Derivatives carbapenem, their pharmaceutically acceptable salts and hydrolyzable in vivo ether (options), the retrieval method (variants), a pharmaceutical composition having antibacterial activity, derived pyrrolidin-4-itiola and protected derivatives pyrrolidine-4 - itiola

 

(57) Abstract:

The invention relates to carbapenems, intended for use in medicine for therapeutic purposes. The invention is a compound of formula (I):

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in which R is hydrogen, R1is oximation or 1-oxyethyl; R2and R3are hydrogen or (C1- C4)alkyl; R4and R5the same or different, represent hydrogen, halogen, amino, cyano, (C1- C4)alkyl, hydroxy-group, carboxypropyl, (C1- C4)alkoxygroup, (C1- C4)alkoxycarbonyl, carbarnoyl, (C1- C4)allylcarbamate, di (C1- C4)allylcarbamate, trifluoromethyl, sulfonylurea group, (C1- C4)alkylamino, di (C1- C4)alkylamino, (C1- C4)alkanolamines, (C1- C4)alkanoyl[N - (C1- C4)alkyl]amino, (C1- C4)alkanesulfonyl, (C1- C4)alkylsulfonyl, (C1- C4)allylthiourea and (C1- C4)alkylsulfonyl provided that in ortho-position to the-N-R3the group has no hydroxyl or carboxyl substituent, or its farmace in the interaction of compounds of the formula (VI) with (VII). The requested pharmacognosie having antibacterial activity comprising a compound of formula (I) or its pharmaceutically acceptable salt or hydrolyzable in vivo broadcast. 7 C. and 23 C. p. F.-ly, 2 tab., 37 other

The invention relates to carbapenems, in particular such compounds that contain a carboxy-substituted phenyl group. In addition, this invention relates to a method of obtaining them, the resulting intermediate products, the use of carbapenems as therapeutic agents containing pharmaceutical compositions.

Compounds of the invention are antibiotics and can be used in the treatment of any disease, which is usually treated with antibiotics, for example, in the treatment of bacterial infections in mammals, including humans.

Carbapenems were first isolated from enzymatic environments in 1974 and it was found that they possess a wide spectrum of antibacterial activity. Since, as was done this discovery were conducted important research new derivatives carbapenem and published many hundreds of patents and scientific papers.

The first and still the only commercially available carbapenems is imipenem ptx2">

The invention provides compounds with a wide range of antimicrobial activity, including activity against gram-positive and gram-negative aerobic and anaerobic bacteria. They show good stability against beta-lactamase (beta-lactamases). In addition, the compounds of the present invention show very favorable duration of action.

Discussed here are derived carbapenem called in accordance with generally accepted policestations nomenclature

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In accordance with the present invention provide a compound of formula (I)

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or its pharmaceutically suitable salt or ester, hydrolyzable in vivo,

where R1is 1-oxyethyl, or oximation;

R2is hydrogen or (C1-4)alkyl;

R3is hydrogen or (C1-4)alkyl;

R4and R5the same or different and selected from hydrogen, halogen, cyano group, (C1-4)alkyl, hydroxy, carboxy, (C1-4)alkoxy groups, (C1-4)alkoxycarbonyl, (C1-4)alkylsulfonyl, (C1-C4)alkylsulfonyl, groups of carbamoyl, (C1-4)allylcarbamate, di(C1-4)-alkylchlorosilanes-, (C1-4)alkanoyl (N-C1-4-alkyl)amino, (C1-4)alkanesulfonyl groups and (C1-4)ancilliary, provided that in ortho-position to the - NR3communication there is no hydroxy or carboxy substituent.

Used in the invention alkali include linear or branched substituents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Preferred R1is 1-oxyethyl.

R2is hydrogen or (C1-4)alkyl, for example, stands, ethyl, n-propylene, isopropyl or n-bootrom. Preferred R2is hydrogen or methyl, in particular methyl.

R3is hydrogen or (C1-4)alkyl, for example, stands, ethyl, n-propylene, isopropyl or n-bootrom. Preferred R3is hydrogen.

R5and R4the same or different, is chosen from hydrogen, halogen, for example fluorine, bromine or chlorine; a cyano group; a (C1-4)alkyl, for example methyl, ethyl, n-propyl, isopropyl or n-butyl; nitro-oxy-, carboxy group; (C1-4)alkoxy group such as methoxy or ethoxy; (C1-4)alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl or n-propoxycarbonyl is; di(C1-4)alkylaminocarbonyl, for example, di-methylaminomethyl, methylaminomethyl and di-ethylaminomethyl; carbamoyl, (C1-4)allylcarbamate, for example, methylcarbamoyl or ethylcarbamate; di(C1-4)allylcarbamate, for example, dimethylcarbamoyl or diethylcarbamoyl; trifloromethyl; sulfoxylates group; amino group; (C1-4)alkylamino group, for example, methylamino or ethylamino groups; di(C1-4)alkylamino group, for example, dimethylamino - or diethylamino group; (C1-4)alkanolamine group, for example, acetamido or propionamido-; (C1-4)alkanoyl(N-C1-4alkyl)amino group, for example, N-methylacetamide-; (C1-4)alkanesulfonyl group, for example, methanesulfonamido-; or (C1-4)alkyl S(O)ngroup, for example, methylthio-, methylsulfinyl or methylsulfonyl group.

A particularly suitable class of compounds is one in which R4and R5the same or different and selected from hydrogen, fluorine, chlorine, hydroxy-, carboxy-, cyano-, nitro, methyl, ethyl, methoxy-, ethoxypropan, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifloromethyl, sulfoxylates group, methylsulfinyl, methylsulfonyl gr, but usually particularly preferred compounds in which at least one of R4and R5is hydrogen.

Particularly preferred such compounds in which R4is hydrogen, carboxyl, fluorine, chlorine, methyl, methoxy group, cyano group, sulfonylurea group or methoxycarbonyl, and R5- hydrogen.

The invention covers all epimeria, diastereoisomers and tautomeric forms of the compounds of formula (I) in which the stereochemistry at position 5 is not limited as shown in the formula (I). When the relationship represented by the wedge, this means that in three-dimensional space communications should be directed upwards from the surface of the paper, and when the bond represented by the dashed line, this means that in three-dimensional space, it should be aimed down at the paper surface. The compounds of formula (I) have a large number of other stereocentres, namely: in group R1(when R1is 1-oxyethyl or 1-foration); at position 6; in position 1 (when R2is (C1-4)alkyl); in position 2' and 4' pyrolidine ring:

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Preferred are such compounds in which the protons beta-lactam ring are in the TRANS configuration relative who had the R-configuration. Thus, a preferred class of compounds is the class corresponding to the formula (III):

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pharmaceutically suitable salts of these compounds and their esters, hydrolyzable in vivo, in which R2, R3, R4and R5such as defined above. If R2is (C1-4)alkyl, such as stands, it is preferable that the compound was in the form of IR-configuration.

Preferred are such compounds in which the pyrolidine ring has the following absolute stereochemistry at positions 2' and 4':

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A preferred class of compounds of the present invention is the following class, represented by the formula (IV):

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pharmaceutically suitable salts of these compounds and their esters, hydrolyzable in vivo, in which R3, R4and R5such as defined above in formula (I).

Particularly preferred compounds of the formula (IV) are those in which R3is hydrogen, and R4and R5- the same or different and selected from hydrogen, fluorine, chlorine, actigraphy, carboxyl, cyano, nitro, methyl, ethyl, methoxy-, ethoxypropan, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methysulfonylmethane.

The most preferred compounds of the formula (IV) are those in which R3and R5both are hydrogens, R4is hydrogen, carboxyl, fluorine, chlorine, methyl, methoxy or cyano, sulfonylurea group or methoxycarbonyl.

Suitable pharmaceutically suitable salts include salts of joining acids such as hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acids. On the other hand, are suitable basic salts such as alkali metal salts, e.g. sodium or potassium, salts of alkaline earth metals such as calcium or magnesium, salts of organic amines, such as triethylamine, research, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylamine or salts of amino acids, for example lysine. To remove doubt can be one, two or three salt-forming cation, depending on the number carboxilated functional groups and valence of these cations.

Preferred pharmaceutically suitable salts are the sodium and potassium salts. However, to facilitate the selection of salts when they are received, salt, less soluble in the selected solvent can be predpochtite the Eski suitable ethers, which upon hydrolysis in the body to give the parent compound. Such esters can be defined by typing, for example, intravenous test animals with subsequent investigation of the total water body. Suitable hydrolyzable in vivo esters are esters formed by carboxyl groups, esters (C1-6)alkoxymethyl, for example, methoxymethyl; esters (C1-6)alkanoyloxy, for example, pivaloyloxymethyl; esters palidin, (C3-8)cycloalkylcarbonyl-(C1-6)alkyl, for example, 1-cyclohexyloxy of carbonylmethyl; esters of 1,3-dioxolan-2-animatie, for example, 5-methyl-1,3-dioxolan-2-animetal; esters(C1-6)alkoxycarbonylmethyl, for example, 1-methoxycarbonylethyl; esters can be formed at any carboxy group in the compounds of the present invention. Suitable hydrolyzable in vivo esters formed by the hydroxyl group include esters formed by acetyl, propionyl, pivaloyl, (C1-4)alkoxycarbonyl, for example, etoxycarbonyl and phenylacetyl.

Specific compounds of the invention are:

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-oxiranylmethyl)- pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,
new acid,

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-chlorpheniramol)- pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylazo)pyrrolidin - 4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S,4'S)-2-(2-(3-carboxy-6-methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4 - tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-2,4 - differencemaker)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3 - carboxylic acid,

(1R, 5S,6S,8R,2'S,4'S)-2-(2-(3,4-dicarboxylicacid)- pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4 - oxiranylmethyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S,6S,8R,2'S,4'S)-2-(2-(3,5-dicarboxylicacid)- pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(2-carbarnoyl-3 - carboxyphenylazo)Pirro who phenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5 - carbamoylbiphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5 - acetaminophenramadol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4 - acetaminophenramadol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3 - carboxylic acid.

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - sulfophenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6 - carbamoylbiphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S,4'S)-2-(2-(3-carboxy-2 - dimethylaminocarbonylmethyl)pyrrolidin-4-ITIL)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(5R, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxyphenylazo)pyrrolidin - 4-ylthio)-6-(1-oxyethyl)carbapenem-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4 - methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,TA,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl - 3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4,6 - dimethoxycinnamoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - methoxycarbonylpropionyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - cyanovinylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5 - cryptomaterial)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carb is 5S, 6S, 8R,2'S,4'S)-2-(2-(3-carboxy-6 - methylsulfinylphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - cyanoaniline)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-N'- methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

their pharmaceutically usable salts and hydrolyzable in vivo ethers.

Preferred compounds of the invention are:

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid.

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - methodology the S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - cyanovinylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - chlorpheniramol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S,8R,2'S,4'S)-2-(2-(3- carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4 - tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6 - tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid,

(1R, 5S,6S,8R,2'S,4'S)-2-(2-(3,4-dicarboxylicacid)- pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S,6S,8R,2'S,4'S)-2-(2-(3,5-dicarboxylicacid)- pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5 - sulfophenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid and

their pharmaceutically suitable salts.

For use of the compounds of formula (I) or their pharmaceutically suitable salts or hydrolyzable in vivo esters for the treatment of mammals, including humans, and in particular for the treatment of infections, they are usually prepared in accordance with standard pharmaceutical practice as Pharma is asepticheskie composition, comprising the compound of formula (I) or its pharmaceutically suitable salt or hydrolyzable in vivo ether and a pharmaceutically suitable carrier.

The pharmaceutical compositions of the present invention can be taken in the usual way, as required for the treatment of diseases, for example, orally, rectally or parenterally. For these purposes the compounds of the present invention is prepared, known in the art methods in the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile aqueous or oily solutions or suspensions for injection.

Compounds of the present invention can be prepared in the form of dry powders and packaged in vesicles, which may contain only the connection of the present invention or a dry mix. For example, acidic compounds of the present invention can be mixed with carbonates or bicarbonates of alkali metals. Possible dried by freezing the compounds of the present invention or their mixtures with standard fillers. Standard fillers include structure of matter, createsite and changing pH such as mannitol, sorbitol, lactose, glucose, PI is vinylpyrrolidone (PVP), derivatives of cellulose, glutamine, Inositol, glutamate, potassium aritra serine and other amino acids and buffering agents, for example, sour centripetal and potassium citrate.

In addition to the compounds of the present invention the pharmaceutical compositions of the present invention may also contain (or you can use them together with one or more known drugs selected from other clinically useful antibacterial agents (for example other beta-lactams or aminoglycosides), inhibitors of beta-lactamase (e.g., clavulanic (clavulanic acid)), agents, blocking kidney channels (for example, probenecid (probenecid)), inhibitors of metabolic enzymes (e.g., inhibitors dehydropeptidase, for example, Z-2-acylamino-3-substituted of propenoate such as cilastatin (cilastatin) and N-acylated amino acids (for example, EP-A-178911), which reduce the harmful effects on the kidneys.

Suitable pharmaceutical compositions of the present invention are suitable for oral administration in the form containing a single dose, for example, the tablet or capsule containing 100 mg to 1 g of compound of the present invention.

The preferred composition of this image is erily the drug for injection, containing from 1 to 50 wt.% compounds of the invention.

Specific examples of compositions consisting of a 1% aqueous solution, which is dried by freezing and can be prepared by adding a 0.9% aqueous solution of sodium chloride to obtain the desired concentration (preferably 1-10 mg/ml), are the following:

Composition 1. The compound of example 1 to 50 mg.

Composition 2. The compound of example 1 50 mg

Glycine - 31 mg

Other specific examples of compositions are the same as above, but containing instead of the compound of example 1, any other compound of examples 2 to 37.

The person should be taken of the composition of the invention in normal cases to combat infections caused by bacteria, in the usual way, as is customary for imipenem (imipenem), if possible, their preparation in dosage forms with a level of efficiency and duration of action of the compounds of the present invention, comparable to the characteristics of the clinical use of imipenem. Thus, each patient must take daily intravenously, subcutaneously or intramuscularly at a dose of from 0.05 to 5.0 g (preferably from 0.1 to 2.5 g) compounds of the invention, and compomising dose can be given a loading dose of a substance. Otherwise intravenous dose can be administered by continuous infusion over a period of time. Otherwise, each patient can receive a daily oral dose, this dose is roughly equivalent to the daily dose for parenteral administration. Thus, a suitable daily dose for oral administration is from 0.05 to 5.0 g of the compound of this invention, when receiving the composition from 1 to 4 times a day.

Another aspect of the present invention provides a method for producing compounds of formula (I) or their pharmaceutically suitable salts or hydrolyzable in vivo esters; the method includes removing the protection from the compounds of formula (V):

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where R2, R4and R5are as previously defined here (suitable R4and R5usually protected); -COOR6and-COOR7are carboxy, or protected carboxy; R8is the group R3or amino-protecting group; R9is hydrogen or amino protective group; R10is the group R1protected oxyethyl or protected by oximation; in the specified connection has at least one protective group, if necessary, the specified connection (i) transferred to pharmaceutically suitable is described in the literature or groups of groups, known in the art as suitable for the protection of the groups under consideration, and enter them in the usual way.

The protective group may be removed by any convenient method, as described in the literature or known to the experts-chemists, using the appropriate method to uninstall the protective groups; these methods are chosen so as to effectively remove the protective group with minimal disruption of other groups present in the molecule.

The compounds of formula (V) are novel and constitute another aspect of the invention.

Specific examples of the protective groups is given below for convenience, they are "lower" means that the group to which the applied protection, mainly has 1-4 carbon atoms. You need to understand that these examples are not exhaustive. Below are specific examples of methods for removing protective groups is not exhaustive. The use of protective groups and methods of removing protection, not specifically mentioned, is also included in the scope of the invention.

Carboxyl-protective groups may be the remains of forming an ester of an aliphatic or alifaticheskih alcohols or silanols (these alcohols or silanol preferably contain 1 to 20 and is, for example, isopropyl, tert-butyl); (lower alkoxy group)lower alkyl (e.g., methoxymethyl, ethoxymethyl, isobutoxide); (the lower aliphatic alloctype)lower alkyl (e.g., acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl); (lower alkoxycarbonyl-group)lower alkyl (e.g., 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); (aryl)lower alkyl (e.g., p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); three(lower alkyl)silyl (for example, trimethylsilyl and tert-butyldimethylsilyl); three(lower alkyl)silyl-lower alkyl (for example, trimethylsilylmethyl); and (2-6C)alkenyl (for example, allyl and vinylaryl).

Ways that are appropriate, in particular for removal of the carboxy-protective group include, for example, hydrolysis catalyzed by acid, base, metal or enzyme.

Examples of hydroxy-protective groups include the lower alkenyl (e.g. allyl); lower alkanoyl (for example, acetyl); lower alkoxycarbonyl (for example, tert-butoxycarbonyl); lower altneratively (for example, allyloxycarbonyl); aryl-lower alkoxycarbonyl (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzyloxy the emer, benzyl).

Examples of amino-protecting groups include formyl, aralkyl (for example, benzyl; substituted benzyl, e.g. p-methoxybenzyl, nitrobenzyl, 2,4-dimethoxybenzyl, triphenylmethyl); di-p-anselmetti and furylmethyl lower alkoxycarbonyl (for example, tert-butoxycarbonyl); lower alkenylbenzenes (for example, allyloxycarbonyl); (aryl)lower alkoxycarbonyl (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example, methylidene); benzyliden and replaced benzyliden.

Methods suitable for removing protection from hydroxyl and amino groups include, for example, hydrolysis catalyzed by acid, base, metal or enzyme; for such groups as the p-nitrobenzisoxazole - hydrogenation and for such groups as the o-nitrobenzisoxazole - photolysis.

Preferred protective groups for carboxy and hydroxyl in the compounds of formula (I) are allyl and p-nitrobenzyl. The preferred method of removal of the allyl group is on palladium catalysis using tetrakis(triphenylphosphine)palladium and acid Meldrum (Meld return or 1,3-dimethyl-2-oxo-tetrahydropyrimidin/tetrahydrofuran or in a mixture of ethanol/tetrahydrofuran, for example, isopropanol/tetrahydrofuran or ethanol/tetrahydrofuran, preferably at room temperature. Alternatively, instead of the acid Meldrum you can use methylaniline in dichloromethane. These conditions allow us to separate the product by precipitation of the sodium salt after the addition of such salts are sodium 2-ethylhexanoate sodium.

The preferred method of removing p-nitrobenzyloxy group is hydrogenation on a palladium catalyst.

Another aspect of the present invention to provide compounds of formula (I) and (V) as follows:

a) reaction of compounds of formula (VI) and (VII):

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where R2, R4- R10such as defined previously, and L is a leaving group, or

b) cyclization of the compounds of formula (VIII):

< / BR>
where

R2, R4- R10such as defined previously, and R11- R13independently selected from (C1-6)alkoxy group, aryloxy-, di(C1-6)-alkylamino and diarylamino groups, or two of R11- R13present-phenyleneoxy group, or one of R11- R13is (C1-4)alkyl, allyl, benzyl or phenyl and the other two are independently selected from (C1-4)alkyl, cryptorhynchinae group in the specified connection is usually protected; if you want, then (i) remove protective group; (ii) receive a pharmaceutically suitable salt; (iii) atrificial getting hydrolyzable in vivo broadcast.

Is appropriate to the compound of formula (VI) L was reactive ether or hydroxyl group, for example, sulfate (for example, (C1-6)alkanesulfonyl, tripterocalyx, benzosulfimide, toluensulfonate group); posteroexternal group (for example, diarylphosphino, such as diphenylphosphinoethyl) or L was a halogen (e.g. chlorine). In an alternative embodiment, L is sulfoxide group, for example, SOCH= CH-NHCOCH3that can be easily replaced. It is preferable diphenylphosphinoethyl group (-OP(O)(OPh)2).

The compounds of formula (VI) and methods for their preparation are well known in the literature on carbapenems (for example, European patents EP-A-126587, EP-A-160391, EP-A-243686 and EP-A-343499).

The reaction between the compounds of formula (VI) and (VII) is usually carried out in the presence of bases such as organic amines, for example, di-isopropylaniline or inorganic bases, for example, carbonates of alkali metals such as potassium carbonate. The reaction is conveniently carried out at a temperature of -2 is storytale, as acetonitrile or dimethylformamide. Usually the reaction is carried out in a manner analogous to those described in literature for such reactions.

The compound of formula (VII) is new and is another aspect of the present invention.

The compound of formula (VII) can be obtained by removing the protection of the compounds of formula (IX)

< / BR>
where R4- R6, R8and R9such as defined here above, and R14- protective group, for example, (C1-6)alkanoyl, (C1-6)alkoxycarbonyl or benzoyl. Preferred R14is acetyl or tert-butoxycarbonyl. The compound of formula (IX) can be converted to the compound of formula (VII) standard methods of removing protection, for example, acetyl group, you can remove the main hydrolysis in aqueous alkanol or alkenol, for example, allyl alcohol.

The compound of formula (IX) is new and is another aspect of the present invention.

The compound of formula (IX) can be obtained by the reaction of an activated derivative of a compound of formula (X), which can be obtained in situ with the compound of the formula (XI)

< / BR>
where R4-R6, R8, R9and R14such as defined previously, Activated pron-benzo[1,2,3]-triazole-1-yl, pentafluorophenyl and 2,4,5-trichlorophenyl or benzimidazole-2-yl and thiocarbonic acid, the corresponding (X). The reaction of compounds of formula (X) and (XI) is carried out by standard methods, for example, in the presence of the reagent of Vilsmeier (Vilsmeier reagent) (and thus, the reactive derivative of compound (X) in place) at a temperature in the range from -30 to 25oC, preferably from -20 to 5oC.

Compounds of formula (X) and (XI) are obtained by standard methods known to experts-chemists, such as the methods described in the examples hereafter, the methods described in EP-A-126587 or similar and similar ways.

Suitable R11- R13in the compounds of the formula (VIII) are substituents, independently selected from (C1-6)alkoxy groups such as methoxy, ethoxy, isopropoxy, n-propoxy or n-butoxy; aryloxy, for example, typically, phenoxy group; di(C1-6)alkylamino group, such as dimethylamino or diethylamino-; diarylamino group such as diphenylamino or any two of R11- R13the same and are (C1-6)alkoxy groups, e.g. methoxy, ethoxy, isopropoxy - or n-butoxy or phenoxy groups.

The compounds of formula (VIII) cyclist in normal usernam organic solvent, such as toluene, xylene or ethyl acetate at a temperature in the range from 60 to 150oC. Usually the reaction is carried out in nitrogen atmosphere and in the presence of acceptor radicals, for example, hydroquinone.

The compounds of formula (VIII) can be obtained and cilitate on the spot. The compounds of formula (VIII) is conveniently obtained by reaction of compounds of formula (XII) and formula (XIII):

< / BR>
where R2and R4- R13such as previously defined here. Suitable compounds of the formula (XIII) are the phosphites or functional equivalents of such compounds.

The reaction between the compounds of formulas (XII) and formula (XIII) is conveniently carried out in such organic solvents as toluene, xylene, ethyl acetate, chloroform, dichloromethane, acetonitrile or dimethylformamide. Usually the reaction is carried out at elevated temperature, for example, 60-150oC.

The compounds of formula (XII) can be obtained by many methods known in the art. For example, the compounds of formula (XII) can be obtained by acylation of compounds of formula (XIV):

< / BR>
where R2, R4- R6and R8- R10such as defined previously, with a compound of formula (XV)

C1-CO-COOR7(XV)

where R7such as previously defined here.

2and R10such as defined here above. The compounds of formula (XVI) are known in the art and can react with compounds of the formula (VII) under known conditions of acylation.

Compounds of formula (VII), (XII) and (XIV) are novel and form another aspect of this invention.

The following biological test methods, data and examples serve to illustrate the present invention.

Antibacterial activity. Pharmaceutically suitable carbapenems connection of the present invention are useful antibacterial agents with broad spectrum of activity in vitro against standard laboratory microorganisms: as gram-negative and gram used to detect activity against pathogenic bacteria. The spectrum of antibacterial activity and efficacy of the individual compounds can be determined in standard test systems. In particular, carbapenems of the present invention show good stability against beta-lactams and are especially good half-life of mammals. Mainly compounds demonstrate significant advantages compared with imipenem.

Antibes>/P>Found that usually join carbapenem are relatively non-toxic to warm-blooded animals, and this generalization is valid for compounds of the present invention. Compounds represented by the present invention, was administered to mice in doses exceeding the amount needed to protect against bacterial infections, whilst there was no evidence of excessive intoxication symptoms or side effects that accompany the introduction of these compounds.

The following results were obtained for the compounds in the standard test system in vitro, using Diagnostic Sensitivity Test (diagnostic test sensitivity). Antibacterial activity is described in terms of the minimum inhibition concentration (MIC) determined by the method of dilution agar (agar-dilution technique with an inoculum of 104cells/spot (colony forming units - CFU)/spot (PL. 1)

Examples:

(a) NMR spectra were obtained at 200 MHz or 400 MHz;

(b) "Aryloxy" means propen-1-yloxy-group-OCH2CH = CH2;

(C) THF refers to tetrahydrofuran;

(g) DMF refers to dimethylformamide;

(d) acid Meldrum is 2,2-dimethyl-1,3-dioxane-4,6-dione;

(e) evaporation dissolve bonyl-2-ethoxy-1,2-dihydroquinoline;

(and) DMSO refers to dimethylsulfoxide;

(K) DXI denotes dicyclohexylcarbodiimide and

(l) the position of the peaks in the NMR spectra of solutions in DMSO and acetic acid-d4varies depending on the ratio of DMSO and acetic acid.

Example 1. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3- carboxy-5-oxiranylmethyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid.

To a solution of allyl (1R,5S,6S,8R,2'S,4'S)-2-(1 - allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate (500 mg, 0,72 mm) and 2,2-dimethyl-1,3-dioxane-4,6-dione (acid Meldrum, 829 mg, 5,75 mm) in a mixture of DMF (8 ml) and THF (4 ml) in an argon atmosphere add tetrakis(triphenylphosphine)-palladium (83 mg, 0,072 mm). The solution is stirred under argon and protected from light for 2 hours the Solution was diluted with diethyl ether (40 ml) and the precipitate centrifuged, the supernatant is separated. The product is washed, re-suspending in ethyl ether, followed by centrifugation and finally dried in high vacuum. The crude product is dissolved in water (10 ml) and pH adjusted to 6.8 by adding NaHCO3. After filtering the solution chromatographic resin Diaion CHP20P and collect FR the memorial plaques of 1.18 (d, 6H); to 1.82 (m, partially closed, 1H); and 2.79 (m, 1H); 3,03 (DD, 1H); up 3.22 (DD, 1H); 3,38 (quintet, 1H); 3,57 (DD, 1H); 3,82 (quintet, 1H); 3,99 (quintet, 1H); 4,19 (DD + m, 2H); 7,13 (t, 1H); 7,44 (t, 1H); the 7.65 (t, 1H).

The initial substance was obtained as follows.

Allyl-3-allyloxy-5-aminobenzoate. 3-Hydroxy-5-nitrobenzoic acid (3.9 g, 21.3 mm) dissolved in DMF (55 ml), added with stirring anhydrous K2CO3(11,78 g, 76.5 mm). Enter allylbromide (5,4 ml, 62,4 mm) and the mixture stirred for 18 h at room temperature. The solvent is removed by evaporation, the residue is treated with water, pH adjusted to 5.5, the product is extracted with ethyl acetate. The combined extracts washed with water NaH2PO4, with water, with brine and dried over MgSO4. The residue after evaporation chromatographic on silicon dioxide, elwira a mixture of petrol/EtOAc (10:1) to give allyl-3-allyloxy - 5-nitrobenzoate (5,94 g, 90%).

NMR (CDCl3): M. D. of 4.66 (dt, 2H); 4,87 (dt, 2H); 5,31-5,52 (m, 4H); 5,94-6,14 (m, 2H); 7,92 (m, 2H); 8,46 (t, 1H).

Ms(Cl) (mass spectrum with chemical inertia): 264 (MH)+.

The above ester (2 g, 7.6 mm) dissolved in ethyl acetate (15 ml) and added dropwise to a suspension of SnCl22H2O (13,7 g, 61 mm) in ethyl acetate (35 ml), heated under reflux under argon is l). The organic layer is separated and make three successive extraction with ethyl acetate. The combined extract washed with diluted ammonia solution, water and saline solution, dried over MgSO4that is evaporated, receiving a yellow oil allyl-3-allyloxy-5-aminobenzoate (1,53 g, 86%).

NMR (CDCl3): M. D. of 3.60 (broad, 2H); 4.53-in (dt, 2H); 4,78 (dt, 2H); 5.25 to 5,44 (m, 4H); 5,96-6,12 (m, 2H); to 6.43 (dt, 1H); 7,00 (m, 2H).

Ms(Cl): 233 (MH)+.

Getting pyrrolidin-4-ylthioacetate in the side chain. Salt cyclohexylamine and 4 acetylthio-1-allyloxycarbonyl-2-carboxy-pyrrolidine (5.6 g, 15 mm) is suspended in ethyl acetate and intensively shaken with 2M HCl (20 ml and 10 ml), water and salt solution, an ethyl acetate layer is dried over MgSO4. Evaporation gives the free acid. The reagent of Vilsmeier cook, affecting dimethylformamide (0.51 ml, 6,6 mm) in dichloromethane (20 ml) oxalylamino (0,52 ml, 6 mm) in dichloromethane (20 ml) under argon. 4 Acetylthio-1-allyloxycarbonyl-2-carboxypropyl (1.64 g, 6 mm) in dichloromethane (7 ml) is added to the reagent in one piece, then add N-methylmorpholine (0,79 ml, 7.2 mm) in dichloromethane (3 ml), stirring is continued for 30 min at -10oC. After cooling to -20oadd drop by drop allyl-3-and the re allowed to rise to 0othe reaction continued for 18 hours After dilution with dichloromethane (100 ml) the mixture was washed with 2M HCl, water and saturated solution of NaHCO3, dried over MgSO4and evaporated. The crude substance is cleaned chromatography on silica at normal pressure, using gradient elution with a mixture of petrol/dichloromethane (3:1 to 2:1) to give (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxy-5-allyl - externalfilename)pyrrolidin-4-ylthioacetate resin (2.37 g, 81%).

NMR (CDCl3): M. D. 2,32 (s, 3H); 2,58 (broad, 2H); 3,39 (DD, 1H); is 4.03 (quintet, 1H); 4,13 (DD, 1H); 4,55 (t, partially, 1H); 4,58 (dt, 2H); and 4.68 (dt, 2H); to 4.81 (dt, 2H); 5,23-5,49 (m, 6H); of 5.84-x 6.15 (m, 3H); of 7.36 (t, 1H); EUR 7.57 (t, 1H); 7,66 (t, 1H); 9,10 (broad, 1H).

Ms (+ ve FAB): 489 (MH)+, 511 (M+Na)+.

Conversion in pyrrolidin-4-intialy. (2S,4S)-4-acetylthio-1 - allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonyl)pyrrolidin (1.89 g, 3.9 mm) was dissolved in allyl alcohol (25 ml) and the solution is rinsed with argon. Add 1 M sodium hydroxide (4 ml, 4 mm), the mixture is stirred at room temperature for 2 h and then evaporated to dryness. The residue is transferred into ethyl acetate (100 ml), washed with 2M HCl, water, NaHCO3salt solution, dried with MgSO4and evaporated, receiving (2S,4S)-1 - allyloxycarbonyl result at the next stage.

Receive secure carbapenems. Allyl (1R, 5S,6S,8R)-6- (1-oxyethyl)-1-methyl-2-difenilfosforilatsetamidnymi-3-carboxylate (1.5 g, 3 mm) was dissolved in dry acetonitrile (18 ml) under argon, cooled to -20oand add diisopropylethylamine (0.63 ml, 3.6 mm), then drop by drop add (2S, 4S)-1-allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonyl)pyrrolidin-4-ILTER (1,57 g, 3.5 mm) in acetonitrile (12 ml). The reaction mixture was then incubated at -20owithin 3 days. The solvent is evaporated and the residue is cleaned chromatographic under normal pressure on silica in a gradient elution (dichloromethane/ethyl acetate) from 40:60 to 70: 30, getting allyl(1R, 5S,6S,8R,2'S,4'S)-2-(1 - allyloxycarbonyl-2-(1-allyloxycarbonyl-2-(3-allyloxy-5 - allyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylate in the form of resin (1.25 g, 60%).

NMR (CDCl3): M. D. of 1.23 (d, 3H); to 1.35 (d, 3H); to 2.65 (broad, 2H); 3,26, and 3.31 (DD overlapping m, 2H); 3.46 in (m, 1H); 3,79 (quintet, 1H); 4,01 (DD, 1H); 4,19-the 4.29 (m, 2H), 4,50-4,78(m, 9H); 5,19-5,46 (m, 8H); of 5.83-6,12 (m, 4H); of 7.36 (broad, s, 1H); to 7.64 (m, 2H); 9,00 (broad, 1H).

Ms (+ ve FAB): 696 (MH)+, 718 (M + Na)+.

Allyl(1R, 5R, 6S, 8R)-6-(1-oxyethyl)-1-methyl-2 - diphenylphosphoryl-carbapenem-3-carboxylate field), cooked on the place of the allyl-2-diazo-3-oxo-4-methyl-4-(3-(1-oxyethyl)-2-oxoazetidin - 4-yl)butanoate and octanoate rhodium (for example, EP-A-208889), and diisopropylethylamine (1.1 equivalent) in acetonitrile at 0oC in argon atmosphere was added drop diphenylchlorophosphine (1.1 equivalent). The solution was stirred at room temperature for 30 min for the formation of the corresponding 2-difenilfosforilatsetamidnymi. In addition, we have received the following examples (table. 2).

Example 2. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2- (2-(3-carboxy-4-chlorpheniramol)pyrrolidin-4-ylthio)-6-(1 - oxyethyl)-1-methylcarbamoyl-3-carboxylic acid get in the usual way, similar to that described in example 1, except that after addition of the palladium catalyst solution was gently heated to dissolve the catalyst and stirred in an argon atmosphere, protect from light for 1 h Add a solution of 2-ethylhexanoate sodium in THF and the combined solution was poured into THF under vigorous stirring. The precipitate and centrifuged to separate the supernatant. The product is washed twice, re-suspending in THF, then centrifuged and finally dried in a high vacuum, receiving the specified connection.

Ms (+ve FAB): 532/534 (MH)+, (Na salt)+, 554/556 (Na2Sol)+.

The initial substance was obtained as follows.

Allyl ester 2-chloro-5-nitrobenzoic acids are extracted as in example 1 except that the solvent in the final extraction is toluene.

NMR (CDCl3): M. D. 4,89 (dt, 2H); 5,33-5,51 (m, 2H); 5,96-x 6.15 (m, 1H); 7,66 (d, 1H); of 8.27 (DD, 1H); 8,72 (d, 1H).

Ms(Cl) : 241/243 M+, 259/261 (M + NH4)+.

The chloride dihydrate tin refluxed in ethanol under argon, getting a solution. The heating is stopped and the above nitrosoaniline placed in ethanol. Then continue boiling under reflux for 3 h, the mixture is cooled and removed the solvent. The residue is dissolved in ethyl acetate and treated with 880 ammonia to the main reaction. The organic phase is decanted from the precipitated salts of tin, and the pasty residue is re-extracted in a similar way with a large amount of solvent. Then the combined organic phases are washed with diluted ammonia solution, water and saline solution, then); to 4.81 (dt, 2H); 5,27-vs. 5.47 (m, 2H); 5,93-6,13 (m, 1H); 6.73 x (DD, 1H); to 7.15 (d, 1H); from 7.24 (d, 1H).

Ms(C1): 212/214 M+, 229/231 (M + NH4)+.

The above amine condensed with Proline (pyrrolidin--carboxylic acid) as described in example 1, purified chromatography using gradient elution with a mixture of dichloromethane/diethyl ether (100:0 to 95: 5) to give (2S, 4S)- 1-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-chlorpheniramol)- pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.33 (s, 3H); 2.57 m (broad, 2H); 3,39 (DD, 1H); is 4.03 (quintet, 1H); 4,13 (DD, 1H); 4,55 (t, 1H); of 4.66 (dt, 1H); of 4.66 (dt, 2H); a 4.83 (dt, 2H), 5,24-vs. 5.47 (m, 4H); 5,85-of 6.02 (m, 2H); of 7.36 (d, 1H); of 7.70 (DD, 1H); a 7.92 (d, 1H); to 9.32 (broad, 1H).

Ms(+ve FAB): 467/469 (MH)+, 489/491 (M + Na)+.

The above thioacetate will deacetylated to thiol, and condensed with carbapenemases as in example 1, peeling chromatography, using a gradient elution from dichloromethane to ethyl acetate) to give allyl(1R,5S,6S, 8R, 2'S, 4'S)-2-(1-allyloxycarbonyl-4 - chlorpheniramol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); of 1.36 (d, 3H); to 2.65 (broad, 2H); 3.25 to (DD overlapping m, 2H); of 3.48 (m, 1H); of 3.80 (quintet, 1H); 3,98 (DD, 1H); 4,20-or 4.31 (DD, overlapping with the quintet, 2H); to 4.52 (t, 1H); 696/698 (M + Na)+.

Example 3. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(5- carboxy-2-chlorpheniramol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid get, using the method of example 2.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.16 (d, 3H); to 1.19 (d, 3H); to 1.82 (m, closed, 1H); 2,70 (DD overlapping m, 2H); up 3.22 (DD, 1H); 3,35-3,60 (overlapping m, 3H); 3.95 to 4,08 (overlapping m, 2H); to 4.16 (DD, 1H); EUR 7.57 (d, 1H); of 7.69 (DD, 1H); at 8.36 (d, 1H).

Ms (+ve FAB): 532/534 (MH)+, (Na salt)+, 554/556 (Na2Sol)+.

The parent compound was obtained as follows.

Allyl ether 4-chloro-3-nitrobenzoic acid get in much the same way as described in example 1.

NMR (CDCl3): M. D. a 4.86 (d, 2H); 5,31-of 5.48 (m, 2H); 5,94-6,13 (m, 1H); 7,50 (d, 1H); 8,18 (DD, 1H); charged 8.52 (d, 1H).

Ms(Cl) : 241/243 M+, 259/261 (M + NH4)+.

The recovery obtained above nitro compound by the method of example 2 gives the allyl-3-amino-4-chlorobenzoate.

NMR (CDCl3): M. D. 4,08 (broad, 2H); 4,79 (dt, 2H); 5.25 to 5,44 (m, 2H); of 5.92-6,11 (m, 1H); 7,30 (d, 1H); 7,38 (DD, 1H); 7,47 (d, 1H).

Ms(Cl) : 212/214 M+, 229/231 (M + NH4)+.

The result of the above amine condensed with Proline as in example 1, purified chromatographically using hail oxycarbonyl-2 - chlorpheniramol)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. 2,32 (s, 3H); 2,56 (broad, 1H); 2,66 (broad, 1H); 3.43 points (DD, 1H); Android 4.04 (quintet, 1H); to 4.16 (DD, 1H); br4.61 (t, 1H); of 4.66 (dt, 2H); 4,82 (dt, 2H); to 5.21-of 5.45 (m, 4H); of 5.84-6,11 (m, 2H); was 7.45 (d, 1H); to 7.77 (DD, 1H); of 9.00 (d, 1H); remaining 9.08 (broad, 1H).

Ms (+ve FAB): 467/469 (MH)+, 489/491 (M + Na)+.

The resulting thioacetate decelerat to thiol, and condensed with carbapenemases as in example 1, purified chromatography, using a gradient elution from dichloromethane to ethyl acetate) to give allyl(1R,5S,6S,8R,2'S, 4'S)-2-(1-allyloxycarbonyl-2-(5 - allyloxycarbonyl-2-chlorpheniramol)-pyrrolidin-4-ylthio)-6-(1 - oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.23 (d, 3H); of 1.36 (d, 3H); to 2.65 (broad, 2H); 3.24 in (DD overlapping m, 2H); 3,88 (quintet, 1H); 4,08 (m, 1H); 4,19-4,30 (DD, overlapping with the quintet, 2H); 4,60 (t, 1H); of 4.67 (m, 4H); 4,82 (dt, 2H); 5,18-of 5.45 (m, 6H); of 5.82-6,01 (m, 3H); 7,44 (d, 1H); 7,76 (DD, 1H); 9,04 (d, 1H); 8,98 (broad, 1H).

Ms (+ve FAB): 674/676 (MH)+, 696/698 (M + Na)+.

Example 4. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2- (2-(3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-(1 - methylcarbamoyl-3-carboxylic acid get, using the method of example 2, except that a mixture of DMCO and THF.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.18 (d, 6H); 1.9 to whom, 1H); 7,71 (d, 1H); 7,86 (d, 1H); of 8.27 (s, 1H).

Ms (+ve FAB): 498 (MH)+, (Na salt)+, 520 (Na2Sol)+.

The parent compound was obtained as follows.

Allyl ester 3-nitrobenzoic acids are extracted as in example 1 except that the final extraction was carried out in diethyl ether.

NMR (CDCl3): M. D. 4,88 (d, 2H); 5,33-5,49 (m, 2H); 5,96-of 6.17 (m, 1H); 7,66 (t, 1H); to 8.41 (TD, 2H); 8,88 (t, 1H).

The recovery obtained above nitro compound by the method of example 2 (except that the solvent is methanol) gives the allyl-3-aminobenzoate.

NMR (CDCl3): memorial plaques to 3.38 (broad, 2H); 4,79 (dt, 2H); 5,24-5,44 (m, 2H); 5,93-6,09 (m, 1H); 6,86 (DM, 1H); 7,21 (t, 1H); 7,37 (t, 1H); was 7.45 (dt, 1H).

Getting pyrrolidin-4-ylthioacetate in the side chain. (2S,4S)-4 - Acetylthio-1-allyloxycarbonyl-2-carboxypropyl (2,54 g, 9.3 mm), allyl-3-aminobenzoate (1.5 g, 8.5 mm) and 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (2,72 g, 11 mm) dissolved in toluene (50 ml) and stirred at room temperature for 18 hours, the Reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2M HCl (3 times 30 ml), water, saturated NaHCO3and salt solution. Drying over MgSO4and evaporation to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3 - ASS="ptx2">

NMR (CDCl3): M. D. 2,32 (s, 3H); 2,60 (broad, 2H); 3.40 in (DD, 1H); is 4.03 (quintet, 1H); 4,13 (DD, 1H); of 4.57 (t, 1H); of 4.66 (dt, 2H); 4,82 (dt, 2H), 5,23 - 5,46 (m, 4H); 5,86 - 6,12 (m, 2H); 7,41 (t, 1H); of 7.82 (d, 1H); to $ 7.91 (d, 1H); 8,07 (t, 1H); 9,18 (broad, 1H).

The above thioacetate will diacetylenic to thiol, and condensed with carbapenemases as in example 1, purified chromatography, using a gradient elution from dichloromethane to a mixture of ethyl acetate/dichloromethane 1:1) to give allyl(1R, 5S,6S,8R,2'S,4'S)-2- (1-allyloxycarbonyl-2-(3-allyloxycarbonyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); of 1.36 (d, 3H); 2,64 (broad, 2H); 3,26, 3,28 (overlapping DD and m, 2H); of 3.48 (m, 1H); 3,81 (quintet, 1H); 4,01 (DD, 1H); 4,22 - 4,32 (m, 2H); of 4.54 (t, 1H); to 4.62 - 4.75 in (m, 4H); 4,82 (m, 2H); 5,19 - of 5.45 (m, 8H); of 5.82 - 6,10 (m, 4H); 7,41 (d, 1H); 7,81 (d, 1H); 7,92 (DM, 1H); 8,11 (t, 1H); 8,98 (broad, 1H).

Ms (+ve FAB): 640 (MH)+, 662 (M + Na)+.

Example 5. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3- carboxy-6-methanesulfonylaminoethyl)pyrrolidin-4-ylthio)-6-(1 - oxyethyl)-1-methylcarbamoyl-3-carboxylic acid is obtained from protected appropriately carbapenem as described in example 1.

NMR (DMCO-d6+ acetic acid - d4): M. D. of 1.20 (d, 6H); to 1.99 (quintet, 1H); to 2.75 (m, partially closed, 2H); of 7.90 (DD, 1H); 8.17 and (d, 1H); 9,00 (d, 1H).

Ms (+ve FAB): 554 (MH)+, 576 (Na salt)+, 598 (Na2Sol)+.

The parent compound was obtained as follows.

Allyl ether 4-methanesulfonyl-3-nitrobenzoic acids are extracted as in example 1, except that the crude product is cleaned chromatography on silica using a gradient elution from dichloromethane to a mixture of dichloromethane/diethyl ether 9:1) to give allyl-4-methanesulfonyl-3-nitrobenzoate.

NMR (CDCl3): M. D. of 3.45 (s, 3H); 4,90 (dt, 2H); 5,30 - 5,49 (m, 2H); 5,96 - 6,12 (m, 1H); 8,29 (d, 1H); 8,40 - 8,46 (m, 2H).

Recovery as described in example 1, except that the solvent is methanol, gives the allyl-3-amino-4 - metasulphobenzoate.

NMR (CDCl3): M. D. of 3.07 (s, 3H); 4,82 (dt, 2H); of 5.05 (broad, 2H), from 5.29 - 5,44 (m, 2H); 5,95 - 6,11 (m, 1H); 7,46 (m, 2H); 7,81 (d, 1H).

Ms (+ve FAB): 256 (MH)+, 273 (M + NH4)+.

The obtained amine condensed with Proline as in example 1, purified chromatography using gradient elution with mixtures of dichloromethane/diethyl ether (100:0 to 90:10) to give (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methanesulfonylaminoethyl)pyrrolidin-4-ylthioacetate.

Ms (+ve FAB): 511 (MH)+, 533 (M + Na)+.

The resulting thioacetate will deacetylated to thiol, and condensed with carbapenemases as in example 1, purified chromatography, using a gradient elution from dichloromethane to ethyl acetate) to give allyl (1R,5S,6S,8R, 2'S, 4'S)-2-(1-allyloxycarbonyl-2-(5 - allyloxycarbonyl-2-methanesulfonylaminoethyl)pyrrolidin-4 - ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): to 1.21 (d, 3H); to 1.35 (d, 3H); 2,43 (m, 1H); to 2.75 (broad, 1H); is 3.08 (s, 3H); 3,23 (DD overlapping m, 2H); 3,55 (DD, 1H); 3,85 - 4,08 (m, 2H); 4,19 - to 4.28 (m, 2H); 4.53-in - and 4.68 (m, 5H); a 4.86 (dt, 2H); 5.17 to - 5,47 (m, 6H); 5,79 - 6,12 (m, 3H); a 7.92 (DD, 1H); 8,00 (d, 1H); 9,16 (broad s, 1H); 10,14 (broad s, 1H).

Ms (+ve FAB): 718 (MH)+, 740 (M + Na)+.

Example 6. (1R, 5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-tortenelmebol)pyrrolidin-4 - ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid. To a solution of allyl(1R, 5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3 - allyloxycarbonyl-4-tortenelmebol)pyrrolidin-4-ylthio)-6-(1 - oxyethyl)-1-methylcarbamoyl-3-carboxylate (199 mg, 0.3 mm) and 2,2-dimethyl-1,3-dioxane-4,6-dione (acid Meldrum, 259 mg, 1.8 mm) in DMF (1.5 ml) in the atmosphere of argon added tetrakis(triphenylphosphine)palladium (Li (5 mg, 0,0045 mm) in THF (0.1 ml). After stirring for 30 minutes, add THF (3 ml) and ether (9 ml), the obtained solid residue is filtered off, washed with ether (9 ml), dried in a high vacuum, getting listed in the name of the product (72 mg, 49%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.30 (d, 6H); 2,00 (m, partially, 1H); 2.91 in (m, partially, 1H); of 3.13 (DD, 1H); to 3.36 (DD, 1H); 3,55 (d, square, 1H); to 3.73 (DD, 1H); 3,95 (m, 1H); of 4.12 (m, 1H); 4,29 (DD, 1H); 7,40 (DD, 1H); 7,98 (m, 1H); 8,32 (DD, 1H).

Ms (+ve FAB): 494 (MH)+, 516 (M + Na)+.

The initial substance was obtained as follows.

Allyl-5-amino-2-perbenzoate. 2-Fluoro-5-nitrobenzoic acid (4,16 g, 22.5 mm) dissolved in DMF (45 ml) and added under stirring anhydrous K2CO3(4,65 g, 33,7 mm). There pour in allylbromide (2.38 ml, 28.1 mm), the mixture is stirred for 18 h at room temperature, then poured into water (450 ml) and extracted with diethyl ether (3 100 ml). The combined extract is dried over MgSO4and evaporated, receiving a yellow oil (5.4 g). The oil is cleaned chromatography on silica, elwira a mixture of ethyl acetate/hexane (12,5 : 87,5) and get allyl-2-fluoro-5-nitrobenzoate (with 4.64 g, 92%).

NMR (CDCl3): M. D. 4,89 (d, 2H); 5,30 - of 5.50 (m, 2H); 5,90 - 6,10 (m, 1H); to 7.32 (t, 1H); scored 8.38 - 8,46 (m, 1H); 8,86 (DD, 1H).

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The obtained ether (2,47 g, 10,97 mm) dissolved in methanol (40 ml), add chloride dihydrate tin (of 9.89 g, 43,76 mm) in concentrated HCl (9 ml) to stir the solution at a temperature of from 5 to 15oC. Then the mixture is stirred over night at room temperature and poured into water (200 ml), neutralized solid NaHCO3(17,6 g) to pH 6. The mixture is extracted with chloroform (3 200 ml), the combined extract is dried over MgSO4and evaporated, getting allyl-5-amino-2-perbenzoate (2,09 g, 98%) as a yellow oil.

NMR (CDCl3) memorial plaques of 3.60 (broad s, 2H); 4,82 (dt, 2H); 5.25 - in of 5.48 (m, 2H); 5,93 - 6,12 (m, 1H); is 6.78 (DDD, 1H); 6,93 (DD, 1H); 7,20 (DD, 1H).

Ms(EI): 195 M+, (Cl): 196 (MH)+, 213 (M + NH4)+.

The result of the above amine condensed with Proline as in example 1. The product is cleaned chromatography on silica with elution with a mixture of ethyl acetate/hexane (42,5 : 57,5) to give (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-tortenelmebol) pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. 2,32 (s, 3H); 2,50 - 2,70 (broad s, 2H); 3.40 in (d, 1H); 3,98 - 4,20 (m, 2H); 4,56 (t, 1H); of 4.67 (dt, 2H); 4,84 (dt, 2H); 5,20 - of 5.50 (m, 4H); of 5.83 - 6,12 (m, 2H); 7,10 (DD, 1H); 7,80 - 7,89 (m, 1H); to 7.93 (DD, 1H); 8,90 - 9,40 (broad s, 1H).

Ms (+ve FAB): 451 (MH)+, 473 (M + Na)+< / BR>
Conversion Pyrrhus is of 1.33 g, 2,96 mm) was dissolved in allyl alcohol (30 ml) and the solution is rinsed with argon. Add 1 M sodium hydroxide (3.1 ml, 3.1 mm), the mixture is stirred at room temperature for 30 min, treated with acetic acid (0.3 ml), stirred for further 5 min and then evaporated to dryness. The residue is placed in ethyl acetate (60 ml), washed with saturated aqueous NaHCO3(60 ml), with brine, dried over MgSO4and evaporated, receiving (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-tortenelmebol) pyrrolidin-4-intial resin (1.07 g, 89%). The crude substance use in the next stage.

Thiol condense with carbapenemases as in example 1, the product is cleaned chromatography on silica, elwira a mixture of ethyl acetate/dichloromethane (75: 25) to give allyl(1R,5S,6S,8R,2'S,4'S)-2- (1-allyloxycarbonyl-2-(3-carboxy-4-forfinal-carbarnoyl)pyrrolidin - 4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

AMN (CDCl3): M. D. of 1.24 (d, 3H); to 1.35 (d, 3H); 2.40 a is 2.80 (broad, 2H); 3,24 of 3.28 (m, 2H); 3.40 in-to 3.58 (broad, 1H), 3,80 (d, kV, 1H), 3,99 (DD, 1H); 4,19-to 4.33 (m, 2H); 4.53-in (t, 1H); 4,59-of 4.77 (m, 4H); 4,77-4,88 (m, 2H); 5,17-5,50 (m, 6H); 5,80-6,13 (m, 3H); 7,10 (DD, 1H); 7,82-to 7.95 (m, 1H); 8,00 (DD, 1H); 8,70-to 9.20 (broad s, 1H).

Ms (+ve FAB): 658 (MH)+.

Example 7. (1R, 5S,6S,8R,2'S,4'S)-2- (2-(5-Carboxy-2-fluoro whom and with appropriate protection, as in example 6.

NMR (DMCO-d6+ acetic acid - d4) : M. D. of 1.30 (d, 6H); of 1.84 (m, 1H); 2,80-of 2.93 (m, 2H); to 3.36 (DD, 1H); to 3.58 (m, 1H); 3,66 (DD, 1H); 3,81 (m, 1H); 4.09 to (l, kV, 1H); is 4.21 (m, 1H); or 4.31 (DD, 1H); 7,56 (DD, 1H); 8,07 (m, 1H); of 8.90 (d, 1H).

Ms (+ve FAB): 494 (MH)+, 516 (M + Na)+.

The parent compound was obtained as follows.

Allyl-3-amino-4-perbenzoate. Allyl-4-fluoro-3-nitrobenzoate obtained from 4-fluoro-3-nitrobenzoic acid as described in example 6.

NMR (CDCl3): memorial plaques to 4.87 (dt, 2H); 5,48-5,32 (m, 2H); 5,95-6,14 (m, 1H); 7,40 (DD, 1H); 8,30 is 8.38 (m, 1H); 8,76 (DD, 1H).

Ms(EI) : 225 (M)+, (Cl): 225 M+, 243 (M + NH4)+.

The above connection restore basically as in example 2, except that the solvent used methanol, getting allyl-3-amino-4-perbenzoate.

NMR (CDCl3): M. D. 3,70 (broad, 2H); 4,79 (dt, 2H); 5.25 to 5,44 (m, 2H); 5,96-6,09 (m, 1H); 7,02 (DD, 1H); 7,41-rate of 7.54 (m, 2H).

Ms (EI) : 195 M+, (Cl) : 196 (MH)+.

The result of the above amine condensed with Proline as in example 1, purified product chromatography on silica using as eluent a mixture of ethyl acetate/hexane (50: 50) and receiving (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2-tortenelmebol) Pirro who 2H); 4,82 (dt, 2H); 5,2-5,5 (m, 4H); 5,8-x 6.15 (m, 2H); 7,16 (DD, 1H); 7,83 (DDD, 1H); 8,97 (DD, 1H); 9,27 (broad, 1H).

Ms(EI) 451 (MH)+, (Cl) : 451 (MH)+.

The above thioacetate will deacetylated to thiol, and condensed with carbapenemases as in example 6, and the product cleaned chromatography (elute with ethyl acetate) to give allyl-(1R, 5S, 6S, 8R,2'S,4'S)-2-(1-allyloxycarbonyl)-2-(5-allyloxycarbonyl - 2-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl - 3-carboxylate.

NMR (DMCO-d6+ acetic acid-d4): M. D. 1,90 (m, partially closed, 1H); 2,78 (m, 1H); up 3.22 (DD, 1H); 3,26 (m, 1H); to 3.52 (m, 1H); 3,83-a 4.03 (m, 2H); 4.09 to (DD, 1H); 4,22 (m, 1H); 4.53-in (m, 1H); 4.53-in-the 4.65 (m, 4H); 4,80 (dt, 2H); of 5.05-5,43 (m, 6H); 5,73 is 5.98 (m, 2H); 5,98-6,09 (m, 1H); 7,38 (DD, 1H); for 7.78 (broad s, 1H); 8,49 (m, 1H); to 8.62 (d, 1H).

Ms (+ve FAB) : 658 (MH)+, 680 (M + Na)+.

Example 8. (1R,5S,6S,2'S,4'S)-2-(2- (3-Carboxy-2,4-differencematerialised-4-ylthio)- 6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid is obtained from carbapenem protected in an appropriate manner as in example 7.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.29 (d, 6H); 1,94 of 1.99 (m, partially closed, 1H); 2,81-of 3.07 (m, 1H); 3,05 (DD, 1H); 3,37 (DD, 1H); of 3.56 (m, 1H); 3.75 to (DD, 1H); to 3.92 (q, 1H); 4,10 (d, kV, 1H); 4,29-to 4.38 (m, 2H); 7,22 (m, 1H); 8,07 (m, 1H).

Ms (+ve FAB): 512 (MH)+, 534 (M + Na)+

NMR (CDCl3): M. D. 4,90 (dt, 2H); 5,33-of 5.50 (m, 2H); 5,95-6,03 (m, 1H); 7,09-7,27 (DDD, 1H); by 8.22-8,27 (DDD, 1H).

Ms(EI) : 244 (MH)+, (Cl): 261 (M + NH4)+.

The above ether restore, as in example 2, except that the solvent used methanol, getting allyl-3-amino-2,6-differentat.

NMR (CDCl3): M. D. a 4.86 (dt, 2H); 5,27-5,49 (m, 2H); 5,95-6,09 (m, 1H); 6,77-6,86 (m, 2H).

Ms(EI): 213 (M)+, (Cl): 214 (MH)+.

The result of the above amine condensed with Proline as in example 1, chromatographic clean, elwira a mixture of ethyl acetate/hexane (40:60) to give (2S, 4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-2,4-differencemaker) pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. 2,32 (s, 3H); 2,60 (broad, 2H); 3.40 in (DD, 1H); 3.95 to 4,19 (m, 2H); of 4.57 (t, 1H); of 4.67 (dt, 2H); a 4.86 (dt, 2H); 5,20-of 5.50 (m, 4H); 5,81-6,13 (m, 2H); to 6.95 (DDD, 1H); 8.4V (DDD, 1H); and 9.2 (broad, 1H).

Ms (+ve FAB): 469 (MH)+.

The above thioacetate will deacetylated to thiol, and condensed with carbapenemases as in example 6. The product is cleaned by chromatographytandem on silicon dioxide, elwira with ethyl acetate, getting allyl (1R,5S,6S,8R,2'S, 4'S)-2- (1-allyloxycarbonyl-2-(3-carboxy-2,4-differencemaker) pyrrolidin-4-ylthio)-6-(1-oxit is to 3.36 (m, 2H); 3,44 (DD, 1H); is 3.08 (q, 1H); of 4.05 (DD, 1H); 4,19-to 4.33 (m, 2H); 4,50-4,80 (m, 5H); a 4.86 (dt, 2H); 5.17 to-5,50 (m, 6H); of 5.82-6,10 (m, 3H); to 6.95 (dt, 1H); scored 8.38 (dt, 1H); 9,00 (broad, 1H).

Ms (+ve FAB): 676 (MH)+, 698 (M + Na)+.

Example 9. Chinatravel salt of (1R,5S,6S,8R,2'S,4'S)-2- (2-(3,4-dicarboxylicacid)pyrrolidin-4-ylthio)-6-(1-oxyethyl) - 1 methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that a mixture of DMCO and THF.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.18 (d, 6H); of 1.84 (m, partially clear, 1H); 2,78 (m, 1H); to 3.02 (DD, 1H); 3,23 (DD, 1H); 3.40 in (quintet, 1H); to 3.58 (DD, 1H); 3,83 (quintet, 1H); 4,00 (quintet, 1H); 4,20 (DD overlapping m, 2H); a 7.92 (DD, 1H), 8,17 (d, 1H), 8,33 (d, 1H).

Ms (+ve FAB): 542 (MH)+, (Na salt), 564 (Na2Sol)+.

Educt receive the following way.

Allyl ester of 2-carboxy-4-nitrobenzoic acid get, as in example 1.

NMR (CDCl3): M. D. is 4.85 (dt, 4H); from 5.29-vs. 5.47 (m, 4H); 5,91-6,12 (m, 2H); 7,88 (d, 1H); scored 8.38 (DD, 1H); 8,63 (d, 1H).

The recovery obtained above nitro compounds by the method according to example 2 and the cleaning chromatographytandem at normal pressure on silica using gradient elution with a mixture of dichloromethane/diethyl ether (100:0 to 90:10) to give allyl-2-allyloxy, H); 6.75 in (d, 1H); 7,74 (d, 1H).

The result of the above amine condensed with Proline as in example 1, chromatographic clean, with an average pressure on silica using a gradient elution from dichloromethane to 20% diethyl ether in dichloromethane) to give (2S, 4S)-1-allyloxycarbonyl-2-(3,4-diallylbarbituric)- pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. 2,32 (s, 3H); 2,59 (broad, 2H); 3,37 (DD, 1H); is 4.03 (quintet, 1H); 4,12 (DD, 1H); 4,56 (t, 1H); of 4.67 (d, 2H); 4,77 (t, 4H); a 5.25-5,42 (m, 6H); of 5.84-6,11 (m, 3H); 7,79 (m, 3H); 9,52 (broad, 1H).

The above thioacetate will deacetylases to the thiol, which condense without further purification with carbapenemases as in example 1, at the end of hold cleaning chromatographic method with an average pressure on silica using as eluent a mixture of dichloromethane/ethyl acetate 3:2, obtain allyl(1R, 5S, 6S, 8R,2'S,4'S)-2- (1-allyloxycarbonyl-2-(3,4-diallylbarbituric) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); to 1.35 (d, 3H); 2,62 (broad, 2H); 3,26 (DD overlapping m, 2H); 3,47 (broad, 1H); 3,81 (quintet, 1H); of 3.97 (DD, 1H); 4,19-the 4.29 (overlapping m, 2H); 4.53-in (t, 1H); 4,62-4,82 (m, 8H); 5,19-5,44 (m, 8H); of 5.84-6,07 (m, 4H); of 7.82 (s, 3H); of 9.30 (broad, 1H).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.17 (d, 6H); 1,95 (m, closed, 1H); 2,87 (m, closed, 1H); 3,17 (DD, 1H); of 3.25 (DD, 1H); 3.42 points (dt, 1H); 3.75 to (DD, 1H); 3,99-of 4.05 (m, 2H); 4,22 (DD, 1H); to 4.33 (t, 1H); 6,76 (d, 1H); 7,56 (DD, 1H); of 7.97 (d, 1H),

Ms (+ve FAB): 492 (MH)+, 514 (M + Na)+.

The parent compound was obtained as a way.

Allyl ester 2-hydroxy-5-nitrobenzoic acid basically get as in example 1 except that the solvent in the last extraction is diethyl ether.

NMR (CDCl3): M. D. 4,82 (m, 4H); 5,26-of 5.55 (m, 4H); 5,97-6,13 (m, 2H); 7,49 (d, 1H); to 8.41 (DD, 1H); charged 8.52 (d, 1H).

The recovery obtained above nitro compounds by the method of example 2 except that the solvent is methanol, and alkalizing use the solution of NaHCO3get allyl-2-allyloxy-5-aminobenzoate.

NMR (CDCl3): M. D. of 3.23 (broad, 2H); 4.53-in (dt, 2H); 4,79 (d, 2H); to 5.21-5,49 (m, 4H); 5,93-6,14 (m, 2H); to 6.80 (m, 2H); 7,16 (d, 1H).

The result of the above amine condensed with Proline as in example 1, peeling chromatography using gradient elution with a mixture of dichloromethane/diethyl ether (100:0 to 85:15) to give (2S, 4S)-is R (CDCl3): M. D. of 2.33 (s, 3H); 2,56 (broad, 2H); 3,39 (DD, 1H); 4,01 (quintet, 1H); 4,13 (DD, 1H); to 4.52 (t, 1H). 4,60 (dt, 2H); of 4.66 (m, 2H); to 4.81 (dt, 2H); 5,23-5,51 (m, 6H); 5,85-6,13 (m, 3H); 6,91 (d, 1H); 7,76 (DD, 1H); 7,81 (d, 1H); 8,97 (broad 1H).

The above thioacetate will deacetylated to thiol, and condensed with carbapenemases as in example 1, peeling chromatography, using a gradient elution from dichloromethane to ethyl acetate) to give allyl (1R,5S,6S, 8R, 2'S, 4'S)-2-(1-allyloxycarbonyl-2- (4-allyloxy-3-allyloxycarbonyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H): of 1.36 (d, 3H); 2.57 m (broad, 2H); 3.25 to, or 3.28 (DD overlapping quintet, 2H); 3,47 (broad, 1H); of 3.78 (quintet, 1H); 4,01 (DD, 1H); 4,18-4,27 (DD overlapping m, 2H); 4,51 (t, 1H); 4,58-4,79 (m, 6H); 4,79 (dt, 2H); 5,19-5,51 (m, 8H); of 5.83-6,12 (m, 4H); 6,93 (d, 1H); 7,79 (DD, 1H); a 7.85 (d, 1H); 8,88 (broad, 1H).

Ms (+ve FAB): 696 (MH)+, 718 (M + Na)+.

Example 11. (1R, 5S, 6S, 8R,2'S,4'S)-2-(2-(3,5- Dicarboxylicacid)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid is obtained by the method of example 1, except that the crude acid is of sufficient purity and does not require chromatography was carried out.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.15 (d, 6H): or 1.77 (m, partially closed, 1H); DD, 1H); 8,18 (t, 1H); to 8.45 (d, 2H).

Ms (+ve FAB): 520 (MH)+, 542 (M + Na)+.

The parent compound was obtained as a way.

Allyl ester of 3-carboxy-5-nitrobenzoic acids are extracted as in example 1, obtaining allyl-3-allyloxycarbonyl-5-nitrobenzoate.

NMR (CDCl3): M. D. 4,89-is 4.93 (m, 4H); 5,33-of 5.50 (m, 4H); 5,97-6,17 (m, 2H); 9,00 (t, 1H); 9,04 (d, 2H).

The recovery obtained above nitro compounds by the method of example 1 receive allyl-3-allyloxycarbonyl-5-aminobenzoate.

NMR (CDCl3): M. D. 3,91 (broad, 2H); 4.80 to 4,84 (m, 4H); 5,26-of 5.45 (m, 4H); 5,96-6,11 (m, 2H); 7,53 (d, 2H); of 8.09 (t, 1H).

The result of the above amine condensed with Proline as in example 1, to obtain (2S, 4S)-1-allyloxycarbonyl-2-(3,5 - diallylbarbituric)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. 2,33 (C. 3H); 2,60 (broad, 2H); 3.40 in (DD, 1H); is 4.03 (quintet, 1H); to 4.14 (DD, 1H); 4,58 (t, 1H); 4,65-4,70 (m, 2H); a 4.83-to 4.87 (m, 4H); 5,24-vs. 5.47 (m, 6H); of 5.84-6,16 (m, 3H); 8,39 (d, 2H); to 8.45 (t, 1H); 9,36 (broad, 1H).

The above thioacetate will deacetylated to thiol, and condensed with carbapenemases as in example 1, obtaining allyl(1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3,5 - diallylbarbituric)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylate.

Ms (+ve FAB): 724 (MH)+, 746 (M + Na)+.

Example 12. (1R,5S,6S,8R,2'S,4'S)-2-(2-(3- Carboxyphenylazo)-pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid. To a solution of 4-nitrobenzyl(1R, 5S,6S,8R,2'S,4'S)-2-(2-(3-allyloxycarbonyl)-1- (4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate (10 g, 12 mm) and acid Meldrum (5,2 g, 36 mm) in THF (70 ml) in an argon atmosphere add tetrakis (triphenylphosphine)palladium (1.4 g, 1.2 mm)protecting the solution from light. The mixture is stirred at room temperature for 30 minutes the Mixture is diluted with ethyl acetate (230 ml) and added to a solution of sodium bicarbonate (1.5 g) in distilled water (200 ml). Add 10% Pd on charcoal (4 g) and the mixture hydronaut in an atmosphere of hydrogen for 3 hours the Catalyst is filtered off, the filtrate is extracted with ethyl acetate (2 100 ml) and ether (2 100 ml), the aqueous layer was concentrated under reduced pressure to 250 ml. of This solution is divided into two portions and each cleaned 1 l HP20SS column using water as eluent. Purified fractions collected and dried by freezing, getting listed in the PTA-d4; the position of the peaks is sensitive to the ratio of solvent): memorial plaques to 1.19 (d, 6H); of 1.94 (dt, 1H); of 2.97 (dt, 1H); of 3.13 (DD, 1H); of 3.25 (DD, 1H); 3.42 points (dt, 1H); 3,68 (DD, 1H); 3,94 (quintet, 1H); was 4.02 (quintet, 1H); 4,22 (DD, 1H); 4,32 (t, 1H); 7,46 (t, 1H); 7,73 (dt, 1H); 7,88 (DM, 1H); of 8.27 (t, 1H).

Ms (+ve FAB): 498 (Na salt), 520 (di-Na salt).

The parent compound was obtained as follows.

Allyl ester 3-nitrobenzoic acid derived from 3-nitrobenzoic acid (50 g, 0.3 M) in the manner described in example 1. The acid in dry DMF (700 ml) is added under stirring solid K2CO3(82.7 g, 0.6 M). The reaction is slightly exothermic and the mixture thickens. After 30 minutes add allylbromide (38,8 ml, 0.45 M) and the mixture is stirred over night. After filtration through diatomaceous earth (kieselguhr) the solution is evaporated to dryness under reduced pressure and the residue is divided mixture of ether and aqueous NaHCO3. The ether layer is washed with diluted HCl, the salt solution and water, dried and evaporated, receiving a yellow oil (62 g).

NMR (DMCO-d6): M. D. 4,85 to 4.92 (m, 2H); 5,27 to 5.5 (m, 2H); 5,97 to 6.2 (m, 1H); a 7.85 (t, 1H); of 8.37 - 8,42 (dt, 1H); 8,48 - 8,54 (d, kV, 1H); 8,64 (t, 1H).

Without further purification this oil is reduced to allyl-3-aminobenzoate (53 g), using the chloride divalent tin of 6.1 (m, 1H); 6,83 - to 6.88 (m, 1H); 7,17 - 7,25 (m, 1H); 7,35 - 7,47 (m, 2H).

The above allyl-3-aminobenzoate (26,6 g, 0.15 M) condense with 4 acetylthio-1-(4-nitrobenzenesulfonyl)-2 - carboxyethylidene (55,2 g, 0.15 M) by suspension in toluene (750 ml), adding EACH (44,5 g, 0.18 M). The mixture is stirred overnight, diluted with EtOAc (2 l) and washed with diluted HCl, water and salt solution. EtOAc-phase is dried and evaporated, the residue is recrystallized from ethanol, receiving (2S,4S)-4-acetylthio-1- (4-nitrobenzenesulfonyl)-2-(3 - allyloxycarbonyl)pyrrolidin (67,7 g).

NMR (DMCO-d6): M. D. of 1.93 (quintet, 1H); 2,9 (m, 1H); to 3.35 (m, 1H); 3,91 - to 4.14 (m, 2H); 4,49 (quintet, 1H); to 4.81 (DD, 2H); 5,22 (DD, 2H); 5.2 to 5,44 (m, 2H); 5,95 - 6,10 (m, 1H); 7,47 (d, 2H); 7,66 (t, 2H); 7,8 - to 7.93 (m, 2H); 8,18 to 8.3 (m, 2H); 10,31 (s, 1H).

The above thioacetate (52.7 g; 0.1 M) converted into thiol, dissolving it in degassed allyl alcohol (1 l) and adding an aqueous solution of NaOH (2 M, 50 ml) at 0oC. After 3 hours, add aqueous HCl (2 M, 52,5 ml), the solution is evaporated and the residue is divided in a mixture of EtOAc and brine. EtOAc-phase is dried over MgSO4, filtered and evaporated. The thiol is used without additional purification. A solution of 4-nitrobenzyl-(1R,5S,6S,8R)-6-(1-oxyethyl)-1-methyl-2 - difenilfosforilatsetamidnymi-3-carboxylate (59,68 pelamin (52,5 ml). (2S,4S)-1-(4-Nitrobenzenesulfonyl)-2-(3-allyloxycarbonyl)pyrrolidin - 4-ILTER (0.1 M) is added to acetonitrile (400 ml) under argon and the mixture left overnight. The solvent is evaporated and the residue chromatographic on silicon dioxide, elwira with methylene chloride, EtOAc and acetonitrile, receiving 4-nitrobenzyl(1R,5S,6S,8R,2'S, 4'S)-2- (1-(4-nitrobenzenesulfonyl)-2-(3-allyloxycarbonyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate as yellow solid (52,6 g).

NMR (DMCO-d6+ CD3OD): M. D. of 1.26 (d, 3H); to 1.35 (d, 3H); 2,2 - 2,4 (m, 1H); 2,7 - 2,95 (m, 1H); 3,28 is 3.40 (m, 2H); 3,54 - 3,63 (m, 1H); and 3.8 (t, 1H); 4,01 - 4,1 (square 1H); 4,21 - to 4.33 (m, 2H); br4.61 (DD, 1H); to 4.73 (d, 2H); 5.17 to - the 5.45 (m, 6H); 5,93 - 6,11 (m, 1H); 7,37 is 8.22 (complex spectrum of d and DD, 12H).

Example 13. Unprotect and hydrogenation carried out in the same manner as described in example 12, except that use 4-nitrobenzyl(1R, 5S,6S,8R,2'S,4'S)-2-(3-allyloxycarbonyl - 5-carbarnoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3 - carboxylate (0,44 g). After hydrogenation of the aqueous layer was freeze dried, chromatographic on HP20SS, obtaining (1R, 5S, 6S, 8R,2'S,4'S)-2-(2-(3-carboxy-5-carbarnoyl)pyrrolidin-4 - ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid as light yellow firmly; 16 - a is 3.21 (m, 1H); 3,26 (DD, 1H); 3.43 points (quintet, 1H); 3,74 (DD, 1H); 3,91 - of 3.97 (m, 1H); 4.0 a (t, 1H); to 4.23 (DD, 1H); 4,39 (t, 1H); 8,24 (t, 1H); with 8.33 (t, 1H); 8,44 (t, 1H).

Educt receive the following way.

5-Nitroisophthalic acid (5 g) was transferred to a mono-allyl ether with one equivalent of allylbromide (2 ml) by the method similar to that described in example 1. The desired acid (2.7 g) is extracted from the organic layer using aqueous NaHCO3. The organic layer contains di-allyl ester (2.7 g). 3-allyloxycarbonyl-5-nitrobenzoyl mono-acid is obtained in the form of a white solid.

NMR (CDCl3): memorial plaques to 4.87 (d, 2H); 5,3 - 5,5 (q, 2H); 5,97 - x 6.15 (m, 1H); 9,01 (t, 3H).

Ms(Cl) : 252 (MH)+.

To the solution obtained above acid (1.5 g) and N-oxysuccinimide (0,76 g) in methylene chloride (50 ml) added DCCI (1.3 g) and the mixture is stirred at room temperature for 2 hours the White solid is filtered off and the solution evaporated to dryness. The active ester purified on silica gel, elwira with methylene chloride, if it is dissolved in methylene chloride and treated with gaseous ammonia at the 5oC. the Precipitated white solid is a 3-allyloxycarbonyl-5 - nitrobenzamide (1.1 g).

NMR (DMCO-d6): M. D. of 4.9 (dt, 2>)+.

3-Allyloxycarbonyl-5-nitrobenzamide (1 g) restore using SnCl2by the way, is similar to that described in example 12, receiving 3-allyloxycarbonyl-5-aminobenzamide (0.5 g).

NMR (DMCO-d6): 4,78 (dt, 2H); 5.2 to about 5.8 (broad, 2H); 5,26 - of 5.45 (m, 2H); 5,91 - 6,13 (m, 1H); 7,22 (broad s, 1H); 7,27 (t, 1H); 7,33 (t, 1H); to 7.59 (s, 1H).

Ms(Cl) : 221 (MH)+.

(2S, 4S)-4-Acetylthio-1-(4-nitrobenzenesulfonyl)-2 - carboxypropyl (0.75 g) was transferred to the acid chloride acid and carry out its reaction with 3-allyloxycarbonyl-5-aminobenzamide (0.45 g) by the method similar to that described in example 12. The crude product chromatographic on silica gel, elwira EtOAc and getting 4 acetylthio-1-(4-nitrobenzenesulfonyl)-2-(3-allyloxycarbonyl-5 - carbarnoyl)pyrrolidin (0,58 g).

NMR (DMCO-d6): M. D. 1,92 - to 2.06 (m, 1H); 2,3 (s, 3H); 2,79 - and 2.83 (m, 1H); to 3.38 (DD, 1H); 3,97 - 4,12 (m, 2H); of 4.49 (DD, 1H); of 4.83 (dt, 2H); 5,19 (DD, 2H); 5.25 to 5,43 (m, 2H); 5,97 - 6,11 (m, 1H); 7,31 (broad s, 2H); rate of 7.54 (d, 2H); of 8.04 (d, 2H); to 8.12 (t, 1H); compared to 8.26 (t, 1H); 8,31 (t, 1H); 10.0 g (s, 1H).

From the obtained above thioacetate get thiol as described in example 12.

A solution of 4-nitrobenzyl-(1R, 5S,6S,8R)-6-(1-oxyethyl)-1-methyl-2 - difenilfosforilatsetamidnymi-3-carboxylate (0.6 g) and (2S,4S)-1-(4-nitrobenzenesulfonyl)-2-(3-allylic is m, similar to that described in example 12. Purification are using the evaporative chromatography elwira EtOAc, then 5% MeOH/EtOAc, receiving 4-nitrobenzyl- (1R, 5S, 6S,8R,2'S,4'S)-2-(1-(4-nitrobenzenesulfonyl)-2- (3-allyloxycarbonyl-5-carbamoylbiphenyl)pyrrolidin-4 - ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate as yellow solid (0,44 g).

NMR (DMCO-d6): M. D. 1,19-1,22 (d, 6H); 2.0 to 2,11 (m, 1H); 2,8-of 2.92 (m, 1H); of 3.32 (DD, 1H); 3,42-3,62 (m, 2H); 3,92-4,2 (m, 2H); or 4.31 (broad d, 1H); 4.53-in (kV, 1H); 4,84 (d, 2H); 4,98 - 5,46 (m, 6H); 5,98-6,14 (m, 1H); 7,42-charged 8.52 (complex spectrum of d and DD, 11H).

Example 14. Unprotect and hydrogenation carried out in the same manner as described in example 12, except that use p-nitrobenzyl-(1R, 5S, 6S, 8R,2'S,4'S)-2-(2- (3-allyloxycarbonyl-6-carbamoylbiphenyl)-1- (4-nitrobenzenesulfonyl)-pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate. After hydrogenation of the aqueous layer was freeze dried, obtaining (1R,5S,6S,8R,2'S,4'S)-2- (2-(3-carboxy-6-carbamoylbiphenyl)pyrrolidin-4-ylthio) -6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid.

NMR (DMCO-d6+ acetic acid-d4): M. D. 1,3-1,38 (2D, 6H); 2.0 to 2,11 (m, 1H); 2,85-2,96 (m, 1H); to 3.09 (DD, 1H); 3,37 (DD, 1H); 3,53 (quintet, 1H); with 3.79 (DD, 1H); of 3.94 (t, 1H); 4.16 the (t, 1H); to 4.33 (DD, 1H); 4,43 (t, 1H); 7,87 (DD, 1H); 9,12 (d, 1HS="ptx2">

Nitroterephthalic acid (6,33 g) in methylene chloride (75 ml) and THF (15 ml) was transferred to a mono-acid chloride of the acid using oxacillin (2,63 ml), DMF (2.55 ml) and N-methylmorpholin (7,95 ml) at -10oC. After 1 h, removed the solvent and the product without further purification was dissolved in allyl alcohol (20 ml) and THF (10 ml), stirred at room temperature overnight. The solvent is removed and the residue is divided between EtOAc and aqueous NaHCO3. Acidification of the solution of NaHCO3and extraction with EtOAc to give the product 4-allyloxycarbonyl-2-nitrobenzoic acid (6.8 g).

NMR (CDCl3): M. D. 4,89 (d, 2H); 5,31-5,49 (m, 2H); 5,95-x 6.15 (m, 1H); 7,94 (d, 1H); at 8.36 (DD, 1H); to 8.45 (d, 1H).

Without treatment the acid transferred in the manner described above, the acid chloride of the acid, which is dissolved in THF (100 ml) at 0oC. In a solution propulsive gaseous ammonia until then, until the reaction. The solution is divided between EtOAc and water, the product from the organic fraction is purified silicon dioxide, elwira with methylene chloride, and then EtOAc. The product (4 g) containing a small amount of impurities, restore using SnCl2by the way, is similar to that described in example 12, receiving 4-allyloxycarbonyl-2-aminobenzamide.

NMR (DMCO-d6): M. D. the Nile)-2 - carboxypropyl (1,58 g) was transferred to the acid chloride acid by suspension in methylene chloride (25 ml) and add oxalicacid (1,52 ml). Add a few drops of DMF. After 2 h the solvent is evaporated and the acid chloride of the acid dissolved in methylene chloride (10 ml) and added under argon to a solution of 4-allyloxycarbonyl-2 - aminobenzamide (0.52 g) in THF (10 ml) and methylene chloride (5 ml) containing N-methylmorpholine (0,38 ml) at 0oC. the Reaction mixture was left overnight, and then divide between methylene chloride and dilute aqueous HCl solution. The fraction of methylene chloride is washed with water, with brine and dried. Cleaning is performed chromatography on silica, elwira solutions EtOAc in methylene chloride with increasing concentrations, get (2S, 4S)-4-acetylthio-1- (4-nitrobenzenesulfonyl)-2-(3-allyloxycarbonyl-6 - carbamoylbiphenyl)pyrrolidine (0.84 g).

NMR (CDCl3): M. D. of 2.25 (quintet, 1H); to 2.29 (s, 3H); and 2.83 (m, 1H); of 3.53 (DD, 1H); was 4.02 (quintet, 1H); 4,2 (DD, 1H); of 4.49 (DD, 1H); 4,85 (d, 2H); 5,23-5,46 (m, 2H); 5,97-6,13 (m, 1H); 7,31-7,5 (broad, 2H); EUR 7.57 (d, 1H); of 7.75 (DD, 1H); 7,81-of 7.95 (broad, 2H); 9,27 (d, 1H).

The thiol is obtained from the above thioacetate manner similar to that described in example 12.

A solution of 4-nitrobenzyl-(1R,5S,6S,8R)-6-(1-oxyethyl)-1-methyl-2 - difenilfosforilatsetamidnymi-3-carboxylate and (2S, 4S)-1- (4-nitrobenzenesulfonyl)-2-(2-carbarnoyl-5 - allyloxycarbonyl the ZIL-(1R, 5S, 6S, 8R,2'S,4'S)-2-(1- (4-nitrobenzenesulfonyl)-2-(3-allyloxy-3-carbonyl-6 - carbamoylbiphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate as a yellow foam (1.24 g).

NMR: 1,23-of 1.35 (m, 6H); 2,2-of 2.38 (m, 1H); 2.77-to of 2.93 (m, 1H); with 3.27 (DD, 1H); 3,28-of 3.42 (m, 1H); 3,65-to 3.92 (m, 2H); 4,17 is 4.35 (m, 3H); 4.53-in (t, 1H); of 4.83 (d, 2H); 4.92 in-5,44 (m, 6H); 5,93-6,11 (m, 1H); from 6.22 to 6.58 (broad, 2H); 7,35-8,23 (complex spectrum of d and DD, 10H); 9,20 (d, 1H).

Example 15. Removing protection and cleaning is performed by methods similar to those described in example 2 (chromatography of the final product is carried out on a column with HP2OSS), except that the use of allyl(1R,5S,6S,8R,2'S,4'S)-2- (1-allyloxycarbonyl-2-(2-dimethylaminoethyl-3 - allyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate. Suitable water fraction from the column is cleaned by freezing, obtaining (1R, 5S, 6S, 8R,2'S,4'S)-2-(2- (2-dimethylaminoethyl-3-carboxyphenylazo)pyrrolidin-4 - ylthio)-6-(1-oxyethyl) -1-methylcarbamoyl-3-carboxylic acid.

NMR (DMCO-d6+ acetic acid-d4, mixture of rotamers): M. D. of 1.17 (d, 6H); to 1.75 (m, 1H); 2,65, 2,72 (2C, block m, 4H); 3,00, 3,01 (2C, block m, 4H); 3,17 (DD, 1H); to 3.41 (quintet, 1H); 3,55 (m, 2H); 3.96 points (m, 2H); 4,15 (DD, 1H); the 7.43 (t, 1H); to 7.68 (m, 1H); 8,20-to 8.40 (2D, 1H).

The initial substance levy ether way similar to that described in example 1 to obtain allyl-3-allyloxy-5-aminobenzoate, it allyl-2-dimethylaminoethyl-3-nitrobenzoate (0.88 g).

NMR (DMCO-d6): M. D. of 2.45 (s, 3H); of 2.97 (s, 3H); 4,79 (DD, 2H); 5,28-vs. 5.47 (m, 2H); 5,9-6,1 (m, 1H); 7,81 (t, 1H); 8,28 an 8.4 (d, kV, 2H).

Ms(Cl) : 279 (MH)+.

Allyl ether (0,44 g) restore the chloride of divalent tin in the same manner as described in example 1, obtaining allyl-2 - dimethylaminoethyl-3-aminobenzoate (0,41 g) as a clear red oil.

NMR (CDCl3): M. D. 2,24 (s, 3H); to 3.06 (s, 3H); to 3.64 (broad, 2H); and 4.68 (DD, 2H); 5.17 to lower than the 5.37 (m, 2H); of 5.82-of 6.02 (m, 1H); 6,83 (DD, 1H); 7,09-6,85 (m, 1H); 7,37 (DD, 1H).

Ms(Cl) : 249 (MH)+.

Allyl-2-dimethylaminoethyl-3-aminobenzoate (0.39 g, 1.4 mm) condensed with (2S,4S)-4-acetylthio-1-allyloxycarbonyl - 2-carboxyethylidene (0,42 g, 1,54 mm), using a method similar AEDH the method described in example 12, to obtain (2S, 4S)-1-allyloxycarbonyl-2-(2-dimethylaminoethyl-3 - allyloxycarbonyl)pyrrolidin-4-ylthioacetate (0.84 g).

NMR (CDCl3, mixture of rotamers): M. D. 2,32 (s, 3H); of 2.38 (broad m, partially closed, 1H); 2,74, was 2.76 (2c covers a broad m, 4H); 3,11, 3,14 (2s, 3H); 3,36 is-3.45 (m, 1H); 3,98-to 4.14 (m, 2H); 4,50 (DD, 1H); 4,56-4,79 (m, 4H); 5,16-5,44 (m, 4H); 5,93-the 6.06 (m, 2H); was 7.45 (t, 1H is thioacetate way similar to that described in example 12.

A solution of allyl-(1R, 5S, 6S,8R)-6-(1-oxyethyl)-1 - methyl-2-difenilfosforilatsetamidnymi - 3-carboxylate (0.73 g, 1,47 mm) and (2S,4S)-1-allyloxycarbonyl)-2- (2-dimethylaminoethyl-3 - allyloxycarbonyl)pyrrolidin-4-itiola in acetonitrile (12 ml) is reacted in a manner similar to described in "obtaining protected carbapenems in example 1, get allyl-(1R, 5S, 6S, 8R,2'S,4'S)-2-(1-allyloxycarbonyl-2- (2-dimethylaminoethyl-3 - allyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate as a white solid (0,63 g).

NMR (CDCl3, mixture of rotamers): M. D. of 1.24 (d, 3H); to 1.35 (2D, 3H); 1,98 (broad, 1H); 2,34 (broad, 1H); 2,73 (c, 3H); 3,11, 3,13 (2s, 3H); 3,22-of 3.46 (m, 3H); 3,66-of 3.85 (m, 1H); 4,00-4.26 deaths (m, 3H); 4,50 (t, 1H); 4,62-4,80 (m, 6H); 5.08 to 5,46 (m, 6H); of 5.83-the 6.06 (m, 3H); 7,46 (TD, 1H); 7,86 (d, 1H); 8,29 (m, 1H); 8,55 (broad, 1H).

Ms (Cl): 711 (MH)+.

Example 16. Diclina salt of (1R,5S,6S,8R,2'S,4'S)-2-(2- (3-carboxy-5-acetaminophenramadol)pyrrolidin-4-ylthio)- 6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid. To a solution of 4-allyl-(1R, 5S,6S,8R,2'S,4'S)-2- (1-(4-nitrobenzenesulfonyl)-2-(3-carboxy-5 - acetaminophenramadol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate (0.4 g, 0.53 mm) in DMF (20 ml) douaud for 1 h at room temperature. After 1 h the solution was added a solution of 1 M califofnia buffer (20 ml) and powdered zinc (0.5 g) at room temperature, the reaction mixture is filtered through diatomaceous earth and bring the pH to 7.5 by adding potassium carbonate. The solution is filtered, concentrated under reduced pressure, the obtained residue is cleaned by way of reverse-phase chromatography (Nucleosil C18), using water as eluent, get mentioned in the title compound after freeze drying (78 mg, 28%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.15 (d, 3H); of 1.17 (d, 3H); 1,74 (m, 1H); to 2.06 (s, 3H); 2,84 (m, 1H); 3,20 (DD, 1H); 3.40 in (m, 2H); 3,70 (m, 1H); of 3.97 (m, 2H); to 4.16 (DD, 1H); 7,92 (s, 1H); 8,19 (s, 1H).

Educt receive the following way.

A solution of (2S, 4S)-4-acetylthio-2-carboxy-1- (4-nitrobenzenesulfonyl)pyrrolidine (1 g, 1.8 mm) and EACH (0,53 g, 3 mm) in chloroform (70 ml) is stirred for 1 h at room temperature. Then there is added 3-acetamido-5-aminobenzoic acid (0,53 g, 2.7 mm) and diisopropylethylamine (0.7 ml, 4 mm), the reaction mixture is stirred for 2 h at room temperature. After evaporation of the solvent the crude compound clean chromatography on HP20SS, using as eluent a mixture of methanol/water (80: 20). Partial viparis the l) pyrrolidin-4-ylthioacetate (1 g, 67%).

(2S, 4S)-1-(4-Nitrobenzenesulfonyl)-2- (3-carboxy-5-acetaminophenramadol) pyrrolidin-4-ylthioacetate dissolved in a mixture of methanol (60 ml) and water (20 ml), the pH of the solution was adjusted to 11 with aqueous solution of NaOH (1 M). After 30 min at room temperature, the reaction mixture was neutralized with methanol, the solvent is evaporated and cleaned chromatography on HP20SS, using as eluent a mixture of methanol/water (80:20). Evaporation and lyophilization to give (2S, 4S)-1-(4 - nitrobenzenesulfonyl)-2-(3-carboxy-5-acetaminophenramadol) pyrrolidin-4-ILTER (0.68 g, 74%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 2.05 (s, 3H); 2.05 is (m, 3H); to 2.75 (m, 1H); 3,20-of 3.80 (m, 2H); 4,00 (m, 1H); was 4.42 (m, 1H); of 5.40 (broad s, 2H); 7,45-8,30 (m, 7H).

To a solution of 4-nitrobenzyl-(1R,5S,6S,8R)-6-(1-oxyethyl) -1-methyl-2-difenilfosforilatsetamidnymi-3 - carboxylate (0.6 g, 1.2 mm) in DMF (12 ml) are added successively diisopropylethylamine (0.6 ml, 3.4 mm), (2S,4S)-1-(4-nitrobenzenesulfonyl) -2-(3-carboxy-5-acetaminophenramadol) pyrrolidin-4-ILTER (0.6 g, 1.2 mm), tri-n-butylphosphine (0.6 ml, 2.4 mm) and water (0.1 ml, 5.5 mm). The reaction mixture was stirred overnight at 4oC, evaporated to dryness and the residue purified chromatography on HP20SS resin, using as eluent a mixture of acetonitrile/the-5 - acetaminophenramadol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl - 3-carboxylate (0.8 g, 88%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.15 (d, 3H); of 1.17 (d, 3H); is 2.05 (s, 3H); 2,17 (m, 1H); of 2.81 (m, 1H); 3,26 (DD, 1H); to 3.36 (TD, 1H); 4,56-4,74 (m, 2H); 5,02-5,73 (m, 4H); 5,91 (m, 1H); 7,47 (d, 1H); to 7.68 (d, 1H); a 7.85-to 7.99 (m, 3H); 8,20-8,29 (m, 2H).

Example 17. Diclina salt of (1R,5S,6S,8R,2'S,4'S)-2-(2- (4-acetamido-3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid. Specified in the title compound is obtained from 4-allyl-(1R, 5S, 6S, 8R,2'S,4'S)-2-(1- (4-nitrobenzenesulfonyl)-2-(4-acetamido)-3-carboxyphenylazo) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate (salt diisopropylethylamine) by the method similar to that described in example 16.

NMR (DMCO-d6+ acetic acid-d4): memorial plaques to 1.14 (d, 3H); to 1.16 (d, 3H); to 1.75 (m, 1H); 2,07 (s, 3H); 2,73 (m, 1H); 2,96 (DD, 1H); 3,21 (DD, 1H); 3,39 (m, 1H); of 3.54 (DD, 1H); of 3.78 (m, 1H); of 3.96 (m, 1H); 4,08 (t, 1H); 4,18 (DD, 1H); of 7.69 (DD, 1H); 8,18 (d, 1H); 8,42 (d, 1H).

Ms (+ve FAB): 571 (MH)+, (K salt).

The source material was obtained as follows.

(2S, 4S)-1-(4-Nitrobenzenesulfonyl)-2- (4-acetamido-3-carboxyphenylazo) pyrrolidin-4-ylthioacetate obtained from 2-acetamido-5-aminobenzoic acid by a method similar to that described in example 16.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.95 (m, 1H); 2,12 is l)-2-(4-acetamido-3 - carboxyphenylazo)pyrrolidin-4-intial obtained from (2S,4S)-1-(4-nitrobenzenesulfonyl)-2-(4-acetamido-3 - carboxyphenylazo)pyrrolidin-4-ylthioacetate way similar to that described in example 16.

Allyl(1R, 5S, 6S,8R,2'S,4'S)-2-(1-(4-nitrobenzenesulfonyl) -2-(4-acetamido-3-carboxyphenylazo)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate (salt diisopropylethylamine) is obtained from (2S, 4S)-1- (4-nitrobenzenesulfonyl)-2-(4-acetamido-3 - carboxyphenylazo)pyrrolidin-4-itiola and allyl-(1R,5R,6S,8R)-6-(1-oxyethyl)-1-methyl-2 - difenilfosforilatsetamidnymi-3-carboxylate by the method similar to that described in example 16.

NMR (CDCl3): M. D. 1,14 and 1.80 (m, 23H); 2,17 (s, 3H); to 2.67 (m, 1H); 3,00-3,30 (m, 3H); 3,35-3,90 (m, 4H); 3,90-and 4.40 (m, 3H); 4,40-of 4.75 (m, 3H); 5,00-of 5.75 (m, 4H); 5,70-6,10 (m, 1H); 7,38-8,65 (m, 7H).

Example 18. (1R, 5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid dikalova salt. Specified in the title compound is obtained from (1R, 5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzenesulfonyl)-2- (3-carboxy-5-methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate by the method similar to that described in example 16.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.16 (d, 3H); of 1.17 (d, 3H); 1,74 (m, 1H); of 2.64 (m, 1H); of 2.81 (DD, 1H); 3,01 (s, 3H); 3,20 (m, 1H); 3.40 in (m, 2H); 3,68 (m, 1H); 3.96 points (m, 2H); to 4.17 (DD, 1H); rate of 7.54 (s, 1H); of 7.82 (s, 1H); 8,00 (s, 1H).

(2S, 4S)-1-(4-Nitrobenzenesulfonyl)-2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-ylthioacetate obtained from 3-amino-5-methylsulfonylbenzoyl acid in a manner analogous to the one described in example 1.

NMR (DMCO-d6+ acetic acid-d4): M. D. 2,00 (m, 1H); 2,30 (s, 3H); 2,84 (m, 1H); 2.95 and (s, 3H); 3,20-3,51 (m, 1H); 3,83-4,20 (m, 2H); 4,30-4,58 (m, 1H); 5,20 (m, 2H); of 7.48 were 8.22 (m, 7H).

(2S, 4S)-1-(4-Nitrobenzenesulfonyl)-2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-intial obtained from (2S,4S)-1-(4-nitrobenzenesulfonyl)-2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-ylthioacetate manner similar to that described in example 16.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 2.10 (m, 1H); 2,78 (m, 1H); 2,99 (s, 3H); 3.43 points (m, 1H); 3,68 (m, 1H); of 4.05 (m, 1H); was 4.42 (m, 1H); 5,13-5,32 (m, 3H); 7,50-8,82 (m, 7H).

Allyl(1R, 5R, 6S,8R,2'S,4'S)-2-(1-(4- nitrobenzenesulfonyl)-2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylate is obtained from (2S,4S)-1-(4-nitrobenzenesulfonyl)-2-(3-carboxy-5 - methylsulfonylbenzoyl)pyrrolidin-4-itiola and allyl (1R,5S,6S,8R)-6-(1-oxyethyl)-1-methyl-2 - difenilfosforilatsetamidnymi-3-carboxylate by the method similar to that described in example 16.

< the, 4H); 4,42 was 4.76 (m, 3H); 5.08 to 5,42 (m, 4H); of 5.92 (m, 1H); 7,22 is 8.22 (m, 7H).

Example 19. (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5 - sulfophenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid dikalova salt. To a stirred solution of 4-nitrobenzyl-(1R,5S,6S, 8R, 2'S,4'S)- 2-(1-(4-nitrobenzenesulfonyl)-2-(3-carboxy-5 - sulfophenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate (0.5 g, 0.56 mm) in DMF (5 ml) and water (5 ml) add a solution of 1 M sodium phosphate buffer (5 ml), and then the powdered zinc (1 g). The reaction mixture was stirred for 1 h and adjusted the pH to 8 by adding saturated aqueous sodium bicarbonate solution. After filtering through diatomaceous earth, the filtrate is concentrated and cleaned by way of preparative chromatography (Nucleosil C-18), using as eluent water. The concentration and liofilizirovannam desired fractions get mentioned in the title compound (44 mg, 12%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.15 (d, 3H); to 1.16 (d, 3H); of 1.78 (m, 1H); 2,73 (m, 1H); 2,92 (m, 1H); 3,21 (DD, 1H); 3.40 in (m, 1H); of 3.48 (m, 1H); 3.75 to (m, 1H); of 3.97 (m, 1H); is 4.03 (m, 1H); 4,18 (m, 1H); to 7.93 (s, 1H); 8,11 (s, 1H); 8,29 (s, 1H).

Ms (-ve FAB): 576 (M - H)-for the mono-sodium salt, 598 (M - H)-for the di-sodium salt

The initial substance poluchili-4-ylthioacetate obtained from 3-amino-5-sulfobenzoic acid method, similar to that described in example 16.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.97 (m, 1H); 2,30 (s, 3H); 2,80 (m, 1H); 3,37 (m, 1H); 3,86-to 4.15 (m, 2H); to 4.46 (m, 1H); of 5.05 is 5.28 (m, 2H); 7,46-a 9.25 (m, 7H).

(2S, 4S)-1-(4-Nitrobenzenesulfonyl)-2-(3-carboxy-5 - sulfophenylazo)pyrrolidin-4-intial obtained from (2S,4S)-1-(4-nitrobenzenesulfonyl)-2-(3-carboxy-5 - sulfophenylazo)pyrrolidin-4-ylthioacetate manner similar to that described in example 16.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.25 (d, 3H); of 1.27 (d, 3H); 2,07 (m, 1H); 2,70 (m, 1H); 3,4 (m, 1H); to 3.67 (m, 1H); 3,99 (m, 1H); of 4.49 (m, 1H); 5,07-and 5.30 (m, 2H); 7,47-to 8.40 (m, 7H).

4-Nitrobenzyl(1R, 5S, 6S,8R,2'S,4'S)-2-(1-(4- nitrobenzenesulfonyl)-2-(3-carboxy-5-sulfophenylazo) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate is obtained from (2S,4S)-1-(4-nitrobenzenesulfonyl)-2-(3-carboxy-5 - sulfophenylazo)pyrrolidin-4-itiola and 4-nitrobenzyl(1R, 5R, 6S,8R)-6-(1-oxyethyl)-1 - methyl-2-difenilfosforilatsetamidnymi-3 - carboxylate by the method similar to that described in example 1.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.20 (d, 3H); to 1.21 (d, 3H); 1,96 (m, 1H); 2,77 (m, 1H); 3,18-3,47 (m, 2H); 3,66-of 4.90 (m, 6H); 5,04-of 5.50 (m, 4H); 7,30-8,35 (m, 11H).

Example 20. (5R,6S,8R,2'S,4'S)-2-(2-(3- Carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxycarbonyl)-2- (3-allyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)carbapenem-3-carboxylate (0,185 g, 0,296 mm) in CH2Cl2(4 ml) at room temperature is added sequentially N-methylaniline (0,190 g, 1,776 mm) water (4 ml), sodium bicarbonate (100 mg) and tetrakis(triphenylphosphine)palladium (34 mg, 0.029 mm). After 10 min, the aqueous phase is separated and injected into the C18 column for preparative high performance liquid chromatography, then getting mentioned in the title compound (43 mg, 27%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.16 (d, 3H); is 1.81 (m, 1H); of 2.64 (m, 1H); 2,84 (m, 1H); 3,26 (m, 3H); 3,4 (m, 1H); to 3.67 (m, 1H); of 3.94 (m, 2H); of 4.12 (m, 1H); 7,42 (t, 1H); the 7.65 (d, 1H); 7,83 (d, 1H); of 8.27 (s, 1H).

Source allyl-(5R,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)carbapenem-3-carboxylate are obtained from 67% yield by the method similar to that described in example 1 for a similar reaction in the interaction of (2S,4S)-1-allyloxycarbonyl-2- (3-allyloxycarbonyl)pyrrolidin-4-thiol as described in example 4, with the allyl-(5R,6S,8R)-6-(1-oxyethyl) -2-difenilfosforilatsetamidnymi-3-carboxylate (EP-A-126780 and EP-A-208889).

Example 21. (1R, 5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5 - cyanovinylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl) -1-methylcarbamoyl-3-carboxylic acid dikalova salt. To a solution of allyl-(1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl (358 mg, 0,54 mm) and 2,2-dimethyl-1,3-dioxane-4,6-dione (388 mg, 2.7 mm) in a mixture of DMF (8 ml) and THF (4 ml) in an argon atmosphere add tetrakis(triphenylphosphine)palladium (62 mg, 0,054 mm). The solution is stirred in an argon atmosphere, protected from light, for 1.75 hours, then remove the solvent by evaporation. The residue is dissolved in a mixture of THF (6 ml) and DMF (2 ml) add a solution of 2-ethylhexanoate sodium (295 mg, 1,77 mm) in THF (4 ml) and then diethyl ether (20 ml). The precipitate centrifuged and the supernatant removed. The product is washed twice, re-suspending in a mixture of THF (4 ml) and diethyl ether (10 ml), then washed with diethyl ether and centrifuged. The crude product is dissolved in water (20 ml) and adjusted pH to 7.4 by adding NaHCO3. After filtering the solution chromatographic on HP20SS-resin, collecting the appropriate fractions, getting listed in the name of the product (206 mg, 70%).

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.17 (d, 6H); 1,95 (m, partially closed, 1H); and 2.83 (m, 1H); to 3.09 (DD, 1H); of 3.25 (DD, 1H); to 3.41 (quintet, 1H); to 3.64 (DD, 1H); 3,88 (quintet, 1H); was 4.02 (quintet, 1H); 4,22 (DD, 1H); or 4.31 (t, 1H); 8,00 (s, 1H); 8,28 (t, 1H); 8,46 (t, 1H),

Ms (+ve FAB): 523 (MH)+, (Na salt).

The initial substance was obtained as follows.

3-Cyano-5-nitrobenzoic acid. 3-Amino-5-nitrobenzoyl to 0oC and after 30 minutes added to a solution of NaNO2(1,38 g, 20 mm) in water (10 ml). the pH was adjusted to 6.2 with a saturated solution NaCO3. The mixture CuSO45H2O (10 g, 42 mm) in water (40 ml) and KCN (10 g, 154 mm) in water (20 ml) is heated to 65oC, after 15 minutes, add a solution of diazonium salts and the mixture is refluxed for 40 minutes After cooling and acidification with 2 M hydrochloric acid, the organic compounds are extracted with ethyl acetate (2 200 ml). The combined extract was washed with water NaH2PO4, with water, with brine and dried over Na2SO4. Evaporation receive 3-cyano-5-nitrobenzoic acid (3.6 g, 94%).

NMR (DMCO-d6): M. D. 8,69 (t, 1H); 8,80 (t, 1H); 8,97 (t, 1H).

Ms (-ve FAB): 191 (M - H)-. IR (nujol) 2220 cm-1.

3-Cyano-5-nitrobenzoic acid is transformed into allyl-3-cyano-5-nitrobenzoate basically according to the method described in example 1, except that when cleaning chromatographytandem use a mixture of gasoline and ethyl acetate (5:1).

NMR (DMCO-d6): M. D. 4,91 (dt, 2H); 5,39-of 5.53 (m, 2H); 5,99-to 6.19 (m, 1H); 8,78 (t, 1H); 8,81 (t, 1H); 9,04 (t, 1H).

Ms (+ve FAB): 202 M+, 232 (M + NH4)+(both for amino-compounds with ammonia).

The recovery obtained above no o
.

NMR (DMCO-d6): M. D. 4,79 (dt, 2H); 5.25 to the 5.45 (m, 2H); 5,94-6,13 (m covers a broad signal, 1H); 7,10 (t, 1H); 7,37 (t, 1H); of 7.48 (t, 1H).

Ms (+ve FAB): 202 M+, 232 (M + NH4)+.

The result of the above amine condensed with Proline in the manner described with example 1, peeling chromatography using gradient elution with a mixture of dichloromethane/ethyl acetate (19:1 to 9:1) to give (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-cyanovinylene)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.33 (s, 3H); 2,59 (broad, 2H); to 3.38 (DD, 1H); 3,97-4,17 (m, 2H); 4,56 (t, 1H); 4,69 (d, 2H); 4,84 (d, 2H); 5,26-of 5.48 (m, 4H); 5,85-6,14 (m, 2H); 8,03 (broad s, 1H); 8,18 (t, 1H); 8,29 (broad s, 1H); RS 9.69 (broad, 1H).

Ms (+ve FAB): 458 MH+, 480 (M + Na)+.

The above thioacetate will deacetylase according to example 1, obtaining (2S, 4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-cyanovinylene) pyrrolidin-4-iltil.

NMR (CDCl3): M. D. 1,90 (d, 1H); 2,52 (broad, 1H); to 2.65 (broad, 1H); 3,34-to 3.52 (m, 2H); 4,07 (DD, 1H); of 4.54 (t, 1H); 4,69 (d, 2H); 4,84 (d, 2H); 5,27-vs. 5.47 (m, 4H); by 5.87-6,11 (m, 2H); 8,01 (s, 1H); 8,21 (t, 1H); of 8.28 (s, 1H); 9,56 (broad, 1H).

The above thiol condense with carbapenemases as described in example 1, peeling chromatography using gradient elution with a mixture of definiltely)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.27 (d, 3H); to 1.35 (d, 3H); to 2.67 (broad, 2H); 3,21-3,33 (overlapping m, 2H); 3,53 (broad, 1H); 3,83 (quintet, 1H); 3,93 (DD, 1H); 4,20-or 4.31 (overlapping m, 2H); of 4.54 (t, 1H); 4.63 to-a 4.86 (m, 6H); to 5.21-vs. 5.47 (m, 6H); of 5.82-6,11 (m covers a wide signal, 3H); with 8.05 (t, 1H); 8,33 (broad s, 1H); of 8.37 (broad s, 1H); 9,35 (broad, 1H).

Ms (+ve FAB): 665 (MH)+, 687 (M + Na)+.

Example 22. Disodium salt 1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methoxyphenylacetyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 21.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.17 (d, 3H); of 1.18 (d, 3H); to 1.83 (m, partially closed, 1H); was 2.76 (quintet, 1H); 2,98 (DD, 1H); up 3.22 (DD, 1H); 3,39 (quintet, 1H); of 3.56 (DD, 1H); 3,81 (overlapped m, 4H); 4,00 (quintet, 1H); 4,15, 4,18 (t overlaps DD, 2H); 7,22 (m, 1H); 7,58 (t, 1H); to 7.84 (t, 1H).

Ms (-ve FAB): 505 (M - H)-, (Na salt).

The parent compound was obtained as follows.

3-Hydroxy-5-nitrobenzoyl the acid was identified in basically as described in example 1, except that allylbromide replace dimethylsulfate, and the chromatography was carried out is not necessary, obtain methyl 3-methoxy-5-nitrobenzoate.

NMR (CDCl3): M. D. of 3.94 (s, 3H); of 3.97 (s, 3H); 7,87 (t, 1H); of 7.90 (t, 1H); 8,44 (t, 1H).

The resulting virechana 5 o'clock After removal of solvent the residue is treated with water (50 ml), acidified with 2 M sulfuric acid and extracted with ethyl acetate (3 60 ml). The combined organic extract was washed with water NaH2PO4, with brine and dried over MgSO4. Evaporation gives 3-methoxy-5-nitrobenzoic acid, from which the allyl ether allyl-3-methoxy-nitrobenzoate way basically similar to that described in example 1, except that when cleaning chromatographytandem use a mixture of benzyl/ethyl acetate (6:1).

NMR (CDCl3): M. D. of 3.95 (s, 3H); 4,87 (dt, 2H); 5,31-of 5.48 (m, 2H); 5,95-x 6.15 (m, 1H); 7,89 (t, 1H); 7,92 (t, 1H); 8,46 (t, 1H).

Ms (Cl): 237 M+, 255 (M + NH4)+.

The recovery obtained above connection method, similar to that described in example 1, get allyl-3-amino-5-methoxybenzoate.

NMR (DMCO-d6): M. D. and 3.72 (s, 3H); 4,50 (very broad, 2H); 4.75 V (dt, 2H); 5.25 to 5,43 (m, 2H); 5,95-6,11 (m, 1H); 6,47 (t, 1H); 6.75 in (t, 1H); 6,93 (t, 1H).

Ms (Cl): 208 (MH)+.

The result of the above amine condensed with Proline as in example 1, peeling chromatography using gradient elution with a mixture of petrol/ethyl acetate (5: 2 to 2:1) to give (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxyphenylacetic, 1H); 4,15 (DD, 1H); 4,55 (t, 1H); and 4.68 (d, 2H); to 4.81 (d, 2H); 5,22-5,46 (m, 4H); of 5.83-6,13 (m, 2H); to 7.35 (t, 1H); 7,58 (broad s, 1H); to 7.64 (t, 1H); 9,12 (broad, 1H).

Ms (+ve FAB): 463 (MH)+, 485 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using gradient elution with a mixture of dichloromethane/ethyl acetate (60:40 to 45:55) to give allyl-(1R, 5S, 6S,8R,2'S,4'S)-2-(1 - allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxyphenylacetyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.25 (d, 3H); to 1.37 (d, 3H); 2,64 (very broad, 2H); 3,21-3,33 (overlapping m, 2H); 3,48 (broad, 1H); of 3.80 (quintet, 1H); 3,85 (s, 3H); 4,01 (DD, 1H); 4,19-the 4.29 (overlapping m, 2H); 4.53-in (t, 1H); 4,62 of 4.83 (m, 6H); 5,20-of 5.45 (m, 6H); of 5.84-6,11 (m, covers a wide signal; 3H); to 7.25 (t, 1H); 7,63 (m, 2H); 8,90 (broad, 1H).

Ms (+ve FAB): 670 (MH)+, 692 (M + Na)+.

Example 23. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2- (5-carboxy-2-methanesulfonylaminoethyl)pyrrolidin-4-ylthio)- 6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained as a mixture of diastereoisomers on sulfoxides the centre by way of example 21.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.18 (d, 6H); to 1.87 (m, partially closed, 1H); 2,64-2,91, 2, H); 7,83 (t, 1H); 7,94 (TD, 1H); to 8.45 (d, 1H).

Ms (+ve FAB): 560 (MH)+, (Na salt), 582 (MH)+(Na2salt).

The parent compound was obtained as follows.

4-Methanesulfonyl-3-nitrobenzoic acid. 4-Methylthio-3-nitrobenzoic acid (4,36 g, 20 mm) was dissolved in acetic acid (200 ml), treated at room temperature H2O2(2.5 ml, 30%, 22 mm). After stirring at room temperature for 4 Nam excess peroxide is decomposed with sodium metabisulfite and the solvent is evaporated. The residue is cleaned chromatography on silica, elwira methanol, receive a 4-methanesulfonyl-3-nitrobenzoic acid (4.1 g, 89%), so pl. 238-239oC.

NMR (DMCO-d6): M. D. 2,90 (s, 3H); 8,29 (d, 1H); 8,56 (DD, 1H); 8,68 (d, 1H).

Ms (-ve FAB): 229 (M - H)-.

The above acid was transferred to allyl ether mostly as in example 1, except that the chromatography was carried out is not necessary, get allyl-4-methanesulfonyl-3 - nitrobenzoate, so pl. 119-121oC.

NMR (DMCO-d6): M. D. only 2.91 (s, 3H); 4,91 (dt, 2H); from 5.29-of 5.50 (m, 2H); 5,99-6,18 (m, 1H); to 8.34 (d, 1H); 8,61 (DD, 1H); 8,69 (d, 1H).

The restoration of the above nitro compound by the method of example 1 receive allyl-3-amino-4-means is H); 7,41 (m, 2H).

Ms (EI): 223 (M - O)+, 239 M+.

The result of the above amine condensed with Proline as in example 1, peeling chromatography using gradient elution with a mixture of hexane/ethyl acetate (3:2 to 1:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methanesulfonylaminoethyl)pyrrolidin-4-ylthioacetate.

NMR (DMCO-d6when 100o): to 1.98 (m, 1H); 2,32 (s, 3H); 2,73 (s, 3H); 2,86 (m, partially closed, 1H); to 3.36 (m, 1H); 3,91-4,10 (overlapping m, 2H); 4,48 (DD, 1H); 4.53-in (m, 2H); a 4.86 (d, 2H); 5,11-5,49 (m, 4H); 5,80-5,97 (m, 1H); 6,01-x 6.15 (m, 1H); of 8.09 (s, 2H); 8,35 (s, 1H).

Ms (+ve FAB): 495 (MH)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using gradient elution with a mixture of ethyl acetate/isopropanol (100:0 to 98:2) to give allyl-(1R, 5S,6S,8R,2'S,4'S)-2-(1 - allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methanesulfonylaminoethyl)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (DMCO-d6, mixture of rotamers): M. D. of 1.18 (d, 6H); 1,99 (broad, 1H); 2,80 (with overlaps m, 5H); of 3.25 (m, overlapped with the solvent, 2H); of 3.54 (m, 1H); 3,90-4,18 (m, 3H); 4,15 (DD, 1H); 4,55 (m, 4H); 4,85 (d, 2H); of 5.06 (d, 1H); 5,14-5,46 (m, 6H); 5,79-6,13 (m, 3H); 7,80-with 8.05 (m, 2H); to 8.12 (m, 1H); 10,10 (m, 1H).

Ms (+ve FAB): 702 (MH)+

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.16 (d, 3H); of 1.18 (d, 3H); of 1.75 (quintet, 1H); 2.63 in (m, 1H); and 2.79 (DD, 1H); 3,20 (overrides the m, 4H); to 3.38 (m, 2H); 3,64 (quintet, 1H); 3,95 (m, 2H); to 4.14 (DD, 1H); of 8.09 (t, 1H); 8,44 (m, 2H).

Ms (-ve FAB): 574 (M - H)-, (Na salt).

The parent compound was obtained as follows.

3-Methylthio-5-nitrobenzoic acid. 3-Amino-5-nitrobenzoic acid (1,82 g, 10 mm) dissolved in concentrated sulfuric acid (1.9 ml), diluted with water (10 ml) and cooled to 5o. Add a solution of NaNO2(0.7 g, 10 mm) in water (3 ml) and the mixture is stirred for 30 minutes, a Cold solution of diazonium salts add to the pasta timetime(I) if 3othe mixture is stirred for 45 minutes Organics extracted with ethyl acetate (5 60 ml) and the combined organic layer was washed with water NaH2PO4, with water, with brine and dried over Na2SO4. Evaporation receive 3-methylthio-5-nitrobenzoic acid (1.77 g, 83%).

NMR (DMCO-d6): M. D. 2,63 (s, 3H); 8,10 (t, 1H); 8,21 (t, 1H), 8,32 (t, 1H); 13,68 (broad, 1H).

Ms (-ve FAB): 213 (M - H)-.

The above acid was transferred to allyl ether as in example 1, except that the eluent when chromatographicaliy is a mixture of benzil/ethyl acetate (6:(m, 1H); to 8.20 (m, 2H); to 8.57 (t, 1H).

Ms (EI): 253 M+.

Allyl-3-methylsulphonyl-5-nitrobenzoate. Allyl-3-methylthio-5 - nitrobenzoate (1.12 g, 4.4 mm) dissolved in methanol (30 ml) and cooled to 2o. Slowly add solution "peroxymonosulfate potassium (2KHSO5KHSO4K2SO4, 8,13 g, 13.2 mm) in water (25 ml) and stirring is continued for 4 hours the Mixture is diluted with water (60 ml) and extracted with ethyl acetate (3 100 ml). The combined organic extract washed with water, with brine and dried over Na2SO4. The crude product is cleaned chromatography on silica using gradient elution with a mixture of petrol/ethyl acetate (3:1 to 2: 1), receive allyl-3-methylsulphonyl-5-nitrobenzoate (0.74 g, 59%).

NMR (DMCO-d6): M. D. 3,44 (s, 3H); 4,94 (dt, 2H); 5,32-of 5.53 (m, 2H); 6,01 and 6.25 (m, 1H); 8,78 (t, 1H); 8,89 (t, 1H); 8,91 (t, 1H).

The recovery obtained above nitro compounds by the method of example 1 receive allyl-3-amino-5-metasulphobenzoate.

NMR (DMCO-d6): M. D. of 3.15 (s, 3H); 4,80 (dt, 2H); 5,26 - vs. 5.47 (m, 2H); 5,95 - x 6.15 (m, overlapping broad signal, 3H); 7,29 (m, 1H); 7,47 (t, 1H); 7,51 (t, 1H).

The result of the above amine condensed with Proline in the manner described in example 1, chromatographic clean, applying gradie the Nile-5 - methanesulfonylaminoethyl)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.34 (s, 3H); 2,48 (m, 1H); 2,62 (m, 1H); 3,17 (s, 3H); to 3.41 (DD, 1H); is 4.03 (quintet, 1H); 4,15 (DD, 1H); 4,58 (DD, 1H); 4,71 (d, 2H); 4,84 (dt, 2H); 5,27 - vs. 5.47 (m, 4H); 5,88 - 6,14 (m, 2H); 8,23 (broad s, 2H); of 8.37 (t, 1H); RS 9.69 (broad, 1H).

Ms (+ve FAB): 511 (MH)+, 533 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, purified chromatography using gradient elution with a mixture of dichloromethane/ethyl acetate (55:45 to 20:80), receive allyl-(1R, 5S,6S,8R,2'S,4'S)-2- (1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5 - methanesulfonylaminoethyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); of 1.36 (d, 3H); 2,54 (broad, 1H); 2,66 (broad, 1H); of 3.12 (s, 3H); 3,19 - 3,22 (overlapping m, 2H); 3,54 (broad, 1H); a 3.87 (quintet, 1H); of 3.94 (DD, 1H); 4.25 in, 4,29 (quintet overlaps DD, 2H); 4,55 (t, 1H); 4,65 - 4,80 (m, 4H); is 4.85 (d, 2H); 5,20 - 5,46 (m, 6H); 5,86 - 6,12 (m, covers a broad signal, 3H); 8,31 (broad, 1H); 8,43 (broad, 1H); charged 8.52 (broad, 1H); 9,40 (broad, 1H).

Ms (+ve FAB): 718 (MH)+, 740 (M + Na)+.

Example 25. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy - 5-cryptomaterial)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid obtained by the method described in example 2.

<3,00 (DD, 1H); 3,21 (DD, 1H); 3,37 (quintet, 1H); 3,59 (quintet, 1H); of 3.80 (quintet, 1H); 3,97 (quintet, 1H); 4,20 (m, 2H); to $ 7.91 (broad s, 1H); of 8.27 (broad s, 1H); 8,44 (broad s, 1H).

Ms (-ve FAB): 542 (M - H)-(acid), 564 (M - H) - (Na salt).

The initial substance was obtained as follows.

3-Nitro-5-triftorperasin acid transferred in the allyl ether basically as described in example 1, except that the product is of sufficient purity to do without chromatography was carried out. Get allyl-3-nitro-5-cryptomelane.

NMR (DMCO-d6): M. D. 4,91 (dt, 2H); 5,30 - 5,51 (m, 2H); 5,99 - of 6.20 (m, 1H); 8,58 (broad s, 1H); 8,77 (broad s, 1H); 8,84 (t, 1H).

Ms (Cl): 275 M+, 293 (M + NH4)+.

The recovery obtained above nitro compounds by the method described in example 2, get allyl-3-amino-5-cryptomelane sufficient purity to do without chromatography was carried out.

NMR (DMCO-d6): M. D. 4,78 (dt, 2H); 5,24 - 5,43 (m, 2H); 5,93 - 6,13 (m, 1H); was 7.08 (t, 1H); 7,27 (broad s, 1H); 7,44 (t, 1H).

Ms (Cl): 245 M+, 263 (M + NH4)+.

The result of the above amine condensed with Proline as in example 1, peeling chromatography using gradient elution with a mixture of dichloromethane/diethyl ether (100 : 0 to 9 : tat.

NMR (CDCl3): M. D. of 2.33 (s, 3H); at 2.59 (m, 2H); 3,39 (DD, 1H); Android 4.04 (quintet, 1H); to 4.14 (DD, 1H); 4,58 (t, 1H); to 4.62 (dt, 2H); 4,85 (dt, 2H); 5,23 - of 5.48 (m, 4H); of 5.84 - x 6.15 (m, 2H); 8,03 (broad s, 1H); 8,23 (broad s, 2H); 9,60 (broad, 1H).

Ms (+ve FAB): 501 MH+, 523 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, purified chromatography using gradient elution with a mixture of dichloromethane/ethyl acetate (from 100:0 to 1:9), get allyl-(1R, 5S, 6S, 8R, 2'S, 4'S)-2- (1-allyloxycarbonyl-2-(3-allyloxycarbonyl)pyrrolidin-4-ylthio)- 6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (DMCO-d6+ acetic acid-d4): memorial plaques to 1.21 (d, 6H); 2,05 (broad, 1H); 2,85 (broad, 1H); 3,29 (DD, 1H); 3,44 (DD, 1H); 3,51 (quintet, 1H); 3,93 (broad, 1H); 4,05 - 4,18 (m, 2H); 4,27 (DD, 1H); 4,43 - 4,71 (overlapping m, 5H); 4,85 (d, 2H); 5,16 - 5,46 (m, 6H); 5,70 - 6,16 (m, 3H); 7,94 (broad s, 1H); of 8.37 (broad s, 1H); 8,53 (broad s, 1H).

Ms (+ve FAB): 708 (MH)+, 730 (M + Na)+.

Example 26. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-2-(5-carboxy-2-methoxyphenylacetyl)pyrrolidin-4-ylthio)- 6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 1.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.20 (d, 6H); 1.93 and (m, partially closed, 1H); 2,86 (quintet, 1H); to 3.02 (DD, 1H); 3,tx2">

Ms (+ve FAB): 528 (MH)+, (Na salt), 550 (MH)+, (Na2salt).

The parent compound was obtained as follows.

4-Methoxy-3-nitrobenzoic acid transferred in the allyl ether basically as described in example 1, except that the product is of sufficient purity to use without chromatography was carried out, get allyl-3-nitro-4-methoxybenzoate.

NMR (CDCl3): M. D. a 4.03 (s, 3H); a 4.83 (dt, 2H); from 5.29 - 5,46 (m, 2H); 5,93 - 6,14 (m, 1H); 7,14 (d, 1H); 8,24 (DD, 1H); charged 8.52 (d, 1H).

Ms (Cl): 237 (M)+, 255 (M + NH4)+.

The recovery obtained above nitro compounds by the method of example 2 to obtain 3-amino-4-methoxybenzoate sufficient purity for use without chromatography was carried out.

NMR (CDCl3): M. D. and 3.72 (broad, 2H); 3,90 (s, 3H); of 4.77 (dt, 2H); 5,24 - 5,43 (m, 2H); 5,95 - 6,10 (m, 1H); 6,79 (d, 1H); 7,41 (d, 1H); to 7.50 (DD, 1H).

Ms (Cl): 208 (MH)+.

The result of the above amine condensed with Proline as in example 4, except that the product is cleaned chromatography on silica using gradient elution with a mixture of dichloromethane/diethyl ether (5:0 to 4:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methoxyphenylacetyl)pyrrolidin-4-ylthioacetate.

Ms (+ve FAB): 463 (MH)+, 485 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1 is cleaned by chromatographytandem using a gradient elution of solvent from dichloromethane to ethyl acetate, getting allyl-(1R, 5S, 6S, 8R, 2'S,4'S)-2- (1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate.

Yarm (CDCl3): M. D. of 1.23 (d, 3H); of 1.36 (d, 3H); 2,52 (broad, 1H); 2,66 (broad, 1H); up 3.22 (DD, 1H); or 3.28 (quintet, 1H); 3,44 (DD, 1H); 3,83 (quintet, 1H); 3,93 (s, 3H); 4.09 to (m, 1H); 4,19 - or 4.31 (overlapping m, 2H); 4.53-in (t, 1H); with 4.65 (m, 4H); to 4.81 (d, 2H); 5,19 - of 5.45 (m, 6H); of 5.83 - 6,11 (m, 3H); 6,91 (d, 1H); 7,83 (DD, 1H); 8,79 (broad, 1H); 9,04 (d, 1H).

Ms (+ve FAB): 670 (MH)+, 692 (M + Na)+.

Example 27. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2- (2-(3-carboxy-4-methoxyphenylacetyl)pyrrolidin)-4-ylthio)- 6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method described in example 2, except that the DMF replaced DMCO.

Yarm (DMCO-d6+ acetic acid-d4): M. D. of 1.17 (d, 6H); to 1.83 (m, partially closed, 1H); 2,75 (quintet, 1H); 2).

Ms (+ve FAB): 528 (MH)+, (Na salt), 550 (MH)+, (Na2salt).

The initial substance was obtained as follows,

2-Methoxy-5-nitrobenzoic acid transferred in the allyl ether basically as described in example 1, except that the product is of sufficient purity to use without chromatography was carried out, get allyl-2-methoxy-5-nitrobenzoate.

NMR (CDCl3): M. D. a 4.03 (s, 3H); 4,85 (dt, 2H); 5,30-5,49 (m, 2H); 5,95-6,14 (m, 1H); was 7.08 (d, 1H); 8,48 (DD, 1H); 8,72 (d, 1H).

Ms (Cl): 238 (MH)+, 255 (M + NH4)+.

The recovery obtained above nitro compounds by the method of example 2 to obtain 5-amino-2-methoxybenzoate sufficient purity for use without chromatography was carried out.

NMR (CDCl3): M. D. 3,39 (broad, 2H); a 3.83 (s, 3H); 4,80 (dt, 2H); 5,23-vs. 5.47 (m, 2H); 5,94-6,13 (m, 1H); 6,83 (d, 2H); 7.18 in (t, 1H).

Ms (Cl): 208 (MH)+.

The result of the above amine condensed with Proline as in example 4, except that the substances cleaned chromatography on silica using a gradient elution from dichloromethane to a mixture of dichloromethane/diethyl ether (4:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-4 - methoxyphenylacetyl)pyrrolidin-4-ylthioacetate.

NMR (CDCl (m, 4H); of 5.84-6,13 (m, 2H); 6,94 (d, 1H); 7,80 (m, 2H); 8,94 (broad, 1H).

Ms (Cl) : 463 (MH)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to ethyl acetate, getting allyl-(1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3 - allyloxycarbonyl-4-methoxyphenylacetyl)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.25 (d, 3H); of 1.36 (d, 3H); to 2.65 (broad, 2H); of 3.25 (DD, 1H); or 3.28 (quintet, 1H); 3,47 (broad, 1H); 3,79 (quintet, 1H); to 3.89 (s, 3H); 4,01 (DD, 1H); 4,18-the 4.29 (overlapping m, 2H); 4,51 (t, 1H); of 4.66 (m, 4H); 4,79 (dt, 2H); 5,19-5,46 (m, 6H); of 5.84-6,11 (m, 3H); to 6.95 (d, 1H); 7,79-7,87 (m, 2H); to 8.70 (broad, 1H).

Ms (+ve FAB): 670 (MH)+, 692 (M + Na)+.

Example 28. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2-methoxyphenylacetyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that the DMF replaced DMCO.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.18 (d, 6H); of 1.85 (m, partially closed, 1H); 2.66 per-2,86 (overlapping m, 2H); 3,21 (DD, 1H); to 3.41 (quintet, 1H); 3,52-3,72 (overlapping m, 2H); is 3.82 (s, 3H); 3,99 (quintet, 1H); 4,08 (DD, 1H); to 4.17 (DD, 1H); 7,17 (t, 1H); was 7.45 (DD, 1H); to 8.41 (DD, 1H).

2-Hydroxy-3-nitrobenzoyl the acid was identified in mainly, as in the corresponding stage of example 1, except that allylbromide replace methyliodide, purification chromatographic method is not necessary to obtain methyl 2-methoxy-3-nitrobenzoate.

NMR (DMCO-d6): M. D. 3,88 (s, 3H); 3,90 (s, 3H); 7,44 (t, 1H); 8,04 (DD, 1H); to 8.12 (DD, 1H).

Ms (Cl): 212 (MH)+, 229 (M + NH4)+.

The above ester (3,45 g, 16 mm) hydrolyzing mainly by way of example 22 except that instead of the THF solvent is DMCO will receive 2-methoxy-3-nitrobenzoyl acid.

NMR (DMCO-d6): memorial plaques to 3.89 (s, 3H); 7,40 (t, 1H); 8,01 (DD, 1H); of 8.06 (DD, 1H).

Ms (Cl): 215 (M + NH4)+.

The above nitrosoaniline transferred to allyl ether mostly as in example 1, except that the product is sufficiently pure for use without chromatography was carried out, get allyl-2-methoxy-3-nitrobenzoate.

NMR (CDCl3): M. D. of 4.00 (s, 3H); a 4.86 (dt, 2H); 5,31-of 5.50 (m, 2H); 5,96-6,16 (m, 1H); 7,27 (d, 1H); 7,92 (DD, 1H); of 8.06 (DD, 1H).

Ms (Cl): 238 (MH)+, 255 (M + NH4)+.

The recovery obtained above nitro compounds by the method of example 1 receive allyl-3-amino-2-methoxime is); to 3.92 (broad, 2H), 4,82 (dt, 2H); 5,26-5,49 (m, 2H); 5,96-6,16 (m, 1H); 6,91 (DD, 1H); 7,00 (t, 1H); 7.23 percent (DD, 1H).

Ms (Cl): 208 (MH)+, 225 (M + NH4)+.

The result of the above amine condensed with Proline as in example 4, to obtain (2S, 4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-2 - methoxyphenylacetyl)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.30 (s, 3H); 2,53 (broad, 2H), 2,65 (broad, 1H); to 3.41 (DD, 1H); 3,86 (s, 3H); Android 4.04 (quintet, 1H); to 4.16 (DD, 1H); 4,58 (t, 1H); of 4.66 (d, 2H); a 4.83 (dt, 2H); 5,20-vs. 5.47 (m, 4H); of 5.83-6,13 (m covers a broad signal, 2H); 7,16 (t, 1H); of 7.60 (DD, 1H); to 8.57 (DD, 1H); 9.15, with the (broad, 1H).

Ms (+ve FAB): 463 (MH)+, 485 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to ethyl acetate, get allyl-(1R,5S,6S,8R,2'S, 4'S)-2-(1-allyloxycarbonyl-2- (3-allyloxycarbonyl-2-methoxyphenylacetyl)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); to 1.35 (d, 3H); 2,53 (broad, 1H); 2,68 (broad, 1H); 3.24 in (DD, 1H); or 3.28 (quintet, 1H); 3.43 points (broad, 1H); of 3.80 (quintet, 1H); a 3.83 (s, 3H); of 4.12 (m, 1H); 4,19-the 4.29 (overlapping m, 2H); of 4.57 (t, 1H); with 4.64 (m, 4H); a 4.83 (d, 2H); 5,18-of 5.48 (m, 6H); 5,81-6,14 (m, 3H); 7,17 (t, 1H); to 7.61 (DD, 1H); 8,56 (DD, 1H); 9,02 (wide is rbxi-2-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that DMF is replaced by DMCO.

NMR (DMCO-d6+ acetic acid-d4): memorial plaques to 1.19 (d, 6H); of 1.88 (m, partially closed, 1H); 2,31 (s, 3H); 2,77 (dt, 1H); of 2.93 (DD, 1H); up 3.22 (DD, 1H); 3.42 points (quintet, 1H); 3,57 (DD, 1H); of 3.77 (quintet, 1H); 4,01 (quintet, 1H); 4.16 the (t, 1H); 4,19 (DD, 1H); to 7.35 (d, 1H); of 7.69 (DD, 1H); 8,39 (d, 1H).

Ms (+ve FAB): 512 (MH)+, (Na salt), 534 (MH)+, (Na2salt), 556 (M + Na)+, (Na2salt).

The parent compound was obtained as follows.

4-Methyl-3-nitrobenzoic acid transferred in the allyl ether as in example 1, except that the chromatographic purification is not necessary, get allyl-4-methyl-3-nitrobenzoate.

NMR (DMCO-d6): memorial plaques at 2.59 (s, 3H); 4,84 (dt, 2H); 5,27-vs. 5.47 (m, 2H); 5,96-6,16 (m, 1H); to 7.67 (d, 1H); 8,16 (DD, 1H); 8,44 (d, 1H).

Ms (EI): 222 (MH)+.

The recovery obtained above nitro compounds by the method of example 2 except that the solvent is methanol, get allyl-3-amino-4-methylbenzoate sufficient purity for use without chromatography was carried out.

NMR (DMCO-d6): M. D. of 2.10 (s, 3H); 4,74 (dt, 2H); further 5.15 (broad, 2H); 5,22-5,43 (m, 2H); 5,93-6,12 (m, 1H);? 7.04 baby mortality (d, 1H); 7,11 (DD, 1H); 7,28 (d, 1H).

Ms (Cl): 192 (MH)+, 209 (M + NH4)+.

Obtained above amarpatan to a mixture of dichloromethane/diethyl ether (9:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methylphenylcarbinol)pyrrolidin-4-ylthioacetate.

NMR (DMCO-d6the mixture of rotamers): M. D. of 1.97 (quintet, 1H); and 2.26 (s, 3H); of 2.34 (s, 3H); 2,80 (broad, 1H); 3,30 (broad, 1H); 3,93-4,08 (broad m, 2H); 4.53-in (broad, 3H); 4,80 (dt, 2H); 5,10-5,44 (m, overlapping broad signal, 4H); 5,78-6,13 (m, overlapping broad signal, 2H); 7,38 (d, 1H); 7,72 (DD, 1H); 7,94 (wide, 0.5 H); 8,01 (wide, 0.5 H); being 9.61 (wide, 0.5 H); 9,67 (wide, 0.5 H).

Ms (Cl): 447 (MH)+, 464 (M + NH4)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/ethyl acetate (1:1), receive allyl-(1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl - 3-carboxylate.

NMR (DMCO-d6+ acetic acid-d4, mixture of rotamers): M. D. of 1.16 (d, 3H); of 1.18 (d, 3H); to 1.98 (quintet, 1H); and 2.27 (s, 3H); 2,86 (broad, 1H); with 3.27 (DD, 1H); 3.33 and (t, 1H); 3,56 (quintet, 1H); 3,95 (quintet, 1H); was 4.02 (DD, 1H); 4,15 (quintet, 1H); 4,27 (DD, 1H); 4,48 - 4,70 (overlapping m, 5H); 4,80 (d, 2H); 5,10 - of 5.45 (m, overlapping broad signal, 6H); 5,81 - 6,14 (m, overlapping broad signal, 3H); 7,38 (d, 1H); of 7.75 (DD, is 30. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3- carboxy-4-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that the DMF replaced DMCO.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.15 (d, 3H); to 1.16 (d, 3H); 1,78 (dt, 1H); 2,48 (s, 3H); 2,60 (dt, 1H); 2,90 (DD, 1H); 3,21 (DD, 1H); 3,39 (quintet, 1H); 3,49 (DD, 1H); to 3.73 (quintet, 1H); 3,99 (quintet, 1H); is 4.03 (t, 1H); to 4.17 (DD, 1H); 7.23 percent (d, 1H); of 7.70 (DD, 1H); to 8.12 (d, 1H).

Me (+ve FAB): 512 (MH)+, (Na salt), 534 (MH)+, (Na2salt), 556 (M + Na)+, (Na2salt).

The parent compound was obtained as follows.

2-Methyl-5-nitrobenzoic acid transferred in the allyl ether as in example 1, except that the chromatography was carried out is not necessary, get allyl-2-methyl-5-nitrobenzoate.

NMR (DMCO-d6): memorial plaques to 2.65 (s, 3H); 4,84 (dt, 2H); 5,28 - vs. 5.47 (m, 2H); 5,99 - 6,18 (m, 1H); the 7.65 (d, 1H); 8,31 (DD, 1H); to 8.57 (d, 1H).

Ms (Cl): 222 (MH)+, 099 (M + NH4)+.

The recovery obtained above nitro compounds by the method of example 2 except that the solvent is methanol, get allyl-5-amino-2-methylbenzoate sufficient purity for use without chromatography was carried out.

NMR (DMCO-d+
, 209 (M + NH4)+.

The result of the above amine condensed with Proline as in example 4, cleaned chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/diethyl ether (9:1) to give (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-methylphenylcarbinol)pyrrolidin-4-ylthioacetate.

NMR (DMCO-d6, mixture of rotamers): memorial plaques at 1.91 (broad m, 1H); 2,33 (c, 3H); was 2.76 (broad m, 1H); 3,28 (overlapping m, 4H); 4,00 (broad m, 2H); to 4.38 (t, 1H); 4,51 (broad, 2H); 4,78 (dt, 2H); 5,01 - 5,46 (m, overlapping broad signal, 4H); 5,68 - 6,16 (m, overlapping broad signal, 2H); 7,27 (d, 1H); 7,72 (DD, 1H); 8,11 (wide, 0.5 H); 8,05 (wide, 0.5 H); 10,17 (broad, 1H).

Ms (+ FAB): 447 (MH)+, 469 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/ethyl acetate (1:1), receive allyl-(1R, 5S, 6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2- (3-allyloxycarbonyl-4-methylphenylcarbinol) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (DMCO-d6+ acetic acid-d4): memorial plaques to 1.19 (d, 6H); 1,92 (broad, partially closed, 1H); 2,48 (s, 3H); and 2.79 (broad, 1H); of 3.25 (DD, 1H); of 3.32 (t, 1H) - ,13 (m, overlapping broad signal, 3H); to 7.25 (d, 1H); 7,76 (DD, 1H); 8,12 (broad m, 1H).

Ms (+ve FAB): 654 (MH)+, 676 (M + Na)+.

Example 31. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3- carboxy-5-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid. Allyl-(1R,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5 - methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate (3 g, 4,59 mm) and 2,2-dimethyl-1,3-dioxane-4,6-dione (of 3.97 g, 27,6 mm) dissolved in a mixture DMCO (15 ml) and THF (5 ml) in argon atmosphere, then added tetrakis(triphenylphosphine)palladium (531 mg, 0.46 mm). The solution is stirred in an argon atmosphere, protected from light for 1 h Add a solution of 2-ethylhexanoate sodium (1,53 g; which 9.22 mm) in THF (5 ml) and then THF (250 ml). The precipitate is filtered off under argon shirt, excluding moisture, and washed successively with two small portions of THF (twice) and diethyl ether. The crude product and NaHCO3(1.5 g) dissolved in water (100 ml) and the solution chromatographic on HP20SS-resin, using gradient elution with a mixture of water/acetonitrile (10: 0 to 9:1). The appropriate fractions are combined and dried by freezing, getting the disodium salt of (1R, 5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-m is O-d6+ acetic acid-d4): M. D. of 1.13 (d, 3H); to 1.15 (d, 3H); 1,76 (dt, 1H); 2,32 (s, 3H); in 2.68 (dt, 1H); 2,87 (DD, 1H); 3,18 (DD, 1H); 3,36 (quintet, 1H); of 3.45 (DD, 1H); 3,71 (quintet, 1H); 3,95 (quintet, 1H); was 4.02 (t, 1H); to 4.14 (DD, 1H); 7,49 (s, 1H); the 7.65 (s, 1H); with 8.05 (s, 1H).

Ms (+ve FAB): 512 (MH)+, (Na salt), 534 (MH)+, (Na2salt), 556 (M + Na)+, (Na2salt).

The parent compound was obtained as follows.

3-Methyl-5-nitrobenzoic acid. 3,5-Dimethylnitrobenzene (30 g, 0,198 M) is heated with stirring to 80oin a mixture of pyridine (400 ml) and water (250 ml). Add KMnO4(62,7 g, 0,396 M) portions through the 0.75 h and continue heating at 85 - 90oin a period of 1.75 hours the Warm solution is filtered through celite, washed with warm water (150 ml). Pink filtrate discolor a few drops of sodium metabisulfite and evaporated to dryness. The residue is dissolved in water (250 ml) and extracted with diethyl ether (290 ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3120 ml). The combined organic extract is washed with a solution of NaH2PO4, with brine and dried over MgSO4. The crude product elute through the packing of silica, using a mixture of ethyl acetate/dichloromethane/acetic acid (25: 25: 1), receive 3-is (t, 1H); 8,42 (t, 1H); of 13.58 (broad, 1H).

Ms (Cl): 181 (MH)+.

3-Methyl-5-nitrobenzoic acid transferred in the allyl ether as in example 1, except that the chromatography was carried out is not necessary, get allyl-3-methyl-5-nitrobenzoate.

NMR (CDCl3): M. D. of 2.53 (s, 3H); 4,87 (dt, 2H); 5,31 - of 5.48 (m, 2H); 5,99 - 6,13 (m, 1H); to 8.20 (s, 1H); 8,23 (s, 1H); 8,68 (s, 1H).

Ms (Cl) : 222 (MH)+.

The recovery obtained above nitro compounds by the method of example 1 receive allyl-5-amino-3-methylbenzoate, sufficiently pure for use without chromatography was carried out.

NMR (CDCl3): M. D. of 2.30 (s, 3H); 3.46 in (broad, 2H); 4,78 (dt, 2H); 5,23 - of 5.45 (m, 2H); 5,93 - 6,12 (m, 1H); of 6.68 (t, 1H); 7,17 (t, 1H); 7,27 (t, 1H).

Ms (Cl): 192 (MH)+, 220 (M + C2H5)+.

The result of the above amine condensed with Proline as in example 4, cleaned chromatography, using as eluent a mixture of hexane/ethyl acetate (3: 1), obtain (2S, 4S)-1-allyloxycarbonyl-2- (3-allyloxycarbonyl-5-methylphenylcarbinol)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.33 (s, 3H); 2,39 (s, 3H); 2,58 (broad, 2H); 3,29 (DD, 1H); was 4.02 (quintet, 1H); 4,13 (DD, 1H); 4,56 (t, 1H); 4,68 (DM, 2H); 4,82 (dt, 2H); 5,23 - 5,44 (m, 4H); 5,68 - 6,12 (m, 2H); 7,63 (s, 1H); a 7.85 (s, 1H); the 7.85 (s, 1H); which is 9.09 (broad, 1H).

Ms (+ FA is in example 1, clean chromatography using a gradient solvent dichloromethane/ethyl acetate (3:2 to 2:3), receive allyl-(1R,5S,6S, 8R, 2'S, 4'S)-2-(1-allyloxycarbonyl-2-(3- (allyloxycarbonyl-5-methylphenylcarbinol)-pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.23 (d, 3H); to 1.35 (d, 3H); of 2.38 (s, 3H); 2.63 in (broad, 2H); 3,23 (DD, 1H); 3.27 to (quintet, 1H); 3.46 in (broad, 1H); of 3.78 (quintet, 1H); 4,00 (DD, 1H); 4,24 (overlapping m, 2H); 4,51 (t, 1H); 4,59-4,63 (m, 4H); 4,79 (d, 2H); 5,17-5,42 (m, 6H); of 5.82-6,09 (m, 3H); to 7.61 (s, 1H); 7,73 (s, 1H); 7,99 (c, 1H); 8,87 (broad, 1H).

Ms (+ve FAB): 654 (MH)+.

Example 32. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methoxycarbonylpropionyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that the DMF replaced DMCO.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.18 (d, 6H); 1,92 (wide partially closed, 1H); of 2.81 (m, 1H); 3,03 (DD, 1H); 3,23 (DD, 1H); to 3.41 (quintet, 1H); 3,61 (m, 1H); 3,90 (overlapping m, 4H); 4,00 (quintet, 1H); 4,21 (overlapping m, 2H); of 8.25 (t, 1H); and 8.50 (m, 2H).

Ms (+ve FAB): 556 (MH)+, (Na salt), 578 (MH)+(Na2salt).

The initial substance was obtained as follows.

3-Methoxycarbonyl-5-nitrobenzoic acid transfer is Oh, get allyl-3-methoxycarbonyl-5-nitrobenzoate.

NMR (DMCO-d6): M. D. of 3.97 (s, 3H); 4,91 (dt, 2H); 5,31-5,51 (m, 2H); 6,00-to 6.19 (m, 1H); is 8.75 (t, 1H); 8,81 (d, 2H).

Ms (EI): 265 M+.

The recovery obtained above nitro compounds by the method of example 2, except that the solvent is methanol, get allyl-3-amino-5-methoxycarbonylbenzyl sufficient purity for use without chromatography was carried out.

NMR (DMCO-d6): M. D. 3,79 (broad, 2H); to 3.92 (s, 3H); 4,82 (dt, 2H); 5,26-5,46 (m, 2H); 5,94-6,14 (m, 1H); 7,53 (m, 2H); 8,07 (t, 1H).

Ms (Cl): 236 (MH)+, 253 (M + NH4)+.

The result of the above amine condensed with Proline as in example 1, peeling chromatography, using a gradient elution solvent from dichloromethane to a mixture of dichloromethane/diethyl ether (9:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5 - methoxycarbonylpropionyl)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.33 (s, 3H) (broad, 2H); 3.40 in (DD, 1H); of 3.94 (s, 3H); Android 4.04 (quintet, 1H); to 4.14 (DD, 1H); 4,58 (t, 1H); 4,68 (DM, 2H); 4,85 (dt, 2H); 5.25-in vs. 5.47 (m, 4H); 5,85-6,16 (m, 2H); at 8.36 (t, 1H); 8,43 (m, 2H); 9,40 (broad, 1H).

Ms (+ve FAB): 491 (MH)+, 513 (M + Na)+.

(2S, 4S)-1-Allyloxycarbonyl-2-(3-allyloxycarbonyl-5 - methoxycarbonyl ethylamine (33% weight/volume, 0.51 g, 5.4 mm). Stirring is continued for 3 h, and then remove the solvent. The residue is treated with 2 M hydrochloric acid and extracted with ethyl acetate. The organic solution is washed with water, saline, aqueous NaHCO3and dried over MgSO4. Removal of solvent gives (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5 - methoxycarbonylpropionyl)pyrrolidin-4-ILTER (1,02 g, 93%). Thiol condense without further purification with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/ethyl acetate (1:1), receive allyl-(1R, 5S, 6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonyl - 5-methoxycarbonylpropionyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); to 1.37 (d, 3H); 2,64 (broad, 2H); 3,26 (DD overlapping quintet, 2H); 3,48 (broad, 1H); 3,86 (quintet, 1H); 3,94 (overlapping m, 4H); 4.25 in (quintet, 1H); 4,29 (DD, 1H); 4,56 (t, 1H); 4,69 (m, 4H); 4,86 (DM, 2H); 5,19-5,46 (m, 6H); 5,85-6,13 (m, 3H); 8,46 (m, 3H); 9,18 (broad, 1H).

Ms (+ve FAB): 698 (MH)+, 720 (M + Na)+.

Example 33. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2- (5-carboxy-2,4-differencemaker)pyrrolidin-4-ylthio)-6- (1-oxyethyl)-1-methylcarbamoyl-3-carboxylic kislotno closed 1H); of 2.81 (m, 1H); 3,14 (DD, 1H); with 3.27 (DD, 1H); 3.43 points (quintet, 1H); to 3.73 (m, 1H); 3,91 (quintet, 1H); Android 4.04 (quintet, 1H); to 4.23 (DD, 1H); 4,43 (t, 2H); 7,29 (m, 1H); 8,54 (t, 1H).

Ms (+ve FAB): 534 (MH)+, (Na salt), 556 (MH)+, (Na2salt).

The parent compound was obtained as follows.

2,4-Debtor-5-nitrobenzoic acid. 2,4-Differentyou acid (5 g, 0,031 M) is dissolved in concentrated sulfuric acid (30 ml) and cooled to 0o. The mixture is stirred and add one drop of fuming nitric acid (1,567 g/ml, at 1.91 ml, 0,047 M), keeping the temperature below 5o. After stirring for 3 h the mixture was poured into ice and extracted with organic dichloromethane (2 75 ml). The combined organic layer was washed with water, dried with MgSO4and evaporated, receiving 2,4-debtor-5-nitrobenzoic acid (3.9 g, 61%).

NMR (DMCO-d6): memorial plaques to 7.18 (t, 1H); 8,88 (t, 1H); to 9.93 (broad, 1H).

Ms (-FAB): 202 (M - H)-.

2,4-Debtor-5-nitrobenzoic acid transferred in the allyl ether as in example 1 except that the reaction time 1.5 h, the DMF before use mix over an ion-exchange resin 1R-120-H and chromatographic purification is not necessary. Get allyl-2,4-debtor-5-nitrobenzoate.

NMR (CDCl

NMR (CDCl3); 3,61 (broad, 2H); to 4.81 (dt, 2H); 5,26-of 5.48 (m, 2H); of 5.92-6,12 (m, 1H); 6,83 (t, 1H); 7,38 (DD, 1H).

Ms (Cl): 214 (MH)+, 231 (M + NH4)+.

The result of the above amine condensed with Proline as in example 1, peeling chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/diethyl ether (9:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl - 2,4-differencemaker)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. of 2.33 (s, 3H); 2.63 in (broad, 2H); 3,39 (DD, 1H); Android 4.04 (quintet, 1H); to 4.14 (DD, 1H); 4,59 (t, 1H); of 4.66 (dt, 2H); a 4.83 (dt, 2H); 5,22-5,49 (m, 4H); of 5.84-6,13 (m, 2H); 6,94 (t, 1H); 8,82 (t, 1H); which 9.22 (broad, 1H).

Ms (+ FAB): 469 (MH)+, 491 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/ethyl acetate (1:1), receive allyl-(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(1-allyloxycarbonyl-2-(5-allyloxycarbonyl - 2,4-differencemaker)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-METI quintet, 2H); of 3.45 (DD, 1H); 3,88 (quintet, 1H); is 4.03 (DD, 1H); 4.25 in (quintet, 1H); 4,29 (DD, 1H); of 4.57 (t, 1H); and 4.68 (m, 4H); 4,82 (DM, 2H); to 5.21-of 5.48 (m, 6H); 5,85-6,10 (m, 3H); 6,94 (t, 1H); cent to 8.85 (t, 1H); 9,12 (broad, 1H).

Ms (+ve FAB): 676 (MH)+, 698 (M + Na)+.

Example 34. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(5-carboxy-2,4-dimethoxyphenylacetic) pyrrolidin-4-ylthio)-6-(1 - oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.20 (d, 6H); 1,95 (m, partially closed, 1H); 2,87 (dt, 1H); is 3.08 (DD, 1H); 3,26 (DD, 1H); to 3.41 (quintet, 1H); 3,71 (DD, 1H); a 3.87 (quintet, partially closed, 1H); 3,91 (s, 3H); of 3.96 (s, 3H); is 4.03 (quintet, 1H); is 4.21 (DD, 1H); 4,39 (t, 2H); 6,76 (s, 1H); 8,44 (s, 1H).

Ms (+ve FAB): 558 (MH)+, (Na salt), 580 (MH)+, (Na2salt).

The parent compound was obtained as follows.

2,4-Dimethoxy-5-nitrobenzoic acid. A solution of sodium methylate is obtained by dissolution of metallic sodium (1.42 g, 0,062 M) in methanol (40 ml) under cooling. Add the allyl-2,4-debtor-5-nitrobenzoate and the mixture is stirred for 2 hours Add a solution of NaOH (2 g, 0,05 M) in water (10 ml) and the mixture is stirred at room temperature for 16 hours the Solvent is evaporated, the residue is dissolved in water (50 ml) and extracted with diethyl ether (40 ml). The aqueous layer is 23 g, 91%).

NMR (CDCl3): M. D. 4,07 (s, 3H); 4.16 the (s, 3H); 6,62 (s, 1H); 8,81 (s, 1H).

Ms (Cl) : 228 (MH)+, 245 (M + NH4)+.

2,4-Dimethoxy-5-nitrobenzoic acid transferred in the allyl ether as in example 1, except that the chromatographic purification is not necessary, get allyl-2,4-dimethoxy-5-nitrobenzoate.

NMR (CDCl3): as 4.02 (s, 3H); Android 4.04 (s, 3H); 4,79 (dt, 2H); 5,26-5,46 (m, 2H); 5,93-6,13 (m, 1H); is 6.54 (s, 1H); 8,63 (s, 1H).

Ms (+FAB): 268 (MH)+, 290 (M + Na)+.

The recovery obtained above nitro compounds by the method of example 1 receive allyl-5-amino-2,4-dimethoxybenzoate.

NMR (CDCl3): M. D. of 3.25 (broad, 2H); a 3.87 (s, 3H); 3,90 (s, 3H); was 4.76 (dt, 2H); 5,22-5,46 (m, 2H); 5,93-6,12 (m, 1H); 6,47 (s, 1H); 7.29 trend (s, 1H),

Ms (Cl): 238 (MH)+.

The result of the above amine condensed with Proline as in example 4, cleaned chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/diethyl ether (4:1), obtain (2S,4S)-1-allyloxycarbonyl-2-(5-allyloxycarbonyl-2,4 - dimethoxyphenylacetic)pyrrolidin-4-ylthioacetate.

NMR (CDCl3): M. D. 2,32 (s, 3H); 2.49 USD (broad, 1H); 2,64 (broad, 1H); 3.40 in (DD, 1H); 3,91 (s, 3H); 3,93 (s, 3H); 4,00 (quintet, 1H); to 4.17 (DD, 1H); 4.53-in (t, 1H); with 4.64 (d, 2H); of 4.77 (dt, 2H); 5,19-5,46 (m, 4H); 5,80-6,14 (m, peceny above thioacetate will deacetylases and condense with carbapenemases, as in example 1, peeling chromatography using a gradient solvent from dichloromethane to ethyl acetate, getting allyl-(1R,5S,6S,8R,2'S, 4'S)-2-(1-allyloxycarbonyl - 2-(5-allyloxycarbonyl-2,4-dimethoxyphenylacetic)pyrrolidin-4 - ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): memorial plaques to 1.22 (d, 3H); of 1.36 (d, 3H); 2,48 (broad, 1H); to 2.65 (broad, 1H); 3,23 (DD, 1H); or 3.28 (quintet, 1H); 3.43 points (DD, 1H); of 3.80 (quintet, 1H); 3,91 (s, 3H); to 3.92 (s, 3H); 4.09 to (DD, 1H); 4,24 (quintet, 1H); 4,27 (DD, 1H); 4,51 (t, 1H); of 4.66 (m, 4H); of 4.77 (dt, 2H); 5,20-of 5.45 (m, 6H); of 5.83-6,11 (m, overlapping broad signal, 3H); of 6.49 (s, 1H); to 8.45 (broad, 1H); 8,82 (s, 1H).

Ms (+ve FAB): 700 (MH)+.

Example 35. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2- (5-carboxy-2-cyanovinylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1 - methylcarbamoyl-3-carboxylic acid obtained by the method of example 2 except that DMF is replaced by DMCO.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.17 (d, 6H); to 1.83 (m, partially closed, 1H); 2,62-2,79 (overlapping m, 2H); 3,18 (DD, 1H); to 3.41 (quintet, 1H); 3,66 (quintet, 1H); 3,98 (quintet, 1H); 4,07 (DD, 1H); to 4.17 (DD, 1H); 7,79 (m, 2H); 8,67 (s, 1H).

Ms (+ve FAB): 523 (MH)+, (Na salt), 545 (MH)+, (Na2salt)

The initial substance was obtained as follows.

4-Cyano-3-nitrobenzoic acid. 4-Chloro-3 who are in an argon atmosphere at 180owithin 3.5 hours After cooling, the mixture is dissolved in concentrated hydrochloric acid (60 ml), diluted with water (80 ml) and extracted with ethyl acetate (3100 ml). The combined organic layer was washed with water NaH2PO4, with brine and dried over MgSO4. The crude product is cleaned chromatography on silica, elwira a mixture of dichloromethane/acetic acid (98:2) to give 4-cyano-3-nitrobenzoic acid (2.65 g, 48%).

NMR (DMCO-d6): M. D. 8,31 (d, 1H); to 8.41 (DD, 1H); 8,68 (d, 1H).

Ms (EI): 192 M+.

Obtained above nitrocellose transferred to allyl ether as in example 1, clean the crude product chromatography on silica using as eluent a mixture of hexane/ethyl acetate (6:1), receive allyl-4-cyano-3-nitrobenzoate.

NMR (CDCl3): M. D. 4,93 (dt, 2H); lower than the 5.37-of 5.50 (m, 2H); 5,97-6,13 (m, 1H); 8,03 (d, 1H); 8,46 (DD, 1H); to 8.94 (d, 1H).

Ms (Cl): 221 (MH)+, 250 (M + NH4)+.

The recovery obtained above nitro compounds by the method of example 1 allyl-3-amino-4-carbamoylmethyl, recrystallized from a mixture of ethyl acetate/petrol, so pl. 149-150o.

NMR (DMCO-d6): M. D. of 4.77 (dt, 2H); 5.25 to 5,43 (m, 2H); 5,96-6,11 (m, 1H); 6,72 (broad, 2H);? 7.04 baby mortality (DD, 1H); to 7.25 (broad, 1H); to 7.35 (d, 1H); 7,63 (d, 1H); 7,87 (re 1, clean chromatography using hexane/ethyl acetate (1:1), obtain (2S, 4S)-1-allyloxycarbonyl-2- (5-allyloxycarbonyl-2-carbamoylbiphenyl)pyrrolidin-4-ylthioacetate.

NMR (CDCl3, mixture of rotamers): M. D. of 2.25 (quintet, 1H); of 2.28 (s, 3H); 2,82 (broad, 1H); to 3.52 (DD, 1H); 4,13 (t, 1H); 4,20 (broad m, 1H); to 4.52 (DD, 1H); br4.61 (broad, 2H); 4,85 (d, 2H); 5,01-of 5.48 (m, overlapping broad signal, 4H); 5,66-6,12 (m, overlapping broad signal, 2H); 6,55 (broad, 1H); 6.89 in (broad, 1H); to 7.64 (broad m, 1H); 7,79 (broad m, 1H); of 9.30 (broad m, 1H); 11,68 (wide, 0.5 H); 12,06 (wide, 0.5 H).

Ms (+ve FAB): 476 (MH)+.

(2S, 4S)-1-Allyloxycarbonyl-2-(5-allyloxycarbonyl-2 - cyanovinylene)pyrrolidin-4-ylthioacetate. DMF (0.2 ml, 2.5 mm) was dissolved in acetonitrile (10 ml), cooled to -5oand treat oxalylamino (0.2 ml, 2.3 mm). After stirring for 30 min add a solution of (2S,4S)-1-allyloxycarbonyl-2- (5-allyloxycarbonyl-2-carbamoylbiphenyl)-pyrrolidone-4 - ylthioacetate (1 g, 2.1 mm) in acetonitrile (15 ml) and then pyridine (0,38 ml, 4.6 mm). After 15 min the mixture was diluted with ethyl acetate (200 ml), washed with hydrochloric acid (2 M, 20 ml), water, aqueous NaHCO3and with brine and dried over Na2SO4. The crude product is clean chromatographic, primeni-2 - cyanovinylene)pyrrolidin-4-ylthioacetate (0.9 g, 93%).

NMR (CDCl3): M. D. 2,32 (s, 3H); 2.63 in (broad, 2H); 3.46 in (DD, 1H); 4,06 (quintet, 1H); to 4.16 (DD, 1H); with 4.64 (t, 1H); 4,71 (dt, 2H); 4,85 (dt, 2H); 5,22-vs. 5.47 (m, 4H); by 5.87-6,14 (m, 2H); to 7.67 (d, 1H); 7,87 (DD, 1H); 8,96 (d, 1H); 9,42 (broad, 1H).

Ms (+ve FAB): 458 (MH)+, 480 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to ethyl acetate, get allyl-(1R,5S,6S,8R,2'S, 4'S)-2-(1-allyloxycarbonyl)-2- (3-allyloxycarbonyl-2-methoxyphenylacetyl)pyrrolidin-4-ylthio) -6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); to 1.35 (d, 3H); 2,60 (broad, 2H); 3.25 to (DD overlapping quintet, 2H); 3,52 (broad, 1H); 3,88 (quintet, 1H); was 4.02 (DD, 1H); 4.25 in (quintet, 1H); to 4.28 (DD, 1H); 4,55-4,74 (m, 5H); 4,85 (dt, 2H); 5,18-5,468 (m, 6H); of 5.83-6,11 (m, 3H); the 7.65 (dt, 1H); 7,87 (DD, 1H); 9,00 (broad s, 1H); 9,25 (broad, 1H).

Ms (+ve FAB): 665 (MH)+, 687 (M + Na)+.

Example 36. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that the DMF replaced DMCO.

NMR (DMCO-d6+ acetic acid-d4): M. D. of 1.20 (d, 6H); 1,99 (dt, 1H); 2.91 in (dt, is 1.81 (DD, 1H); 8,00 (t, 1H).

Ms (+ve FAB): 516 (MH)+, (Na salt), 538 (MH)+, (Na2salt).

The initial substance was obtained as follows.

2-Fluoro-5-nitrobenzoic acid. Intensively mixed paste nitrosodiethanolamine (3,53 g, 30.2 mm) in acetonitrile (50 ml) cooled in an ice bath in an argon atmosphere and add three servings of 3-amino-5-nitrobenzoic acid (5.0 g, 27,5 mm). Then allow the temperature to rise to room values and stirred the mixture for 48 hours Add 1,2-dichlorobenzene (50 ml) and distilled from a mixture of acetonitrile under reduced pressure. The mixture is then heated to +170owithin 30 min, when the formation of gas. After cooling, the mixture was poured into dichloromethane (200 ml) and extracted with a solution of NaHCO3. After washing the aqueous phase with dichloromethane her acidified (2 M hydrochloric acid and the organics extracted with ethyl acetate (2 100 ml). The combined organic layer is washed with brine and dried over MgSO4. The crude product is cleaned chromatography on silica, elwira gradient method from a mixture of dichloromethane/acetic acid (99:1) to a mixture of dichloromethane/isopropanol/acetic acid (80:20:1), receive 3-fluoro-5-nitrobenzoic acid (3,26 g, 64%).oa molecular sieve. After cooling, the mixture is neutralized with triethylamine and remove the solvent. The residue is dissolved in ethyl acetate, washed with 2 M hydrochloric acid, aqueous NaHCO3and with brine and dried over MgSO4. The crude product is cleaned chromatography on silica using gradient elution solvent from dichloromethane to a mixture of dichloromethane/ethyl acetate (1:3), receive allyl-3-fluoro-5-nitrobenzoate.

NMR (CDCl3): M. D. 4,89 (dt, 2H); 5,33-5,49 (m, 2H); 5,95-x 6.15 (m, 1H); 8,11 (m, 2H); to 8.70 (t, 1H).

Ms (Cl): 226 (MH)+, 253 (M + C2H5)+.

The recovery obtained above nitro compounds by the method of example 1 receive allyl-3-amino-5-perbenzoate.

NMR (CDCl3): memorial plaques to 3.89 (broad, 2H); 4,79 (dt, 2H); 5.25 to the 5.45 (m, 2H); of 5.92-6,12 (m, 1H); is 6.54 (dt, 1H); 7,07-to 7.15 (m, 2H).

Ms (Cl): 196 (MH)+< / BR>
The result of the above amine condensed with Proline as in example 1, peeling chromatography using a gradient solvent from dichloromethane to a mixture of dichloromethane/diethyl ether (85:13), obtain (2S,4S)-1-allyloxy is of 2.33 (s, 3H); 2,59 (broad, 2H); of 3.48 (DD, 1H); is 4.03 (quintet, 1H); 4,13 (DD, 1H); 4,56 (t, 1H); and 4.68 (dt, 2H); 4,82 (dt, 2H); 5.25 to 5,46 (m, 4H); 5,86-6,11 (m, 2H); 6,47 (dt, 1H); 7,72 (t, 1H); 7,87 (dt m, 1H); 9,38 (broad, 1H).

Ms (+ve FAB): 451 (MH)+, 473 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography using a gradient solvent from dichloromethane to ethyl acetate, get allyl-(1R,5S,6S,8R,2'S, 4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3): M. D. of 1.24 (d, 3H); of 1.36 (d, 3H); 2.63 in (broad, 2H); 3,26 (DD, 1H); 3,29 (quintet, 1H); 3,48 (broad, 1H); 3,81 (quintet, 1H); of 3.97 (DD, 1H); 4,27 (DD overlapping m, 2H); of 4.54 (t, 1H); 4,62 was 4.76 (m, 4H); to 4.81 (dt, 2H); 5,20-5,46 (m, 6H); 5,85-6,10 (m, overlapping broad signal, 3H); of 7.48 (dt, 1H); 7,83 (broad s, 1H); 7,88 (dt, 1H); 9,18 (broad, 1H).

Ms (+ve FAB): 658 (MH)+, 680 (M + Na)+.

Example 37. Disodium salt of (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-N'-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid obtained by the method of example 2, except that the DMF replaced DMCO, the product is cleaned by a method chromatography on a column of CHP20P, elwira water.

NMR (DMCO-d6 is d, 1H); 3,28 (overlapping m, 5H); the 3.65 (broad, 1H); 3,98 (quintet, overlapping m, 2H); 4,12 (DD, 1H); 7,58 (d, 1H); to $ 7.91 (d, 1H); 7,98 (m, 1H).

Ms (+ve FAB): 512 (MH)+, (Na salt), 534 (MH)+, (Na2salt).

The parent compound was obtained as follows.

Allyl-3-methylaminomethyl. Allyl-3-aminobenzoate (5 g, 28,2 mm) dissolved in triethylorthoformate (50 ml) and add triperoxonane acid (5 drops). The solution is stirred and refluxed in 3oa molecular sieve for 5 hours to Remove the solvent and the residue is dissolved in ethanol (50 ml), and then add acetic acid (8,08 ml) and cyanoborohydride sodium (6.85 g, to 0.108 M) in several portions. The mixture is stirred at room temperature for 16 h to remove the solvent. The residue is dissolved in diethyl ether, washed with water, with brine and dried over MgSO4. The crude product is cleaned chromatography over silica, elute with a gradient solvent from dichloromethane to a mixture of dichloromethane/ethyl acetate (95:5) to give allyl-3-methylaminomethyl (0,93 g, 17%).

NMR (CDCl3): M. D. is 2.88 (s, 3H); to 4.81 (dt, 2H); 5,23-of 5.45 (m, 2H); 5,94-6,13 (m, 1H); 6,83 (DD, 1H); to 7.25 (DD, 1H); 7,33 (t, 1H); 7,43 (DM, 1H).

Ms (Cl): 192 (MH)+.

Obtained above changing gradient elution solvent from dichloromethane to a mixture of dichloromethane/diethyl ether (4: 1), obtain (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbonyl-N'-methylphenylcarbinol)pyrrolidin-4-ylthioacetate.

NMR (CDCl3the mixture of rotamers): M. D. of 1.93 (m, 1H); 2,32 (s, 3H); 2,48 (m, partially closed, 1H); 3,28, 3,31 (2 s, 3H); 3.40 in (quintet, 1H); 3,76 (m, 1H); 4,01 (m, 1H); 4,24 (m, 1H); 4,50-4,74 (m, 2H); a 4.86 (d, 2H); 5,18-of 5.48 (m, 4H); of 5.84 6,13 (m, 2H); 7,38-to 7.68 (m, 2H); of 7.90-8,11 (m, 2H).

Ms (+ve FAB): 447 (MH)+, 469 (M + Na)+.

The above thioacetate will deacetylases and condense with carbapenemases as in example 1, peeling chromatography, using a gradient elution solvent from dichloromethane to ethyl acetate, get allyl-(1R, 5S, 6S, 8R,2'S,4'S )- 2-(1-allyloxycarbonyl-2-(3-allyloxycarbonyl-N'- methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylate.

NMR (CDCl3, mixture of rotamers): M. D. 1,20 (2 d, 3H); 1,34 (2 d, 3H); to 1.87 (broad, 1H); 2,30 (broad, 1H); 3,29, 3,31 (2 with overlapping m, 6H); 4,05-4,30 (m, 4H); 4,50-to 4.81 (m, 5H); 4,96 (d, 2H); 5,20-of 5.48 (m, 6H); 5,85-6,13 (m, 3H); 7,39-to 7.68 (m, 2H); to $ 7.91-8,11 (m, 2H).

Ms (+ve FAB): 654 (MH)+, 676 (M + Na)+.

1. Derivatives carbapenem General formula I

< / BR>
in which R1- oxymethyl or 1-oxyethyl;

R2is hydrogen or (C1- C4)-alkyl;

R3is hydrogen or (C1- C4)-alkyl;1
- C4)-alkyl, hydroxy-group, carboxypropyl, (C1- C4)alkoxygroup, (C1- C4)alkoxycarbonyl, carbarnoyl, (C1- C4)allylcarbamate, di(C1- C4)allylcarbamate, trifluoromethyl, sulfonylurea group, (C1- C4)alkylamino, di(C1- C4)alkylamino, (C1- C4)alkanolamines, (C1- C4)alkanoyl [N-(C1- C4)alkyl]amino, (C1- C4)alkanesulfonyl, (C1- C4)alkylsulfonyl, (C1- C4)allylthiourea and (C1- C4)alkylsulfonyl provided that in anthopology K-N-R3the group has no hydroxyl or carboxyl substituent, their pharmaceutically acceptable salts and hydrolyzable in vivo ethers.

2. Connection on p. 1, in which R1- 1-oxyethyl.

3. Connection PP.1 and 2, in which R2is hydrogen or methyl.

4. Connection PP.1 and 2, in which R2is methyl.

5. Connection PP.1 to 4, in which R3- hydrogen.

6. Connection PP.1 - 5 of General formula IV

< / BR>
in which R3, R4and R5are as defined in paragraph 1.

7. Connection on p. 6, cotorobai, methyl, ethyl, metoxygroup, ethoxypropan, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifloromethyl, sulfoxylates group, methylsulfinyl group, methylsulfonyl group, methanesulfonamido or acetaminopen.

8. Connection PP.6 and 7, in which at least one of R4and R5is hydrogen.

9. Connection on p. 6, in which R4is hydrogen, carboxyl, fluorine, chlorine, methyl, methoxy group, cyano, sulfonylurea group or methoxycarbonyl, and R5- hydrogen.

10. Connection on p. 1, representing one of the following connections:

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-oxiranylmethyl) pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-chlorpheniramol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-chlorpheniramol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S,4'S)-2-(2-(3-carboxy-6-methane-sulfonylpiperidinylmethylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-2,4-differencemaker)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3,4-dicarboxylicacid)-pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-oxiranylmethyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S,4'S)-2-(2-(3,5-dicarboxylicacid)-pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(2-carbarnoyl-3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-carbamoylbiphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-carbamoylbiphenyl)pyrrolidin-4-ylthio)-6-(1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-acetaminophenramadol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-acetamidophenyl the C-5-methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-sulfophenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-carbamoylbiphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-2-dimethylaminocarbonylmethyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(5R, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)carbapenem-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-methylphenylcarbinol)pyrrolidin-4-ylthio-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-2-methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-metoxy(3-carboxy-6-methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4,6-dimethoxycinnamoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-methoxycarbonylpropionyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-cyanovinylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-cryptomaterial)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4,6-differencemaker)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-methylsulfinylphenyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-methylsulfonylbenzoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-cyanoaniline)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R the PTA or their pharmaceutically suitable salts.

11. Connection on p. 1, characterized in that it is

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-methylphenylcarbinol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-methoxyphenylacetyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-methoxy-phenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-Carboniferous)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-cyanovinylene)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-chlorpheniramol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-4-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-6-tortenelmebol)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3,5-dicarboxylicacid)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

(1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxy-5-sulfophenylazo)pyrrolidin-4-ylthio)-6-(1-oxyethyl)-1-methylcarbamoyl-3-carboxylic acid,

or their pharmaceutically suitable salts.

12. (1R, 5S, 6S, 8R, 2'S, 4'S)-2-(2-(3-carboxyphenylazo)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbamoyl-3-carboxylic acid, or its pharmaceutically acceptable salt or hydrolyzable in vivo broadcast.

13. Connection on p. 12 in the form of a carboxylic acid.

14. Connection on p. 12 in the form of a monosodium salt.

15. Connection on p. 12 in the form of a disodium salt.

16. Connection on p. 12, which is a mixture of monosodium salt and disodium salt.

17. Pharmaceutical composition having antibacterial activity, containing the active principle is a derivative of 2-(pyrrolidin-4-yl)thio-substituted carbapenem and a pharmaceutically acceptable carrier, characterized in that the active agent it contains an effective amount of the compounds of General formula I according to any one of paragraphs.1 - 16, or its pharmaceutically acceptable salt or hydrolyzable in vivo ether.

19. The pharmaceutical composition under item 17, characterized in that the active agent it contains a connection on p. 13, or its pharmaceutically acceptable salt or hydrolyzable in vivo broadcast.

20. The pharmaceutical composition under item 17, characterized in that the active agent it contains a connection on p. 14.

21. The pharmaceutical composition under item 17, characterized in that the active agent it contains a connection on p. 15.

22. The pharmaceutical composition under item 17, characterized in that the active agent it contains a mixture of salts under item 16.

23. The method of obtaining compounds of General formula I, as described in paragraph 1, and their pharmaceutically acceptable salts and esters, hydrolyzable in vivo, characterized in that the compound of General formula V

< / BR>
where R2, R4and R5are as defined in paragraph 1, and R4and R5if necessary, can be protected;

-COOR6and-COOR7represent a carboxyl group or a protected carboxyl group;

R8are R3defined in paragraph 1, or aminoamide defined in paragraph 1, the protected oxymethyl or protected 1-oxyethyl,

moreover, the connection has at least one protective group,

subjected to removal of the protective group and, if necessary, the obtained target product was transferred to its pharmaceutically acceptable salt and/or etherification with the formation of ether, hydrolyzable in vivo.

24. Protected derivatives carbapenem in General formula V, as defined in paragraph 23.

25. The compound of General formula Y on p. 24, where R2is methyl, R10- 1-oxyethyl, R4and R5the hydrogen and hydroxyl group in the 1-hydroxyethyl group is unprotected or protected.

26. The method of obtaining compounds of General formula I, as defined in paragraph 1, their derivatives containing at least one protective group, and their pharmaceutically acceptable salts and their esters hydrolyzable in vivo, characterized in that the compound of General formula VI

< / BR>
where R2matter specified in paragraph 1;

R10is an R1defined in paragraph 1, the protected oxymethyl or protected 1-oxyethyl;

-COOR7- carboxyl group or a protected carboxyl group;

L is a leaving group;

put usaimage which may be protected;

-COOR6- carboxyl group or a protected carboxyl group;

R8is an R3defined in paragraph 1, or aminoamides group;

R9is a hydrogen atom or aminoamides group;

provided that at least one of the interacting compounds contains at least one of the protective groups with the subsequent removal of the protective group and, if necessary, the obtained target product was transferred to pharmaceutically acceptable salts and/or etherification with the formation of ether, hydrolyzable in vivo.

27. Derivative pyrrolidin-4-yl-thiol of General formula VII, as defined in paragraph 26.

28. Derivative pyrrolidin-4-yl-thiol of General formula VII by p. 27, where R4and R5represent hydrogen.

29. Protected derivative pyrrolidin-4-yl-thiol of General formula IX

< / BR>
where R14- protective group, and R4, R5, R6, R8and R9such as in p. 26.

30. The compound of General formula IX to p. 29, where R4and R5represent hydrogen.

 

Same patents:

The invention relates to new antibiotics that have carbapenemases skeleton

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to ethanol adducts of compounds with formula 1

< / BR>
where R(1) phenyl which may be substituted by 1-2 methyl groups and/or chlorine,

R(2) and R(3) may be the same or different and are H, stands or stands, and

n number 3 and 4

m number 1 and 2, the method of their production and their use as tools for inhalation diseases

The invention relates to the field of new biologically active compounds

The invention relates to physiologically active compounds and relates to derivatives of succinic acid, specifically nitrate N-alkanolamines or imides, method of production thereof, and also N-alkanolamines or imides

The invention relates to new N-acylated compounds of arilpirolul General formula

< / BR>
in which x represents Cl, Br,

Y represents Cl, Br or trifluoromethyl,

L represents hydrogen or halogen; M and Q each independently represents hydrogen or halogen,

R represents a C1-C4-alkyl, C3-C6alkenyl,

C3-C6cycloalkyl; phenyl, does not necessarily substituted by 1 to 2 halogen atoms, one C1-C4is an alkyl group, trifluoromethyl, nitro, fenoxaprop or furyl

-phenylazomethine and its analogues, derivatives-phenylazomethine, derivatives of azetidinone" target="_blank">

The invention relates to a method for producing beta-phenylazomethine and its analogues of General formula (I) of the aromatic aldehyde and alpha methylaniline-S with an intermediate passage of the lactam of General formula (II)

-lactam or its enantiomer for the synthesis of tokalov and a method of producing tokalov" target="_blank">

The invention relates tothe lactam of formula III

< / BR>
or its enantiomer, where R1means1-C6-alkyl,or-naphthyl or phenyl, unsubstituted or substituted C1-C6alkoxygroup; R2means hydroxyamino group, such as ethoxyethyl; and R3means1-C6-alkyl,or-naphthyl or phenyl, unsubstituted or substituted C1-C6alkoxygroup, for the synthesis of tokalov, and to a method of obtaining tokalov as natural Taxol, and tokalov not found in nature

The invention relates to a new method of obtaining premovic esters in accordance with acceptable derivative slit acid and the corresponding azetidinone

The invention relates to new derivatives of azetidinone General formula

in which R1represents hydroxyamino group;

R2represents an alkyl group having from 1 to 3 carbon atoms;

R3represents pyridyloxy a group which is not substituted or substituted C1-C3is an alkyl group;

unsubstituted pinolillo group or phenyl group, which has a Deputy formula СYNR5R6and/or C1-C3is an alkyl group, Y represents an oxygen atom or sulfur, and R5and R6the same or different and each represents an alkyl group having from 1 to 6 carbon atoms, or phenyl group;

or R5and R6together form pyrrolidinyl, piperidyl, morpholinyl, or azepine;

R4represents a hydrogen atom;

Z represents a sulfur atom or an oxygen atom
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