-(amino)phenylacetylamino]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid

3. [6R, 7S]-7-b-[D-a-(amino)-4 - perforazione]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid

4. [7S, 6R]-7-([2-amino-4 - thiazolyl(methoxyimino)acetyl]amido)-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid

5. [7S, 6R]-7-([2-amino-4 - thiazolyl(oxyimino)acetyl]amido)-3-trifluoromethyl-1-carb-(1-Zetia)-3-cefem-4-carboxylic acid

6. [6R, 7S] -7-b-[D-a-(amino)-3 - atlantomediterranean]-3-trifluoromethyl-1-carb (1 detya)-3 - cefem-4-carboxylic acid

7. [6R, 7S]-7-b-[D-a-(amino)-3 - bromophenylacetate]-3-trifluoromethyl-1-carb (1 detya)-3-cefem-4-carboxylic acid

8. [6R, 7S]-7-b-[D-a-(amino)-3 - perforazione]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid

9. [6R, 7S]-7-b-[-a-(amino-3 - triftormetilfullerenov]-3-trifluoromethyl-1-carb(1 detya)-3-cefem-4-carboxylic acid.

1. Derivatives of 3-trifluoromethyl-1-carb-1 Detia-3-cefem-4-karbonovy acid of General formula

< / BR>
where R2hydrogen or carboxyamide group;

R is a substituted methyl group of the General formula

R4-CH-Q

where Q NH2, R4phenyl or substituted phenyl General formula

< / BR>
where a and a' are hydrogen, halogen, hydroxy or WITH the1- C4-alkylsulfonamides, or R4thiazolyl, C is Ruppel, R6hydrogen or C1WITH4-alkyl, or, when R2hydrogen

their pharmaceutically acceptable salts.

2. Derivatives of 7-amino-3-tryptomer-1-carb-1 Detia-3-cafema General formula

< / BR>
where R2hydrogen or carboxyamide group,

or their acid additive salt.

3. Connection on p. 2, wherein R2the hydrogen.

4. Connection on p. 2, wherein R2carboxyamide group.

5. Derivatives of 1-carb-1 Detia-3-cefem-4 carboxylic acid of General formula

< / BR>
where R2hydrogen or carboxyamide group;

RtWITH1WITH6-alkyl;

W aminosidine group.

6. Connection on p. 1 of General formula

< / BR>
where R4phenyl or substituted phenyl General formula

< / BR>
where a and a' have the specified values.

7. Connection on p. 6, wherein R4substituted phenyl group of the General formula

< / BR>
where a and a' have the specified values.

8. Connection on p. 7, characterized in that a hydrogen and a' is hydroxy.

9. Connection on p. 7, wherein a and a' are hydrogen.

10. Connection on p. 7, characterized in that a fluorine.

11. With

 

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< / BR>
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< / BR>
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3 cl, 5 dwg

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