Phenyloxazolidine substituted in the ring heteroaromatic rings, as antimicrobial agents

 

(57) Abstract:

Describes new connections - phenyloxazolidine substituted in the ring heteroaromatic rings of the formula (Ia) or its pharmaceutical acceptable salts, where Q represents a heteroaromatic 5-membered ring, associated with the aromatic ring of 1 nitrogen atom, the structural formula i, ii, iii, iv, v, vi, vii, viii or ix, or in another embodiment, Q may represent condensed with benzene heteroaromatic 5-membered ring, associated with the aromatic ring of 1 nitrogen atom, the structural formula X, R1independently represents H, F or Cl; R2independently represents C1-C8-alkyl, optionally substituted by one or more atoms of F or Cl; R3each independently selected from: (a) H, (b) OR4(c) SR4, (d) NHSO2R4, (e) CO2R4and (f) COR4(g) saturated or unsaturated C1-C8-alkyl, branched or unbranched, optionally substituted by one or more Deputy selected from (e), (j) -C(R5)=NR6where R5represents C1-C6-alkyl, and R6is OH or OC1-C6-alkyl; R4represents: (a) H, (b) C1-C6branched or protiv a number of pathogens of humans and animals, including gram-positive aerobic bacteria such as multi-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. 10 C.p. f-crystals, 8 ill., 3 table.

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In the present invention discloses a new and useful compounds of phenyloxazolidine, substituted nitrogen-containing heteroaromatic ring attached on one of the nitrogen atoms. More specifically, it is a 5-membered nitrogen-containing aromatic ring containing 1 to 4 nitrogen atoms, one of which is associated with phenyloxazolidine. These compounds are useful antimicrobial agents, effective against a number of pathogens of humans and animals, including gram-positive aerobic bacteria such as multi-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

Background of the invention

Compounds of the present invention is similar in structure phenyloxazolidine ring compounds disclosed in prevtick ring, containing nitrogen, which is attached to phenyloxazolidine through one of the nitrogen atoms. This point of connection facilitates different, but easier synthesis than the corresponding carbon-carbon linked structure, and thus provides an advantage compared to compounds with carbon-carbon linked structure. Compounds of the present invention are unique and possess useful antibacterial activity.

In the application PCT/US93/03570 revealed oxazolidinone containing fragment substituted diazine, and their use as antimicrobial agents.

In PCT/US92/08267 application discloses substituted aryl and heteroaryl-oxazolidinone, suitable as antibacterial agents. In one aspect of the disclosed 5-membered nitrogen-containing heteroaromatic ring is attached to phenyloxazolidine, although there is not disclosed a method of their synthesis, which would allow connection through a nitrogen atom (See. scheme C (V, W, ee and ff)).

In PCT/US89/03548 application discloses 5'-indolinyl-5-aminoethylethanolamine, 3-(substituted condensed ring)phenyl-5-aminoethylethanolamine, and 3-(nitrogen substituted)phenyl-5-aminoethylethanolamine, t is oxazolidinone, include U.S. patent 4801600, 4921869, Gregory W. A., et. al., J. Med. Chem., 32, 1673-81 (1989); Gregory W. A., et. al., J. Med. Chem., 33, 2569-78 (1990); C. Wang et. al., Tetrahedron, 45, 1323-26 (1989); and Brittelli et. al., J. Med. Chem. , 35, 1156 (1992).

In European patent publication 352781 disclosed phenyl and pyridyl substituted phenyloxazolidine.

In European patent publication 316594 discloses 3-substituted sterilisation.

In European patent publication 312000 revealed phenylmethyl and pyridylmethylamine phenyloxazolidine.

In U.S. patent 5254577 disclosed nitrogen-containing heteroaromatic ring is attached to phenyloxazolidine, but not through heteroaromatic nitrogen (see column 19 and 43).

Summary of the invention

In one aspect of the invention proposed compound of structural formula 1:

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or its pharmaceutically acceptable salt, where Q represents a heteroaromatic 5-membered ring, associated with the aromatic ring 1 through the nitrogen of the following form: i, ii, iii, iv, v, vi, vii, viii or ix:

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or in another embodiment, Q may be benzododecinium heteroaromatic 5-membered ring, associated with the aromatic ring 1 via the nitrogen, the following structure: x, xi, xii, xiii, xiv, xv, xvi, xv is: (a) hydrogen,

(b) C1-C8alkyl, optionally substituted by one or more Deputy selected from F, Cl, hydroxy, C1-C8alkoxy, C1-C8acyloxy;

(c) C3-C6cycloalkyl;

(d) amino;

(e) C1-C8alkylamino;

(f) C1-C8dialkylamino;

(g) C1-C8alkoxy;

R3each independently chosen from:

(a) H,

(b) F, Cl, Br,

(c) OR4,

(d) SR4,

(e) S(O)nR4(n = 1 or 2),

(f) CN

(g) O2CR4,

(h) NHCOR4,

(i) NHCO2R4,

(j) NHSO2R4,

(k) CO2R4,

(l) CON(R4)2,

(m) COR4,

(n) a C1-C8branched or unbranched alkyl or C3-C8cycloalkyl, optionally substituted by one or more Deputy selected from (a) to (m), or

(o) phenyl, optionally substituted by one or more Deputy of the preceding groups (a) to (n); and

R4is:

(a) H,

(b) C1-C6branched or unbranched alkyl or C3-C8cycloalkyl, optionally substituted by one or more Deputy selected from fluorine, chlorine, hydroxy, C1-C4alkoxy, C1-C is Ino substituted by one or more Deputy selected from fluorine, chlorine, C1-C4branched or unbranched alkyl, hydroxy, C1-C4alkoxy, C1-C4acyl, C1-C4acyloxy or O2CCH2N(CH3)2. Detailed description of the invention

In the present invention discloses new substituted 5-membered nitrogen-containing heterocycle of phenyloxazolidine in accordance with structural formula 1 above.

"Alkyl" means a chain of carbon atoms containing the specified number of carbon atoms which may be branched or unbranched.

"Alkoxy" means the specified number of carbon atoms attached to the oxygen with the formation of groups such as methoxy (-OCH3), ethoxy, butoxy and so on, and their isomeric forms.

"Acyloxy" means the specified number of carbon atoms forming the organic acid, which was excluded OH group, for example acetyl: CH3CO-; benzoyl: C6H5CO.

"Cycloalkyl" means the specified number of carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth, and their isomeric forms.

"Amino" means the NH2"alkylamino" corresponds to the structure in which one ate pami.

"Pharmaceutically acceptable salt" is a salt accession acids that you can get well-known specialists of ways. Usually salt accession acids include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, succinate, tartrate, cyclohexylsulfamate, methansulfonate, econsultancy, bansilalpet, toluensulfonate, fumarate, and other pharmaceutically acceptable counterions amines.

These compounds are suitable as antimicrobial agents, effective against a number of pathogens of humans and animals, especially against aerobic gram-positive bacteria, including resistant to many antibiotics Staphylococcus and Streptococcus, as well as anaerobic organisms, as bacteroids and species of clostridia, as well as acid-fast organisms like Mycobacterium tuberculosis and other Mycobacterium species.

The pharmaceutical compositions of the present invention can be obtained by combining the compounds of formula 1 of the present invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvantly and excipients using standard and convenient ways. Solid form compositions including the at least one substance that can also act as a diluent, flavoring agent, solubilizer, moving, suspendisse agent, a binder agent, giving the tablets friability, and the encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulose materials, low melting wax, cocoa butter, etc. Liquid form compositions include solutions, suspensions and emulsions. For example, it is possible to prepare solutions of the compounds of the present invention in water and a mixture of water and propylene glycol, water and glycol, optionally containing suitable conventional tinted agents, flavoring agents, stabilizers and thickeners.

It is preferable to prepare the pharmaceutical compositions using conventional methods, in unit dose forms containing effective or appropriate amount of the active component, i.e. the compounds of formula 1 of the present invention.

The number of the active component, i.e. the compounds of formula 1 of the present invention, in the pharmaceutical compositions and unit dose form, it may vary or be adjusted in a wide range depending in the active component varies in the range from 0.5 to 90% by weight of the composition.

In therapeutic use for treating, or combating bacterial infections in warm-blooded animal patient suffering from such a microbial infection, the compounds or pharmaceutical compositions of the present invention administered orally and/or parenteral doses to achieve and maintain a concentration, that is, the amount or level in the blood of active connections at a subject to treatment of an animal, in an amount which is effective antibacterial. Usually this antibacterial effective amount or dose of the active component is in the range from about 0.1 to 100, more preferably from about 3.0 to about 50 mg/kg of body weight/day. Note that the dosage may vary depending on the needs of the patient, the severity of the bacterial infection to be treated, and the specific intended for use for the connection. In addition, note that the initial injected dose can be increased above the upper limit, in order to quickly reach the desired level in the blood, or the initial dose may be less than optimal, and the daily dose can progressively increase during treatment, depending on the specific situation. If desired, the daily dose can also rasteniya administered parenteral, that is, by injection, such as intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral introduction usually contain a pharmaceutically acceptable amount of the compounds of formula 1 in the form of soluble salts (salt accession acid or base), in a pharmaceutically acceptable liquid carrier, such as, for example, water for injection, or a buffer that will receive accordingly superyoung isotonic, for example, with a pH of about 3.5-6. Suitable buferiruemoi solutions include, for example, trinatriumfosfaat, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine, as several representatives superyoshi agents. The compounds of formula 1 are typically dissolved in the medium in amounts sufficient to provide pharmaceutically acceptable injectively concentration in the range of from about 1 to about 400 mg/ml. The liquid pharmaceutical composition should be introduced in such a way as to provide the above-mentioned antibacterial effective dose. The compounds of formula 1 of the present invention advantageously administered orally in solid or liquid dose forms.

Most p is oracea in accordance with the notation Cahn-Ingold-Prelog C5oxazolidinone rings. Optically pure material can be obtained through one or multiple methods of asymmetric synthesis or by separation from the racemic mixture by selective crystallization of salt from, for example, racemic modification of the intermediate amine 10 (scheme II) with an appropriate optically active acid, such as dibenzoyltartaric or 10-camphorsulfonic acid, followed by treatment with a base to obtain optically active amine. Although (S)-enantiomer of this series of compounds is preferred, as it is pharmacologically active as an antibacterial agent, racemic modification can also be used in the same way as pure (S)-enantiomer: the difference is that to achieve the same antibacterial effect will need twice the racemic material. In addition, professionals should be clear that if a chiral center exists in any of the Vice associated with Q, then possible diastereoisomer. Such diastereoisomer, both in racemic and configuration enriched forms, are included in the scope of the compounds of structural formula 1 of the present invention.

The preferred method of obtaining with.

As shown in scheme I, 5-membered heterocycles of the General structure 1 (where n = the number of atoms in the ring) that are either available commercially, or obtaining them are described in the literature (see, for example, Katritzky et. al., in "Comprehensive Heterocyclic Chemistry"), process substituted derivatives of nitrobenzene 2 (Y represents halogen or tripterocalyx) in a suitable base in a combination of solvents such as potassium carbonate in DMSO at a suitable temperature, usually from room temperature up to 90oC, to obtain the adduct 3. This method works well for such 5-membered heterocycles, as imidazole, pyrazole, etc., To 5-membered heterocycles 1, such as pyrrole or indole, etc., heterocycl added to the suspension of such strong bases like sodium hydride, tert.-piperonyl or potassium, etc., in THF or DMF, or a similar solvent to obtain a salt of an alkali metal 4 which is then treated reduction compound 2 at a temperature in the range of 0oC to the boiling temperature under reflux of the solvent to obtain the adduct 3. Then nitro-derivatives 3 restore due to catalytic hydrogenation in the presence of such a suitable catalyst like palladium on coal, W-2 Nickel of Renee or platinum on servicego aniline 5. If the solvent for this recovery using THF, there is no need to filter the solvent or to highlight the aniline derivative 5, but you can just purge the reactor with inert gas such as nitrogen, and add saturated sodium bicarbonate solution, and treating the resulting reaction mixture, or benzyl, or methylchloroform to obtain the corresponding benzyl (R is CH2Ph), or methylcarbamate (R is CH3derivative 6.

Any of the derivatives of carbamate 6 can be deprotonate by such a lithium base, as n-utility, sitedisability /LDA/ or letibit/(trimethylsilyl)/amide/LHMDS/ in a suitable solvent, such as THF, N, N-dimethylformamide (DMF), or mixtures thereof, at an appropriate temperature, typically -78oC -40oC, to obtain literaturnogo intermediate compound, which is directly treated with (R)-(-)-glycidylether. Heating this reaction mixture to room temperature or higher results /the hydroxymethyl/oxazolidinone 7 in substantially enantiomerically enriched form.

In scheme II presents the conversion /hydroxymethyl/oxazolidinone 7 oxazolidinone Antibes(R = CH3or tosylate (R = n-CH3C6H4) by processing methanesulfonamido in the presence of triethylamine or pyridine, or paratoluenesulfonyl in the presence of pyridine, respectively. The resulting sulfonate 8 can be treated with alkali metal azide such as sodium azide or potassium in an appropriate aprotic dipolar solvent such as DMF or N,N-organic /NMP/ with optional catalyst such as 18-crown-6 at a temperature in the range of 50-90oC to obtain the azide 9. This azide 9 can be restored to the corresponding amine 10 by hydrogenation in the presence of palladium, platinum or Nickel catalyst, in an appropriate solvent such as ethyl acetate, THF or methanol. In another embodiment, azide 9 can be restored to the amine 10 by treatment with triphenylphosphine or other compounds of trivalent phosphorus in a solvent such as THF, followed by addition of water. Amin 10 can also be obtained by processing sulfonate 8 phthalimide potassium in DMF at 40-60oC or boiling under reflux acetonitrile to obtain phthalimide II, which removes the protection, processing, for example, aqueous methylamine in boiling with obratno in a mixture of isopropyl alcohol-THF in a sealed ampoule, heated to 75-105oC in an oil bath. Then Amin 10 acelerou in reactions well known in the art to obtain (acylaminoacyl) oxazolidinones structural formula 12. So, for example, Amin 10 can be treated with acid chloride or acid anhydride in the presence of such bases as pyridine or triethylamine at a temperature in the range -40 - 40oC to obtain the acyl derivative 12. It is obvious that such other acyl derivatives, as carbamates, can be obtained in similar conditions of reaction. It is easy to see that the product 12 is an example of a compound of structural formula 1. It is also seen that in some cases 12 can be converted into other compounds of structural formula 1 by treatment with 40% aqueous formaldehyde in dimethyl sulfoxide at temperatures in the range of 90-150oC, optionally in the presence of an acid catalyst to obtain the corresponding hydroxymethylene derivative 13.

In another embodiment, compound 13 can be obtained with a more complex way in which you may receive other regioisomers, which are difficult to obtain due to hydroxymethylpropane. As shown in scheme III, alkoxycarbonyl derivatives of 5-membered ring heterocycles 14 (GMO, you can handle the derivatives of nitrobenzene 2 in a suitable solvent such as DMSO, DMF or the like, in the presence of such a suitable base, like potassium carbonate, at a corresponding temperature in the range from room temperature up to 90oC to obtain burilovo derivative 15. Then the nitro-derivatives restore due to catalytic hydrogenation in the presence of such a suitable catalyst like palladium on coal, W-2 Nickel of Renea, or platinum on carbon, in a suitable solvent such as ethyl acetate, THF, methanol or in combination, to obtain a derivative of aniline 16. If such recovery using THF as solvent, there is no need to filter the catalyst, or to allocate a derivative of aniline 16, but you can just purge the reactor with inert gas such as nitrogen, and add a saturated solution of sodium bicarbonate and process the corresponding mixture or benzyl, or methylchloroform to obtain the corresponding benzyl (R = CH2Ph), or methyl (R = CH3) urethane derivatives 17. Ester group, any of the urethane derivatives 17 can be restored either by literalized or possibly a complex of borane-THF to receive the s a hydroxyl group. This can be accomplished, for example, receiving tert.-butyldimethylsilyl (TBS) ether 19 (R = Si(CH3)2so-Bu) by processing 18 tert.-butyldimethylchlorosilane in the presence of such grounds, as imidazole or Diisopropylamine, optionally in the presence of 4-dimethylaminopyridine as a catalyst, in a suitable solvent such as DMF, THF or dichloromethane. Any of the urethane derivatives 19 can be subjected to deprotonation by such a lithium base, as sitedisability (LDA) or letibit(trimethylsilyl)amide (LHMDS) in a suitable solvent such as THF, DMF or mixtures thereof, at a suitable temperature, typically -78oC -40oC, to obtain literaturnogo derivative, which is directly treated with (R)-(-)-glycidylether. Then heating this reaction mixture to room temperature or higher temperatures, results in (hydroxymethyl)oxazolidinone 20 in highly enantiomerically enriched form.

In scheme IV presents the transformation (hydroxymethyl)oxazolidinone 20 in oxazolidinone antibacterial agents of structural formula 1. As you can see, the connection 20 can be converted into the corresponding (acylaminoacyl)oxazolidinone 21 (R = this, which is used for the conversion of 7 to 12 in scheme II. Then one of the many ways you can remove the protection (acylaminoacyl)oxazolidinone 21, for example, by processing a methanol solution of HCl at boiling under reflux, or by mixtures of acetic acid in THF-water at a temperature of 40-90oC to obtain alcohol 22. Alcohol 22 is an example oxazolidinone antibacterial agent of the structural formula 1.

Further transformation, presented in scheme IV can be used to obtain other compounds of structural formula 1 from the compound 22. As you can see, alcohol 22 can oxidize due to the processing of such reagents as pyridinediamine in DMF), or by treatment with gaseous oxygen in the presence of a catalyst is a noble metal in an aqueous solution, or other known in the art methods, to obtain carboxylic acid 23. Carboxylic acid 23 can be converted into an ester by processing the corresponding alkylhalides in the presence of such a base as potassium carbonate, in an appropriate solvent, such as acetone, to obtain a complex ester 24 (R = branched or unbranched alkyl chain). In drugovi in the corresponding alcohol, or other well-known specialists of ways.

In scheme V presents the methods of conversion of alcohol 22 in other compounds of structural formula 1. As you can see, 22 can be converted into the corresponding mesilate (R = CH3or tosylate (R = p-CH3C6H4) by processing methanesulfonamido in the presence of triethylamine or pyridine, or p-toluensulfonate in the presence of pyridine. Derived sulfonate 25 can be processed salt of an alkali metal or mercaptan (R = branched or unbranched alkyl chain or aryl) in an aprotic dipolar solvent such as DMF, DMSO or acetonitrile in the presence of such an optional catalyst, as 18-crown-6 at a temperature in the range from room temperature up to 90oC to obtain sulfide 26. Then the sulphide 26 can be turned to either the sulfoxide 27 or sulfon 28, by oxidation of the corresponding stoichiometric quantities of a suitable oxidizing agent such as m-chloroperoxybenzoic acid (MCPBA) in a suitable solvent such as dichloromethane, diethyl alcohol etc In another embodiment, a sulfon 28 can be obtained directly by treatment with osmium tetroxide or tetroxide ruthenium examples of compounds of structural formula 1.

Other possible transformations of alcohol 22 presented in scheme V. As can be seen, the derived sulfonate 25 can be treated with azide of an alkali metal in such a dipolar aprotic solvent like DMF, DMSO, acetonitrile or etc., optionally in the presence of such a catalyst as 18-crown-6 at a temperature in the range from 50-90oC to obtain azide 29. Then azide 29 can be restored to the corresponding amine 30 by hydrogenation in the presence of platinum, palladium or Nickel catalyst, in a suitable solvent such as ethyl acetate, THF or methanol. In another embodiment, azide 29 can be restored by treatment with triphenylphosphine or other compounds of trivalent phosphorus, in a solvent such as THF, followed by addition of water. Then Amin 30 can be used to obtain the corresponding derivative sulfonamida 31 by processing the corresponding sulphonylchloride (R = branched or unbranched alkyl chain or aryl) in a suitable solvent such as pyridine. It is easy to see that the derived sulfonamida 31 is an example of the compounds of structural formula 1.

Due to the lack of commercially available 3-substituted heterocycles R to obtain ways, described previously in schemes. As a result, methods of obtaining other heterocyclic derivatives oxazolidinone derived from aniline 37 presented in schemes VI, VII, VIII, IX.

Obtaining a derivative of aniline 37 presented in scheme VI. As can be seen, reduction compound 2 is treated with benzylamine in the presence of such a suitable base, like triethylamine or N,N-diisopropylethylamine, in a solvent such as acetonitrile, to obtain a substitute product 32. Then nitrosoaniline 32 can be converted into optically active derivative oxazolidinone 36 methods presented in schemes I and II for the conversion of the nitro-derivatives 3 in the oxazolidinone 12. At this stage of the synthesis hydrogenolysis 36 using as a catalyst of palladium on coal and methanol as a solvent is used both for removal of the CbZ protective group, and the benzyl protecting group, to obtain the aniline 37.

Obtaining 3-substituted derivatives of pyrrole can be accomplished as shown in scheme VI. Aniline 37 treated with commercially available 3,5-dimethoxy-3-tetrahydrobenzaldehyde under conditions of acid catalysis, for example, by boiling under reflux in acetic acid, Thu the, the hat as hydroxymethylfurfural 39, ester 40 or derived oxime 41 known in the art methods. It is seen that the pyrrole 30, 40, and 41 are examples of compounds of structural formula 1.

The conversion of aniline 37 in derivatives substituted triazole presented in scheme VII. As you can see, diazotization aniline 37 by processing nitrous acid followed by the addition of sodium azide leads to the formation of azide 42, which is a useful precursor to obtain triazoles through 1,3-dipolar cycloaddition of substituted acetylene 43. As can be seen, the processing azide 42 substituted derivatives of acetylene 43 in such a solvent as benzene, toluene, etc. at a temperature in the range from room temperature up to 120oC, optionally in the presence of Lewis acid as a catalyst, such as aluminised, apirat boron TRIFLUORIDE, titanium tetrachloride or so on , leads to the production of substituted triazole derivative 44. In another embodiment, in that case, if one of R3groups 43 represents an acyl group, for example, R4CO acetylene 45, cycloaddition of the above conditions results in mainly 4-illtreating derived 46 with less to R344 can be used for turning 44 in the acyl derivative 46 and/or 47. 4 alltransactions 46 can be turned into a derived oxime 48 or gidroksosoedinenii 49 known in the art methods. You can see that 46, 48 and 49 are examples of compounds of structural formula 1.

The conversion of aniline 37 in both possible regioisomers substituted derivatives of pyrazole presented in scheme VIII. As you can see, diazotization aniline 37, followed by reduction of diazonium salt or chloride of tin [II] or in situ produced sodium sulfite, gives the derivative of hydrazine 50. It is seen that hydrazin 50 can be subjected to interaction with reformulation 51 (Synthesis, 1989, 858) to obtain the pyrazole-4-carboxaldehyde 52. In another embodiment, the processing of hydrazine 50 4-methoxy-2-oxo-but-3-ene acid ethyl ether complex (Helv. Chim. Acta, 1967, 50, 128) leads to the formation of regioisomeric 3-carbamaxepine 54. It is seen that the aldehyde 52 and ester 54 can be turned into another series of analogues in the result of the transformations described in schemes IV, V and VI. Shows that 52 and 54 are examples of compounds of structural formula 1.

Examples heteroaryl-phenyloxazolidine, which can be obtained as part of the on the;

(S)-N-[[3-[3-fluoro-4-(3-carbomethoxy-1H-pyrrol-1-yl)phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-pyrrol-1-yl-3-carboxaldehyde)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[[3-fluoro-4-(3-(gidroksilaminami)-1H-pyrrol-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-(methoxyaminomethyl)-1H-pyrrol-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-(hydroxymethyl)-1H-pyrrol-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-(2-carboethoxy)-1H-pyrrol-1-yl)phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-(2-carboethoxy)-1H-pyrrol-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-(3-hydroxypropyl)-1H-pyrrol-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-(3-methanesulfonylaminoethyl)-1H-pyrrol - 1-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-ethyl-1H-imidazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[4-(carbomethoxy)-1H-imidazol-1-yl] phenyl]-2 - oxo-5-oxa is Teal]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[4-(2-hydroxyethyl)-1H-imidazol-1-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[1H-imidazol-1-yl-4-carboxaldehyde] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-(gidroksilaminami)-1H-imidazol-1 - yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-(methoxyaminomethyl)-1H-imidazol-1 - yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-pyrazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-methyl-1H-pyrazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-(hydroxymethyl)-1H-pyrazole-1-yl] phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-(carbomethoxy)-1H-pyrazole-1-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-pyrazole-1-yl-3-carboxaldehyde)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-(gidroksilaminami)-1H-pyrazole-1 - yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-(methoxyaminomethyl)-1H-pyrazole-1 - yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[4-(hydroxymethyl)-1H-pyrazole-1-yl] phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[4-(carbomethoxy)-1H-pyrazole-1-yl] phenyl] -2-leinil]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-gidroksilaminami)-1H-pyrazole-1-yl)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-methoxyaminomethyl)-1H-pyrazole-1-yl)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-mercapto-4H-1,2,4-triazole-4-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[3-methylthio-4H-1,2,4-triazole-4-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-[4H-1,2,4-triazole-1-yl] phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-carbomethoxy-1H-1,2,3-triazole-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-(hydroxymethyl)-1H-1,2,3-triazole-1-yl)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-(1-hydroxyethyl)-1H-1,2,3-triazole-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl-4-carboxaldehyde] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-(gidroksilaminami)-1H-1,2,3-triazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide the oxime;

(S)-N-[[3-[3-fluoro-4-(4-methoxyaminomethyl)-1H-1,2,3-triazole-1 - yl)phenyl] -2-l]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-(1-hydroxyimino)-1H-1,2,3-triazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(4-(1-methoxymethyl)-1H-1,2,3-triazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(2H-1,2,3-triazole-2-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(2H-1,2,3,4-tetrazol-2-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-indol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl] ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(7-Aza-1H-indol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl] methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-benzimidazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-indazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(1H-benzotriazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide; and

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazolo[4,5 b] -pyridine-1-yl)phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

Antibacterial activity

Oxazolidinone antibacterial agents of the present invention possess useful activity against different organisms. In vitro activity of the compounds of the present invention can ocentric) at the expense of the agrarian dilution method "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria^ that Grow Aerobically" (MFT), published in January 1983 National Committee for Chimical Laboratory Standarts 771 East Lancaster Avenue, Villanov Pensilvania 19084, USA. The activity of selected compounds of the present invention against Staphylococcus aureus and Streptococcus preumoniae presented in table 1.

Antimicrobial activity tested in vivo using the procedure of analysis in mice. The group of mice females (six mice for 18-20 g each) was injected intraperitoneally bacteria that thawed immediately prior to use, and suspended in brain fluid with 4% brewer's yeast UC9213 (Staphylococcus aureus) or cerebral fluid (Staphylococcus species). Treatment antibiotic at 6 dose levels of drugs administered after one hour and after five hours after infection or through oral inkubirovanija or subcutaneously ("Subcut. "). The survival estimate daily for 6 days. The considered compounds is compared with the well-known antimicrobial agent (vancomycin are) as a control. The values of the ED50calculated on the basis of mortality data using probit analysis. The obtained data are presented in table 2.

Example 1

(S)-N-[[3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

3-fluoro-1-nitro-(1H-pyrrol-1-yl)benzene:

Suspension 403 mg (630 mg, 60% in oil, of 15.75 mmole is within 15 minutes. Then the solution process of 2.51 g (1,74 ml of 15.75 mmole) of 3,4-deformirovannoe followed by heating at boiling under reflux for 18 hours. The resulting mixture is cooled and treated with 10 ml of saturated solution of ameriglide. The resulting mixture was diluted with ethyl acetate and extracted with water (2 x). After drying over sodium sulfate and concentration in vacuo get a solid dark brown color, which process chromatography on 75 g of silica gel (230-400 mesh mesh), elwira 30% of /the volume of/the amount of/ a mixture of dichloromethane in hexane. The result of 2.05 g (66%) specified in the title derivative of pyrrole in the form of a solid of light yellow color.

1H NMR /CDCl3/ : 14, EUR 7.57, 7,16 and 6,44

3-fluoro-1-(formatactionname)-4-(1H-pyrrol-1-yl)benzene:

A solution of 500 mg (2,43 mmole) obtained previously derived pyrrole in 50 ml of a mixture of 4: 1 THF:water treated with 75 g of 5% platinum on carbon disulfide, followed by hydrogenation at a pressure of one atmosphere for 18 hours. Then the mixture is treated with 10 ml of saturated solution of sodium bicarbonate and cooled to -20oC. the resulting mixture is treated 477 mg (0,42 ml, and 2.79 mmole) of benzylchloride with subsequent nagrevaniyu cake with methanol. The resulting mixture was concentrated in vacuo to approximately half the original volume, the mixture is diluted with ethyl acetate and extracted with water (4×) and saturated NaCl solution. After drying over sodium sulfate and concentration in vacuo get a solid brown color, which process chromatography on 35 g of silica gel (230-400 mesh mesh), elwira mix 1:3:32 methanol:dichloromethane:hexane and then with a mixture of 1: 3: 16 methanol: dichloromethane: hexane. The result 581 mg specified in the title CBZ derivative in the form of a brown solid, suitable for use in the next stage

1H NMR /CDCl3/ : 7,50, 7,40, 7,30, 7,09, 6,98, 6,35, 5,23.

(S)-N-[3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] methanol:

A solution of 300 mg (0.97 mmole) CBZ derivative 2 in 5 ml of THF at -78oC handle of 1.06 ml (1.0 M of 1.06 mmole) letibit(trimethylsilyl)amide, and then stirred at -78oC for 30 minutes. The resulting solution was treated with 153 mg (0.15 mmol) of (R)-(-)glycidylether followed by warming to 0oC, and then gradually heated at room temperature for 48 hours. The resulting mixture was diluted with ethyl acetate and extracted with water and saturated salt solution. As a result, anywayt using radial chromatography on a 2 mm chromatotron plate, elwira 2% /volume/volume/ methanol in dichloromethane and then 5% volume/volume/ methanol in dichloromethane. As a result of these procedures obtain 157 mg (59%) indicated in the title of oxazolidinone as light Golden-brown solid. Mass spectrum high resolution: Calculated for C14H13FN2O3: 276,0910. Found: 276,0918.

(S)-[3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] mutilated:

A solution of 1.94 g (7.0 mmole) obtained earlier alcohol and 1.24 g (1,71 ml, 12,25 mmole) of triethylamine in 60 ml of dichloromethane at 0oC is treated with 1.0 g (0.68 ml, 8,78 mmole) of methanesulfonamide, followed by stirring at 0oC for 30 minutes. The resulting solution was warmed to room temperature and diluted with dichloromethane, followed by extraction with water (3×) and saturated salt solution. In the drying over sodium sulfate and concentration in vacuo receive oil amber color, which is dissolved in 120 ml of DMF, treated with 4.5 g (70 mmol) of sodium azide and heated at 60oC for 18 hours. The resulting mixture is cooled and diluted with 75 ml of a mixture of 1:1 ether: ethyl acetate and extracted with water (6 x 40 ml). In the drying over sodium sulfate and concentration under vacuum the floor is of use in the next stage. Mass spectrum high resolution: Calculated for C14H12FN5O2: 302,1053. Found: 302,1056.

(S)-N-[3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl] ndimethylacetamide:

A solution of 1.0 g (3.32 mmole) obtained previously azide in 30 ml of methanol and 15 ml of THF is treated with 200 mg of platinum on carbon disulfide, followed by hydrogenation at a pressure of one ATM. within 24 hours. The resulting solution was filtered through celite, washed filter cake THF. The obtained filtrate was concentrated in vacuo, and the residue is dissolved in pyridine and treated with acetic anhydride, followed by stirring for 48 hours at room temperature. The resulting solution was concentrated in vacuo and the resulting brown solid was dissolved in ethyl acetate and extracted twice with water. In the drying over sodium sulfate and concentration in vacuo get a brown solid, which process chromatography on 50 g of silica gel (230-400 mesh mesh), elwira 1% /vol/vol/ methanol in dichloromethane and then 2% /volume/volume/ methanol in dichloromethane. As a result of these procedures receive 582 mg (56%) specified in the title as off-white solids with so pl. 198-199,5oC. Mass Spectr-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

3-fluoro-1-nitro-4-(1H-pyrazole-1-yl)benzene:

A solution of 2.0 g (29,37 mmole) of pyrazole and of 8.12 g (58,75 mmole) of potassium carbonate in 70 ml of DMSO process of 4.67 g (3.25 ml, 29,37 mmole) of 3,4-deformirovannoe followed by heating at 90oC for 18 hours. The resulting solution is cooled and diluted with 100 ml of water and extracted with ethyl acetate (2 x 100 ml). The organic layers extracted with water (5 x 100 ml) and saturated brine (75 ml). In the drying over sodium sulfate and concentration in vacuo get dirty-white solid, which is recrystallized from hot hexanol to obtain 5.3 g (87%) specified in the title derivative of pyrazole in the form of an off-white solid. So pl. 128-129oC.

3-fluoro-1-(formatactionname)-4-(1H-pyrazole-1-yl)benzene:

The solution obtained previously pyrazole in 120 ml of THF is treated with 1.5 g of W-2 Nickel of Renee with subsequent hydrogenation at 40 psi (2,812 kg/cm2) of hydrogen for 16 hours. The resulting solution was filtered through celite, washed filter cake with acetone and concentrate the filtrate in vacuo. The resulting yellow residue was dissolved in 100 ml of THF and treated with 75 ml saturated sodium bicarbonate solution followed ohlazhdeniya at 0oC for 30 minutes, and then warming to room temperature for 1 hour. The resulting mixture was diluted with 125 ml ethyl acetate and 100 ml of water. The layers are separated and the aqueous layer was extracted with 100 ml of ethyl acetate. The combined organic layers extracted with saturated sodium bicarbonate solution (2 x 100 ml) and saturated NaCl solution. In the drying over sodium sulfate and concentration in vacuo get a light beige solid product, which is recrystallized from a mixture of chloroform-hexane to obtain of 5.92 g (79%) specified in the title compound in the form of a brilliant white plates, so pl. 82-83oC.

(S)-[3-[3-fluoro-4-(1H-pyrazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methanol:

A solution of 3.0 g (9,63 mmole) CBZ derivative 2 in 130 ml of THF at -78oC handle of 10.6 ml (1.0 M, or 10.60 mmole) letibit(trimethylsilyl)amide in THF, followed by stirring at -78oC for 30 minutes. Then the resulting solution is treated 1,53 g (1.50 ml, or 10.60 mmole) of pure (R)-(-)glycidylether, followed by stirring at -78oC for 30 minutes, and then warming to room temperature for 18 hours. The resulting mixture was treated with 2 ml of saturated solution of ameriglide with further dilution with 400 ml atilas the hell sodium sulfate and concentration in vacuo get solid yellow, which is recrystallized from hot methanol to obtain 2.28 g (85%) of compound 3 as white needles. So pl. 180-181oC.

(S)-[3-[3-fluoro-4-(1H-pyrazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] methylmethanesulfonate:

Suspension 403 mg (1.45 mmol) obtained earlier connection and 882 mg (1,22 ml, 8,71 mmole) of triethylamine in 15 ml dichloromethane at 0oC treated with 500 mg (0,34 ml, 4,36 mmole) of methanesulfonamide dropwise. The resulting solution was stirred at 0oC for 30 minutes followed by warming to room temperature. The resulting mixture was diluted with 20 ml dichloromethane and extracted twice with water (25 ml) and saturated sodium bicarbonate solution. In the drying over sodium sulfate and concentration in vacuo obtain 520 mg (approximately 100%) specified in the title nelfinavir, pure enough for further use.

1H NMR /DMSO-d6/ : 8,16, 7,80, 7,48, 6,55, 5,05, 4,53, 4,23, 3,89, 3,25.

(S)-[3-[3-fluoro-4-(1H-pyrazole-1-yl)phenyl] -2-oxo-5-oxazolidinyl] - methylated:

A solution of 518 mg (1,45 mmole) obtained previously nelfinavir in 15 ml of N,N-dimethylformamide is treated with 1.89 g (29,07 mmole) of sodium azide followed by heating at 70oC for 48 hours. The resulting mixture is diluted with 100 of loud over sodium sulfate and concentration in vacuo get a solid beige color which process chromatography on 50 g of silica gel (230-400 mesh mesh), elwira 3% volume/volume/ acetone in dichloromethane, and then 3.5 per cent /amount/volume/ methanol in dichloromethane. The result of 355 mg (81%) specified in the title azide as solid white.

1H NMR /CDCl3/ : 7,99, 7,92, 7,76, 7,24, 6,49, 4,83, 4,12, 3,99, 3,74, 3,62

(S)-N-[[3-[3-fluoro-4-(1H-pyrazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

A solution of 355 mg previously obtained azide in 30 ml of ethyl acetate is treated with 150 mg of palladium on calcium carbonate, followed by hydrogenation at a pressure of 1 ATM. within 18 hours. The resulting solution was treated then 15 ml of pyridine and 10 ml of acetic anhydride, and then stirred at room temperature for 18 hours. The resulting mixture is diluted with 100 ml ethyl acetate and filtered through celite, washed filter cake with ethyl acetate. The resulting mixture was concentrated in vacuo, and the remaining pyridine and acetic anhydride are removed through molecular distillation in a high vacuum (0.2 mm RT. senior /hot water bath). The obtained solid residue is recrystallized from a hot mixture of acetone-hexane to obtain 192 mg (51%) specified in the title compound in the form of solid white is etil]ndimethylacetamide:

3-fluoro-4-(1H-imidazol-1-yl)nitrobenzene:

A solution of 2.14 g (of 31.4 mmole) of imidazole and 10.9 g (62.8 mmole) secondary hydrogen phosphate potassium in 190 ml of DMSO is treated with a 5.25 g (3,7 ml, 32,9 mmole) of 3,4-deformirovannoe followed by heating at 90oC for 18 hours. The resulting solution was diluted with ethyl acetate and extracted with water. The aqueous layer was subjected to back extraction with ethyl acetate, and the combined organic layer is then extracted with water twice. The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain a solid brown color. This material is processed chromatography on 250 g of silica gel (230-400 mesh mesh), elwira dichloromethane and then 1% /vol/vol/ methanol in dichloromethane and finally, 2% of /amount of/volume of/ methanol in dichloromethane. The result is 6.0 g (92%) specified in the title compound in the form of solid bronze color.

1H NMR /CDCl3/ : 8,17, 7,96, 7,63, 7,35, 7,26

3-fluoro-4-(1H-imidazol-1-yl)-1-(formatactionname)benzene:

A solution of 500 mg (2,41 mmole) obtained previously nitrocompounds in 50 ml of THF is treated with 100 mg of 10% palladium on coal, followed by hydrogenation at atmospheric pressure for 20 hours. The resulting mixture was processing the scientists mixture is filtered through celite, wash the filter cake with methanol. The obtained filtrate was concentrated in vacuo to obtain a brown oil, which was dissolved in 50 ml of THF followed by treatment of 405 mg (4,82 mmole) of solid sodium bicarbonate. The resulting solution was cooled to -20oC followed by the addition 493 mg (of 0.43 ml, 2,89 mmole) of benzylchloride dropwise. The resulting mixture was warmed to room temperature for 18 hours, then diluted with ethyl acetate. The resulting solution was extracted with water (three times) and saturated NaCl solution. In the drying over sodium sulfate and concentration in vacuo get a light brown solid, which is recrystallized from a hot mixture chloroformate to obtain 692 mg (92%) specified in the title compound as light brown crystals. Mass spectrum high resolution: Calculated for C17H14FN3O2: 311,1070. Found: 311,1092.

(S)-[3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methanol:

A solution of 500 mg (1,61 mmole) obtained previously derived CBZ in 22 ml of THF and 4 ml of DMF at - 78oC handle 1,69 ml (1,69 mmole) letibit(trimethylsilyl)amide under stirring at -78oC for 20 minutes. Received RASO room temperature. After stirring for 3 hours at room temperature according to TLC it turns out that the reaction is not. The resulting solution was then heated at 40oC for 2 hours followed by cooling and stirring at room temperature for 18 hours. Then the resulting solution was diluted with ethyl acetate and extracted with water (three times). After drying over sodium sulfate and concentration in vacuo get a solid brown color, which process chromatography on 40 g of silica gel (230-400 mesh mesh), elwira 2% /volume/volume/ methanol in dichloromethane and then 5% volume/volume/ methanol in dichloromethane. The result is 214 mg (48%) specified in the title compound in the form of a solid of light yellow color. Mass spectrum high resolution: Calculated for C13H12FN3O3: 277,0863. Found: 277,0876.

(S)-[3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]mutilated:

A solution of 150 mg (0.54 mmole) obtained previously oxazolidinone and 96 mg (of 0.13 ml, 0.95 mmole) of triethylamine in 5 ml dichloromethane at 0oC handle 77 mg (52 μl, 0.68 mmole) of methanesulfonamide, followed by stirring at 0oC for 30 minutes. The resulting solution of resultate drying over sodium sulfate and concentration in vacuo get the foam light brown color. This material is dissolved in 10 ml DMF and treated with 525 mg (8.1 mmole) of sodium azide, and then heated at 60oC for 48 hours. This solution is cooled and diluted with ethyl acetate, and then extracted three times with water. In the drying over sodium sulfate and concentration in vacuo obtain 163 mg (100%) specified in the title azide in the form of a yellow oil.

1H NMR /CDCl3/ : 8,15, 7,74, 7,46, 7,35, 7,29, 4,85, 4,12, 3,90, 3,76, 3,59

(S)-N-[[3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] methyl]ndimethylacetamide:

A solution of 163 mg (0.54 mmole) azide in 8 ml of pyridine is treated with 85 mg of palladium on calcium carbonate and 110 mg (0.10 ml, of 1.08 mmole) of acetic anhydride. The resulting mixture hydronaut at a pressure of one atmosphere for 20 hours. Then the mixture is treated with 80 mg of palladium on calcium carbonate, and then hydronaut at a pressure of one atmosphere for 4 hours. The resulting solution was filtered through celite, washed filter cake with ethyl acetate. The obtained filtrate was concentrated in high vacuum, and the residue is treated using radial chromatography on a 2 mm chromatron plate, elwira 2% /volume/volume/ methanol in dichloromethane and then 5% volume/volume/ methanol in dichloromethane. In achiev is high resolution: Calculated for C15H15FN4O3: 318,1128. Found: 318,1140.

Example 4

(S)-N-[[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

3-fluoro-1-nitro-4-(1H-1,2,4-triazole-1-yl)benzene:

A solution of 5.0 g (72,4 mmole) of 1H-1,2,4-triazole and to 25.22 g (144,8 mmole) of the secondary acid potassium phosphate in 150 ml of DMSO treated to 11.52 g (72,4 mmole) of 3,4-deformirovannoe, and then heated at 90oC for 3 hours. The resulting solution is cooled and added to 500 ml of water, the obtained solid white filtered and washed with water. The obtained white solid is dried in vacuum (60oC/10 mm RT. Art.) to obtain 10,79 g (72%) specified in the title compound in the form of a solid white color. Mass spectrum high resolution: Calculated for C8H5FN4O2: 208,0396. Found: 208,0408

3-fluoro-4-(1H-1,2,4-triazole-1-yl)aniline:

A solution of 8.7 (41,83 mmole) obtained previously nitrocompounds in 350 ml of a mixture of 1:1 methanol-THF is treated with 3.5 g of 10% palladium on charcoal, and then hydronaut at a pressure of 45 psi (3,164 kg) of hydrogen for 18 hours. The resulting solution was filtered through celite, washed filter cake with methanol. The obtained filtrate was concentrated in vacuo and the resulting residue processing is m 3% volume/volume/ methanol in dichloromethane. The result is 4.0 g (54%) of the aniline derivative in the form of an off-white solid. Mass spectrum high resolution: Calculated for C8H7FN4: 178,0655. Found: 178,0673.

3-fluoro-1-(formatactionname)-4-(1H-1,2,4-triazole-1-yl)benzene:

A solution of 4.0 g (22.5 mmole) obtained previously derived aniline in 50 ml of acetone is treated with 50 ml saturated sodium bicarbonate solution, then cooled to 0oC. the resulting solution was treated with 8.0 g (of 6.78 ml, 47,26 mmole) of benzylobromide. The resulting solution was warmed to room temperature for 1 hour, and then add 300 ml of water and extracted with ethyl acetate (2 x 300 ml). The organic layer is extracted with 300 ml of water and dried over sodium sulfate. In the result, concentration in vacuo get a solid beige color, which is recrystallized from a mixture of chloroform-hexane to obtain 2.6 g (37%) specified in the title CBZ derivative. Mass spectrum high resolution: Calculated for C16H13FN4O2: 312,1022. Found: 312,1033.

(S)-[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] methanol:

A solution of 2.5 g (8.0 mmole) obtained previously derived CBZ in 115 ml of THF at -78oC handle 8,8 my solution is treated with 1.27 g (1.25 ml, 8.8 mmole) of (R)-(-)glycidylether, and then stirred, followed by heating to 0oC, and then at -78oC for 15 minutes. The resulting solution was then warmed to room temperature for 18 hours. The resulting mixture was treated with 2 ml of saturated solution of ameriglide, then diluted with 100 ml of water and extracted with ethyl acetate (2 x 100 ml). In the drying over sodium sulfate and concentration in vacuo get solid, which is triturated with chloroform to obtain 1.4 g (57%) indicated in the title of oxazolidinone. Mass spectrum high resolution: Calculated for C12H11FN4O3: 278,0815. Found: 278,0836.

(S)-[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] mutilated:

A suspension of 1.0 g (3.6 mmole) obtained previously oxazolidinone and 548 mg (0,76 ml, 5,42 mmole) of triethylamine in 20 ml dichloromethane at 0oC handle 495 mg (0.33 ml, 4,32 mmole) of methanesulfonamide. Then the resulting solution was warmed to room temperature for 2 hours. The resulting solution was treated with 20 ml of water, and the layers separated. The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain 1.0 g (75%) intermediate nelfinavir in the form of solid Vaticana 18 hours. The resulting solution is cooled and diluted with 100 ml of ethyl acetate, and then extracted with water (5 x 75 ml). In the drying over sodium sulfate and concentration in vacuo get 1 g (88%) specified in the title azide as off-white solid product.

1H NMR /CDCl3/ : 8,6, 8,13, 7,91, 7,83, 7,32, 4,85, 4,14, 3,92, 3,77, 3,63.

(S)-N-[[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

A solution of 100 mg (of 0.36 mmole) azide in 3 ml of pyridine is treated with 50 mg of palladium on calcium carbonate, and then hydronaut when the pressure of hydrogen at one atmosphere for 18 hours. The resulting solution was treated with 0.2 ml of acetic anhydride, and then stirred at room temperature for 18 hours. The solvent is removed in vacuo, and the residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain a solid light beige color. This material is treated using radial chromatography on a 2 mm plate, elwira 2% /volume/volume/ methanol in dichloromethane, and then 4% /volume/volume/ methanol in dichloromethane. The result is 62 mg (54%) specified in the title compound in the form of a solid white color is LASS="ptx2">

Example 5

(S)-N-[[3-[3-fluoro-4-(1H-indol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl] ndimethylacetamide:

3-fluoro-4-(1H-indol-1-yl)nitrobenzene:

Suspension 334 mg (374 mg, 60% in oil, 9,35 mmole) of sodium hydride in 5 ml of THF is treated with a solution of 1.0 g (8.5 mmole) of indole in 5 ml of THF and then stirred at room temperature for 15 minutes. The resulting solution was treated with 1.35 g (8.5 mmole) of 3,4-deformirovannoe. The resulting solution was stirred at room temperature for 48 hours, then concentrated in vacuo to obtain a brown oil, which was dissolved in ethyl acetate and washed with water. In the drying over sodium sulfate and concentration in vacuo get oil, which process chromatography on 100 g of silica gel (230-400 mesh mesh), elwira 20% volume/volume/ ethyl acetate in hexane. The result is 1.1 g (51%) specified in the title compound in a solid yellow color.

1H NMR /CDCl3/ : 8,23, 7,74, 7,40, 7,35, 7,30 6,80.

3-fluoro-4-(1H-indol-1-yl)-1-(formatactionname)benzene:

A solution of 1.0 g (3.9 mmole) obtained previously nitrocompounds in 5 ml of THF is treated with 200 mg W-2 Nickel of Renee, and then hydronaut when the pressure of hydrogen at one atmosphere for 18 hours. The floor is comfort in vacuum, and the residue is dissolved in 10 ml of acetone and treated with 8.2 ml of saturated sodium bicarbonate solution, then cooled to 0oC and add 699 mg (4.1 mmole) of benzylchloride. The resulting solution was warmed to room temperature for 18 hours, diluted with ethyl acetate and extracted with water. In the drying over sodium sulfate and concentration in vacuo get oil, which process chromatography on 75 g of silica gel (230-400 mesh mesh), elwira 50% /volume/volume/ ethyl acetate in hexane. The result of 1.03 g (71%) specified in the title compound in a solid yellow color.

1H NMR /CDCl3/ : 7,69, 7,60, 7,40, 7,25, 7,15, 6,70.

(S)-N-[3-[3-fluoro-4-(1H-indol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methanol:

A solution of 1.0 g (2,77 mmole) obtained previously CBZ derivative in 5 ml of THF at -78oC handle of 3.05 ml (1.0 M 3,05 mmole) letibit(trimethylsilyl)amide in THF, and then stirred at -78oC for 45 minutes. The resulting solution was treated with 440 mg (0,43 ml of 3.05 mmole) of (R)-(-)glycidylether, and then stirred at -78oC for 15 minutes, warmed to room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate and extracted with water. As a result, the 60 g of silica gel (230-400 mesh mesh), elwira 2% /volume/volume/ methanol in dichloromethane. The result is 630 mg (70%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,69; 7,50; 7,38; 7,25; 6,71; 4,80; 4,09; 3,79.

(S)-[3-[3-fluoro-4-(1H-indol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]mutilated:

A solution of 484 mg (1.2 mmole) obtained previously nelfinavir in 10 ml of DMF is treated with 390 mg (6 mmol) of sodium azide, and then heated at 90oC for 18 hours. The resulting solution is cooled and diluted with ethyl acetate, then extracted with water. In the drying over sodium sulfate and concentration in vacuo obtain 336 mg (80%) specified in the title azide resin, pure enough for further use.

1H NMR /CDCl3/ : 7,72, 7,68, 7,51, 7,37, 7,20, 6,71, 4,85, 4,13, 3,91, 3,77, 3,62.

(S)-N-[[3-[3-fluoro-4-(1H-indol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl] ndimethylacetamide:

A solution of 336 mg (0.96 mmole) obtained previously azide in 5 ml of ethyl acetate is treated with 150 mg of 10% palladium on charcoal, and then hydronaut when the pressure of hydrogen at 1 atmosphere for 18 hours. The resulting solution was filtered through celite, the filter cake washed with ethyl acetate. The obtained filtrate was concentrated in vacuo to obtain an oil which was stirred at room temperature for 60 hours. The resulting solution was concentrated in high vacuum, and the residue is dissolved in chloroform and extracted with water. In the drying over sodium sulfate and concentration in vacuo get the resin, which is treated using radial chromatography on a 4 mm chromatotron plate, elwira 1.5 per cent /amount/volume/ methanol in dichloromethane, and then a 2.5% volume/volume/ methanol in dichloromethane. The result is 277 mg (81%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,70, 7,51, 7,33, 7,20, 6,71, 6,11, 4,84, 4,12, 3,87, 3,70, 2,06

Example 6

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

3-fluoro-1-nitro-4-(1H-1,2,3-triazole-1-yl)benzene:

The secondary suspension of acid phosphate of potassium, 38.0 g (0,218 mol) and 1H-1,2,3-triazole, 7,53 g (6.3 ml, 0,109 mol) in 325 ml of dimethylsulfoxide is treated, prokopeva 3,4-diplomarbeit, 17.3 g (12.1 ml, 0,109 mol) by heating to 90oC for 18 hours. The resulting mixture was cooled to room temperature, diluted with 500 ml of water and extracted with ethyl acetate (4 x 50 ml). In the drying over sodium sulfate and concentration in vacuo get solid pale yellow color. This material is treated with nametranslation to get 11,38 g (50%) of 3-fluoro-1-nitro-4-(1H-1,2,3-triazole-1-yl)benzene in the form of a solid of light yellow color. So pl. 123-124,5oC, apart from 9.66 g (43%) of regioisomer 3-fluoro-1-nitro-4-(2H-1,2,3-triazole-1-yl)benzene in the form of a solid of light yellow color. So pl. 137-139oC.

3-fluoro-1-(formatactionname)-4-(1H-1,2,3-triazole-1-yl)benzene:

A solution of 5.0 g (24,0 mmole) obtained earlier connection in 400 ml of a mixture of 1: 1 methanol-THF is treated with 3 g W 2 Nickel of Renee. The resulting mixture hydronaut in a Parr apparatus under hydrogen pressure of 45 psi (3,164 kg/cm2for 18 hours, then filtered and the filter cake washed with methanol. In the result, concentration in vacuo get a solid white substance, which is dissolved in 500 ml of anhydrous THF, cooled to -20oC and treated with sodium bicarbonate, 4.0 g (48,0 mmole) and benzylchloride, 4.9 g (4,3 ml of 28.8 mmole). After stirring for 72 hours while gradually warming to room temperature the solvent is removed under reduced pressure and the remaining oil is dissolved in 200 ml of ethyl acetate. The resulting mixture was extracted with water (3 x 50 ml), dried over sodium sulfate and concentrated in vacuo to obtain a solid yellow color. The resulting material is processed chromatography on 400 g of silica gel (230-400 mesh mesh), elwira methylthio is inane in a solid white color. So pl. 121-122oC.

(R)-[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] methanol:

A solution of 2.0 g (6.4 mmole) of the previously obtained compound in 100 ml of anhydrous THF at -78oC handle of 6.7 ml (1.0 M, 6.7 mmole) letibit(trimethylsilyl)amide in THF, followed by stirring at -78oC for 30 minutes. The resulting mixture is treated 960 mg (6.7 mmole) of (R)-(-)-glycidylether, and then heated to 0oC and slowly warmed to room temperature. After 18 hours, the resulting mixture was quenched with a saturated aqueous solution of ammoniaand (30 ml) and extracted with ethyl acetate (3 x 30 ml). In the drying over sodium sulfate and concentration in vacuo get a solid oily yellow substance. The crude material is recrystallized from a boiling mixture of methanol:ethyl acetate 2:1 to obtain 1.10 g (62%) specified in the title compound as white solid. So pl. 179-180,5oC.

(R)-[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl] -2-oxo-5 - oxazolidinyl] mutilated:

A suspension of 1.35 g (4,85 mmole) obtained earlier connection and 859 mg (1,18 ml, 8,49 mmole) of triethylamine in 60 ml of dichloromethane at 0oC handle 695 mg (of 0.47 ml, 6,07 mmole) of methanesulfonamide followed by heating on, 59 mg (8,49 mmole) and methanesulfonamide, 695 mg (6,07 mmole). After 5 minutes the mixture is extracted with water (3 x 20 ml), saturated aqueous NHCO3(2 x 20 ml), saturated aqueous NaCl (1 x 20 ml). In the drying over sodium sulfate and concentration in vacuo get 1,89 g corresponding nelfinavir in the form of a solid of light yellow color, which is dissolved in 90 ml of DMF and treated to 4.73 g (72.8 mmole) of sodium azide at 60oC for 18 hours. The resulting mixture was cooled to 0oC and diluted with 200 ml of water. The resulting mixture was extracted with a mixture of 1:1 ethanol-ethyl acetate (5 x 50 ml). The combined organic layers are then extracted with water (4 x 50 ml), dried over sodium sulfate and concentrated in vacuo to obtain 1.48 g (about 100%) specified in the title azide as off-white solid, sufficiently pure for further use.

1H NMR /CDCl3/ : 8,09, 7,98, 7,87, 7,29, 4,86, 4,16, 3,94, 3,70.

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

A solution of 300 mg (0.99 mmole) of the specified previously azide in 12 ml of THF is treated with 750 mg W-2 Nickel of Renee. The resulting mixture hydronaut at atmospheric pressure for 18 hours. Polychem by stirring for 2 hours. The resulting mixture was filtered through celite, washed filter cake with ethyl acetate. The obtained filtrate is extracted with water (3 x 30 ml) and saturated brine (1 x 20 ml). In the drying over sodium sulfate and concentration in vacuo get dirty-white solid. The crude material is recrystallized from a boiling mixture of 10:1 ethyl acetate:hexane to obtain 210 mg (66%) specified in the title compound as white solid. So pl. 193-194oC.

Example 7

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]-2,2-dichloroacetamide:

A solution of 275 mg (of 0.91 mmole) of (R)-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methylated (from example 6) in 15 ml THF is treated with 1.5 g of W-2 Nickel of Renee and hydronaut at atmospheric pressure. After 18 hours the mixture is filtered through celite, washed filter cake with methanol. The obtained filtrate was concentrated in vacuo and the resulting oil was stirred in 15 ml of methylene chloride, cooled to 0oC and treated with 138 mg (0,19 ml of 1.36 mmole) of triethylamine and 161 mg (0.11 ml, 1.09 mmole) of dichloroacetylene. After stirring at ambient temperatures for 24 hours the mixture is diluted with methylenchlorid sodium and concentration in vacuo get dirty-white solid. The crude material is treated using radial chromatography on a 4 mm chromatotron plate, elwira dichloromethane and 2% volume/volume/ ethanolgasoline. The result is 182 mg (52%) specified in the title compound as white solid. So pl. 195-198oC (decomposition).

Example 8

(S)-N-[[3-[3-fluoro-4-(2H-1,2,3-triazole-2-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

3-fluoro-1-(formatactionname)-4-(2H-1,2,3-triazole-2-yl)benzene:

A solution of 6.0 g (28,82 mmole) of 3-fluoro-1-nitro-4-(2H-1,2,3-triazole-2 - yl)benzene in 150 ml of ethyl acetate and 25 ml of methanol is treated with 750 mg W-2 Nickel of Renee. The resulting mixture hydronaut in a Parr apparatus under hydrogen pressure of 45 psi (3,164 kg/cm2) within 24 hours. The resulting mixture was filtered through celite and the resulting filtrate concentrated in vacuo. The residue is dissolved in 150 ml of acetone, treated with 72 ml of saturated sodium bicarbonate solution, then cooled to 0oC. the resulting mixture is treated 6,15 g (5,14 mmole) of benzylchloride, stirred at 0oC for 1 hour and then warmed to room temperature for 3 hours. The resulting mixture was diluted with 500 ml of water and 400 ml of ethyl acetate. The aqueous phase is washed with 250 ml of ethyl acetate, and obyedinenie and concentration in vacuo receive oil amber which is recrystallized from a hot mixture of chloroform:hexane to obtain 7,52 g (84%) specified in the title compound in the form of a solid white color. So pl. of 99.5-101oC.

(R)-[3-[3-fluoro-4-(2H-1,2,3-triazole-2-yl)phenyl] -2-oxo-5 - oxazolidinyl] methanol:

A solution of 1.0 g (3,20 mmole) obtained earlier connection in 45 ml of THF at -78oC handle to 3.52 ml (1.0 M, to 3.52 mmole) letibit(trimethylsilyl)amide in THF, and then stirred at -78oC for 30 minutes. The resulting solution is treated 508 mg (0,50 ml, to 3.52 mmole) of (R)-(-)-glycidylether, followed by stirring at 0oC for 30 minutes and then at room temperature for 18 hours. The resulting mixture was diluted with 75 ml ethyl acetate and extracted with water (2 x 75 ml) and saturated brine (75 ml). In the drying over sodium sulfate and concentration in vacuo receive oil amber color, which is dissolved in 75 ml of methanol and treated with 1.0 g K2CO3and then stirred for 2 hours. The resulting mixture was filtered and concentrated in vacuo to obtain an oil of amber, which process chromatography on 50 g of silica gel (230-400 mesh mesh), elwira 3% volume/volume/ methanol in dichloromethane. The result p is

(R)-[3-[3-fluoro-4-(2H-1,2,3-triazole-2-yl)phenyl] -2-oxo-5 - oxazolidinyl] mutilated:

A solution of 350 mg (1,26 mmole) obtained earlier alcohol and 2 ml of triethylamine in 8 ml of dichloromethane at 0oC handle 362 mg (1,64 mmole) of nailhead, and then stirred at 0oC for 30 minutes and warmed to room temperature for 1 hour. The resulting mixture is diluted with 50 ml dichloromethane and extracted with water (215,8 g x 50 ml). In the drying over sodium sulfate and concentration in vacuo obtain 540 mg (92%) of the corresponding nosilca which is dissolved in 12 ml of N,N-dimethylformamide and treated with 2 g of sodium azide, and then stirred at room temperature for 48 hours. The resulting solution was diluted with 125 ml ethyl acetate and extracted with water (5 x 50 ml). In the drying over sodium sulfate and concentration in vacuo get a solid yellow product, which process chromatography on 50 g of silica gel (230-400 mesh mesh), elwira dichloromethane and then 5% volume/volume/ acetone in dichloromethane. In this way receive 333 mg (94%) specified in the title azide as solid pale yellow color.

1H NMR /CDCl3/ : 7,87, 7,70, 7,38, 4,84, 4,13, 3,91, 3,75, 3,63.

(S)-N-[[3-[3-fluoro-4-(2H-1,2,3-triazo is 00 mg W-2 Nickel of Renee, and then hydronaut in a Parr apparatus at a pressure of 30 psi (2,109 kg/cm2) of hydrogen for 18 hours. The resulting mixture was filtered through celite and the resulting filtrate concentrated in vacuo. The residue is dissolved in 8 ml of pyridine and treated with 4 ml of acetic anhydride, followed by stirring at room temperature for 24 hours. The solvent is removed under high vacuum (0.2 mm RT. century), and the residue is dissolved in 75 ml ethyl acetate and extracted with water (2 x 50 ml) and saturated saline (50 ml). In the drying over sodium sulfate and concentration in vacuo receive oil amber color, which is treated using radial chromatography on a 4 mm chromatotron plate, elwira 4% /volume/volume/ methanol in dichloromethane. The resulting material is recrystallized from a mixture of chloroform-hexane to obtain 164 mg (47%) specified in the title compound.

1H NMR /CDCl3/ : 7,87, 7,82, 7,70, 7,32, 6,21, 4,83, 4,10, 3,84, 3,68, 2,03.

Example 9

(S)-N-[[3-[3-fluoro-4-(3-mercapto-4H-1,2,4-triazole-4-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

4-(N-benzylamino)-3-ftorirovannom:

A solution of 23.9 g (16,9 ml of 0.15 mol) of 3,4-deformirovannoe and 29.1 g (39,2 ml of 0.23 mol) of N,N-diisopropylethylamine in 285 ml acetonitrile 5 hours. The resulting mixture was concentrated in vacuo, and the residue is dissolved in 200 ml of ethyl acetate, followed by extraction with water (3 x 50 ml). In the drying over sodium sulfate and concentration in vacuo get a solid yellow color, which is recrystallized from a hot mixture of ethyl acetate-hexane to obtain 32,25 g (87%) specified in the title compound in the form of needles yellow-orange color. So pl. is 97.5-99oC.

4-(N-benzyloxycarbonylamino)-1-(benzyloxycarbonylamino)-3-torbenson:

A solution of 14.25 g (0,058 mole) of the previously obtained compound in 800 ml of THF is treated with 1.0 g of 5% platinum on charcoal, and then hydronaut in a Parr apparatus at a pressure of 30 psi (2,109 kg/cm2) of hydrogen for 18 hours. The resulting mixture was filtered through celite, washed filter cake with ethyl acetate. The obtained filtrate was concentrated in vacuo to obtain an oily residue which is dissolved in 1.0 l of THF and treated with 15.8 g (16.5 ml of 0.13 mole) of N,N-dimethylformamide. The resulting solution was cooled to 0oC and added dropwise 21,72 g (18,18 ml, to 0.127 mole) of benzylchloride within 30 minutes. The solution was stirred at 0oC for 30 minutes and then leave to gradually warm to room temperature after the l of ethyl acetate. The resulting mixture was washed with 80 ml of cold 1N HCl solution, 80 ml of water and 80 ml of saturated sodium bicarbonate solution. The resulting solution was dried over magnesium sulfate and concentrated in vacuo to obtain the oil, which process chromatography on 500 g of silica gel (230-400 mesh mesh), elwira 10-15 per cent /amount/volume/ ethyl acetate in hexane. The result 12,42 g (44%) specified in the title compound in the form of a solid white color. So pl. 101-102,5oC.

(R)-[3-[3-fluoro-4-(N-benzylbenzimidazole)phenyl]-2-oxo-5 - oxazolidinyl]methanol:

The solution 12,42 g (0,026 mol) previously specified connection in 375 ml of THF at -78oC handle of 16.7 ml (1.6 M, or 0.027 mol) n-utility in hexane dropwise over 6 minutes, and then stirred at -78oC for 30 minutes. The resulting solution was treated then 4.6 g (4.5 ml, to 0.032 mol) of (R)-(-)-glycidylether, and then stirred at -78oC for 1 hour, then warmed to room temperature for 20 hours. The resulting solution was treated with 25 ml of saturated solution of ameriglide, then adding 25 ml of water and 300 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic layers are dried over magnesium sulfate and concentrated in vacuo. the volume/ methanol in dichloromethane. The result 7,56 g (66%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,48, 7,25, 7,07, 6,95, 5,15, 4,18, 4,67, 3,91, 3,69.

(S)-N-[3-[3-fluoro-4-(N-benzylbenzimidazole)phenyl] -2 - oxo-5-oxazolidinyl]methylacetamide:

The solution 8,23 g (to 18.3 mmole) obtained earlier connection or 3.24 g (4.5 ml, 32.0 mmole) of triethylamine in 107 ml of dichloromethane at 0oC handle 5,47 g nailhead, and then stirred at 0oC for 4 hours. The resulting mixture was diluted with dichloromethane and extracted with water (2 x). In the drying over sodium sulfate and concentration in vacuo get a yellow foam, which was dissolved in 58 ml of isopropyl alcohol, 93 ml of acetonitrile and 116 ml of ammonium hydroxide, and then heated at 40oC for 18 hours. The resulting mixture is cooled, diluted with ethyl acetate and extracted with water (3×) and saturated salt solution. In the drying over sodium sulfate and concentration in vacuo get a yellow foam, which was dissolved in 200 ml of ethyl acetate and process of 4.67 g (4.3 ml, 45,75 mmole) of pyridine and of 7.24 g (7,4 ml of 91.5 mmole) of acetic anhydride. The resulting solution was stirred at room temperature for 18 is of the atrium and concentration in vacuo get the foam is amber, which process chromatography on 450 g of silica gel (230-400 mesh mesh), elwira 1% /vol/vol/ methanol in dichloromethane. The result? 7.04 baby mortality g (78%) specified in the title compound in the form of foam a light yellow color. The mass spectrum of high resolution (electron impact): Calculated for C27H26FN3O5: 491,1856. Found: 491,1860.

(S)-N-[3-[3-fluoro-4-AMINOPHENYL]-2-oxo-5-oxazolidinyl]methylacetamide:

A solution of 5.6 g (11.4 mmole) of the previously obtained compound in 200 ml of ethanol is treated with 200 mg of 10% palladium on coal with subsequent hydrogenation in a Parr apparatus under hydrogen pressure of 45 psi (3,16 kg/cm2) within 24 hours. The resulting mixture was filtered through celite, washed filter cake with methanol. The obtained filtrate was concentrated in vacuo to obtain off-white solid, which is recrystallized from a hot mixture of ethyl acetate-hexane to

receipt of 2.81 g (92%) specified in the title compound as off-white substance.

1H NMR /CDCl3/ : 8,20, 7,29, 6,95, 6,76, 5,00, 4,65, 4,00, 3,63, 3,37, 1,83.

(S)-N-[3-[3-fluoro-4-isothiocyanates]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

A solution of 960 mg (4,12 mmol) of 1,1'-thiocarbonyldi-2(1H)-pyridone in 30 ml of dichloromethane PI 0oC for 2.5 hours, and then warmed to room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the resulting solid is triturated with 15 ml of water. The product is filtered and washed with a small amount of water, followed by drying overnight in a vacuum Cabinet. The result of 1.09 g (94%) specified in the title compounds as white solids. So pl. 172,5-176oC.

(S)-N-[3-[3-fluoro-4-[3-mercapto-4H-1,2,4-triazole-4-yl] phenyl]-2 - oxo-5-oxazolidinyl]methylacetamide:

A solution of 11.1 g (3,59 mmole) obtained earlier connections in 26 ml of THF is treated with 230 mg (of 3.77 mmole) moravcikova hydrazide followed by heating at 70oC for 3.5 hours. The resulting mixture is cooled and the residue is filtered and washed with ethyl acetate. The hard part is dried in a vacuum Cabinet at 60oC to obtain 1.2 g of solid product. From this material, 100 g, or 0.27 mmole) are suspended in 2 ml of water and treated, and 0.28 ml (0,97 M of 0.27 mmole) of KOH solution, followed by stirring for 45 minutes. Then the solution process of 0.28 ml (1.0 n, and 0.28 mmole) of HCl solution. The precipitate is filtered off and washed with a small amount of 1N. HCl solution. The hard part is dried in a vacuum Cabinet in white color. So pl. 269-271oC.

Example 10

(S)-N-[[3-[3-fluoro-4-[3-methylthio-4H-1,2,4-triazole-4-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A suspension of 200 mg (0.57 mmole) of the compound of example 9 and 121 mg (53 μl, of 0.85 mmole) under the conditions in 5 ml of methanol is treated with 53 mg (0,63 mmole) of solid sodium bicarbonate. The resulting mixture was stirred at room temperature for 23 hours, the solid precipitate is filtered and the filter cake washed with methanol. The obtained filtrate was concentrated in vacuo to obtain a resin, which is treated chromatography on 25 g of silica gel (230-400 mesh mesh), elwira 5% volume/volume/ methanol and 0.5% volume/volume/ ammonium hydroxide in dichloromethane. The result is a solid white color, which is recrystallized from methanol to obtain 128 mg (61%) specified in the title compound as white solid. So pl. 188,5-to 190.5oC.

Example 11

(S)-N-[[3-[3-fluoro-4-(4H-1,2,4-triazole-4-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

330 mg (0,938 mmole) of the mercaptan of example 9 is added to 0.6 ml of 20% solution of nitric acid, followed by heating on a steam bath for approximately 1 minute. Then add an additional 0.6 ml of 20% nitric acid with the placenta. the received mixture is cooled to 0oC and pH set to 9 by adding ammonium hydroxide solution. The resulting mixture was concentrated in vacuo to obtain a resinous brown oil, which process chromatography on 25 g of silica gel (230-400 mesh mesh), elwira 5% volume/volume/ methanol and 0.5% volume/volume/ ammonium hydroxide in dichloromethane to obtain a solid, which is recrystallized from acetonitrile and get listed in the title compound. So pl. 204,5-206oC.

Example 12

(S)-N-[[3-[3-fluoro-4-(1H-pyrrol-1-yl-3-carboxaldehyde)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 2.0 g (7.5 mmole) of aniline derivative of example 9 and 1.68 g (10.5 mmole) of 2,5-dimethoxy-3-tetrahydrobenzaldehyde in 55 ml of glacial acetic acid is refluxed for 2 hours. The resulting solution was cooled and the solvent is removed in vacuum, azeotropic driving the residue with toluene to remove the last traces of acetic acid. The residue is treated chromatography on silica gel 300 g (230-400 mesh mesh), elwira dichloroethane, and then 1-3% /volume/volume/ methanol in dichloromethane. The result of 2.21 g specified in the title compound as an amorphous solid substance is Found: 345,1129.

Example 13

(S)-N-[[3-[3-fluoro-4-(3-hydroxymethyl-1H-pyrrol-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 125 mg (0,36 mmole) of the previously obtained compound in 4 ml of methanol and 2 ml of dichloromethane at 0oC is treated with 7 mg (0,18 mmole) sodium borohydride. The resulting solution was left to warm to room temperature for 4 hours, then diluted with 30 ml dichloromethane and extracted with water. In the drying over sodium sulfate and concentration in vacuo get a solid white color, which is recrystallized from a mixture of ethyl acetate-methanol-hexane. The result is 106 mg (84%) specified in the title compound in the form of a solid white color. The mass spectrum of high resolution (electron impact): Calculated for C17H18FN3O4: 347,1281. Found: 347,1274.

Example 14

(S)-N-[[3-[3-fluoro-4-(3-carbomethoxy-1H-pyrrol-1-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide:

A solution of 220 mg (of 0.64 mmole) of the compound of example 12 in 10 ml of a mixture of 1:1 acetonitrile-methanol process 164 mg (of 0.64 mmole) of sodium cyanide and 1.15 g (13.2 mmole) of activated manganese dioxide and 60 mg (58 μl, 1.0 mmole) in glacial acetic acid. The resulting mixture was stirred at room temperature) of glacial acetic acid. The resulting solution was stirred for further 24 hours and filtered through celite, washed filter cake with methanol. The obtained filtrate was concentrated in vacuo, diluted with ethyl acetate and shaken out three times with water. The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain a solid pink color. This material is treated using radial chromatography on a 2 mm chromatotron plate, elwira dichloromethane, and then 1-2% /volume/volume/ methanol in dichloromethane. The result is 170 mg (71%) specified in the title compound in the form of a solid white color. Elemental analysis: Calculated for C18H18FN3O5: C 57,60; H A 4.83; N 11,20. Found: C 57,29; H 5,19; N 11,07.

Example 15

(S)-N-[[3-[3-fluoro-4-(1H-pyrrol-1-yl-carboxaldehyde)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide metoxi:

A solution of 150 mg (0.43 mmole) of the compound of example 12 in 5 ml of a mixture of 1:1 methanol:dichloromethane is treated with 44 mg (0,52 mmole) of methoxyamphetamine and 36 mg (0,26 mmole) of potassium carbonate, followed by stirring at room temperature for 18 hours. The resulting mixture was diluted with dichloromethane and extracted three times with water. In the drying over sodium sulfate and autographically 2 mm chromatotron plate, elwira dichloromethane, and then 1-2% /volume/volume/ methanol in dichloromethane. The result is 101 mg (63%) specified in the title compound in the form of a solid white color that is a mixture of E - and Z-stereoisomers at the double bond. The mass spectrum of high resolution (electron impact): calculated for C18H19FN4O4: 347,1390. Found: 347,1390.

Example 16

(S)-N-[[3-[3-fluoro-4-(3-(gidroksilaminami)-1H-pyrrol-1 - yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 150 mg (0.43 mmole) of the aldehyde of example 12 and 36 mg (0,26 mmole) of potassium carbonate in 10 ml of a mixture of 1:1 methanol:dichloromethane is treated with 36 mg (0,52 mmole) of hydroxylaminopurine, followed by stirring at room temperature for 48 hours. The resulting mixture was diluted with ethyl acetate, extracted three times with water, dried over sodium sulfate and concentrated in vacuo to obtain a solid substance. This material is treated using radial chromatography on a 2 mm chromatotron plate, elwira 2-4% /volume/volume/ methanol in dichloromethane. The result is 90 mg (58%) specified in the title compound in the form of a solid white color.

1H NMR /DMSO/ : 11,07, 10,05, 8,24, 8,01, 7,85, 7,70, 7,62, 7,40, 7,30, 7,�Soldini]methyl]ndimethylacetamide:

(S)-N-[[3-[4-azido-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 4.0 g (14,96 mmole) of (S)-N-[3-[3-fluoro-4-AMINOPHENYL]-2 - oxo-5-oxazolidinyl]methylacetamide example 9 in 40 ml of 6 n HCl solution at 0oC handle portions of 4.12 g (59,84 mmole) of sodium nitrite, followed by stirring at 0oC for 2 hours. Then the resulting mixture was treated with several portions with a solution of 1.94 g (29,92 mmole) of sodium azide and 24,52 g (0,30 mol) of sodium acetate in 50 ml of water. After complete addition, the solution is extracted with ethyl acetate, the organic layer dried over sodium sulfate and concentrated in vacuo to obtain 4.1 g (93%) specified in the title compound in the form of a solid of light yellow color, pure enough for further use.

1H NMR /CDCl3/ : 8,22, 7,59, 7,33, 4,72, 4,10, 3,72, 3,40, 1,90.

(S)-N-[[3-[3-fluoro-4-(4-acetyl-1H-1,2,3-triazole-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 500 mg (1.7 mmole) obtained previously azide in 25 ml of benzene is treated 347 mg (5.1 mmole) of 3-butyn-2-it is followed by heating at boiling under reflux for 18 hours. The resulting mixture is cooled and allocate filtering 407 mg (66%) specified in the title compounds. The mass spectrum in the CLASS="ptx2">

Example 18

(S)-N-[[3-[3-fluoro-4-(4-(1-hydroxyethyl)-1H-1,2,3-triazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 150 mg (0.40 mmole) of the compound of example 17 in 10 ml of a mixture of 1:1 THF: methanol is treated with 15 mg (0.4 mmole) of sodium borohydride, followed by stirring at room temperature for 18 hours. The resulting mixture was concentrated in vacuo, dissolved in a mixture of 1:1 methanol:dichloromethane and filtered. The obtained filtrate was concentrated in vacuo, and the residue is treated using radial chromatography on a 2 mm chromatotron plate. The result is 120 mg (80%) specified in the title compound in the form of a solid white color. Mass spectrum (electron impact): m/z: 363, 291, 276, 232, 217, 207, 191, 179, 163, 148, 135, 123, 85, 56.

Example 19

(S)-N-[[3-[3-fluoro-4-(4-(1-gidroksilaminami)-1H-1,2,3-triazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 150 mg (0.40 mmole) of the compound of example 17 in 10 ml of a mixture of 1:1 THF: methanol is treated with 66 mg (0.96 mmole) of hydroxylamine hydrochloride and 66 mg (0.48 mmole) of potassium carbonate, followed by stirring at room temperature for 8 hours, and then heated at the boil under reflux for 2 hours. The resulting mixture was concentrated in vacuo, and hem/ methanol in dichloromethane. The result is 30 mg (20%) specified in the title compound in the form of a solid white color. Mass spectrum (electron impact): m/z: 376, 332, 318, 287, 274, 245, 220, 202, 187, 175, 163, 149, 139, 82, 56.

Example 20

(S)-N-[[3-[3-fluoro-4-(4-carbomethoxy-1H-1,2,3-triazole-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 1.0 g (3.4 mmole) azide of example 17 in 50 ml of benzene is treated 573 mg (6.8 mmole) of methylpropionate followed by heating at boiling under reflux for 24 hours. The result is 880 mg specified in the title compound in the form of a solid white color. The mass spectrum of high resolution (electron impact): Calculated for C16H16FN5O5: 377,1135. Found: 377,1131.

Example 21

(S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl-4-carboxaldehyde)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 1.70 g (5.8 mmole) azide of example 17 in 50 ml of benzene is treated to 4.46 g (to 34.8 mmole) 1,1-diethoxy-2-propene followed by heating at boiling under reflux for 18 hours. The resulting solution was treated with 1.0 g (7,80 mmole) 1,1-diethoxy-2-propene followed by boiling under reflux for additional 3 hours. The resulting solution is cooled and conc is UYa 2-3% /volume/volume/ methanol in dichloromethane to obtain 2.0 g (80%) of (S)-N-[[3-[3-fluoro-4-(4-(diethoxylate)-1H-1,2,3-triazole-1 - yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide and

(S)-N-[[3-[3-fluoro-4-(5-(diethoxylate)-1H-1,2,3-triazole-1 - yl)phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide as an inseparable mixture of isomers. 410 mg (0,973 mmole) of this material was dissolved in THF and treated with 1N. HCl solution, followed by stirring at room temperature for 48 hours, and then heated at the boil under reflux for 1 hour. The resulting mixture was dissolved in ethyl acetate and extracted with water. In the drying over sodium sulfate and concentration in vacuo get oil, which is treated using radial chromatography on a 2 mm chromatotron plate, elwira 7% /volume/volume/ methanol in dichloromethane. The less polar fraction 110 mg (33%) according to the chromatography is specified in the title compound and is solid white.

1H NMR /CDCl3/ : 8,60, 7,99, 7,85, 7,36, 6,1, 4,86, 4,12, 3,89, 3,72, 2,04.

Example 22

(S)-N-[[3-[3-fluoro-4-(4-hydroxymethyl-1H-pyrazole-1-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

10 ml of methanol at 0oC handle, prokopeva 1 ml acetylchloride followed by the addition of 2.0 g (17,84 mmole) 4-pyrazolylborate acid followed by heating the mixture at boiling under reflux is glavie compounds in a solid white color.

1H NMR /CD3OD/ : 8,25, 3,86.

4-(4-carbomethoxy-1H-pyrazole-1-yl)-3-fluoro-1-nitrobenzene:

A solution of 2.9 g (17,84 mmole) obtained earlier connection and 4.93 g (35,68 mmole) of potassium carbonate in 85 ml of DMSO treated 2.83 g (17,84 mmole) of 3,4-deformirovannoe. The resulting solution was heated at 90oC for 16 hours then cooled, diluted with chloroform and extracted with water (5 x). In the drying over sodium sulfate and concentration in vacuo get to 4.17 g (88%) specified in the title compound as off-white solid.

1H NMR /CDCl3/ : 8,65, 8,28, 3,91.

4-(4-carbomethoxy-1H-pyrazole-1-yl)-3-fluoro-1- (formatactionname)benzene:

A solution of 4.17 g (15.7 mmole) of the previously obtained compound in 200 ml of THF is treated with 1 g W-2 Nickel of Renee with subsequent hydrogenation in a Parr apparatus under hydrogen pressure of 45 psi (3,164 kg/cm2) for 18 hours. The resulting mixture was filtered through celite, and the filtrate was concentrated in vacuo to obtain off-white solid, which was dissolved in 30 ml of THF and 5 ml of acetone and treated with 34 ml of saturated sodium bicarbonate solution, and then cooled to 0oC and add 3,21 g (2,69 ml of 18.8 mmole) benzylglycine temperature for 18 hours. The resulting mixture was concentrated in vacuo, the resulting aqueous layer was extracted with ethyl acetate (3 x). The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain 3.1 g (53%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 8,41, 8,10, 7,79, 7,64, 7,40, 7,10, 6,88, 5,23, 3,88.

4-(4-hydroxymethyl-1H-pyrazole-1-yl)-3-fluoro-1- (formatactionname)benzene:

A solution of 3.0 g (8,13 mmole) of the previously obtained compound in 20 ml of anhydrous THF is treated with 1.42 g (65,04 mmole) of lithium borohydride, followed by stirring at room temperature for 18 hours. The resulting solution handles 5 ml saturated aqueous sodium bicarbonate solution, followed by concentration in vacuo. The resulting mixture was diluted with ethyl acetate and extracted with water. In the drying over sodium sulfate and concentration in vacuum to get a residue that process chromatography on 150 g of silica gel (230-400 mesh mesh), elwira 2% /volume/volume/ methanol in dichloromethane. The result 1.63 g (59%) specified in the title compound in the form of a solid white color. The mass spectrum of high resolution (electron impact): Calculated for C18Hthe R-1- (formatactionname)benzene:

A solution of 1.6 g (of 4.77 mmole) of the previously obtained compound in 30 ml of dichloromethane is treated with 400 mg (4.75 mmole) dihydropyran and 10 mg p-toluensulfonate acid. The resulting solution was stirred at room temperature for 18 hours, followed by extraction with 30 ml of saturated sodium bicarbonate solution and water (30 ml). In the drying over sodium sulfate and concentration in vacuo get a solid substance, which chromatographic process on 85 g of silica gel (230-400 mesh mesh), elwira 20% volume/volume/ ethyl acetate in hexane. The result is 2.0 g (99%) specified in the title compound in the form of a solid white color. The mass spectrum of high resolution (electron impact): Calculated for C23H24FN3O4: 425,1751. Found: 425,1747.

(R)-[3-[3-fluoro-4-(4-[(tetrahydropyran-2-yl)oxymethyl] -1H-pyrazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methanol:

A solution of 1.4 g (3,36 mmole) of the previously obtained compound in 10 ml of THF at -78oC is treated with 3.7 ml (1.0 M, 3.7 mmole) letibit(trimethylsilyl)amide in THF, followed by stirring at -78oC for 30 minutes. The resulting solution is treated 533 mg (of 0.52 ml, 3.7 mmole) of (R)-(-)-glycidylether, followed by stirring at -78othe URS for 18 hours. The resulting solution was treated with 1 ml of saturated solution of ameriglide and diluted with ethyl acetate. The resulting mixture is extracted with water, dried over sodium sulfate and concentrated in vacuo. The residue is treated chromatography on 70 g of silica gel (230-400 mesh mesh), elwira 2% /volume/volume/ methanol in dichloromethane. The result is 910 mg (70%) specified in the title compound as white solid. The mass spectrum of high resolution (electron impact): Calculated for C19H22FN3O5: 391,1543. Found: 391,1542.

(R)-[3-[3-fluoro-4-(4-[(tetrahydropyran-2-yl)oxymethyl] -1H-pyrazole-1 - yl)phenyl]-2-oxo-5-oxazolidinyl]methanesulfonanilide:

The solution 0,820 mg (2.1 mmole) obtained earlier connection and 318 mg (3,15 mmole) of triethylamine in 25 ml of dichloromethane at 0oC is treated with 360 mg (2,62 mmole) of methanesulfonamide. The resulting solution was stirred at 0oC for 1 hour. This solution was diluted with dichloromethane and extracted with water. In the drying over sodium sulfate and concentration in vacuo receive 986 mg (99%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,95, 7,92, 7,74, 7,25, 4,97, 4,75, 4,50, 4,20, 4,01, 3,93, 3,59, 3,12, 1,85, 1,74, 1,5 Zid:

The solution 986 mg (2.1 mmole) obtained earlier connection and 683 mg (10.5 mmole) of sodium azide in 20 ml of DMF is heated at 60oC for 18 hours, followed by dilution with ethyl acetate and extraction with water. In the drying over sodium sulfate and concentration in vacuo receive 874 mg (990) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,98, 7,87, 7,74, 7,23, 4,82, 4,72, 4,50, 4,11, 3,90, 3,73, 3,61, 3,55, 1,81, 1,73, 1,58.

(S)-N-[[3-[3-fluoro-4-(4-[(tetrahydropyran-2-yl)oxymethyl] -1H - pyrazole-1-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide:

The solution 874 mg (2.1 mmole) of the previously obtained compound in 15 ml of ethyl acetate is treated with 200 mg of 10% palladium on coal with subsequent hydrogenation under hydrogen pressure of 1 ATM. within 1.5 hours. The resulting solution was filtered through celite, and the filtrate was concentrated in vacuo to obtain a solid brown color, which is dissolved in 3 ml of pyridine and treated 428 g (4.2 mmole) of acetic anhydride, followed by stirring at room temperature for 18 hours. The solution is diluted with ethyl acetate and extracted with water. In the drying over sodium sulfate and concentration in vacuo receive the solid product to ethane. As a result, 626 mg (69%) specified in the title compound as white solid. The mass spectrum of high resolution (electron impact): Calculated for C21H25FN4O5: 432,1809. Found: 432,1811.

(S)-N-[[3-[3-fluoro-4-(4-hydroxymethyl-1H-pyrazole-1-yl)phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 300 mg (0,693 mmole) of the previously obtained compound in 15 ml of methanol is treated with 40 mg of p-toluensulfonate acid, followed by stirring at room temperature for 18 hours. The resulting mixture was concentrated in vacuo, and the residue is dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution and water. In the drying over sodium sulfate and concentrated in vacuum to obtain 140 mg (58%) specified in the title compound in the form of a solid white color. The mass spectrum of high resolution (electron impact): Calculated for C16H17FN4O4: 349,1312. Found: 349,1321.

Example 23

(S)-N-[[3-[3-fluoro-4-[3-(2-carboethoxy)-1H-pyrrol-1-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide:

A solution of 805 mg (3,19 mmole) diisopropylperoxydicarbonate in 7 ml of THF at 0oC handle 3,19 ml (1M, 3,19 mmole) of solution required the PR cooled to -78oC and treated via cannula with a solution of 500 mg (1,45 mmole) of the compound of example 12 in 4 ml of THF. The resulting solution was stirred at -78oC for 30 minutes, then warmed to room temperature for 2 hours. The resulting solution was quenched by adding 1 ml of saturated solution of ameriglide followed by dilution with ethyl acetate and extraction with water. In the drying over sodium sulfate and concentration in vacuo get a solid yellow color, which process chromatography on 100 g of silica gel (230-400 mesh mesh), elwira 1-2% /volume/volume/ methanol in dichloromethane. The result is 497 mg (83%) specified in the title compound in the form of a solid of light yellow color.

1H NMR /CDCl3/ : 7,65, 7,37, 7,27, 7,20, 6,97, 6,56, 6,17, 6,02, 4,82, 4,24, 4,08, 3,83, 3,70, 2,04, 1,33.

Example 24

(S)-N-[[3-[3-fluoro-4-[3-(2-carboethoxy)-1H-Perrot-1-yl] phenyl] -2 - oxo-5-oxazolidinyl]methyl]acetamide:

A solution of 150 mg (0,36 mmole) of the compound of example 23 and 54 mg (0.54 mmole) of copper chloride [1] in 15 ml of a mixture of 1:1 methanol:THF at 0oC handle 136 mg (3.6 mmole) of sodium borohydride. The resulting solution was stirred at 0oC for 30 minutes and then warmed to room temperature for 1 hour. The obtained filtrate was concentrated in vacuo, and the residue is diluted with ethyl acetate and shaken out three times with water. In the drying over sodium sulfate and concentration in vacuo receive 150 mg (99%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,60, 7,34, 7,33, 6,91, 6,81, 6,21, 5,97, 4,81, 4,15, 4,08, 3,82, 3,72, 3,65, 2,87, 2,62, 2,04, 1,26.

Example 25

(S)-N-[[3-[3-fluoro-4-[3-(3-hydroxypropyl)-1H-pyrrol-1-yl]phenyl]-2 - oxo-5-oxazolidinyl]methyl]acetamide:

A solution of 275 mg (0,66 mmole) of the compound of example 24 in THF (15 ml) is treated with 287 mg (13.2 mmole) of lithium borohydride, followed by stirring at room temperature for 18 hours. The resulting solution was treated with 1 ml of saturated solution of ameriglide, diluted with ethyl acetate and extracted with water (3 x). In the drying over sodium sulfate and concentration in vacuo get oil, which process chromatography on 20 g of silica gel (230-400 mesh mesh), elwira 2-4% /volume/volume/ methanol in dichloromethane. The result is 96 mg (39%) specified in the title compound in the form of a solid white color.

1H NMR /CDCl3/ : 7,74, 7,66, 7,38, 7,27, 7,18, 6,95, 6,61, 5,98, 4,82, 4,37, 4,27, 4,09, 3,83, 3,68, 2,88, 2,82, 2,62, 2,04, 1,79.

Example 26

(S)-N-[[3-[3-fluoro-4-[3-(3-methansulfonate example 25 (pre-dried at 60oC and a pressure of 0.1 mm RT. Art. for 18 hours before use) and 88 mg (120 μl, from 0.88 mmole) of triethylamine in 2 ml of dichloromethane at 0oC is treated with 85 mg (58 μl, 0.73 mmole) of methanesulfonamide, followed by stirring at 0oC for 30 minutes. The resulting solution was diluted with dichloromethane and extracted with water twice and saturated sodium bicarbonate solution. In the drying over sodium sulfate and concentration in vacuo get a solid substance that is dissolved in 2 ml DMF and treated via cannula at 0oC a solution of 38 mg (0.4 mmole) of methanesulfonamide in 2 ml of DMF, which was pre-treated with a 10 mg (17 mg, 60% in oil, 0.43 mmole) of sodium hydride. Then the resulting solution was heated at 60oC for 18 hours. The resulting solution is cooled and the DMF removed in vacuo, and the residue is dissolved in ethyl acetate and extracted twice with water. In the drying over sodium sulfate and concentration in vacuo get a solid product, which is treated using radial chromatography on a 2 mm chromatotron plate, elwira 1-4% /volume/volume/ methanol in dichloromethane. The result is 31 mg (26%) specified in the title compound in the form of a solid white color.

Example 27

(S)-N-[[3-[3-Fluoro-4-(2H-1,2,3,4-tetrazol-2-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide.

< / BR>
Stage 1. The solution 15,83 g 1H-tetrazole, 7,19 g of 3,4-debtor-nitrobenzene and 22,85 g of triethylamine in 90 ml of acetonitrile is heated at the boil under reflux for 18 hours then cooled and concentrated in vacuum. The residue is dissolved in 250 ml ethyl acetate and extracted with water (I ml) and saturated NaCl solution (100 ml). In the drying (Na2SO4) and concentration in vacuo gain of 7.1 g of black oil. It is treated chromatographic 360 g of silica gel (230-400 mesh mesh), elwira 3% (V/V) mixture of acetone in dichloromethane. The result of 0.93 g of the less polar 2H-regioisomeric adduct in the form of a yellow solid and 0.38 g of the more polar 1H-regioisomeric adduct as a yellow-brown solid.

2H-regioisomer:

1H NMR (DMSO) : 9,71 (s, 1H), to 8.57 (DD, J = 9,6, and 1.6 Hz, 1H), 8,32 (om, 2H);

1H-regioisomer:

1H NMR (DMSO) : 10,04 (s, 1H), to 8.57 (DD, J = 10,4, 2.0 Hz, 1H), 8.34 per (d, J = 8,9 Hz, 1H), 8,23 (t, J = 8,1 Hz, 1H).

Stage 2. A solution of 500 mg of 2H-regioisomer obtained in stage 1, 50 ml 1:1 mixture of methanol-ethyl acetate is treated with 500 mg N. the apparatus Parra. The mixture is filtered through celite, washed filter cake with ethyl acetate. The filtrate was concentrated in vacuo to obtain a white solid, which was dissolved in 20 ml of acetone, treated with 5 ml saturated NaHCO3followed by cooling to 0oC. the Mixture is treated with 448 mg (range 0.38 ml, 2,63 mmol) of benzylchloride, then stirred at 0oC for 1 hour and warmed to ambient temperature for 18 hours. The mixture is diluted with 100 ml of ethyl acetate, extracted with water (I ml) and saturated NaCl solution (50 ml). In the drying (Na2SO4) and concentration in vacuo get a reddish-brown solid, which is recrystallized from a hot mixture of chloroform-hexane to obtain 633 mg (85%) of the carbamate in the form of a light beige needles, so pl. 120-122oC.

1H NMR (CDCl3) : to 8.70 (s, 1H), of 7.75 (t, J = 8.7 Hz, 1H), of 7.70 (DD, J = 13,7, 1H), 7,40 (om, 5H), 7,21 (DK, J = 8,8 Hz, 1H), 6,94 (Shir.s, 1H), 5,24 (s, 2H).

The mass spectrum of high resolution (FAB): calculated for C15H12FN5O2+H1: 314,1053. Found: 314,1060.

Stage 3. A solution of 554 mg of the carbamate, obtained in stage 2, in 25 ml THF at -78oC handle of 1.94 ml (1.0 M, 1.94 mmol) of bis(trimethylsilyl)amide lithium in THF, SaaS followed by warming to 0oC and gradual warming to ambient temperature for 18 hours. The mixture was then treated with 1 ml of saturated solution of ammonium chloride and diluted with 100 ml dichloromethane. The mixture is extracted with water (I ml) and a saturated solution of ammonium chloride (50 ml). In the drying (Na2SO4) and concentration in vacuo receive a white solid, which was filtered through a sep-pakand process using radial chromatography on a 4 mm chromatotron plate, elwira 5% (V/V) mixture of methanol in dichloromethane to obtain 275 mg of hydroxymethylcytosine as not quite white solid. So pl. 145,5-147,5oC.

1H NMR (DMCO) to 9.66 (s, 1H), of 7.96 (t, J = 8.7 Hz, 1H), 7,88 (DD, J = 13,5, 2.4 Hz, 1H), to 7.64 (DD, J = 8,9 and 1.7 Hz), a 5.25 (t, J = 5,6, 1H), 5,78 (m, 1H), 4,17 (t, J = 9.1 Hz, 1H), 3,92 (DD, J = 8,9, 6.0 Hz, 1H), 3,71 (DDD, J = 12,4, 5,5, 3.3 Hz, 1H) and 3.59 (DDD, J = 12,3, 5,6, 4.0 Hz, 1H);

Analysis: Calculated for C11H10FN5O3: C 47,32; H 3,61; N 25,08. Found: C 47,48; H 3,70; N 24,73.

Stage 4. A suspension of 180 mg of hydroxymethylcytosine, obtained in stage 3, in 4 ml of dichloromethane and 0.5 ml of triethylamine at 0oC handle 171 mg nailhead, followed by stirring at 0oC for 3 hours and heated to Teng a result of drying (Na2SO4and concentrating obtain 230 mg of the corresponding nosilca. This material is dissolved in 6 ml of DMF and treated with 2 g of sodium azide, followed by stirring at room temperature for 18 hours. The mixture is diluted with 75 ml ethyl acetate, then extracted with water (I ml) and saturated NaCl solution (50 ml). In the drying (Na2SO4) and concentration in vacuo obtain 187 mg azide as not quite white solid, sufficiently pure for further use.

1H NMR (CDCl3) 8,71 (s, 1H), 7,85 (t, J = 8,8 Hz, 1H), 7,79 (DD, J = 12,6, 2.4 Hz, 1H), 7,43 (dt, J = 8,8, 1.1 Hz, 1H), 4,88 (m, 1H), 4,16 (t, J = 8,8 Hz, 1H), 3,94 (DD, J = 8,9, 6.2 Hz, 1H), 3,79 (DD, J = 13.3-inch and 4.2 Hz, 1H), to 3.64 (DD, J = 13,4, 4,2 Hz, 1H);

Stage 5. A solution of 187 mg of the azide obtained in stage 4, 60 ml of 2:1 solution of ethyl acetate: methanol is treated with 300 mg of Nickel Raney W-2, then subjected to hydrogenation at a hydrogen pressure of 45 psi (3,164 kg/cm2) in a Parr apparatus for 18 hours. The mixture is filtered through celite, the filter cake washed with methanol. The filtrate was concentrated in vacuo and the residue is dissolved in 15 ml of pyridine, treated with 6 ml of acetic anhydride, followed by stirring at ambient temperature for 24 hours. The solution CH ml). In the drying (Na2SO4) and concentration in vacuo get solid, which is filtered through a Sep-Pakand subjected to radial chromatography on a 4 mm chromatotron plate, elwira 3% (V/V) solution of methanol in dichloromethane. The result is 109 mg specified in the connection header in the form of not-quite-white solid, so pl. 185-186oC (with decomp.).

1H NMR (DMCO) 9,65 (s, 1H), 8,25 (m, 1H), of 7.96 (t, J = 8.6 Hz, 1H), a 7.85 (d, J = a 13.4 Hz, 1H), 7,60 (d, J = 8.5 Hz, 1H), 4,79 (m, 1H), 4,20 (t, J = 8,9, 1H), 3,82 (DD, J = 8,8, 6.4 Hz, 1H), 3,44 (m, 1H) and 1.83 (s, 3H);

Analysis: Calculated for C13H13FN6O31/4H2O: C 48,08; H 4,19; N 25,88; Found: C 48,22; H 3,94; N 25,75;

Example 28

(S)-N-[[3-[3-Fluoro-(1H-1,2,3,4-tetrazol-1-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide.

< / BR>
This oxazolidinone can be obtained from the 1H-regioisomer obtained in stage 1 (above) followed the procedures described in stages 2-5. In reality, however, the compound was obtained with an alternative method (see tab. 3 at the end of the description).

1. Phenyloxazolidine substituted in the ring heteroaromatic rings, of the formula I

< / BR>
or its pharmaceutical acceptable salt,

where Q represents a hetero is, v, v, vi, vii, viii, or ix:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or in another embodiment, Q may represent condensed with benzene heteroaromatic 5-membered ring, associated with the aromatic ring of 1 nitrogen atom, the structural formula x:

< / BR>
R1independently represents H, F or Cl;

R2independently represents C1- C8-alkyl, optionally substituted by one or more atoms of F or Cl;

R3each independently selected from: (a) H, (b) or SIG4, (C) SR4, (d) NSO2R4(e) CO2R4and (f) R4(g) saturated or unsaturated WITH1- C8-alkyl, branched or unbranched, optionally substituted by one or more Deputy selected from (e), (j) -C(R5)=NR6where R5is1-C6-alkyl, and R6is IT or OS1-C6-alkyl;

R4represents: (a) H, (b) (C1-C6branched or unbranched alkyl chain.

2. Connection on p. 1, where Q represents a group of formula i, ii, iii or v.

3. Connection under item 1 or 2, where Q represents a group of formula X.

4. The compound according to any one of the preceding paragraphs, where R1independently pred. The compound according to any one of the preceding paragraphs, where R2represents methyl or dichloromethyl.

7. The compound according to any one of the preceding paragraphs, where R3represents hydrogen, C1- C8-hydroxyalkyl,1-C8-alkyl or (C1-C4alkoxy)carbonyl.

8. Connection on p. 1, which represents the (S)-N-[[3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide; (S)-N-[[3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide; (S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl] -2-oxo-5-oxazolidinyl] methyl]ndimethylacetamide.

9. Connection on p. 1, representing: (S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]-2,2-dichloroacetamide; (S)-N-[[3-[3-fluoro-4-(1H-pyrrol-1-yl-3-carboxaldehyde)phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide", she metoxi or (S)-N-[[3-[3-fluoro-4-(1H-1,2,3-triazole-1-yl-4-carboxaldehyde)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

10. Connection on p. 1, selected from the group including: (S)-N-[[3-[3-fluoro-4-(3-gidroksilaminami)-1H-pyrrol-1-yl)phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide; (S)-N-[[3-[3-fluoro-4-(4-(1-hydroxyimino)-1H-1,2,3-triazole-1-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide; (S)-N-[[3-[3-fluoro-4-(4-(1-hydroxyimino-1-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

11. Connection on p. 1, showing antimicrobial activity.

 

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The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

The invention relates to new derivatives of phenyloxazolidine General formula (I) in which Q is chosen from formulaV, R1represents hydrogen, OR7where R7is hydrogen, fluorine, C1-C8-alkyl, NR8R4where R8and R4is C1-C8-alkyl which may be substituted by fluorine, C1-C8-acyl which may be substituted by gidroksila, C1-C8-alkoxy, benzoyl, R2represents hydrogen, a hydroxy-group, OR, where R is a C1-C6-alkyl, R3represents hydrogen, C1-C3-alkyl, R4represents C1-C8-alkyl which can be substituted one to three substituents selected from fluorine, chlorine, C3-C6-cycloalkyl, R6is oxygen, NR10where R10is OR7where R7have the above values, O(CH2)mO, n is 0 or 1 and m is 2 or 3, and pharmaceutically acceptable salts

The invention relates to a derivative of oxazolidinone

The invention relates to new benzododecinium the compounds containing pharmaceutical compositions, method of production thereof, and to a method for producing an intermediate product

The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds used for the synthesis of these compounds

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to compounds that should be applied in the pharmaceutical industry as biologically active substances to obtain drugs

The invention relates to diclofenaco salt formed by clavulanic acid and Daminova ether having the formula (I) described in the description, in which R1is C1-C4-alkylene, and each of the radicals R2and R3is a hydrogen or C1-C8the alkyl

The invention relates to medicine, in particular to pharmacology relates to stable water-soluble compositions of triiodide 1,2,3-dialkylanilines formula I, where R1, R3=alk; R2= alk, H
The invention relates to pharmacology relates to pharmaceutical or veterinary composition having antibacterial activity, and how you can get

The invention relates to new methods and intermediate products to obtain pharmaceutically acceptable salts of the acids of formula afterinvoke of the antibiotic 7- (1,5,6)- (6-amino-3-azabicyclo[3,1,0]Gex - 3-yl)-1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

The invention relates to chemistry and medicine and relates to a new hydroxyethylphosphonate the guanidine of the General formula

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where n = 4-30, highly antiseptic and antidote properties, exceeding the efficiency properties are widely known foreign antiseptic - of chlorhexidine digluconate
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