Antimicrobial phenyloxazolidine

 

(57) Abstract:

The invention relates to new derivatives of phenyloxazolidine General formula (I) in which Q is selected from formula V, 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 their pharmaceutically acceptable salts. 8 C.p. f-crystals, 1 tab., 15 schemes.

Prior

This invention discloses a new and useful compounds of phenyloxazolidine having either pyrrolidinyloxy or azetidinol the ESA and pathogens of 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.

Information

These related compounds, due to their structure phenyloxazolidine ring, the compounds disclosed in the publications below, except that the compounds of the invention have multiplexing pyrrolidinyloxy or azetidinol part. The compounds being considered unique and possess useful antibacterial activity.

PCT/US93/03570 application discloses oxazolidinone containing substituted casinobuy part and their use as antimicrobial agents.

PCT/US92/08267 application discloses substituted aryl - and heteroaryl-phenyl-oxazolidinone used as microbicides.

PCT/US89/03548 application discloses 5' indolyl-5-aminoethylethanolamine, 3-(condensed-ring substituted)phenyl-5 - aminoethylethanolamine, and 3-(nitrogen substituted)phenyl-5-aminoethylethanolamine, which is used as a bactericidal substances, t 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); Brittelli, et al., J. Med. Chem., 35, 1156 (1992).

Heb. Pat. publication 352 781 discloses phenyl and pyridyl substituted phenyloxazolidine.

Heb. Pat. publication 316 594 discloses 3-substituted of still oxazolidinone.

Heb. Pat. publication 312 000 reveals phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinone.

The invention

In one aspect the subject invention is a compound of formula I:

< / BR>
or its pharmaceutically acceptable salt, where

Q is selected from structures i, ii, iv and v:

< / BR>
< / BR>
R1is

(a) H,

(b) OR7,

(c) NR8R9,

(d) C1-C8acyl which may be substituted by hydroxyl, C1-C8alkoxy - benzoyl;

each R2choose from

(a) H,

(b) OH,

(c) OR, where R represents a C1-C6by alkyl;

each R3choose from

(a) H,

(b) C1-C3alkyl;

R4represents fluorine;

R5represents a

(a) C1-C8alkyl, optionally substituted with one to three substituents selected from F, Cl,

(b) C3-C6C is UP> has the meanings stated below,

(c) O(CH2)mO;

R7is

(a) H,

(b) fluorine,

(c) C1-C8alkyl;

R8and R9are C1-C8the alkyl which may be substituted by fluorine;

n is 0 or 1 and m is 2 or 3.

In one aspect the subject invention is a compound of structural formula i:

< / BR>
In another aspect of the subject invention is a compound of structural formula ii:

< / BR>
In another aspect of the subject invention is a compound of structural formula iv:

< / BR>
In another aspect of the subject invention is a compound of structural formula v:

< / BR>
Compounds have very low toxicity.

A method of treating microbial infections in humans or other warm-blooded animals is accomplished by injecting the patient, optionally, an effective amount of the above compounds of formula I (i-v). The connection can be entered in the pharmaceutical composition or oral, parenteral or locally. Preferably the compound is administered in an amount of from about 0.1 to about 100 mg/kg body weight/day, more preferably from about 3.0 to about 50 mg/kg body weight/day.

R4the substituents preferably both represent fluorine, and more preferably fluorine and hydrogen.

R5Deputy preferably represents hydrogen, methyl, dichloromethyl, hydroxymethyl or methoxy. More preferably R5represents hydrogen, methoxy or methyl. Most preferably, R5was represented by methyl.

R6Deputy preferably is O, OCH2CH2O, NOH and NOCH3.

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

"Alkoxy" means the group having the specified number of carbon atoms connected with oxygen, such as methoxy (-OCH3), ethoxy, butoxy etc. and its isomeric form.

3CO-; benzoyl, C6H5CO.

"Cycloalkyl" means a group with the specified number of carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and their isomeric forms.

"Ph" means phenyl. "Carbonyl" means-C(=O)-part. "Amino" means the NH2"alkylamino" means a group where one of the positions of hydrogen, substituted alkyl, and dialkylamino" means a group in which both hydrogen substituted alkyl group.

The term "pharmaceutically acceptable salt" means a salt accession acid, which can be obtained by any known in this field by the way. Typical salts accession acid include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, cyclohexylsulfamate, methansulfonate, econsultancy, bansilalpet, toluensulfonate, fumarate and other pharmaceutically acceptable counterions for amines.

Azetidine-phenyloxazolidine.

The preferred absolute configuration at C-5 oxazolidinone ring compounds claimed in this invention is the configuration illustrated in the structures of the EP, which is pharmacologically active as an antibacterial agent. The racemic mixture is used the same way and for the same purpose as pure (S)-enantiomer; the difference is that for the same antibacterial effect, it is necessary to use twice the racemic substance. For the person skilled in the art it is obvious that when a chiral center (R is not H) is present in azetidinone fragment compounds of structural formula i, ii, diastereoisomer. These diastereoisomer in racemic and enantiomerically enriched forms, are also covered by the scope of the compounds of formula i, ii inventions.

The preferred method of obtaining oxazolidinones formula i, ii in enantiomerically pure form is represented by Schemes I-VI. Schemes I-VI contain a General structural view of obtaining the various compounds of the present invention, the center of which is a circular structure of the nucleus, where Q is i, ii.

As shown in Scheme I, 3-hydroxyazetidine structure 1 can be deprotonirovannym a suitable base, for example sodium hydride, in a suitable solvent, for example tetrahydrofuran (THF), and then alkylated alkyl halides, such as methyliodide, with the pkwn was substituted phenyl) can be obtained from azetidinol 1, using known methods (Taylor, C. R. , Jr. , ; Cale, A. D., Jr.; Stauffer, H. F., Jr. U. S. Patent 4 956 359, 1990). Benzhydryl group 1 and 2 are removed by hydrogenolysis in the presence of a mineral acid, for example hydrochloric acid, in the presence of a suitable catalyst such as palladium hydroxide-on-charcoal, in a suitable solvent, such as methanol, obtaining azetidinol 3 (R13= H, alkyl, phenyl). Then the connection structure 3 is subjected to interaction with functionalized with nitrobenzene 4 (X = halogen or trifluromethanesulfonate) in the presence of a suitable combination of the base/solvent, such as dibasic potassium phosphate in dimethyl sulfoxide or N,N-diisopropylethylamine in acetonitrile or THF, and at a corresponding temperature, typically from ambient temperature up to 70oC, receiving adduct 5. If you want to R1compounds of structural formula i or converted intermediate was hydroxy, a suitable protective group such as tert-butyldimethylsilyl part, introduced by reacting 5 (R13= N) with tert-butyldimethylsilyl chloride in the presence of imidazole in an appropriate solvent, such as N,N-dimethylformamide (DMF) at ambient temperature, receiving 5 (R2O. When using this last system of the solvent, the reaction mixture is first filtered to remove the catalyst, and the filtrate containing the intermediate aniline, then treated, for example, sodium bicarbonate and benzyl or methyl chloroformate to give the corresponding benzyl (R14= CH2Ph) or methyl (R14= CH3) urethane derivative 6. Urethanes 6 then deprotonate a suitable base, such as n-utility (n-BuLi), lithium diisopropylamide (LDA, LDA) or lithium bis(trimethylsilyl)amide, in an appropriate solvent, such as tetrahydrofuran (THF), and at an appropriate temperature, such as -78oC -40oC, receiving lithium ion intermediate, which is then treated with commercially available (-)-(R)-glycidyl by butyrate. Heated to ambient temperature and then directly gives 5-(guinanie 7 is transformed into the corresponding mesilate 8 (R15= methyl) or arylsulfonate 8 (R15= ArSO2for example p-toluensulfonyl) by action, for example, methanesulfonyl chloride/pyridine or methanesulfonyl chloride/triethylamine/dichloromethane or n-toluensulfonyl chloride/pyridine. Received sulphonate derivative 8 then subjected to interaction with a source of azide such as sodium azide or potassium, in an aprotic solvent such as N,N-dimethylformamide (DMF) or 1-methyl-2 - pyrrolidine, optionally in the presence of a catalyst such as 18-crown-6 at a temperature of 50-90oC, receiving azide 9. Then azide restore the hydrogenation catalyst palladium-on-coal or platinum catalyst in an appropriate solvent, such as ethyl acetate or methanol, receiving the appropriate amine 10. Alternatively, the azide 9 can be restored by treatment with a compound of trivalent phosphorus, such as triphenylphosphine, in an appropriate solvent, such as tetrahydrofuran, followed by addition of water. Intermediatry Amin 10 can also be obtained by processing phthalimide derivative 11 (obtained by reacting the sulfonate 8 phthalimide potassium in a suitable solvent, for example acetonitrile, at a temperature of boiling reverse the but Amin 10 can be obtained directly from nelfinavir 8 by ammonolysis of aqueous ammonium hydroxide in a solvent system consisting of H2O/isopropanol/THF in a sealed reaction vessel placed in 70-95oC oil bath. Then Amin 10 acelerou using reactions known to specialists in this field, receiving oxazolidinone structure 12. For example, the amine may be subjected to interaction with the acid chloride or anhydride in a basic solvent such as pyridine, at a temperature in the range from -30 to 30oC, to obtain the acylated compound 12 (R5= arbitrarily substituted alkyl). Specialists in this field it is obvious that other carbonyl groups inside the scope of the present invention, can be easily introduced in Amin 10 using standard acylation techniques, such as described March, J. "Advanced Organic Chemestry", 3rd ed.; John Wiley & Sons: New York, 1985; p. 370-375, with additional examples 12. If you want to R13was H, then entered tert-butyldimethylsilyl protective group selected examples 12 are removed using appropriate conditions, such as marked Greene, T. W.; Wuts, P. G. M. "Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons, New York, 1991, in particular water-holdem the unity of the structure 12 (R13= H, alkyl, optionally substituted phenyl) represent examples of microbicides-azetidinone of oxazolidinones formula I, which are the subject of this invention.

Azetidin-containing oxazolidinone 12, in themselves, examples of antibacterial agents of structural formula I, can also be converted into further compounds of formula i and also examples of structural formula ii as shown in Scheme III. For example, 12 (R13= N) can oxidize in the appropriate azetidine 13 by its interaction with a catalytic amount of Tetra-n-propylammonium of perruthenate in the presence of N-methylmorpholine N-oxide and molecular sieves in acetonitrile/dichloromethane. The connection 13 is an example of the antibacterial agents of structural formula ii. Ketone part 13 amenable to further modification. Reaction of 13 with Lawesson''s reagent or alternative reagents, described March, J. "Advanced Organic Chemistry", 4rd ed.; John Wiley & Sons: New York, 1992; p. 893-894, gives the corresponding thioketone 14 (R6= s).

Oximes 14 (e.g., R6= NOH and NOCH3) get easy interaction 13 with, for example, hydroxylamine hydrochloride or hydrochloride methoxylamine, in the presence of an appropriate OS the environment. Various hydrazone derivative (R6= NNHR7) can be obtained by reacting 13 with hydrazines as described in Greene, T. W.; Wuts, P. G. M. "Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons, New York, 1991, p. 212-213 and March, J. "Advanced Organic Chemistry, 4rd ed.; John Wiley & Sons: New York, 1992; p. 904-905. Imine 14 (R6= N-alkyl or N-aryl) synthesized by treating 13 with primary amines, as described in March, J. "Advanced Organic Chemestry", 4rd ed.; John Wiley & Sons: New York, 1992; p. 896-897. Olefinic derivatives (14: R6= CR11R12) get the interaction with 13 different olefination reagents such as uledi phosphorus, etc. that are known to specialists in this field of technology. Illustrative examples described in March, J. "Advanced Organic Chemistry", 4rd ed.; John Wiley & Sons: New York, 1992; p. 956-963. For the case when R6is CF2you should include the treatment of ketone 13 (NaO2CCF2Cl) sodium diperchlorate and triphenyl as described in Tetrahedron Letters 1964, R. 1461. The obtained olefinic bond can be restored by catalytic hydrogenation or by other methods known to experts in this field to get examples of structural formulas i. Other compounds of structure 14, for example, cyclic and acyclic ketals, ditio the ketals, can be obtained by the interaction with Groups in Organic Synthesis", 2nd.; John Wiley & Sons, New York, 1991, p. 177-201. Compound 12 (R13= H) can also be converted into various derivatives 15 (R16= arbitrarily substituted acyl, alkoxycarbonyl, carboxamide and so on) by processing 12 various carbonyl derivatives, such as anhydrides, alkyl chloroformiate, isocyanates, etc., in the presence of appropriate bases, and in suitable solvents known to specialists in this field. Compounds 14 and 15 are examples of oxazolidinone - microbicides structural formulas i and ii.

Scheme IV-VI describe in General terms the technique of obtaining examples of structural formula i, in which R1is a group other than OR7. As shown in Scheme IV, mesilate 16, obtained by the interaction of azetidinol - educt 1 methanesulfonyl chloride in the presence of triethylamine and dichloromethane, is subjected to the interaction with a number of nucleophiles. For example, processing 16 ammonia, primary amines or secondary amines leads to 3-aminoacridine structure 17. Similarly, processing 16 thiolate or cyanide gives adducts 18 and 19, respectively. Compound 19 can be restored by sociallyengaged, etc. into the corresponding 3- (aminomethyl)azetidin 20. United, to transform the carboxylate portion 21 in the corresponding carboxamide or different acyl groups, which after further transformations are additional examples of antibacterial agents of structural formula i. Compounds 17 and 20 can optionally N-alkilirovanii methods known to experts in this field, including processing 17 and 20 alkylhalogenide or tozilaty in the presence of a suitable base. Alternatively, the selected alkyl groups can be entered nitrogen 17 and 20 by reductive alkylation as described March, j. "Advanced Organic Chemistry", 4rd ed; John Wiley & Sons: New York, 1992; p. 898-900. In the cases of amino intermediates 17 and 20, when there is free NH, you must secure these parts to allow the flow in the usual way some of sequential reactions. The amino group can be converted into the corresponding t-butyl carbamate (BOC), benzyl carbamate (Cbz), triptorelin, or derivative phthalimide and so on, as required, using the methods described in Greene, T. W.; Wuts, P. G. M. "Protective Groups in Organic Synthesis, 2nd ed.; John Wiley & Sons, New York, 1991, p. 309-403. Benzhydryl protective group 17-21 then removed by hydrogenolysis in the presence of a suitable catalyst, for example a hydroxide is omegatech of azetidinol 22 (R1no OR7).

Scheme V describes in General terms the conversion of the intermediate azetidinol 22 examples of structural formula i (R1no OR7). Chemistry is largely identical to those described in Scheme I. Compound 22 is first transformed into a nitrobenzene derivative 23. The restoration and transformation of the carbamates of structure 24 is carried out, as described previously. As described in Scheme I, the intermediate connection 24 is converted into an optically active 5-(hydroxymethyl)oxazolidinone 25. Application of the methods described in General terms in Scheme II, then allows you to turn 25 in the connection structure 26. Remove any introduced protective group, for example BOC groups on the compounds, where R1there are amino reach of ways, known to specialists in this field, for example, described in Greene, T. W., Wuts, P. G. M. "Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons, New York, 1991. Received a free amino group can then be N-alkylated or N-allyawan, if necessary, additional compounds of structure 26, which are examples of oxazolidinone antibacterial agents of structural formula i.

Scheme VI shows the variation of the chemistry described in General terms in Scheme IV, where intermediate 12-hydroxyacetic chloride in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, for example dichloromethane. The same nucleophilic substitution described in Scheme IV for nelfinavir 16 can be carried out on more funktsionirovania the mesilate 27 obtaining compounds 28-30. Using methods similar to the methods described in Scheme IV, 30 can be converted into compounds 31 and 32. Connection 28-32 are examples of oxazolidinone - antibacterial agents of structural formula i, which are the subject of this invention. For specialists in this area it is obvious that the compounds 28-32 are merely illustrative examples, and these compounds, by themselves, are amenable to further chemical modification of obtaining additional examples of structural formulas i. 2-azetidinone structure 33 is treated with an appropriate base, such as sodium hydride, in an appropriate solvent, for example THF, getting deprotonirovannoi intermediate compound, which is then treated funktsionirovanii derivatives of nitrobenzene 4 (X = halogen) to give adduct 34. The person skilled in the art it is obvious that appropriate protective group, for example, described in Greene, T. W.; Wuts, P. G. M. "Protective Groups in Organic Synthesis", 2nd ed. ; John Willey & Sons, New York, 19 through stages, broadly described in Schemes I and II into compounds of structure 35, in themselves examples of structural formula iii, which are the subject of this invention. Alternatively, azetidine-substituted intermediate 36, obtained according to the technology described in Schemes I and II, are oxidized to the corresponding azetidine 35 (R17= O) by using, for example, catalytic amounts of ruthenium tetroxide in the presence of a suitable oxidant, such as metaperiodate sodium, and in a suitable solvent system such as ethyl acetate/water. To get examples of compounds 35, where R17there's selected azetidinone intermediates are subjected to interaction with Lawesson''s reagent or etc.

Examples of azetidine-phenyloxazolidine, which can be obtained as part of this invention, are the following:

1. (S)-N-[[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide

2. (S)-N-[[3-[3-fluoro-4-(3-hydroxy-1-azetidine)phenyl] -2-oxo - 5-oxazolidinyl]methyl]ndimethylacetamide

3. (S)-N-[[3-[3-fluoro-4-[3-[N-(2-foradil)-N-methylamino] -1-azetidine] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

4. (S)-N-[[3-[3-fluoro-4-(3-oxo-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide

5. (S)-N-[[3-[3-fluoro-4-[3-(Metodi)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

7. (S)-N-[[3-[3-fluoro-4-(3-hydroxy-2-methyl-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

8. (S)-N-[[3-[3-fluoro-4-(2-oxo-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide

9. (S)-N-[[3-[3-fluoro-4-(3-hydroxy-2-oxo-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

10. (S)-N-[[3-[3-fluoro-4-(3-methoxy-2-oxo-1-azetidine)phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide

11. N-[[3-[3-fluoro-4-(3-methyl-2-oxo-1-azetidine)phenyl]-2-oxo-(5S)- oxazolidinyl]methyl]ndimethylacetamide

12. (S)-N-[[3-[3-fluoro-4-(3,3-dimethyl-2-oxo-1-azetidine)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

13. (S)-N-[[3-[3-fluoro-4-[3-(hydroxyimino)-1-azetidine] phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

14. N-[[3-[3-fluoro-4-[(2R)-methyl-3-oxo-1-azetidine] phenyl] - 2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

15. N-[[3-[3-fluoro-4-[(2S)-methyl-3-oxo-1-azetidine] phenyl] - 2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

16. N-[[3-[3-fluoro-4-[3-(methoxyimino)-(2R)-methyl-1-azetidine] phenyl]-2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

17. N-[[3-[3-fluoro-4-[3-(methoxyimino)-(2S)-methyl-1-azetidine] phenyl] - 2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

18. (S)-N-[[3-[3-fluoro-4-[3-(deformation)-1-azetidine] phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

19. (S)-N-[[3-[3-fluoro-4-[3-(methoxymethyl)-1-azetidine] phenyl]-2-leinil]methyl]ndimethylacetamide

21. (S)-N-[[3-[3-fluoro-4-[3-(methoxyamino)-1-azetidine] phenyl] 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

22. N-[[3-[3-fluoro-4-[2,4-dimethyl-3-oxo-1-azetidine] phenyl]-2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

23. N-[[3-[3-fluoro-4-[2,4-dimethyl-3-(methoxyimino)-1-azetidine] phenyl] -2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

24. N-[[3-[3-fluoro-4-[2,4-dimethyl-3-methoxy-1-azetidine] phenyl] -2-oxo-(5S)-oxazolidinyl]methyl]ndimethylacetamide

25. (S)-N-[[3-[3-fluoro-4-[(3S)-methoxy-(2R)-methyl-1-azetidine] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

26. (S)-N-[[3-[3-fluoro-4-[(3R)-methoxy-(2S)-methyl-1-azetidine] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

27. (S)-N-[[3-[3-fluoro-4-[(3S)-hydroxy-(2R)-methyl-1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

28. (S)-N-[[3-[3-fluoro-4-[(3R)-hydroxy-(2S)-methyl-1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

29. (S)-N-[[3-[3-fluoro-4-(3-fluoro-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide

30. (S)-N-[[3-[3-fluoro-4-[3-fluoro-(2R)-methyl-1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

31. (S)-N-[[3-[3-fluoro-4-[3-fluoro-(2S)-methyl-1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

32. (S)-N-[[3-[3-fluoro-4-[3-[(hydroxyacetic)amino]-1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

33. (S)-N-[[3-[3-fluoro-4-[3-[(methanesulfonyl]phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

35. (S)-N-[[3-[3-fluoro-4-[3-[(acetyl)amino] -1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

36. (S)-N-[[3-[3-fluoro-4-[3-[(methoxycarbonyl)amino]-1-azetidine] phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

37. (S)-N-[[3-[3-fluoro-4-[3-[(benzyloxycarbonyl)amino] -1-azetidine] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Pyrrolidinyl-phenyloxazolidine.

This invention discloses new substituted pyrrolidinyl phenyloxazolidine according to the above formulas iv and v. The compounds are useful antimicrobial agent, effective against a number of pathogens of human and animal pathogens, in particular aerobic gram-positive bacteria, including resistant to many antibiotics Staphylococcus and Streptococcus, as well as anaerobic organisms such as bacteroids and clostridia species, and acid-resistant organisms, such as Mycobacterium tuberculosis and other mycobacterial species.

The most preferred compounds in this series it is desirable to obtain in the form of optically pure enantiomers, with (S)-configuration according to the Cahn-Ingold-Prelog system of notation, when C5 ring oxazolidinone. Optically pure substance is usually produced by one of a number of asymmetric synthesis, or by vyd intermediator amine 11 (described in Scheme IX ) with a suitable optically active acid, such as Dibenzoyl tartrate or 10-camphorsulfacid, followed by treatment with a base, receiving optically active amine. Although (S)-enantiomer of this series of compounds preferred because it is pharmacologically active as a bactericidal agent, racemic modification is also used in the same way as pure (S)-enantiomer; the difference is that racemic substances required twice more to achieve the same bactericidal action. In addition, the person skilled in the art it is obvious that when there is a chiral center on pyrrolidinone part of the compounds of structural formula iv and v possible diastereoisomer. These diastereoisomer, either in racemic or enriched in the configuration forms, also included in the scope of the compounds of formulas iv and v of this invention.

The preferred method of obtaining pyrrolidinyl phenyloxazolidine formula iv and v in enantiomerically pure form are presented Schemes VIII-XVI. Scheme VIII-XVI contain a common structural representation for various compounds of the invention, the center of which is a circular structure of the nucleus, where Q is iv or v.

As shown in Scheme VIII, derivatives of structure 1, liboiron, such as ethylene glycol, under conditions of acid catalysis with azeotropic removal of water, to obtain the acetal 2. N-benzyl group 2 is then removed by hydrogenolysis in the presence of a catalyst of a noble metal such as palladium-on-coal or hydroxide of platinum-on-charcoal, in a suitable solvent, getting pyrolidine derivative 3. Pyrolidine derivative 3 can be processed derivatives of nitrobenzene 4 (Y = halogen or triftorbyenzola) in the appropriate combination of base and solvent, for example Dooney potassium phosphate in DMSO (DMSO), and the appropriate temperature, typically from ambient temperature to 90oC, to obtain the adduct 5. The nitrogroup 5 then restore catalytic hydrogenation in the presence of catalysts, such as palladium-on-coal or W-2 Raney Nickel, in an appropriate solvent such as ethyl acetate, or tetrahydrofuran (THF), obtaining the derivative of aniline 6. When using THF as solvent for this recovery, it is not necessary to remove the catalyst by filtration or select aniline derivative of 6, and you can just purge the reaction vessel with an inert gas, such as nitrogen, add saturated aqueous solution of bicarbona the appropriate benzyl (R14= CH2Ph) or methyl urethane (R14= CH3) derivative 7. Each of the urethane derivatives 7 can be deprotonated lithium base such as n-utility, lithium aminobutiramida amide (LDA, LDA) or lithium bis (trimethylsilyl)amide (LHMDS ), in an appropriate solvent, such as THF, N,N-dimethylformamide (DMF), or mixtures thereof, at an appropriate temperature, such as -78oC -40oC, receiving lithium intermediate compound which is directly treated with commercially available (R)-(-)-glycidyl by butyrate. Heating this reaction mixture to ambient temperature then gives (hydroxymethyl)oxazolidinone 8 in highly enantiomerically enriched form.

As shown in Scheme IX, compound 8 can be converted into the corresponding mesilate (R15= CH3or tosylate (R15= p-CH3C6H4by processing methanesulfonyl chloride in the presence of triethylamine or pyridine or toluensulfonyl chloride in the presence of pyridine.

Received sulphonate derivative 9 can then be treated with alkali metal azide such as sodium azide or potassium, in an aprotic dipolar solvent such as DMF or N-methylpyrrolidinium azide 10. Azide 10 can be restored to the corresponding amine 11 by hydrogenation in the presence of palladium, platinum or Nickel catalyst, in an appropriate solvent, such as ethyl acetate, THF or methanol. Alternatively, the azide 10 can be restored by treatment with triphenylphosphine or other compounds of trivalent phosphorus in a solvent such as THF, followed by addition of water. Amine 11 can be obtained by processing sulfonate 9 phthalimide potassium in DMF at 40-90oC or boiling acetonitrile getting phthalimide 12, which is then deprotonated processing, for example, aqueous methylamine, in boiling ethanol, receiving 11. A more direct way of obtaining amine 11 is in the handling sulfonate 9 with an aqueous solution of ammonia in the system solvent isopropyl alcohol-THF in a sealed tube heated at 75-105oC in the oil bath. Amin 11 then acelerou using reactions known to specialists in this field, receiving (acylaminoacyl)oxazolidinone structure 13. For example, amine 11 can be treated with acid chloride of the acid or anhydride in the presence of a base such as pyridine or triethylamine, at a temperature in the range -40 - 40oC, to obtain the acyl production is t to be received other acyl derivatives, such as carbamates. Finally, processing 13 aqueous acid, such as p-toluensulfonate in aqueous acetone, can hydrolyze acatalog functionality, receiving the corresponding carbonyl derivative 14, which represents an example of pyrrolidine-substituted microbicides formula iv. For specialists in this area it is obvious that out of 14 you can get other variants of embodiment of the compounds of formula iv. The reaction of 14 with Lawesson''s reagent or other alternative reagents, such as hydrogen sulfide, usually gives the derivative of diacetone 15 (R6= S). Oximes (R6= NHOH and NHOCH3) can be obtained from the 14 treatment or hydroxylamine hydrochloride or hydrochloride methoxamine in the presence of a base such as pyridine or sodium acetate, in a solvent such as methanol. Derived hydrazone (R6= NNHR12) can be obtained by treatment of 14 with hydrazine derivatives. Similarly, imine (R6= NR12) can be obtained by treatment of 14 primary amine. Olefinic derivatives (R6= CR11R12) can be obtained by treatment of 14 different reagent referirovanija, such as uledi phosphorus (Witting reagent), phosphonate esters (Horner-Emmons Reagent) or other Rea is practical by hydrogenation or by other means may result in examples of structural formula V.

Scheme X-XII describe, in General terms, obtaining examples of structural formula v, where R1= OR7, R3= H and n = 0. As shown in Scheme X, intermediate 1 as described in Scheme VIII, restore the alcohol 16 by processing any of several standard hydride reducing agents, such as borohydride sodium, sociallyengaged or etc., Benzyl protective group 16 then can be removed by hydrogenolysis using a catalyst such as palladium hydroxide-on-charcoal, or 10% palladium-on-charcoal, receiving amerosport 17. It should be noted that some of the examples 17 may be commercially available, but you should consider the possibility of de novo synthesis of 17 in order to include more complex examples, which are of great interest from the point of view of their antibacterial action. Amerosport 17 can then be subjected to interaction with a nitrobenzene derivative, such as 4 (Y = halogen or triftorbyenzola), in the presence of an appropriate base, such as Dooney potassium phosphate, in a suitable solvent, such as dimethylsulfoxide, at temperatures in the range of 40-90oC to get 18. For specialists in this area it is obvious that may require the placenta is the obtain tert-butyldimethylsilyl ether 19 (R = Si(CH3)2t-Bu) processing 18 tert-butyldimethylchlorosilane in the presence of a base such as imidazole or diisopropylethylamine, optionally in the presence of 4-dimethylaminopyridine as a catalyst, in a suitable solvent, such as DMF, THF or dichloromethane. The nitrogroup 19 can be restored by hydrogenation in the presence of a catalyst such as 10% palladium-on-coal or W-2 Raney Nickel, in a solvent such as THF or ethyl acetate, getting aniline derivative 20. Aniline derivative 20 does not emit a routine way, but directly treated with saturated sodium bicarbonate and alkyl chloroformate derivatives, such as benzil chloroformate or methyl chloroformate to get the corresponding benzyl (R14= CH2Ph) or methyl (R14= CH3) urethane derivative 21. Urethane derivative 21 can then be deprotonate using a base, such as n-utility or lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl) amide (LHMDS), in a solvent such as THF or DMF or mixtures thereof at a temperature in the range from -78 to -40oC, receiving lithium derivative, which is treated with commercially available (R)-(-)-glycidyl by butyrate. The resulting mixture tx2">

Specialists in this field it is clear that the intermediate oxazolidinone 22 can be used for a number of ways to obtain different variants of embodiment of compounds of structural formula iv. As shown in Scheme XI, the oxazolidinone 22 can be turned into (acylaminoacyl)oxazolidinone 23 using the sequence of reactions is identical to that used for the conversion of compound 8 to compound 13 in accordance with the Scheme IX. The protective group 23 (R = Si(CH3)2t-Bu) can be removed by standard methods known to experts in this field, such as the processing of tetrabutylammonium fluoride in THF to obtain alcohol 24, which is an example of a compound of structural formula v. Compound 24 can be turned into a variety of derivative 23 (R = R7= arbitrarily substituted acyl, alkoxycarbonyl, carboxamide, and so on) by processing the various carbonyl derivatives, such as anhydrides, anhydrides of acetic acid, alkyl and aryl, chloroformiate, isocyanates, etc., using appropriate bases and catalysts in suitable solvents known to the person skilled in the art. Thus, compounds 23 and 24 are examples of oxazolidinone - antibacterial agents structural is shown, 22 (R = Si(CH3)2t-Bu) can be protected, for example, by treatment with tributyltinchloride and an appropriate base, such as diisopropylethylamine, and a catalyst such as 4-dimethylaminopyridine, in an appropriate solvent, such as dichloromethane, THF, or so on, getting bis-protected derivative 25 (R = Si(CH3)2t-Bu, R1= SiPh2t-Bu). Bis-protected derivative 25 selectively deprotonated to remove tert-butyldimethylsilyl ether protective group by treatment with acetic acid, using a co-solvent of water and THF in a whole number ratios at temperatures in the range of 50-100oC, receiving alcohol 26. Alcohol 26 can be preaccelerated on unprotected hydroxyl group by treatment with a suitable base such as sodium hydride, in a dipolar aprotic solvent such as THF, DMF or similar , in the presence of an alkyl halide such as methyl iodide, or its substituted derivatives, to get silloway ether 25 (R = R7alkyl with an unbranched or branched chain, R1= SiPh2t-Bu). Containing silicon protective group 25 can then be removed by treatment with tetrabutylammonium fluoride in a solvent such as THF, receiving alcohol 27 (R = alkyl with prazwell the water 28 (R7= alkyl with an unbranched or branched chain) using the sequence of reactions identical to that used for the conversion of 8 to 13 according to Scheme IX. (Acylaminoacyl)oxazolidinone derivative 27 is an example of oxazolidinone - antibacterial agent of the structural formula v.

Schema XIII-XVI describe, in General terms, obtaining examples of structural formula v, where R1is a substituted amino part. Scheme XVI outlines the case where R1= Other and n = 0. As shown, aminopyrrolidine 29 either commercially available or obtained by methods known in this field, optionally protected as either triptorelin (R = COCF3or tert-butoxycarbonyl derivative (R=CO2t-Bu), hydronaut in the presence of a suitable catalyst such as palladium hydroxide-on-charcoal, in an appropriate solvent, such as methanol, to remove the benzyl protective group, receiving pyrrolidin 30. Pyrrolidin 30 may be subjected to interaction with the reduction compound, such as 4, in the presence of a suitable base, such as Dooney potassium phosphate, in an appropriate solvent, such as dimethyl sulfoxide (DMSO) or DMF, to poluch of Raney Nickel in a suitable solvent, such as THF or ethyl acetate, obtaining the derivative of aniline 32.

Aniline derivative 32 do not emit a routine way, and usually treated directly with a saturated aqueous solution of sodium bicarbonate and alkyl chloroformate derivatives, such as benzil chloroformate or methyl chloroformate, receiving the corresponding benzyl (R14= CH2Ph) or methyl (R14= CH3) urethane derivative 33. When 33-protected acyl derivative, it is necessary to remove the protective group in an appropriate way known to specialists in this field, to obtain the derived primary amine 34. Amin 34 then processes derived dialkyl urea such as N, N-dimethyl urea or N,N-dibenzyl urea, in the presence of formaldehyde, in conditions of open Knapp, et al.2to get either of dimethyl (R = CH3), or dibenzyl (R = CH2Ph) treason derivative 35. Treason 35 can then be deprotonate using a base, such as n-utility, lithium Diisopropylamine (LDA) or lithium bis(trimethylsilyl)amide in a solvent such as DMF or a mixture of DMF and THF, at temperatures ranging from -78oC -40oC, to obtain a lithium derivative, which directly obrawalsa environment, receiving (hydroxymethyl)oxazolidinone 36.

Scheme XIV describes in General terms the transformation of treason derived 36 in the compounds of formula v. As shown, treason derived 36 can be turned into (acylaminoacyl)oxazolidinone 37 way, identical to those used for the conversion of compound 8 to 13 in Scheme IX. Treason group 37 can be removed by hydrolysis aqueous chloride-hydrogen acid or by treatment with a saturated solution of ammonium chloride, receiving 38. Compound 38 can be turned into a number of carbonyl derivatives 39 (R = randomly substituted alkyl, alkoxy, alkylamino, and so on) handling of various carbonyl derivatives, such as anhydrides of carboxylic acids, anhydrides, alkyl and aryl, chloroformiate, isocyanates, etc., using appropriate bases and catalysts, in appropriate solvents known to the person skilled in the art. In addition, the connection 38 can be turned into a series of alkyl derivatives 40 (R = randomly substituted unbranched or branched chain alkyl) by treatment with the appropriate aldehyde or ketone in the presence of gas of hydrogen and a catalyst such as 10% palladium-on-charcoal, or reagent, such as cyanoborohydride sodium is Kil-halide in the presence of a base, such as sodium carbonate, in a suitable solvent, such as THF or acetonitrile, optionally in the presence of water. Thus, the compounds 39 and 40 are examples of compounds of formula v where n = 0.

Scheme XV describes obtaining examples of compounds of structural formula v, where R3= H, R1= NR8R9and n = 1. As shown, pyrrolidin derived 41, available by known methods 1a, 3 arbitrarily protected as either triptorelin (R = COF3or tert-butoxycarbonyl derivative (R = CO2t-Bu), dibenzyline by hydrogenolysis in the presence of a catalyst such as palladium hydroxide-on-coal or 10% palladium-on-charcoal, in a suitable solvent, such as methanol, receiving 42. Pyrrolidin 42 can then be subjected to interaction with nitrobenzene derivative, such as 4, in the presence of a base, such as Dooney potassium phosphate, in a solvent such as dimethyl sulfoxide (DMSO) to obtain the product 43 aromatic substitution. Aryl pyrrolidin 43 can be restored by hydrogenation in the presence of a catalyst such as 10% palladium-on-coal or W-2 Raney Nickel, in a solvent such as THF or ethyl acetate, to obtain the aniline derivative is the thief of sodium bicarbonate and alkyl-chloroformiate, such as benzyl or methyl chloroformate to obtain the corresponding benzyl (R14= CH2Ph) or methyl (R14= CH3) carbamate derivative 45. In that case, when 45 protects as acyl derivative, it is necessary to remove the protective group by an appropriate method known to specialists in this field, to derive 46 primary amine. Amin 46 is then treated derivatives of dialkyl urea such as N,N'-dimethyl urea or N,N'-benzyl urea, in the presence of formaldehyde in the conditions of open Knapp et al.2receiving or dimethyl (R = CH3), or dibenzyl (R = CH2Ph) treason derivative 47. Treason 47 may be deprotonated using a base, such as n-utility, lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide, in a solvent such as DMF or a mixture of DMF and THF, at temperatures ranging from -78oC -40oC, to obtain a lithium derivative, which is directly treated with commercially available (R)-(-)glycidyl by butyrate. The resulting mixture was then heated to ambient temperature, receiving (hydroxymethyl) oxazolidinone 48.

Scheme XVI describes the transformation of treason derived 48 in the structural connection is om, identical to those used for the conversion of compound 8 to 13 in Scheme IX. Treason group 49 can be removed by hydrolysis with an aqueous solution of hydrochloric acid or by treatment with a hot saturated solution of ammonium chloride, getting amine 50. Amin 50 can then be converted into a number of carbonyl derivatives 51 (R = randomly substituted alkyl, alkoxy, alkylamino and so on) by processing the various carbonyl derivatives, such as anhydrides of acetic acid, anhydrides, alkyl and aryl, chloroformiate, isocyanates, etc., using appropriate bases and catalysts in suitable solvents known to the person skilled in the art. In addition, Amin 50 can be turned into a series of alkyl derivatives 52 (R = randomly substituted unbranched or branched chain alkyl) by treatment with 50 corresponding aldehyde or ketone in the presence of gas of hydrogen and a catalyst such as 10% palladium-on-charcoal, or reagent, such as cyanoborohydride sodium, proton solvent such as methanol. Alternatively, 50 usually handle arbitrarily substituted alkyl-halide in the presence of a base such as sodium carbonate, in a suitable solvent, such as THF or acetone is a career of oxazolidinone-microbicides structural formula v, where n = 1.

For specialists in this area it is obvious that the described synthesis methods are merely illustrative in nature, and that well-known alternative methods of synthesis, for example, some of those that are here referred to.

Examples of pyrrolidinyl-phenyloxazolidine, which can be obtained as part of this invention, are the following:

1. (S)-N-[[3-[3-fluoro-4-(3-oxopyrrolidin)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide

2. (S)-N-[[3-[3-fluoro-4-(3-oxo-4-methylpyrrolidinyl)-phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide

3. (S)-N-[[3-[3-fluoro-4-(2,4-dimethyl-3-oxopyrrolidin)phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide

4. (S)-N-[[3-[3-fluoro-4-(2,2-dimethyl-3-oxopyrrolidin)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

5. (S)-N-[[3-[3-fluoro-4-(4,4-dimethyl-3-oxopyrrolidin)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

6. (S)-N-[[3-[3-fluoro-4-(2,4-dimethyl-3-oxopyrrolidin) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

7. (S)-N-[[3-[3-fluoro-4-(3-isomitraphylline)phenyl] -2-oxo - 5-oxazolidinyl]methyl]ndimethylacetamide

8. (S)-N-[[3-[3-fluoro-4-(O-methyl-3-isomitraphylline)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

9. (S)-N-[[3-[3-fluoro-4-(3-hydroxypyrrolidine)-phenyl] -2-oxo-5 - oxazolidinyl

11. (S)-N-[[3-[3-fluoro-4-(TRANS-3-hydroxy-4-methylpyrrolidinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

12. (S)-N-[[3-[3-fluoro-4-(3-ethoxypyrrolidine)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide

13. (S)-N-[[3-[3-fluoro-4-(CIS-3,4-dihydroxypyrrolidine)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

14. (S)-N-[[3-[3-fluoro-4-(TRANS-3,4-dihydroxypyrrolidine)phenyl]- 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

15. (S)-N-[[3-[3-fluoro-4-(3-(hydroxyacetylamino)pyrrolidinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

16. (S)-N-[[3-[3-fluoro-4-[3-(formatexception) pyrrolidinyl]phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

17. (S)-N-[[3-[3-fluoro-4-(3-(methoxyethylamine)pyrrolidinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

18. (S)-N-[[3-[3-fluoro-4-(3-methoxycarbonylamino)pyrrolidinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

19. (S)-N-[[3-[3-fluoro-4-(3-ethoxycarbonylphenyl)-pyrrolidinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

20. (S)-N-[[3-[3-fluoro-4-(CIS-3-(formatexception)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

21. (S)-N-[[3 [3-fluoro-4-(CIS-3-(hydroxyacetylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

22. (S)-N-[[3-[3-fluoro-4-(CIS-3-(methoxyethylamine)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

24. (S)-N-[[3-[3-fluoro-4-(CIS-3-(ethoxycarbonyl)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

25. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(formatexception)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

26. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(hydroxyacetylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

27. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(methoxyethylamine)-4 - methylpyrrolidinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

28. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(methoxycarbonylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

29. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(ethoxycarbonyl)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

30. (S)-N-[[3-[3-fluoro-4-(3-(formatexception)- methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

31. (S)-N-[[3-[3-fluoro-4-(3-(hydroxyacetylamino) methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

32. (S)-N-[[3-[3-fluoro-4-(3-(methoxyethylamine) methylpyrrolidinyl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

33. (S)-N-[[3-[3-fluoro-4-(3-(methoxycarbonylamino)methyl - pyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

34. (S)-N-[[3-[3-fluoro-4-(3-(ethoxycarbonyl) methylpyrrolidinyl)hair dryer is rollitini)phenyl]-2-oxo-5-oxazolidinyl]methyl] ndimethylacetamide

36. (S)-N-[[3-[3-fluoro-4-(CIS-3-(hydroxyacetylamino) methyl-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] ndimethylacetamide

37. (S)-N-[[3-[3-fluoro-4-(CIS-3-(methoxyethylamine)methyl-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

38. (S)-N-[[3-[3-fluoro-4-(CIS-3-(methoxycarbonylamino)methyl 4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

39. (S)-N-[[3-[3-fluoro-4-(CIS-3-(ethoxycarbonyl)methyl-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

40. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(formatexception) methyl-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] ndimethylacetamide

41. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(hydroxyacetylamino)methyl-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

42. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(methoxyethylamine)methyl-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetylated

43. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(methoxycarbonylamino)methyl-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

44. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(ethoxycarbonyl)methyl-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

45. (S)-N-[[3-[3-fluoro-4-[TRANS-3-(phenylmethoxy)acetylamino-4 - hydroxypyrrolidine]phenyl]-2-oxo-5-oxazolidinyl]methyl]ACE ethyl]ndimethylacetamide

47. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(methoxycarbonylamino)-4 - hydroxypyrrolidine)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

48. (S)-N-[[3-[3-fluoro-4-(TRANS-3-(ethoxycarbonyl)-4 - hydroxypyrrolidine)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Antibacterial activity

Oxazolidinone antibacterial agents of this invention have useful activity against a number of organisms. In vitro activity of the compounds of this invention can be evaluated using standard methods of testing, such as determining the minimum inhibitory concentration (MIC, MIC) by agar dilution, as described in "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically" (MFT) published Jan. 1983 by the National Committee for Clinical Laboratory Standards, 771 East Lancaster Avenue, Villanova, Pennsylvania 19084, USA. The activity of selected compounds of this invention against Staphylococcus aureus and streptococcus pneumoniae are presented in the table.

Azetidine-phenyloxazolidine

Example 1: (S)-N-[[3-[3-fluoro-4-(3-methoxy-1-azetidine) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: 1-(diphenylmethyl)-3-methoxyisatin

A suspension of sodium hydride (0,440 g 60% dispersion in oil, 11.0 mmol) in dry tetrahydrofuran (125 ml) under nitrogen atmosphere is cooled with a bath with ice to 0who tion for 30 min at 0oC add iodomethane (1,490 g, 0,654 ml, 10.5 mmol). Upon completion of the addition the cooling bath removed and the reaction mixture was allow to warm overnight to room temperature. The reaction mixture is poured into pH 7 phosphate buffer and extracted with ethyl acetate. The combined organic extracts washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product chromatographic on silica gel (300 ml), filled with dichloromethane, elwira gradient mixture 1-10% ethyl acetate/dichloromethane. Concentration of the appropriate fractions gives 2,081 g (82%) of the named compound as a pale yellow syrup with MS (EI) 253 (M+).

Stage 2: 3-fluoro-4-(3-methoxy-1-azetidine) nitrobenzene

A solution of 1-(diphenylmethyl)-3-methoxyacridine (2.00 g, to $ 7.91 mmol) in a mixture of 25% tetrahydrofuran/ethanol (100 ml) is treated with 5 HCl (5.0 ml) and palladium hydroxide-on-coal (Pearlman''s catalyst, 0,500 g). The mixture was shaken on the Parr apparatus at 3,164 kg/cm2(45 psi) H2. After 16 h some amount of the original substance still remains, as shown by TLC (TLC) analysis (silica gel, 6% acetonitrile/chloroform). Additional 0,500 g Pearlman''s catalyst is added and hydrogeol is UP>
and the filtrate concentrated under reduced pressure until the oil is amber in color. This substance was dissolved in dimethyl sulfoxide (30 ml) and treated with acid disodium phosphate (6,88 g, to 39.6 mmol) and 3,4-diplomirovannym (1,05 ml, 9,49 mmol). The reaction mixture was stirred at ambient temperature for 16 h, and at this time TLC analysis (silica gel, 6% acetonitrile/chloroform) shows that the reaction is complete. The reaction mixture was diluted with water (150 ml) and extracted with chloroform (3 x 40 ml). The combined organic extracts washed with water (3 x 25 ml), brine, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the crude product. Purification is carried out by means of chromatography was carried out on silica gel (100 g), elwira gradient mixture 0-1% acetonitrile/chloroform. Concentration of the appropriate fractions give 1.50 g (84%) of the named compound as a pale yellow solid with so pl. of 57.5-58oC and MS (EI) 226 (M+).

Stage 3: N-(carbobenzoxy)-3-fluoro-4-(3-methoxy-1-azetidine) aniline

A solution of 3-fluoro-4-(3-methoxy-1-azetidine)-nitrobenzene (1.50 g, only 6.64 mmol) in a mixture of 1:1 methanol/tetrahydrofuran (35 ml) is treated with 10% palladium-on-coal, and then ammonium formate (1.26 g, 19,9 promo mixture is filtered through Celitethe filtrate is concentrated under reduced pressure. Selected oil immediately dissolved in a mixture of 3:1 acetone/water (25 ml) and treated with sodium carbonate (2,75 g to 19.9 mmol) and benzyl-chloroformate (1.31 g, 8,30 mmol). After 30 min TLC analysis (6% acetonitrile/chloroform) showed that the reaction is complete. The reaction mixture was extracted with chloroform (3 x 20 ml). The combined organic extracts washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to an oil Magenta. This substance chromatographic on silica gel (100 ml), elwira gradient mixture of 1-3% acetonitrile/chloroform, getting after concentration of appropriate fractions 1.24 g (56%) of the named compound as a whitish solid with so pl. 95-96,5oC and MS (EI) 330 (M+).

Stage 4: (R)-[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methanol

A solution of N-(carbobenzoxy)-3-fluoro-4-(3-methoxy-1-azetidine) aniline (0,865 g, 2,62 mmol) in dry tetrahydrofuran (10 ml) cooled to -78oC in nitrogen atmosphere and treated with n-butyllithium (1.65 ml, 1.6 M solution in hexano, to 2.65 mmol). After stirring at -78oC for 15 min, the reaction mixture was treated with (R)-glycidyl by butyrate (0,374 ml, 2,65 surrounding environment. After 1 h according to TLC analysis considered that the reaction was completed. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (0.5 ml) and concentrate under reduced pressure to a yellow solid. Chromatographytandem on silica gel (10 g) with elution with a gradient mixture of 1-2% methanol/chloroform obtained after concentration of appropriate fractions 0,530 g (68%) of the named compound as a whitish solid with so pl. 131-132oC and MS (EI) 296 (M+).

Stage 5: (R)-[[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl]-2 - oxo-5-oxazolidinyl]methyl]methanesulfonate

A solution of (R)-[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl] methanol (0,492 g of 1.66 mmol) in dry dichloromethane (25 ml) under nitrogen atmosphere is cooled with a bath with ice to 0oC, treated with triethylamine (0,254 ml and 1.83 mmol) and then methanesulfonyl chloride (0,141 ml and 1.83 mmol). After 1 h treatment with 0oC TLC analysis (10% methanol/chloroform) showed that the reaction was completed. The reaction mixture is washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to a whitish solid. Chromatographytandem on silica gel (100 g) with elution with a gradient mixture of 1-3% IU the de white solids with so pl. 122,5-123,5oC and MS (EI) 374 (M+).

Stage 6: (R)-[[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methyl]azide

(R)-[[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl] methyl] methanesulfonate (0,508 g of 1.36 mmol) are combined with sodium azide (0,106 g, and 1.63 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture is heated to 65oC in nitrogen atmosphere. After 2 h, a small number of source nelfinavir still remains, as shown by TLC analysis (5% methanol/chloroform). Add additional 0,044 g of sodium azide and the reaction mixture is heated for another 1.5 h, and at this time TLC analysis showed that the reaction was completed. The reaction mixture was filtered and concentrated in vacuo. The remainder chromatographic on silica gel (25 g), elwira gradient mixture of 1-3% methanol/chloroform. The appropriate fractions are combined and concentrated in vacuo, getting 0,426 g (98%) of the named compound as a whitish solid. An analytical sample obtained by recrystallization of this substance from a mixture of 3:1 ethyl acetate/hexane, getting a white solid with so pl. 111-112,5oC and MS (EI) 321 (M+).

Stage 7: (R)-N-[[3-[3-fluoro-4-(3-methoxy-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

methanol/dichloromethane (20 ml) is treated with 10% palladium-on-coal (0,030 g) in a stream of nitrogen. Then the atmosphere replaced with hydrogen (balloon). After stirring for 3 hours in hydrogen atmosphere about recovery completion is judged according to TLC analysis (5% methanol/chloroform). The reaction mixture was filtered through Celiteand concentrate under reduced pressure. The crude 5-(aminomethyl)oxazolidinone was dissolved in dichloromethane (15 ml) and treated with pyridine (amount of 0.118 ml of 1.46 mmol) and acetic anhydride (was 0.138 ml of 1.46 mmol) in a nitrogen atmosphere at ambient temperature. After 2 h, the reaction was completed, judged according to TLC. The reaction mixture is washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatographytandem on silica gel (50 g) with elution with a gradient mixture of 1-3% methanol/chloroform obtained after concentration of appropriate fractions 0,281 g (68%) of these antibacterial agents in the form of a white solid. An analytical sample obtained by recrystallization from a mixture of 2:1 ethyl acetate/hexane, was a white solid with so pl. 160-161,5oC and MS (EI) 337 (M+).

Example 2: (S)-N-[[3-[3-fluoro-4-(3-hydroxy-1-azetidine) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: 3-fluoro-4-(3-hydroxy (75 ml) and treated with 6N HCl (1.20 ml, 7,29 mmol). Then add in a stream of nitrogen palladium hydroxide-on-coal (0,200 g). Then the reaction mixture was shaken on the Parr apparatus at 2,81 kg/cm2(40 psi) H2. After 16 h, TLC analysis (5% methanol/chloroform) showed that starting material had been consumed. The reaction mixture was filtered through Celiteand the filtrate concentrated under reduced pressure until the oil is amber in color. This substance was dissolved in dimethyl sulfoxide (29 ml) and the atmosphere replaced with nitrogen. Add sour disodium phosphate (5,07 g, 29.2 mmol) and then 3,4-differentpoints (0,966 ml of 8.75 mmol). The mixture was stirred at ambient temperature under nitrogen atmosphere. After 3 h, TLC analysis (5% methanol/chloroform) showed that the reaction is complete. The reaction mixture was diluted with water (250 ml) and extracted with chloroform (4 x 50 ml). The combined organic extracts washed with water (2 x 50 ml) and brine, dried over sodium sulfate, filtered and concentrated in vacuo, receiving a yellow solid. Chromatographytandem on silica gel (100 g) with elution with a gradient mixture of 3-7% acetonitrile/chloroform obtained after concentration of appropriate fractions of 1.00 g (65%) of the titled compound as an orange solid substance with so pl. 130,5-132oC and M Is the Solution of 3-fluoro-4-(3-hydroxy-1-azetidine)nitrobenzene (5,51 g, 26.0 mmol) in N,N-dimethylformamide (104 ml) under nitrogen atmosphere cooled to 0oC in a bath with ice and treated with imidazole (1.86 g, 27,3 mmol) and then tert-butyldimethylsilyl chloride (4.12 g, 27,3 mmol). The reaction mixture was stirred at 0oC for 30 min and then at room temperature overnight. TLC analysis (5% methanol/chloroform) showed that a small amount of the original substance still remains to this time. Add a further quantity of tert-butyldimethylsilyl chloride (0,392 g). After stirring overnight, TLC analysis showed that the reaction was completed. The reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (4 x 70 ml). The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to a yellow solid. Chromatographytandem on silica gel (200 g) with elution with mixtures of 5 and 10% ethyl acetate/hexane obtained after concentration of appropriate fractions 6,30 g (74%) of the named compound as a yellow solid with so pl. of 98.5-99,5oC and MS (EI) 326 (M+).

Stage 3: N-(carbobenzoxy)-4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidine] -3-ftoranila

4-[3-[(tert - mixture in 3:1 tetrahydrofuran/water (25 ml) under nitrogen atmosphere. The atmosphere replaced with hydrogen (balloon), repeating the evacuation and filling. After 2 h the initial yellow color of the reaction solution disappears and TLC analysis (15% ethyl acetate/hexane) showed that the restore is completed. The reaction mixture c was filtered through Celiteand the filtrate is immediately placed in an atmosphere of nitrogen and treated with sodium bicarbonate (1,41 g, a 16.8 mmol) and benzyl-chloroformate (0,528 ml of 3.69 mmol). After 30 min at ambient temperature according to TLC analysis (15% ethyl acetate/hexane), the reaction is finished. The reaction mixture was concentrated under reduced pressure until a whitish solid. Chromatographytandem on silica gel (125 g) with elution with a mixture of 5-30% ethyl acetate/hexane obtained after concentration of appropriate fractions 0.565 g (43%) of the titled compound as white solids with so pl. 91-93oC and MS (EI) 430 (M+).

Stage 4: (R)-[3-[4-[3-[(tert-butyldimethylsilyl)oxy] -1-azetidine]-3-forfinal]-2-oxo-5-oxazolidinyl]methanol

A solution of N-(carbobenzoxy)-4-[3-[(tert-butyldimethylsilyl) oxy]-1-azetidine]-3-foronline (6,30 g, 14.7 mmol) in dry tetrahydrofuran (100 ml) under nitrogen atmosphere cooled to -78oC and treated with n-butyllithium (9,16 ml of 1.6 is Uchenie 15 min and then treated with (R)-glycidyl by butyrate (2,21 ml, 14.7 mmol). At the end of the addition the cooling bath removed and the reaction mixture was allowed to mix at ambient temperature for 1.5 hours then add saturated aqueous ammonium chloride (20 ml). After 3 min to the reaction mixture is added saturated aqueous sodium bicarbonate solution (10 ml) and the organic solvent is removed by rotary evaporation under reduced pressure. Add dichloromethane (100 ml) and the mixture is washed with water and brine. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographytandem on silica gel (200 g) with elution with a gradient mixture of 1-3% methanol/chloroform obtained after concentration of appropriate fractions 4,39 g (75%) of the titled compound in the form of a whitish solid with so pl. 183-186oC and MS (EI) 396 (M+).

Stage 5: (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidine]-3 - forfinal]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate

The crude (R)-[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidine]-3 - forfinal] -2-oxo-5-oxazolidinyl]methanol (5,38 g of 13.6 mmol) dissolved in dry dichloromethane (70 ml), cooled to 0oC in a bath with ice, and treated with triethylamine (of 2.08 ml, 14.9 mmol) and ZAT is) the reaction is finished. The reaction mixture was washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure until a whitish solid. An analytical sample is obtained by grinding the crude product from isopropanol and diethyl ether, followed by filtration and drying in vacuo gives a whitish solid with so pl. 142-145oC and MS (EI) 474 (M+).

Stage 6: (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1 - azetidine]-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]azide

The crude (R)-[[3-[4-(3-[tert-butyldimethylsilyl)oxy] -1-azetidine] -3-forfinal] -2-oxo-5-oxazolidinyl]methanesulfonate (9,42 mmol) dissolved in dry N,N-dimethylformamide (50 ml) and treated with sodium azide (4.42 g, 68,0 mmol) at ambient temperature. The reaction mixture is heated to 65oC in nitrogen atmosphere for 4 hours TLC analysis (5% methanol/chloroform) to this time shows that the reaction was completed. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (3 x 25 ml) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to a solid amber color. Chromatographytandem on silica gel (125 g) PR is the second of 2.21 g (56% for 3 stages) named azide as a white solid with so pl. 121-122,5oC and MS (EI) 421 (M+).

Stage 7: (S)-N-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1 - azetidine] -3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1 - azetidine]-3-forfinal] -2-oxo-5-oxazolidinyl] methyl] - azide (2,04 g is 4.85 mmol) in a mixture of 1:1 ethyl acetate/methanol (200 ml) is treated with 10% palladium-on-coal (0,300 g) in a stream of nitrogen. Then the atmosphere replace H2(balloons), repeating the evacuation and filling. After 3 h according to TLC analysis (5% methanol/chloroform), the reaction is finished. The reaction mixture was filtered through Celiteand the filtrate concentrated under reduced pressure to a white solid. The crude 5-(aminomethyl)oxazolidinone was dissolved in dichloromethane (100 ml), cooled to 0oC in the atmosphere and treated with pyridine (0,431 ml, 5.33 mmol) and acetic anhydride (0,503 ml, 5.33 mmol). After 30 min at 0oC according to TLC analysis (5% methanol/chloroform) acetylation is completed. The reaction mixture is washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the crude product is yellowish-brown color. Chromatographytandem on silica gel (125 g) with elution with a gradient of 1-3% methane the logo solids with so pl. 183,5-184oC and MS (EI) 437 (M+).

Step 8: (S)-N-[[3-[3-fluoro-4-(3-hydroxy-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

The combined acetonitrile (55 ml) solution of (S)-N-[[3-[4-[3- [(tert-butyldimethylsilyl)oxy] -1-azetidine] -3-forfinal]- -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (1,23 g of 2.81 mmol) in a polypropylene flask handle 38% aqueous hydrofluoric acid (15 ml) at ambient temperature. According to TLC analysis unprotect is completed after 3 hours the Reaction mixture was diluted with water (15 ml) and neutralized with solid sodium bicarbonate. Add water (50 ml) and the mixture extracted with chloroform. The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo, getting called oxazolidinone antibacterial agent in the form of a whitish solid with so pl. 174-177oC and MS (EI) 323 (M+)

Example 3: (S)-N-[[3-[3-fluoro-4-[3-[N-(2-foradil)-N-methylamino] -1-azetidine]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: 1-(Diphenylmethyl)-3-[N-(2-foradil)-N-methylamino] azetidin

2-(Diphenylmethyl)-3-(methylamino)azetidin (5,00 g of 19.8 mmol) is combined with sodium carbonate (16.4 g, 119 mmol) and 2-foradil tosylate (6.50 g, 29,8 moenia under reflux according to TLC analysis (5% methanol/chloroform) remains small amount of substance. Add 1.8 g 2-foradil tosilata and the reaction mixture is refluxed for another 2 h, the Reaction mixture was cooled to ambient temperature and concentrate under reduced pressure. Chromatographytandem on silica gel (200 g) with elution with a gradient of 1-5% acetonitrile/chloroform obtained after concentration of appropriate fractions 4,07 g (69%) of the named compound in the form of syrup amber color with IR 1598, 1452, 1362, 1029 cm-1.

Stage 2: 3-fluoro-4-[3-[N-(2-foradil)-N-methylamino]-1-azetidine] nitrobenzene

The vessel Parra download 1-(diphenylmethyl)-3-[N-(2-foradil)-N - methylamino] azetidin (3.88 g, 13,0 mmol) and the mixture is 25% tetrahydrofuran/ethanol (130 ml). Then in a stream of nitrogen was added palladium hydroxide-on-coal (1.9 grams). The mixture is then shaken in a Parr apparatus at 3,16 kg/cm2(45 psi) H2. After 20 h according to TLC analysis (5% methanol/chloroform) hydrogenolysis ends. The reaction mixture was filtered through Celiteand concentrate under reduced pressure to a colorless oil. This substance was dissolved in dimethyl sulfoxide (50 ml) and treated with disodium acid phosphate (13,6 g, 78,0 mmol), followed by treatment of 3,4-diplomirovannym (1,72 ml, 15.6 mmol). Then the reaction mixture is displaced the ORM). After 4 h the reaction mixture was poured into H2O (500 ml) and extracted with dichloromethane (4 x 75 ml). The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to a yellow syrup. Chromatographytandem on silica gel (200 g) with elution with a gradient of 0-2,5% acetonitrile/dichloromethane obtained after concentration of appropriate fractions 2,87 g (81%) of the named compound as a yellow solid with so pl. is 46.5-48oC and MC (the Belarusian library Association, FAB) 272 (M+H)+.

Stage 3: N-(Carbobenzoxy)-3-fluoro-4-[3-[N-(2-foradil)-N - methylamino] -1-azetidine]aniline

A solution of 3-fluoro-4-[3-[N-(2-foradil)-N-methylamino] -1-azetidine]nitrobenzene (2.66 g, 9,82 mmol) in a mixture of 2:1 tetrahydrofuran/water (50 ml) and acetic acid (2.0 ml) is treated with 10% palladium/carbon in a stream of nitrogen.

The atmosphere replace H2(balloons) by repeating the evacuation and filling, and the reaction mixture was stirred in an atmosphere of H2throughout the night. According to TLC analysis (6% acetonitrile/chloroform) by this time the restoration is completed. The reaction mixture was filtered through Celite. Exposure to air is reduced to a minimum, since under these conditions quickly develops p is (6.8 g, 49 mmol) and benzylchloride (1,63 ml of 10.3 mmol). The reaction mixture is stirred at about 0oC for 1 h and then warmed to room temperature for 30 minutes According to TLC analysis (6% acetonitrile/chloroform) to this time the reaction is terminated. The reaction mixture was diluted with water (200 ml) and extracted with chloroform (3 x 75 ml). The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to a syrup, dark amber color. Chromatographytandem on silica gel (200 g) with elution with a gradient of 1-3% methanol/chloroform obtained after concentration of appropriate fractions 3,71 g (100%) of the titled compound in the form of syrup amber color. An analytical sample is prepared by using additional chromatographic purification, getting a solid substance with a light amber color with so pl. 57-59oC and MS (EI) 375 (M+).

Stage 4: (R)-N-[3-[3-fluoro-4-[3-N-(2-foradil)-N-methylamino] -1-azetidine]phenyl]-2-oxo-5-oxazolidinyl]methanol

A solution of N-(carbobenzoxy)-3-fluoro-4-[3-[N-(2-foradil)-N-methylamino]-1 - azetidine] aniline (3,38 g, 9,01 mmol) in dry tetrahydrofuran (40 ml) under nitrogen atmosphere cooled to -78oC and treated with n-butyllithium -78oC and treated with (R)-glycidyl by butyrate (1,29 ml, 9,10 mmol). After complete addition, reaction mixture was allow to warm to ambient temperature. After 1 h according to TLC analysis (5% methanol/chloroform) believe that the reaction was completed. The reaction mixture was quenched with saturated aqueous ammonium chloride (1 ml), diluted with water (100 ml) and extracted with chloroform (3 x 50 ml). The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to an amber syrup color. Chromatographytandem on silica gel (200 g) with elution with a gradient mixture of 1-4% methanol/chloroform obtained after concentration of appropriate fractions 1,69 g (55%) of the named compound as a whitish solid with so pl. 124-125oC and MS (EI) 341 (M+).

Stage 5: (R)-[[3-[4-[3-[N-(2-foradil)-N-methylamino] 1-azetidine]-3-forfinal]-2-oxo-oxazolidinyl]methyl]methanesulfonate

A solution of (R)-N-[3-[3-fluoro-4-[3-[N-(2-foradil)-N-methylamino] -1-azetidine] phenyl] -2-oxo-5-oxazolidinyl] methanol (1.40 g, 4,11 mmol) in dry dichloromethane (16 ml) is treated with triethylamine (0,628 ml, to 4.52 mmol) and then cooled to 0oC in nitrogen atmosphere. Then add metsulfuron) showed there is a small amount of the original substance. Add additional portion methanesulfonyl chloride (0.100 ml, of 1.30 mmol) and the reaction continued for another 1 h at 0oC. the Reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo, getting 1.88 g (100%) of the named compound as a light orange solid.1H NMR analysis showed that this substance is of high quality. An analytical sample is obtained by chromatography was carried out 200 mg of the crude product on silica gel (10 g), elwira gradient of 1-4% methanol/ chloroform, after concentration of appropriate fractions 99 mg of the above compound in the form of a whitish solid with so pl. of 96.5-98oC and MS (EI) 419 (M+).

Stage 6: (R)-[[3-[4-[3-[N-(2-foradil)-N-methylamino]-1-azetidine]-3 - forfinal]-2-oxo-5-oxazolidinyl]methyl]azide

A solution of (R)-[[3-[4-[3-[N-(2-foradil)-N-methylamino] -1-azetidine] -3 - forfinal]-2-oxo-5-oxazolidinyl]methyl]methansulfonate (1,65 g of 3.94 mmol) in dry N,N-dimethylformamide (15 ml) is treated with solid sodium azide (0,768 g of 11.8 mmol). The reaction mixture is heated to 65oC in nitrogen atmosphere. After 3 h, a small amount ishowu portion of sodium azide (0,256 g, of 3.94 mmol) and the reaction mixture is heated at 65oC for 1 h, the Reaction mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel (100 g), elwira gradient mixture of 1-4% methanol/chloroform, getting after concentration of appropriate fractions 1.24 g (86%) of the titled compound in the form of a whitish solid with so pl. 60-63oC and MS (EI) 366 (M+).

Stage 7: (S)-N-[[3-[3-fluoro-4-[3-[N-(2-foradil)-N-methylamino]-1-azetidinol]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (R)-[[3-[4-[3-[N-(2-foradil)-N-methylamino] -1-azetidine]-3-forfinal] -2-oxo-5-oxazolidinyl] methyl] - azide (1,14 g, 3.11 mmol) in methanol (20 ml) is treated with 10% palladium/carbon (0,114 g) in a stream of nitrogen. The atmosphere replaces the H2(balloons), repeating the evacuation and filling. After 2.5 h according to TLC analysis (5% methanol/chloroform) believed that recovery was complete. The reaction mixture was filtered through Celiteand the filtrate was concentrated in vacuo to a whitish solid. This substance is dissolved in dichloromethane (20 ml) and treated with pyridine (0,264 ml of 3.27 mmol) and acetic anhydride (0,309 ml of 3.27 mmol) under nitrogen atmosphere. 30 is Oh and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, obtaining the oil is amber in color. Chromatographytandem on silica gel (125 g) with elution with a gradient mixture of 1-4% methanol/chloroform obtained after concentration of appropriate fractions 0,892 g (75%) of the named oxazolidinone - antibacterial agent in the form of a whitish solid with so pl. output reached 125.5-127oC and MS (EI) 382 (M+).

Example 4: (S)-N-[[3-[3-fluoro-4-(3-oxo-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (S)-N-[[3-[3-fluoro-4-(3-hydroxy-1-azetidine)phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (Example 2, 0,440 g of 1.36 mmol) in a mixture of 10% acetonitrile/dichloromethane (100 ml) is treated with powdered molecular sieves with pore size of 4 Angstrom (0,682 g), 4-methylmorpholine N-oxide (0,319 g of 2.72 mmol) and then Tetra-n-propylammonium perruthenate (0,024 g, 0,068 mmol) at ambient temperature. After stirring for 1.5 hours at ambient temperature TLC analysis (10% methanol/chloroform) showed that there is still a small amount of the original alcohol. Adding an additional amount of 4-methylmorpholine N-oxide none of the original substance. The reaction mixture was concentrated under ponizhennaya gradient mixture 1-3,5% methanol/chloroform, receiving, after concentration of appropriate fractions 0,204 g (47%) mentioned oxazolidinone-an antibacterial agent in the form of a white solid with so pl. 192-193oC and MS (EI) 321 (M+).

Example 5: (S)-N-[[3-[3-fluoro-4-[3-(methoxyimino)-1-azetidine] phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (S)-N-[[3-[3-fluoro-4-(3-oxo-1-azetidine)phenyl] -2-oxo - 5-oxazolidinyl] methyl] ndimethylacetamide (Example 4, 0,200 g, 0,623 mmol) in a mixture of 5% methanol/dichloromethane (10 ml) is treated with pyridine (0,201 ml, 2.49 mmol) and then the hydrochloride methoxylamine (0,052 g, 0,623 mmol) at ambient temperature. After 1.5 h, TLC analysis (10% methanol/chloroform) showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to a white solid. Chromatographytandem on silica gel (10 g), elwira gradient mixture of 1-3% methanol/chloroform, obtained after concentration of appropriate fractions 0,204 g (94%) of the named oxazolidinone-antibacterial agent in the form of a whitish solid. In another experience in synthesis have a substance with so pl. 189 - 192oC and MS (EI) 350 (M+).

Example 6: (S)-N-[[3-[3-fluoro-4-(3-methoxy-3-methyl-1-azetidine) phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: 1-(g,2 mmol) in dry tetrahydrofuran (200 ml) under nitrogen atmosphere is cooled with a bath with ice to 0oC and treated with sodium hydride (2,10 g 60% dispersion in oil, to 51.8 mmol). The cooling bath removed and the mixture is refluxed for 15 minutes. After cooling to room temperature, add iodomethane (7,40 g, up 3.22 ml, to 51.8 mmol). Upon completion of addition the reaction mixture is refluxed for 15 hours TLC analysis (9:1 hexane/ethyl acetate) showed that methylation was completed. The reaction mixture was quenched with saturated aqueous ammonium chloride. The mixture is transferred into a separating funnel with ethyl acetate and water and then extracted with ethyl acetate. The combined organic extracts washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product chromatographic on silica gel, elwira a mixture of 9:1 ethyl acetate/hexane. Concentration of the appropriate fractions gives 2.30 g (50%) of the named compound as a colourless oil, MS (EI) 267 (M+).

Stage 2: 3-fluoro-4-(3-methoxy-3-methyl-1-azetidine)nitrobenzene

A solution of 1-(diphenylmethyl)-3-methoxy-3-methylaziridine (2.20 g, 8.2 mmol) in a mixture of 25% tetrahydrofuran/ethanol is treated with glacial acetic acid (1.60 g, 1.50 ml of 24.7 mmol) and then palladium hydroxide-on-coal (0,220 g) in patch (TLC) analysis (9:1 hexane/ethyl acetate) showed that reaction was completed. The mixture is filtered through Celite(washed with ethyl acetate and the filtrate was concentrated in vacuo, obtaining oil. This substance was dissolved in dimethyl sulfoxide (15 ml) and the solution treated with acid disodium phosphate (at 8.60 g, and 49.2 mmol) and 3,4-diplomirovannym (1.30 grams, 0,886 ml, 8.0 mmol) at ambient temperature. The yellow reaction mixture was stirred at ambient temperature for 18 hours, the Reaction mixture was diluted with water and extracted with dichloromethane. The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo, receiving a yellow solid. Chromatographytandem on silica gel, elwira a mixture of 8:1 hexane/ethyl acetate, obtained after concentration of appropriate fractions of 1.80 g (90%) of the named compound as a yellow solid with so pl. 110-111oC and MS (EI) 240 (M+).

Stage 3: N-(carbobenzoxy)-3-fluoro-4-(3-methoxy-3-methyl-1 - azetidine)aniline

A solution of 3-fluoro-4-(3-methoxy-3-methyl-1-azetidine)nitrobenzene (1.60 g, 6.7 mmol) in a mixture of 25% tetrahydrofuran/methanol (35 ml) Tegaserod, repeating the evacuation and filling of the N2and then treated with 10% palladium/carbon (0,160 g). is the atur environment for 20 min, and during this time the color of the reaction mixture changed from yellow to colorless. TLC analysis (2:1 hexane/ethyl acetate) shows that the reaction is complete. The reaction mixture was filtered through Celite(washed with dichloromethane and methanol and the filtrate was concentrated in vacuo, receiving a purple resin, which is immediately dissolved in a mixture of 1:1 acetone/water (30 ml) under nitrogen atmosphere. The mixture is cooled in a bath with ice to 0oC and treated with sodium bicarbonate (1.10 g, a 13.4 mmol) and benzyl-chloroformate (1.20 g, and 1.00 ml, 7,37 mmol). The cooling bath provide an opportunity to gradually heated within 3 hours After mixing for an additional 2 h at ambient temperature the reaction mixture was transferred into a separating funnel with dichloromethane (50 ml). The organic phase is separated, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo, receiving a purple oil. Chromatographytandem on silica gel, elwira a mixture of 6:1 hexane/ethyl acetate, obtained after concentration of appropriate fractions 2,04 g (89%) of the named compound as a viscous oil, which solidifies upon standing with the formation of waxy substance so pl. 73-75oC and MS (EI) 344 (M+).

Scilacci)-3-fluoro-4-(3-methoxy-3-methyl-1 - azetidine)aniline (1.85 g, 5.4 mmol) in dry tetrahydrofuran (20 ml) cooled to -78oC in the bath with a mixture of dry ice/acetone and treated with n-butyllithium (3,50 ml of 1.6 M solution in hexane, 5.7 mmol) via syringe. After 5 min at this temperature with a syringe add (R)-glycidyl butyrate (0,823 g, 0,807 ml, 5.7 mmol) and the reaction mixture is left overnight with gradual warming of the cooling bath to ambient temperature. According to TLC analysis (5% methanol/chloroform) original Cbz derivative spent. The reaction mixture was concentrated under reduced pressure, getting a waxy yellow solid. The residue is dissolved in a mixture of 20% methanol/dichloromethane, washed sequentially with a saturated solution of ammonium chloride, saturated sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the crude product. Radial chromatography on silica gel with elution 2, 3 and then 5% methanol/chloroform gives, after concentration of appropriate fractions 0,811 g (48%) of the named compound as a colourless resin, which is a very clean according to the 1H NMR analysis. An analytical sample is prepared by recrystallization from a mixture >/P>Stage 5: (R)-[[3-[3-fluoro-4-(3-methoxy-3-methyl-1-azetidine) phenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate

A solution of (R)-[3-[3-fluoro-4-(3-methoxy-3-methyl-1-azetidine)phenyl] -2-oxo-5 - oxazolidinyl]methanol (0,700 g, 2.25 mmol) in dry dichloromethane (10 ml) is cooled with a bath with ice to 0oC. Then add triethylamine (0,250 g, 0,345 ml, 2.48 mmol) and methanesulfonyl chloride (0,271 g, 0,183 ml, is 2.37 mmol) and the reaction mixture was stirred in nitrogen atmosphere up until the cooling bath is warm. After 3 h, TLC analysis (5% methanol/chloroform) showed that metilirovanie was essentially completed. The reaction mixture was diluted with additional dichloromethane and washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. Radial chromatography on silica gel with elution with a mixture of 3% methanol/chloroform, gives, after concentration of appropriate fractions of 0.022 g of unreacted source of alcohol and 0,700 g (80%) of the titled compound as white solids with MS (EI) 388 (M+).

Stage 6: (S)-N-[[3-[3-fluoro-4-(3-methoxy-3-methyl-1-azetidine) phenyl]-2-oxo-5-oxazolidinyl]met lithonate (0,680 g, a 1.75 mmol) in a mixture of 2:1 ammonium hydroxide/isopropanol (30 ml) is refluxed (refrigerator, cooled with dry ice). After 7 h, TLC analysis (5% methanol/chloroform) revealed the presence of a large number of original substance in the mixture. The reaction continued for another 46 hours After cooling to ambient temperature, TLC analysis showed that the source mesilate mostly spent. The reaction mixture was transferred into a separating funnel with dichloromethane (100 ml) and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude 5-(aminomethyl)oxazolidinone was dissolved in dry dichloromethane (10 ml) cooled to 0oC using baths with ice, and treated with pyridine (0,698 g, 0,708 ml of 8.75 mmol) and acetic anhydride (0,357 g, 0,330 ml, 3.50 mmol). Then the cooling bath removed and the reaction mixture stirred at ambient temperature overnight. The reaction mixture was diluted with additional dichloromethane (60 ml) and washed with 5% aqueous hydrochloric acid solution, saturated aqueous sodium carbonate, water and brine. Then the organic layer is dried over sodium sulfate, filtered and concentrated in vacuo, receiving untreated centering of the corresponding fractions 0,481 g (78%) mentioned oxazolidinone-an antibacterial agent in the form of a white foam solid. Dried sample has so pl. 132-134oC and MS (EI) 351 (M+).

Example 7: (S)-N-[[3-fluoro-4-(3-hydroxy-3-methyl-1-azetidine)phenyl-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: 3-fluoro-4- (3-hydroxy-3-methyl-1-azetidine) nitrobenzene

A solution of 1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride (3.00 g, 10.4 mmol) in 2: 1 methanol/tetrahydrofuran (60 ml) is treated with triethylamine (1,00 g of 1.40 ml, 10.4 mmol) and then a catalyst of palladium hydroxide/carbon (0,300 g) in a stream of N2. The mixture was shaken on the Parr apparatus at a pressure of 2.81 kg/cm2(40 psi) H2. According to TLC analysis (2:1 hexane/ethyl acetate) after 2.5 h the hydrogenolysis is completely finished. The reaction mixture was filtered through Celite(washed with dichloromethane and the filtrate concentrated under reduced pressure, obtaining oil, which immediately placed in dry dimethylsulfoxide (15 ml) and treated with dicale acid phosphate (3,40 g of 19.8 mmol) and 3,4-diplomirovannym (1.60 g, 1,10 ml, 9.9 mmol) at ambient temperature in an atmosphere of N2. After stirring 16 h at this temperature, according to TLC analysis (2:1 hexane:ethyl acetate), the reaction is largely completed. The reaction mixture was transferred into a separating funnel with H2O (150 morethana and the combined organic extracts washed with water, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining oil. Chromatography on silica gel with elution with a mixture of 3:1 hexane/ethyl acetate to give, after concentration of appropriate fractions 2.15 g (98%) of the titled compound as an orange solid substance with so pl. 109-110oC and MS (EI) 226 (M+).

Stage 2: 4-[3-[(tert-butyldimethylsilyl)oxy]-3-methyl-1 - azetidine]-3-ftorirovannom

A solution of 3-fluoro-4-(3-hydroxy-3-methyl-1-azetidine)nitrobenzene (1.80 g, 8.0 mmol) in dry N,N-dimethylformamide (15 ml) cooled to 0oC using baths with ice and then treated with imidazole (0,572 g, 8.4 mmol) and tert-butyldimethylsilyl chloride (1,30 g, 8.4 mmol) in an atmosphere of N2. The reaction mixture was stirred overnight with gradual warming of the cooling bath surrounding air. Then the reaction mixture was transferred into a separating funnel with water and a mixture of 1:1 hexane/diethyl ether. After shaking, the layers are separated and the aqueous phase is again extracted with an additional mixture of 1: 1 hexane/diethyl ether. The combined organic extracts washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining oil. Chromatography on silica gel PNIA appropriate fractions 0,536 g source of alcohol and 1.90 g (70%) of the named compound as a pale yellow solid with so pl. 98-99,5oC and MS (EI) 340 (M+).

Stage 3: N-(carbobenzoxy)-4-[3-[(tert-butyl-dimethylsilane)oxy]-3-methyl-1 - azetidine]-3-ftoranila

A solution of 4-[3-[(tert-butyldimethylsilyl)oxy] -3-methyl-1 - azetidine]-3-peritrabecular (1.70 g, 5.0 mmol) in a mixture of 2:1 methanol/tetrahydrofuran (30 ml) Tegaserod, repeating the evacuation and filling of the N2and then treated with 10% palladium/carbon (0,170 g) in a nitrogen atmosphere. Add solid ammonium formate, the reaction mixture Tegaserod some time and the mixture is cooled with a bath of ice due to heat it. The color of the reaction mixture changed from yellow to colorless. According to TLC analysis (2:1 hexane/ethyl acetate) restore completes. The reaction mixture was filtered through Celiteand the filtrate was concentrated in vacuo, receiving the intermediate aniline in the form of a solid substance, which immediately dissolved in a mixture of 1:1 acetone/water, cooled to 0oC using baths with ice and treated with sodium bicarbonate (0,840 g, 10.0 mmol) and then benzyl-chloroformate (0,938 g, 0,785 ml, 5.5 mmol). The reaction mixture was allowed to mix overnight in an atmosphere of N2with the gradual warming of the cooling bath surrounding air. In sum, after 16 hours the practical phase is separated, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure, obtaining the crude oil. Chromatographytandem on silica gel with elution with a mixture of 9:1 hexane/ethyl acetate obtained after concentration of appropriate fractions 1.68 g (76%) of the named compound in the form of resin with MS (EI) 444 (M+).

Stage 4: (R)-[3-[-4-[3-[(tert-butyldimethylsilyl)oxy]-3-methyl - 1-azetidine]-3-forfinal]-2-oxo-5-oxazolidinyl]methanol

A solution of N-(carbobenzoxy)-4-[3-[(tert-butyldimethylsilyl)oxy] -3 - methyl-1-azetidine]-3-foronline (1.60 g, 3.8 mmol) in dry tetrahydrofuran (20 ml) in an atmosphere of N2cooled to -78oC using baths with a mixture of dry ice/acetone and treated with n-butyllithium (2,40 ml of 1.55 M solution in hexane, 3.8 mmol) via syringe. After 5 min at this temperature, add (R)-glycidyl butyrate (0,548 g, 0,538 ml, 3.8 mmol). At the end of the addition the cooling bath removed and the reaction mixture allowed to warm to ambient temperature in an atmosphere of N2. After 2 h at this temperature, TLC analysis (2:1 hexane/ethyl acetate) showed that the original Cbz derivative spent. The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate, washed with water what cromatografierea on silica gel with elution 30% ethyl acetate/dichloromethane obtained after concentration of appropriate fractions 1.10 g (71%) of these 5-(hydroxymethyl)oxazolidinone in the form of a white solid with so pl. 143,5-144,5oC and MS (EI) 410 (M+).

Stage 5: (R)-[[3-[4-[3-[(tert-butyldimethylsilyl) oxy]-3-methyl-1-azetidine]-3-forfinal]-2-oxo-5-oxazolidinyl] methyl]methanesulfonate

A solution of (R)-[3-[4-[3-[(tert-butyldimethylsilyl)oxy] -3-methyl - 1-azetidine] -3-forfinal] -2-oxo-5-oxazolidinyl]methanol (1,00 g, 2,43 mmol) in dry dichloromethane (15 ml), cooled to 0oC in a bath with ice, and treated with triethylamine (0,295 g 0,406 ml of 2.92 mmol) and then methanesulfonyl chloride (0,321 g, 0,217 ml, 2,80 mmol) in an atmosphere of N2. After 2 h at 0oC according to TLC analysis (5% methanol/chloroform), the reaction is finished. The reaction mixture was transferred into a separating funnel together with additional dichloromethane (75 ml). The organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining of 1.03 g (94%) of the titled compound as white solids with so pl. 113-115oC and MS (EI) 488 (M+).

Stage 6: (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy] -3-methyl-1-azetidine]-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]azide

A solution of (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)hydroxy-3-methyl-1-azetidine] -3-forfee N2treated with sodium azide (0,273 g, 4.2 mmol) at ambient temperature. The reaction mixture is heated to 70oC for 3 h and then cooled to room temperature. TLC analysis (5% methanol/chloroform) to this time shows that the reaction was completed. The solvent is removed in vacuum and the residue is transferred in dichloromethane (100 ml) and water. The organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuo, getting 0,820 g (90%) of the titled compound as white solids with so pl. 127-128oC and MS (EI) 435 (M+).

Stage 7: (S)-N-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-3 - methyl-1-azetidine]-3-forfinal-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy] - 3-methyl-1-azetidine]-3-forfinal]-2-oxo-5-oxazolidinyl]methyl] - azide (0,750 g, 1,72 mmol) in ethyl acetate (20 ml) Tegaserod, repeating the evacuation and filling of the N2. Then the solution is treated with 10% palladium/carbon (0.075 g) in a stream of nitrogen. Then the atmosphere replace H2(balloons), repeating the evacuation and filling, and the reaction mixture stirred at ambient temperature. After 6 hours, according to TLC analysis (5% methanol/chloroform), the reaction is finished. The reaction to shift the Hom dichloromethane (10 ml), cooled with a bath of ice and treated with pyridine (0,680 g, 0,696 ml, 8.60 mmol) and acetic anhydride (to 0.263 g, 0,243 ml, 2.58 mmol). The cooling bath removed and the reaction mixture stirred at ambient temperature in an atmosphere of N2. After 3 h the reaction mixture was transferred into a separating funnel with dichloromethane (100 ml). The mixture is washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Radial chromatography on silica gel with elution 3% and then 5% methanol/chloroform, gives, after concentration of appropriate fractions 0,643 g (83%) of the titled compound as white solids with so pl. 137-138oC and MS (EI) 451 (M+).

Step 8: (S)-N-[(3-[3-fluoro-4-(3-hydroxy-3-methyl-1-azetidine) phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (S)-N-[[3-[4-[3-[(tert-butyldimethylsilyl) oxy]-3-methyl-1-azetidine] -3-forfinal] -2-oxo-5-oxazolidinyl]methyl] ndimethylacetamide (0,550 g, 1,22 mmol) in acetonitrile 20 ml) in a polypropylene flask is treated with 40% aqueous hydrofluoric acid (5 ml) at ambient temperature. According to TLC analysis (5% methanol/chloroform) removing the protection savta dichloromethane (150 ml). Stir the mixture was carefully treated with saturated aqueous sodium bicarbonate (300 ml gas). After cessation of gas evolution, the mixture is transferred into a separating funnel and the phases are separated. The aqueous phase is neutralized to pH 7 by adding 6 N hydrochloric acid and extracted with dichloromethane. The combined organic extracts dried over sodium sulfate, filtered and concentrated in vacuo. Radial chromatography on silica gel with elution with 5% methanol/chloroform gives, after concentration of appropriate fractions 0,374 g (91%) of the named oxazolidinone-antibacterial agent in the form of a white solid with so pl. 152-153oC and MS (EI) 337 (M+).

Examples of pyrrolidine-phenyloxazolidine

Example 8: (S)-N-[[3-[4-(1-Aza-5,5-dimethyl-4,6-dioxabicyclo [3.3.0]Octan-1-yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

3-Fluoro-1-nitro-4-(2,5-dihydropyrrol)benzene

A solution of 2.30 g (14,47 mmol) of 2,4-dinitrofluorobenzene and 5,04 (28,93 mmol) Doonbeg potassium phosphate in 30 ml of DMSO is treated with 1.0 g (14,47 mmol) 3-pyrroline, and then heated at 60oC for 24 hours the Solution is cooled and diluted with 100 ml of chloroform and then extracted with water (5 x 75 ml). Drying (Na2SO4oC.

3-Fluoro-1-nitro-4-(CIS-3,4-dihydroxypyrrolidine)benzene

A solution of 1.25 g (of 6.02 mmol) of the previous compound and 881 mg (7,52 mmol) N-metalforming N-oxide in 60 ml of acetone and 13 ml of water is treated with 4 ml of 2.5% solution of phosphorus tetroxide in tert-butyl alcohol, followed by stirring at ambient temperature for 24 hours of a Solution of 500 mg of sodium bisulfite, 2 g of Magnesol (magnesol) and 10 ml of water is added with stirring for 20 minutes the Mixture is filtered through celite, wash the precipitate on the filter with acetone. The filtrate was concentrated in vacuo and diluted with 100 ml ethyl acetate and 150 ml of water. The aqueous layer was extracted with ethyl acetate (3 x 100 ml) and the combined organic layers are dried (Na2SO4) and concentrated in vacuo, receiving a yellow solid. This substance is recrystallized from a hot mixture of acetone-hexane, obtaining of 1.33 g (91%) of the named compound as a yellow solid, so pl. 151-153oC.

1-(1-Aza-5,5-dimethyl-4,6-dioxabicyclo[3.3.0]Octan-1-yl)-2-fluoro - 4-nitrobenzene (3)

A solution of 1.27 g (5,24 mmol) previous diol in 10 ml of dimethylformamide is treated 1,09 g (1.3 ml, 10,49 mmol) of 2,2-dimethoxypropane and and W is H. The solution was diluted with 50 ml of chloroform and extracted with water (5 x 30 ml). Drying (Na2SO4) and concentration in vacuo gives 1.45 g (98%) of the named compound as a yellow solid, sufficiently pure for further use. An analytical sample obtained by recrystallization from a hot mixture of acetone-hexane, so pl. 113-114oC.

1-(1-Aza-5,5-dimethyl-4,6-dioxabicyclo[3.3.0]Octan-1-yl)-2- (phenylmethanesulfonyl)aminobenzoyl

A solution of 1.45 g (5,14 mmol) of the previous compound in 50 ml of tetrahydrofuran is treated with 260 mg of 10% palladium-on-charcoal, and then hydronaut at one atmosphere for 3 hours, the Reaction vessel is rinsed with nitrogen and treated with 20 ml saturated sodium bicarbonate solution and then cooled to 0oC and the addition of 1.75 g (1,47 ml, 10,27 mmol) of benzyl chloroformate. The solution was stirred at 0oC for 30 min followed by warming to ambient temperature for 18 hours the Mixture is diluted with 50 ml ethyl acetate and 50 ml of water and filtered through celite, washing the filter cake with ethyl acetate. The filtrate is separated and the organic phase is extracted with 50 ml of water and 50 ml saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo gives Toluca 1.56 g (79%) of the named compound as fine white crystals.1H NMR (CDCl3) 7,39, 7,25, 6,93, 6,67, 5,19, 4,80, 3,73, 2,97, 1,53, 1,37.

(R)-[3-[4-(1-Aza-5,5-dimethyl-4,6-dioxabicyclo[3.3.0]Octan-1 - yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methanol (5)

A solution of 1.36 g (3,52 mmol) Cbz derivative of the previous compound in 48 ml of tetrahydrofuran at -78oC handle, adding dropwise, to 2.41 ml (1.6 M, a 3.87 mmol) n-utility in hexane, followed by stirring at -78oC for 30 minutes Then a solution process 558 mg (0,55 ml, a 3.87 mmol) of pure (R)-(+)-glycidyl of butyrate, and then heated to 0oC for 30 min and then at ambient temperature for 18 hours Then the solution is cooled to 0oC and treated with 4 ml saturated aqueous ammonium chloride and then diluted with 200 ml dichloromethane and extracted with water (2 x 50 ml) and a saturated solution of ammonium chloride (50 ml). Drying (Na2SO4) and concentration in vacuo gives a brown solid, which chromatographic 80 g of 230-400 mesh mesh silica gel, elwira 2% (vol./about.) methanol in dichloromethane. These operations give 840 mg of the above compound in the form of a whitish solid. 1H NMR (CDCl3) : 7,34, 7,06, 6,71, 4,80, 4,75, 4,01, 3,73, 3,67, 3,56, 2,95, 1,50, 1,36.

(S)-[[3-[4-(1-Aza-5,5-dimethyl-4,6-dioxabicyclo[3.3.0] Octan-1 - yl)-3-FPO is ml, of 2.81 mmol) of triethylamine in 11 ml of dichloromethane at 0oC handle 296 mg (0,20 ml, 2.58 mmol) methanesulfonyl chloride, and then stirred at 0oC for 30 minutes the Mixture is heated to ambient temperature and diluted with 75 ml of dichloromethane, followed by extraction with water (2 x 30 ml) and saturated sodium bicarbonate solution (30 ml). Drying (Na2SO4) and concentration in vacuo gives 810 mg (84%) of these nelfinavir in the form of a whitish solid, sufficiently pure for further use.1H NMR (CDCl3) : 7,36, 7,07, 6,73, 4,90, 4,82, 4,48, 4,41, 4,10, 3,89, 3,77, 3,10, 3,02, 1,51, 1,37.

(S)-N-[[3-[4-(1-Aza-5,5-dimethyl-4,6-dioxabicyclo[3.3.0] Octan-1 - yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of 810 mg (1.88 mmol) of the previous nelfinavir in 8 ml of a mixture of 1:1 tetrahydrofuran-isopropyl alcohol and re-pressurized thick-walled ampoule treated with 8 ml of ammonium hydrochloride. The vial sealed and heated at 100oC for 22 hours, the Ampoule is cooled, and the reaction mixture is distributed between chloroform and water. The organic layer is dried (Na2SO4) and concentrated in vacuo, getting 520 mg of a yellowish-brown solid, which is used dissolved in 2 ml of peridiniales environment for 18 PM The solution was diluted with chloroform (20 ml) and extracted with water (4 x 20 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo and the resulting solid is recrystallized from a mixture of chloroform/hexane, receiving 350 mg (59%) of these ndimethylacetamide in the form of white needles, so pl. 195-7oC.

Example 9: (S)-N-[[3-[4-(3,4-CIS-dihydroxypyrrolidine)-3 - forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (9)

A solution of 249 mg (0,63 mmol) of the compound obtained in Example 8, in 2 ml of tetrahydrofuran is treated with 2 ml of 2 N hydrochloric acid, then stirred at ambient temperature for 18 hours the Mixture was concentrated in vacuo and the residue is treated with 30 ml saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate (2 x 50 ml), dried (Na2SO4) and concentrated in vacuo, receiving 110 mg whitish solid.

This substance is subjected to radial chromatography on a 2 mm chromatotron plate, elwira 7% (vol./about.) methanol in dichloromethane. These operations give 60 mg (28%) mentioned diol as a white solid, so pl. 183-189oC (decomposes).

Example 10: (S)-N-[[3-[4-(3-hydroxypyrrolidine)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]acetasol (3.0 g) in dimethylformamide (30 ml) is added sodium carbonate (3.94 g). The mixture is stirred at room temperature overnight and then filtered, followed by washing with dichloromethane. The combined filtrate is concentrated under reduced pressure. The obtained residue chromatographic on a column of silica gel with a mixture of ethyl acetate/hexane with increasing content of ethyl acetate (50 to 60%). The appropriate fractions are combined and concentrated under reduced pressure, obtaining the titled compound (4.83 g);1H NMR (CD3OD, 270 MHz): 0,85 (2H, m), of 2.25 and 2.7 (4H, m), 3,26 (1H, m), vs. 5.47 (1H, t, J = 8.6 Hz), 6,62 (1H, DD, J= 2,4, of 14.0 Hz), 6,69 (1H, DD, J = 2,4, 8.6 Hz).

3-Fluoro-4-[3-(tert-butyldimethylsilyloxy)pyrrolidinyl]nitrobenzene

A mixture of the previous compound (4.83 g), triethylamine (9.5 ml) and dimethylaminopyridine (2,79 g) in tetrahydrofuran (100 ml) is treated with tert-butyldimethylsilyl chloride (5,15 g) at 0oC and stirred at room temperature for 2 days. The mixture is filtered and the insoluble matter is washed with dichloromethane. The combined filtrate was washed with brine, dried over sodium sulfate and concentrate under reduced pressure. The obtained residue chromatographic on a column of silica gel, elwira a mixture of ethyl acetate/hexane (70/30). The appropriate fractions are combined and koncentrere (2H, m), 3,42-of 3.78 (4H, m) to 4.52 (1H, m), 6,53 (1H, t, J= 8,9 Hz), 7,87 (1H, DD, J = 2,4, of 14.0 Hz), 7,94 (1H, DD, J = 2,4, 8,9 Hz).

3-Fluoro-4-[3-(tert-butyldimethylsilyloxy)pyrrolidinyl]aniline

Palladium-on-coal (10%, 500 mg) is added to a mixture of the previous compound (5.0 g) in a mixed solvent of dichloromethane (20 ml) and methanol (100 ml). The mixture is stirred under 1 atmosphere of hydrogen for 6 h, then filtered and palladium-on-coal washed with methanol and dichloromethane. The combined filtrates are concentrated under reduced pressure, obtaining the titled compound (4.52 g);1H NMR (CDCl3) : of 0.08 (6H, s) to 0.88 (9H, s) to 1.87 (1H, m), 2,11 (1H, m), 3,05 (1H, m), 3,29 (2H, m), of 3.56 (1H, m), 4,48 (1H, m), 6,38 (1H, DD, J = 2,4, and 8.9 Hz), 6,44 (1H, DD, J = 2,4, of 14.0 Hz), is 6.61 (1H, t, J = 8,9 Hz).

1 Benzyloxycarbonylamino-4-[3-(tert-butyldimethylsilyloxy) pyrrolidinyl]-3-torbenson

Benzyl chloroformate (3.0 ml) is added to a mixture of the previous compound (4.52 g) and sodium bicarbonate (1,76 g) in tetrahydrofuran (50 ml) at 0oC. the Mixture is stirred at room temperature overnight and then filtered, followed by washing with tetrahydrofuran. The combined filtrates are dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is subjected to a processing on a column of silica gel, elwira Huck the cell connection (4,40 g);1H NMR (CDCl3) / : of 0.08 (6H, s) to 0.88 (9H, s) to 1.87 (1H, m), 2,11 (1H, m), 3,05 (1H, m), 3,29 (2H, m), of 3.56 (1H, m), 4,48 (1H, m), is 5.18 (2H, s), 6,59 (1H, t, J = 8,9 Hz), to 6.88 (1H, DD, J = 2,4, and 8.9 Hz), 7,10 (1H, DD, J = 2,4, of 14.0 Hz), was 7.36 (5H, m).

(S)-[[3-[4-[3-(tert-butyldimethylsilyloxy)pyrrolidinyl] -3 - forfinal]] -2-oxo-5-oxazolidinyl]methanol

The solution of the previous compound (4,40 g) in dry tetrahydrofuran (50 ml) cooled to -78oC in nitrogen and treated with 7.3 ml (1.6 M in hexane) of n-BuLi under stirring for 5 minutes the Mixture was treated with 1.65 ml (R)-(+)-glycidyl of butyrate and allow it to slowly warm to room temperature over night. The reaction is quenched by adding a saturated solution of ammonium sulfate (10 ml) and the mixture extracted with dichloromethane (3 x 50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and concentrate under reduced pressure. The obtained residue chromatographic on a column of silica gel, elwira a mixture of hexane/ethyl acetate with increasing content of ethyl acetate (50 to 70%). The appropriate fractions are combined and concentrated under reduced pressure, obtaining the titled compound (1.44 g); 1H NMR (CDCl3) : of 0.08 (6H, s) to 0.88 (9H, s), 1,91 is 2.10 (2H, m), 3,18 (1H, m), 3,39-of 3.48 (2H, m), 3,63 (1H, m), of 3.78 (1H, m), a 3.87-4,01 (3H, m), 4,48 (1H, m), of 4.66 (1H, m), 6,63 (1H, t, J=0 9.5 Hz), ? 7.04 baby mortality (12-oxo-5-oxazolidinyl]methyl]methanesulfonate

To a solution of the previous compound (1.44 g) in pyridine (10 ml) is added under stirring p-toluensulfonyl chloride (0.88 g) at 0oC. the Mixture is stirred at room temperature overnight. Slowly to the mixture with stirring, water (40 ml) and the mixture is additionally stirred for 1 h, the receiving crystals. The crystals are collected by filtration, washed with water and dried at 40oC under reduced pressure overnight, getting a named connection (1,96 g);1H NMR (CDCl3) : 0,09 (6H, s) to 0.88 (9H, s), 1,90-of 2.08 (2H, m), the 2.46 (3H, s), 3,21 (1H, m), 3,40-to 3.49 (2H, m), the 3.65 (1H, m), 3,81 (1H, DD, J = 5,9, and 8.9 Hz), a 4.03 (1H, t, J=8,9 Hz), 4,24 (2H, m), of 4.49 (1H, m), 4,80 (1H, m), 6,63 (1H, t, J=9.5 Hz), of 6.96 (1H, DD, J =2,4, 9.5 Hz), 7.23 percent (1H, DD, J=2,4,, 14.6 Hz), was 7.36 (2H, d, J=7.8 Hz), 7,79 (2H, d, J= 7,8 Hz).

(S)-N-[[3-[4-[3-(tert-butyldimethylsilyloxy)pyrrolidinyl] -3 - forfinal] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A mixture of the previous compound (1,96 g) in dimethylformamide (20 ml) is treated with sodium azide (455 mg) and heated at 60oC during the night. After cooling to room temperature the mixture is filtered and the precipitate washed with dichloromethane. The combined filtrates are concentrated under reduced pressure. The obtained residue chromatographic on a column of silica gel, elwira a mixture of hexane/Aceto. actor of this compound in dry tetrahydrofuran (20 ml) is treated with triphenylphosphine (868 mg) and stirred at room temperature for 2 hours the Mixture is treated with water (0.5 ml) and stirred at 40oC for 4 h, then at room temperature overnight. The mixture is concentrated under reduced pressure and dried by azeotropic distillation with toluene. The resulting residue is suspended in dichloromethane (20 ml) and treated with pyridine (0.5 ml) and acetic anhydride (0.6 ml) at 0oC. the Mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue is subjected to processing on a column of silica gel, elwira a mixture of methanol/dichloromethane with increasing methanol content (1% to 3%). The appropriate fractions are combined and concentrated under reduced pressure, obtaining a named connection (1,502 g);1H NMR (CDCl3) : of 0.08 (6H, s) to 0.88 (9H, s), 1,89-of 2.09 (2H, m), 2,02 (3H, s) 3,18 (1H, m), 3,36-to 3.67 (6H, m) 3,71 (1H, DD, J= 6,8, and 8.9 Hz), 3,99 (1H, t, J= 8,9 Hz), 4,48 (1H, m), was 4.76 (1H, m), of 6.20 (1H, broad, NH), of 6.61 (1H, t, J = 9,2 Hz), 6,98 (1H, DD, J =2,4, 9,2 Hz), 7,30 (1H, DD, J = 2,4, and 15.1 Hz).

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

A mixture of the previous compound (1.50 g) in dry tetrahydroindole to warm to room temperature while stirring for 4 hours The mixture is treated with water (50 ml) and extracted with dichloromethane (30 ml x 4). The combined organic layer was washed with brine, dried over sodium sulfate and concentrate under reduced pressure. The residue is subjected to processing on a column of silica gel, elwira a mixture of acetone/hexane (80/20). The appropriate fractions are combined and concentrated under reduced pressure, obtaining a named connection (0,77 g);1H NMR (DMSO-d6) : 1,78 is 2.00 (2H, m), of 1.80 (3H, s), of 3.12 (1H, m), 3,26-of 3.54 (5H, m) to 3.67 (1H, DD, J = 6,8, and 8.9 Hz), Android 4.04 (1H, t, J = 8,9 Hz), 4,34 (1H, m), and 4.68 (1H, m), 4,91 (1H, d, J = 4,1, OH), 6,72 (1H, t, J= 9.7 Hz), 7,07 (1H, DD, J = 2,4, 9.7 Hz), 7,38 (1H, DD, J = 2,4, 16.2 Hz), 8,23 (1H, t, J = 5.7 Hz, NH).

Example 11: (S)-N-((3-(3-fluoro-4-(3-oxopyrrolidin)phenyl)-2 - oxo-5-oxazolidinyl)methyl)ndimethylacetamide

7-Benzyl-7-Aza-1,4-dioxaspiro(4,5)nonan

To a suspension of 1-N-benzyl-3-pyrrolidinone (1.92 g) and ethylene glycol (for 6.81 g) in benzene (70 ml) is added monohydrate p-toluenesulfonic acid (1,93 g). The mixture is boiled with azeotropic removal of water using traps Dean-stark (Dean-Stark) for 6 hours After cooling to room temperature the mixture was washed with saturated aqueous sodium bicarbonate (50 ml x 3). Then the aqueous layer was extracted with dichloromethane (30 ml x 3). The organic layers are combined, washed with brine, dried over l3) : to 2.06 (2H, t, J = 7,3 Hz) of 2.64 (2H, s) to 2.66 (2H, t, J = 7,3 Hz), 3,61 (2H, s) to 3.89 (4H, m), 7,28 (5H, m).

7-Aza-1,4-dioxaspiro(4,5)nonan

The palladium hydroxide-on-coal (20%, 200 mg) are added to a solution of the previous compound (1,57 g) in a mixed solvent of dichloromethane (10 ml) and methanol (20 ml). The mixture is stirred under a pressure of 3 kgf/cm2hydrogen for 2 days, then filtered and palladium hydroxide-on-coal washed with methanol and dichloromethane. The combined filtrate is concentrated under reduced pressure, obtaining a named connection (1,38 g);1H NMR (CDCl3) : 2,17 (2H, t, J=7,3 Hz), the 3.35 (2H, s), 3,52 (2H, t, J=7,3 Hz) to 3.99 (4H, s).

4-(7-Aza-1,4-dioxaspiro(4,5)nonan-7-yl)-3-fluoro-nitrobenzene

Following the General method of Example 9 and making minor changes, except that used as the starting material a previous connection (1,38 g) get the named compound (1.50 g),1H NMR (CDCl3) : to 2.18 (2H, t, J = 7,3 Hz) to 3.67 (2H, s), and 3.72 (2H, t, J=7,3 Hz), was 4.02 (4H, s), 6,53 (1H, t, J=7,3 Hz), 7,88 (1H, DD, J=2,4, of 14.0 Hz), 7,94 (1H, DD, J= 2,4, 8,9 Hz).

4-(7-Aza-1,4-dioxaspiro(4,5)nonan-7-yl)-3-fluoro-1- (formatactionname)-benzene

Following the General method of Example 9 and making minor changes, except that used as ihadnt, J= 6,8 Hz) to 3.41 (2H, t, J = 6.8 Hz), of 3.46 (2H, s), 3,98 (4H, s), is 5.18 (2H, s), 6,60 (1H, t, J=9,2 Hz), 6,91 (1H, DD, J =2,4 9,2 Hz), 7,22 (1H, DD, J =2,4, of 14.0 Hz), 7,37 (5H, m).

(R)-(3-(3-fluoro-4-(7-Aza-1,4-dioxaspiro(4,5)nonan-7-yl)phenyl) -2-oxo-5-oxazolidinyl)methanol

The solution of the previous compound (2,44 g) in dry dimethylformamide (25 ml) cooled to -78oC in nitrogen and treated with 6.6 ml (1.0 M in tetrahydrofuran) lithium bis(trimethylsilyl)amide under stirring for 5 minutes the Mixture is treated with 0.93 ml (R)-(-)-glycidyl of butyrate and slowly warmed to room temperature over night. A slight excess of lithium bis(trimethylsilyl)amide quenched by adding water (5 ml). The mixture is concentrated under reduced pressure and dried via azeotropic distillation with toluene. The residue is suspended in dichloromethane (100 ml) and the insoluble matter is removed by filtration. The filtrate is concentrated under reduced pressure and the resulting residue is subjected to a processing on a column of silica gel, elwira a mixture of hexane/acetone (50/50). The appropriate fractions are combined and concentrated under reduced pressure, obtaining a named connection (1,79 g);1H NMR (DMSO-d6) : 2,07 (2H, t, J = 7,3 Hz), the 3.35 (4H, overlapped signals, caused by solvent), 3,50 at 3.69 (2H, m), of 3.78 (1H, DD, J=7,3, 9.2 Grams the ptx2">

(R)-N-((3-(3-fluoro-4-(7-Aza-1,4-dioxaspiro(4,5)nonan-7-yl)phenyl) -2-oxo-5-oxazolidinyl)methyl)azide

Following the General method of Example 9 and making minor changes, except that used as the starting material of the previous compound (1.78 g), get a named connection (1,76 g),1H NMR (CDCl3) : and 2.14 (2H, t, J= 7,3 Hz), 2,44 (3H, s), of 3.45 (2H, t, J= 7,3 Hz), 3,49 (2H, s), of 3.73 is 4.13 (2H, m), 3,98 (4H, s), 4,24 (2H, m), 4,80 (1H, m), 6,60 (1H, t, J= 9.5 Hz), of 6.96 (1H, DD, J=2,4, 9.5 Hz), 7.23 percent (1H, DD, J=2,4,, 14.6 Hz), was 7.36 (2H, d, J=7.8 Hz), 7,78 (2H, d, J=7,8 Hz).

(R)-N-((3-(3-fluoro-4-(7-Aza-1,4-dioxaspiro(4,5)nonan-7-yl)phenyl) -2-oxo-5-oxazolidinyl)methyl)ndimethylacetamide

Following the General method of Example 9 and making minor changes, except that Lindlar catalyst (150 mg) were then added to the mixture of the previous compound (17) (1.45 g) in a mixed solvent of dichloromethane (10 ml) and methanol (40 ml). The mixture is stirred under atmospheric pressure of hydrogen for 2 days, then filtered and the catalyst washed with methanol and dichloromethane. The combined filtrate is concentrated under reduced pressure. The resulting residue is suspended in dichloromethane (20 ml) and treated with pyridine (0.3 ml) and acetic anhydride (0.7 ml) at 0oC. the Mixture is stirred at room temperature telewire a mixture of methanol/dichloromethane with increasing methanol content (2 to 5%). The appropriate fractions are combined and concentrated under reduced pressure, obtaining a named connection (0,72 g);1H NMR (CDCl3) : a 2.01 (3H, s) of 2.16 (2H, t, J=7,3 Hz), of 3.43 (2H, t, J=7,3 Hz), 3,47 (2H, s), 3,53-to 3.67 (2H, m), 3,71 (1H, DD, J=6,8, and 9.2 Hz), 3,98 (5H, m), and 4.75 (1H, m), 6,27 (1H, broad), of 6.61 (1H, t, J=9,2 Hz), of 6.99 (1H, DD, J=2,4, 9,2 Hz), 7,33 (1H, DD, J= 2,4, and 15.1 Hz).

(S)-N-((3-(3-fluoro-4-oxopyrrolidin)phenyl)-2-oxo-5-oxazolidinyl) methyl)ndimethylacetamide

A mixture of the previous compound (610 mg) in acetone (12 ml) and water (3,7 ml) is treated with monohydrate p-toluenesulfonic acid (609 mg) and refluxed for 3 hours After cooling to room temperature the mixture is concentrated under reduced pressure. The residue is treated with 5 ml of triethylamine and extracted with dichloromethane (30 ml x 5). The organic layers are combined, washed with brine, dried over sodium sulfate and concentrate under reduced pressure. The residue is subjected to processing on a column of silica gel, elwira a mixture of hexane/acetone (50/50). The appropriate fractions are combined and concentrated under reduced pressure, obtaining the titled compound (390 mg);1H NMR (CDCl3) : 2,03 (3H, s) to 2.65 (2H, t, J=6.8 Hz), 3,47-of 3.78 (7H, m), was 4.02 (1H, t, J = 8,9 Hz), was 4.76 (1H, m), 6,18 (1H, t, J=5,9 Hz, NH), 6,77 (1H, t, J=9,2 Hz), to 7.09 (1H, DD, J= 2,4, 9,2 Hz), the 7.43 (1H, DD, J=2,4, a 15.1 G is Teal)ndimethylacetamide

Stage 1: 3-Fluoro-1-nitro-4-(3-triptoreline)- pyrrolidineethanol

A solution of 4.49 g (20,54 mmol) 3-(triptorelin)-pyrrolidine hydrochloride and of 2.97 g (18,68 mmol) of 3,4-deformirovannoe 7,16 and g (41,10 mmol) Doonbeg potassium phosphate in 87 ml of DMSO is heated at 90oC for 18 hours the Mixture is cooled and diluted with 300 ml of ethyl acetate. The solution is extracted with water (5 x 100 ml) and dried (Na2SO4). Concentration in vacuo gives a yellow solid which is recrystallized from a hot mixture of ethyl acetate-hexane, receiving 5.0 g (84%) of the named product as a yellow crystalline solid, so pl. 165-167oC.

Stage 2: 3-Fluoro-1-(phenylmethanesulfonyl)amino-4- (3-triptoreline)pyrrolidineethanol

A solution of 4.10 g (of 12.76 mmol) of nitro compounds in 100 ml of ethyl acetate is treated with 500 mg of 10% palladium-on-coal, followed by hydrogenation at atmospheric pressure for 4 hours. The mixture is filtered through celite, washing the filter cake with ethyl acetate. The filtrate was concentrated in vacuo and the residue is dissolved in 50 ml of acetone and treated with 75 ml of a saturated solution of NaHCO3followed by cooling to 0oC and processing 4,36 g (of 3.64 ml, 25,53 mmol) of benzyl chloroformate. Then the solution is heated is) followed by drying (Na2SO4). Concentration in vacuo gives a beige solid, which is recrystallized from a hot mixture of ethyl acetate-hexane, getting to 4.41 g (81%) of these Cbz derivative in the form of pale beige needles, so pl. 143-145oC.

Stage 3: 3-Fluoro-1-(phenylmethanesulfonyl)amino-4-(3-(1,3 - dimethylhexane-2-oxo-1,3,5-triazine-5-yl)pyrrolidinyl)benzene

A solution of 1.86 g (4,37 mmol) Cbz derivative in 36 ml of THF is treated with 50 ml of 2 N NaOH, followed by boiling under reflux for 36 hours the Solution is cooled and diluted with 50 ml of water followed by extraction with ethyl acetate (4 x 75 ml). The combined organic layers extracted with saturated NaCl solution, followed by drying (Na2SO4) and concentration in vacuo. The resulting oil is amber in color, dissolved in 20 ml of dioxane and 40 ml of toluene and the resulting solution treated with 385 mg (4,37 mmol) N,N'-dimethyloxetane and 5 ml of 37% aqueous formaldehyde solution. The mixture is heated at the boiling temperature of phlegmy up until approx. 5 ml of water is collected in the trap Dean-stark. The solution is cooled and concentrated in vacuo. The remainder chromatographic 180 g of 230-400 mesh mesh silica gel, elwira 2% (vol./about.) methanol in dichloromethane. These operations give 1.40 g (73%) named the hydro-2-oxo-1,3,5 - triazine-5-yl)pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl)methanol

A solution of 737 mg (1,67 mmol) of treason in 10 ml of DMF at -50oC handle of 1.84 ml (1,84 mmol) lithium hexamethyldisilazide in THF. The solution is stirred at -50oC for 5 min, then add 265 mg (0.26 per ml, of 1.84 mmol) of (R)-(+)-glycidyl of butyrate. Then the solution is heated to ambient temperature for 18 hours the Mixture was concentrated in vacuo (0.3 mm Hg) and the residue chromatographic 36 g of 230-400 mesh mesh silica gel, elwira 3% (vol./about.) methanol in dichloromethane. These operations give 400 mg (59%) of the named product as a white solid.1H NMR (CDCl3) : 7,36, 7,05, 6,65, 4,72, 4,27, 4,18, 3,95, 3,77, 3,46, 2,88, 2,17, 1,94.

Stage 5: (R)-(3-(3-Fluoro-4-(3-(1,3-dimethylhexane-2-oxo-1,3,5-triazine-5-yl)pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl) methanesulfonate

A solution of 395 mg (0.97 mmol) of oxazolidinone and 146 mg (0,20 ml of 1.45 mmol) of triethylamine in 5 ml dichloromethane at 0oC handle 471 mg (0,32 ml) methanesulfonyl chloride. The solution was stirred at 0oC for 30 min followed by warming to ambient temperature. The solution is treated with water and the aqueous layer was extracted with dichloromethane. The combined organic layers are dried (Na2SO4) and concentrated in vacuo, getting 460 mg (98%) of the named product as be, 4,12, 3,89, 3,76, 3,55, 3,47, 3,38, 3,10, 2,88, 2,16, 2,08, 1,92.

Stage 6: (S)-N-((3-(3-Fluoro-4-(3-(formatexception)- pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)ndimethylacetamide

A solution of 460 mg (0.97 mmol) of nelfinavir in 15 ml of isopropyl alcohol and 15 ml of ammonium hydroxide in a sealed tube heated at 100oC for 18 hours the Mixture is cooled and diluted with water followed by extraction with chloroform. The organic layer is dried (Na2SO4) and concentrated in vacuo. The residue is dissolved in 4 ml of pyridine and treated with 0.5 ml acetic anhydride, followed by stirring at ambient temperature for 18 hours the Mixture was concentrated in vacuo, obtaining oil, which is dissolved in chloroform and extracted with water. The organic layer is dried (Na2SO4) and concentrated in vacuo, getting 472 mg derived ndimethylacetamide, which is directly dissolved in 4 ml of 1N HCl solution, followed by stirring at ambient temperature for 18 hours. The mixture was concentrated in vacuo and dissolved in 4 ml acetone and treated with 2 ml of a saturated solution of NaHCO3with the subsequent processing of 217 mg (about 0.14 ml, 1.18 mmol) benzyloxyethyl chloride, followed by stirring at the temperature of environment is irua a mixture of 2% (vol./about.) methanol in dichloromethane and then with 3% (vol./about.) methanol in dichloromethane. These operations give 189 mg (40%) of product - derived benzyloxyacetaldehyde in the form of a white solid.1H NMR (CDCl3) : 7,33, 7,02, 6,81, 6,68, 6,08, 4,75, 4,60, 4,01, 3,71, 3,61, 3,34, 2,32, 2,02, 1,91.

Example 13: (S)-N-((3-(3-Fluoro-4-(3-(hydroxyacetylamino) pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)ndimethylacetamide

Continuing the procedure of Example 12, stage 6, a solution of 189 g (0,39 mmol) benzyloxyacetaldehyde in 5 ml methanol and 5 ml of THF is treated with 200 mg of 10% palladium-on-coal, followed by hydrogenation at atmospheric pressure for 1 h the Solution was diluted with methanol and filtered through celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo, obtaining oil, which chromatographic on 10 g of 230-400 mesh mesh silica gel, elwira a mixture of 7% (about. /about.) methanol in dichloromethane. These operations give 95 mg (62%) of product-derived hydroxyacetamido in the form of a pink solid.1H NMR (CDCl3) : 7,41, 7,10, 6,78, 4,77, 4,53, 4,10, 4,00, 3,77, 3,57, 3,32, 2,30, 1,99, 1,98.

Example 14: (S)-N-[[3-Fluoro-4-(CIS-3-(methoxycarbonylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Step 1: CIS-3-(1,1-dimethylethylenediamine)-4 - methylpyrrolidine

A solution of 1.5 g (5.2 mmol) of CIS-1-phenylmethyl-3- (1,1-dimethylethylenediamine)-4-IU the ne atmosphere of H2within 3.5 hours the Mixture is filtered through celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo, obtaining a colorless oil which is used directly in the next stage. 1H NMR (CD3OD) : 4,85, 4,03, 3,14, 3,05, 2,66, 2,45, 2,23, 1,46, 0,95.

Stage 2: 3-Fluoro-1-nitro-4-[CIS-3-(1,1 - dimethylethylenediamine)-4-methylpyrrolidinyl]benzene

A solution of the previously obtained compound and 1.8 g (10.3 mmol) Doonbeg phosphate in 40 ml of DMSO is heated at 90oC for 18 hours the Mixture is cooled and diluted with 125 ml of ethyl acetate, then extracted with water (4 x 75 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo, obtaining of 1.75 g of yellow solid, sufficiently pure for further use. MS (EI) m/z 339 (M+), 339, 282, 266, 223, 222, 208, 207, 154, 70, 57.

Stage 3: 3-Fluoro-1-nitro-[CIS-3-(1,3-dimethylhexane-2-oxo - 1,3,5-triazine-5-yl)-4-methylpyrrolidinyl]benzene

A solution of 1.75 g (5.17 mmol) of the previous compound in 50 ml triperoxonane acid was stirred at ambient temperature for 18 hours the Solution was concentrated in vacuo and the resulting red-brown oil is dissolved in ethyl acetate and carefully extracted with a saturated solution of NaHCO3(4). Merge the center in a vacuum. The residue is dissolved in 90 ml of toluene and 45 ml of dioxane and treated with 1.12 g (12.7 mmol) of N, N'-dimethyloxetane and 35 ml of aqueous formaldehyde, and then refluxed for 2.5 hours. The mixture is cooled and concentrated in vacuo. The remainder chromatographic on 200 g of 230-400 mesh mesh silica gel with a mixture of 1-2% (about. /about.) methanol in chloroform. These operations yield of 3.65 g (86%) of the desired product as an oily yellow substance. MS (EI) m/z 351 (M+), 223, 222, 221, 208, 207, 182, 169, 154, 130, 113.

Stage 4: 3-Fluoro-1-(phenylmethanesulfonyl)amino-[CIS-3-(1,3 - dimethylhexane-2-oxo-1,3,5-triazine-5-yl)-4-methylpyrrolidinyl] benzene

The solution is 1.82 g (5.17 mol) in 200 ml THF is treated with 750 mg of 10% palladium-on-charcoal, and then hydronaut at a pressure of hydrogen of 3.16 kg/cm2(45 psi) for 3 hours the Mixture is cooled to -20oC, followed by adding 30 ml of a saturated solution of NaHCO3. The mixture is then treated with 1.10 g (0,92 ml, 6,46 mmol) of benzyl chloroformate, followed by warming to ambient temperature for 18 hours the Mixture is filtered through celite, washing the filter cake with methanol and dichloromethane. The filtrate was concentrated in vacuo and the residue is dissolved in dichloromethane and extracted with water (3 x 30 ml). Drying (Na2SO4) and conc is the ethanol in dichloromethane. These operations yield of 1.74 g (74%) of the named compound in the form of a froth.1H NMR (CDCl3) : 7,34, 6,92, 6,53, 5,18, 4,19, 4,13, 3,69, 3,58, 3,52, 3,41, 3,15, 2,86, 2,37, 1,05.

Stage 5: (R)-(3-(3-Fluoro-4-(CIS-3-(1,3-dimethylhexane-2-oxo - 1,3,5-triazine-5-yl)-4-methylpyrrolidinyl)phenyl)- 2-oxo-5-oxazolidinyl)methanol

A solution of 860 mg (1,89 mmol) of the previous compound in 25 ml of THF at -78oC is treated with 1.3 ml (2,08 mmol) n-utility in hexane, followed by warming to -50oC. After stirring at -50oC for 20 min add 286 mg (0.28 in ml, of 1.98 mmol) of (R)-(-)-glycidyl of butyrate. The mixture is heated to 0oC for 30 min and then to ambient temperature for 18 hours the Mixture was treated with saturated solution of NH4Cl and diluted with ethyl acetate and then extracted with water (3 x). The aqueous phase is extracted with ethyl acetate and the combined organic layers are dried (Na2SO4) and concentrated in vacuo, obtaining a brown oil. This substance chromatographic 40 g of 230-400 mesh mesh silica gel, elwira methanol in dichloromethane. These operations give 512 mg (64%) of the named compound as a white froth.1H NMR (CDCl3) : 7,35, 7,03, 6,60,4,72, 4,22, 4,14, 3,94, 3,75, 3,70, 3,60, 3,54, 3,43, 3,18, 2,87, 2,39, 1,05.

Stage 6: (R)-(3-(3-Fluoro-4-(CIS-3-(1,3-Dimen

A solution of 1 g (2,37 mmol) of the previous compound and 480 mg (0,66 ml, 4,74 mmol) of triethylamine in 15 ml dichloromethane at 0oC handle 407 mg (0.28 in ml, of 3.56 mmol) methanesulfonyl chloride. The solution was stirred at 0oC for 1.5 h followed by heating, diluted with dichloromethane and extracted with water (3 x). The organic layer is dried (Na2SO4) and concentrated in vacuo, obtaining a named connection.1H NMR (CDCl3: 7,45, 7,02, 6,92, 4,92, 4,50 (1H), 4,43, 4,23, 4,17, 3,91, 3,83, 3,65, 3,50, 3,29, 3,11, 2,89, 2,48, 1,12.

Stage 7: (S)-(N-((3-Fluoro-4-(CIS-3-(1,3-dimethyl-hexahydro-2 - oxo-1,3,5-triazine-5-yl)-4-methylpyrrolidinyl)phenyl)-2-oxo - 5-oxazolidinyl)methyl)ndimethylacetamide

The solution of the previous nelfinavir in 6 ml of THF and 6 ml of isopropyl alcohol and treated with 6 ml of concentrated ammonium hydroxide. The mixture is heated to 100oC in a sealed tube for 48 hours the Mixture is cooled and diluted with ethyl acetate and water. The mixture is extracted with ethyl acetate (2 x). The mixture is treated with saturated solution of NaCl and extracted with chloroform (3 x). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The residue is dissolved in 15 ml of pyridine and cooled to 0oC. the Solution is treated with 0.5 ml acetic anhydride with PEFC is omatography 75 g of 230-400 mesh mesh silica gel, elwira methanol in dichloromethane. These operations give 934 mg (85%) of the named compound as a white froth. MS (the Belarusian library Association, FAB) m/z 463 (M+H), 464, 463, 462, 461, 364, 363, 361, 333, 101, 44.

Step 8: (S)-(N)-((3-Fluoro-4-(CIS-3-amino-4-methyl-pyrrolidinyl) phenyl)-2-oxo-5-oxazolidinyl)methyl)ndimethylacetamide

A solution of 875 mg (1,89 mmol) of the previous compound in 5 ml of 2N HCl was stirred at ambient temperature for 20 h the Solution was concentrated in vacuo and the residue dried by azeotropic distillation with toluene. These operations give 662 mg (approx. 100%) of the titled compound in the form of froth amber color. MS (the Belarusian library Association) m/z 351 (M+H), 427, 352, 351, 350, 349, 255, 123, 101, 89, 44. VRMS(BAA) Rasch. for C17H23FN4O3+H1351, 1832, found 351, 1840.

Stage 9: (S)-N-[[3-Fluoro-4-(CIS-3-(methoxycarbonylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of 150 mg (0.43 mmol) of the previous compound in 6 ml of acetone and 3 ml of water is treated with 108 mg (1,29 mmol) and NaHCO3and cooled to 0oC. the Solution is then treated with 89 mg (73 μl, 0.95 mmol) of methyl chloroformate. The solution is then diluted with ethyl acetate and extracted with water (3 x). Drying (Na2SO4) and concentration in vacuo gives a white solid, which is perezii give 155 mg (53%) of the named compound as a white solid. MS (EI) m/z 408 (M+), 409, 408, 364, 334, 333, 318, 289, 276, 215, 56.

Example 15: (S)-N-[[3-Fluoro-4-(CIS-3-(hydroxyacetylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: (S)-N-[[3-Fluoro-4-(CIS-3-(formatexception)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of 300 mg (0.90 mmol) amine (Example 14, step 8) in 14 ml of acetone and 7 ml of water is treated 302 mg (of 3.60 mmol) and NaHCO3and cooled to 0oC. the Solution is then treated with 414 mg (0.35 ml, 2.25 mmol) benzyloxyethyl chloride, followed by warming to ambient temperature for 72 hours the Mixture is diluted with ethyl acetate and water and the organic layer extracted with water (3 x). The organic layer is dried (Na2SO4) and concentrated in vacuo, obtaining a brown oil. This substance chromatographic on 30 g of 230-400 mesh mesh silica gel, elwira methanol in dichloromethane. These operations give 132 mg (30%) of the named compound as a white solid.1H NMR (CDCl3) : 7,57, 7,36, 7,03, 5,98, 4,77, 4,67, 4,63, 4,04, 3,74, 3,70, 3,63, 3,55, 3,45, 3,38, 2,71, 2,03, 1,07.

Stage 2: (S)-N-[[3-Fluoro-4-(CIS-3-(hydroxyacetylamino)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of 107 mg (0.21 mmol) of the previous compound in 2572 PM The mixture is filtered through celite, and the filtrate was concentrated in vacuo. The residue is subjected to radial chromatography on a 2 mm chromatotron plate, elwira methanol in dichloromethane. These operations give 24 mg (8%) of the named compound as a light beige solid. MS (EI) m/z 408 (M+), 408, 334, 333, 318, 289, 215, 70, 57, 56, 55.

Example 16: (S)-N-[[3-Fluoro-4-(CIS-3-(methanesulfonamido)-4 - methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A suspension of 200 mg (or 0.57 mmol) amine (example 14, step 8) in 10 ml of dichloromethane is treated with 144 mg (0,20 ml of 1.43 mmol) of triethylamine followed by cooling the resulting solution to 0oC. the Mixture is treated with 83 mg (56 μl, 0.73 mmol) methanesulfonyl chloride followed by heating at ambient temperature for 18 hours the Mixture is diluted with 50 ml of ethyl acetate followed by extraction with water (3 x 30 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo, getting a whitish solid, which is subjected to radial chromatography on a 2 mm chromatotron plate, elwira methanol in dichloromethane. These operations give 11 mg (45%) of the named compound as a white solid. MS (EI) m/z 428 (M+), 429, 428, 384, 300, 280, 238, 236, 177, 70, 56.

represents H, OR7where R7is H, F, C1- C8-alkyl, NR8R9where R8and R9are C1- C8-alkyl which may be substituted by F; C1- C8-acyl which may be substituted by hydroxyl, C1- C8-alkoxy, benzoyl;

R2represents H, OH, OR where R is a C1- C6-alkyl;

R3represents H, C1- C3-alkyl;

R4is F;

R5represents C1- C8-alkyl which can be substituted one to three substituents selected from F, Cl; C3- C6-cycloalkyl;

R6represents O, NR10where R10is OR7where R7have the above values, O(CH2)mO;

n is 0 or 1;

m is 2 or 3,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which Q represents the structure of

3. Connection on p. 1, in which Q represents the structure of

4. Connection on p. 1, in which Q represents the structure of

5. Connection on p. 1, in which Q represents the structure (V).

6. Connection on p. 1, in which each R4is fluoride.

7. Connection on p. 1, in which one of R4

9. Connection on p. 1, in which R6is oxygen, -OCH2CH2-O-.

 

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