Method of synthesis of 5-hydroxymethyl-substituted oxazolidinones, method of synthesis of 5-aminomethyl-substituted oxazolidinone amines, oxazolidinone sulfonate

TECHNICAL FIELD The present invention relates to methods for producing 5-hydroxymethyl substituted oxazolidinone alcohols (III). Also disclosed is a process for the conversion of 5-hydroxymethyl substituted oxazolidinone alcohols (III) to the corresponding oxazolidinone amines (VII), which is used to prepare oxazolidinone antibacterial pharmaceuticals (VIII).

BACKGROUND ART U.S. Patent N 5164510, 5182403 and 5225565 describe the use as antibacterial agents 5'-indoliniloksazolidinony, 3- (5'-indazolyl) oxazolidinones and fenoloksazolidinony substituted in the 3-position of the fused ring.

US Patents 5231188 and 5247090 are used as antibacterial agents in various tricyclic [6.5.5] and [6.6.5] -kondensirovannye cyclic oxazolidinones.

In published international application WO 93/09103 describes antibacterial compounds of mono- and di-halophenyl-oxazolidinone, which are useful as pharmaceutical agents because of their anti-bacterial action.

U.S. Patent N 4150029, 4250318, 4476136, 4340606 and 4461773 describe the synthesis of 5-gidroksimetiloksazolidinonov from amines (R-NHX1, where X1 is -H or p-toluolsulfonilom) and R, S-glycidol (C * H2-OC * H-CH2 -OH), in which the carbon atoms marked with * are linked and cyclized to form an epoxide. The mixture of enantiomers produced by this process (represented by the formula R-NH-CH2-CHOH-CH2-OH), is separated by fractional crystallization of the mandelic acid salts. The enantiomerically pure R-diol is then converted into the corresponding 5R-hydroxymethyl substituted oxazolidinones (III) by condensation with diethyl carbonate in the presence of sodium methoxide. These 5R-hydroxymethyl substituted oxazolidinones are used as synthetic precursors used in pharmacology oxazolidinones. The disadvantages of this method are excessive multistage process.

In J. Med. Chem., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and U.S. Patent N 4,948,801 discloses a method of producing oxazolidinones by reacting an isocyanate (RN = C = O) with (R) -glycidyl butyrate in the presence of a catalytic amount of lithium bromide complex - tributilfosfinoksid to produce the corresponding 5R-butyryloxymethyl substituted oxazolidinone. The process is carried out at 135-145oS. Then in the next step butyric acid ester is hydrolyzed to form the corresponding 5-hydroxymethyl substituted oxazolidinone. The relatively high cost and / or availability of the isocyanate starting material and as the need for high temperatures significantly reduces the attractiveness of this method.

Abstracts of Papers, 206th National Meeting of the American Chemical Society, Chicago, IL, August, 1993; American Chemical Society: Washington, DC, 1993; ORGN 089; J. Med. Chem. 39, 673 (1996); J. Med. Chem. 39, 680 (1996); International applications WO 93/09103, WO 93/09103, WO 95/07271 and WO 93/23384; Application PCT PCT / US95 / 12751 and PCT / US95 / 10992; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract N F208; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract N F207; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract No. F206; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract N F227 describe the reaction of a carbamate with n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide at -78 to -40 ° C and then with glycidyl butyrate at -78 ° followed by warming to 20-25 ° to produce 5-hydroxymethyl substituted oxazolidinones (III), where ester is cleaved during the reaction.

U.S. Patent N 4062862 and 4236012 disclose a method of producing oxazolidinones which comprises reacting an epoxide with a primary (in the absence of any substituent on the nitrogen atom) carbamate in the presence of a catalyst. The "most preferably carried out at a temperature of from 100 to 150 ° C for several hours."

Canadian Patent N 681 830 describes a method of producing oxazolidinones which comprises reacting an aryl ether of glycidol with a primary carbamate in the presence of an alkaline catalyst (preferably lithium amide or lithium hydroxide). The process is performed in the "preferred temperature range of 150 to 165 ° C." The products are aryl ethers of 5-hydroxymethyl substituted oxazolidinones and thus the yield is low (40-78%).

The publication J. Am. Chem. Soc. , 64, 1291 (1942) and in U.S. Patent N 3,547,951 describes a process for converting primary alcohols to amines that involves treatment with methanesulfonyl chloride to produce the mesylate (methanesulfonate), followed by reaction of the mesylate with anhydrous ammonia at high pressure in a sealed vessel at ambient temperature.

It is also known that the mesylates of primary alcohols react with liquid ammonia to form the corresponding primary amines, but this requires high temperature and high pressure (6 atm). Normally this process can not be used in ordinary general purpose reactors and must be carried out in special reactors operating at high pressures.

International Application WO 95/07271 discloses the ammonolysis of oxazolidinone mesylate.

U.S. Patent N 4476136 describes a process for the conversion of 5-hydroxymethyl substituted oxazolidinones (III) to the corresponding 5 (S) -aminomethyl substituted oxazolidinones (VII), which comprises treating with methanesulfonyl chloride followed by treatment with potassium phthalimide and then with hydrazine. This sequence of reactions accompanied by the formation of by-products which are difficult to separate from the desired product.

J. Med. Chem., 32, 1673 (1989) and Tetrahedron 45, 1323 (1989) propose a method of converting the 5-hydroxymethyl substituted oxazolidinones into the corresponding 5S-acetamidomethyl substituted oxazolidinones which comprises reacting with methanesulfonyl chloride or tosyl chloride (tolilsulfonilhloridom) followed by treatment with sodium azide, and then trimethylphosphite or platinum dioxide / hydrogen, followed by treatment with acetic anhydride or acetyl chloride to obtain the desired 5 (S) -atsetamidometil substituted oxazolidinones. It is known that sodium azide is an explosion hazard.

U.S. Patent N 5210303 proposes a method conversion of various substituted benzyl chlorides into the corresponding benzylamines by heating with aqueous ammonia in the presence of aromatic aldehydes to suppress dialkylation. The dialkylated impurity is generally difficult to remove, see. Chem. Lett., 1057 (1978).

SUMMARY OF THE INVENTION A process for producing 5-hydroxymethyl substituted oxazolidinones of formula (III): wherein R1 is wherein X1 is -H or -F; X2 is -H or -F; Q1 is: Q1 and X2, taken together is where Z1 is: a) -CH2-, b) -CH (R4) -CH2-, c) -C (O) -, or d) -CH2CH2CH2-; Z2 is: a) -O2S-, b) -O-, c) -N (R7) -, d) -OS-, or e) -S-; Z3 is: a) -O2S-, b) -O-, c) -OS-, or d) -S-; A1 is: a) H- or b) CH3; A2 is: a) H-, b) HO-, c) CH3-, d) CH3O-, e) R2O-CH2-C (O) -NH-, f) R3O-C (O) -NH-, g ) (C1-C2) alkyl-OC (O) -, h) HO-CH2-, i) CH3O-NH-, j) (C1-C3) alkyl-O2C-, k) CH3-C (O) -, l) CH3-C (O) -CH2-, A1 and A2, taken together, represent: b) = O wherein R1 is: a) -CHO, b) -COCH3, c) -COCHCl2, d) -COCHF2, e ) -CO2CH3, f) -SO2CH3 or g) -COCH2OH; R2 is: a) H-, b) CH3-, c) phenyl-CH2-, or d) CH3C (O) -; R3 is: a) (C1-C3) alkyl- or b) phenyl-; R4 is: a) H- or b) HO-; R5 is: a) H-, b) (C1-C3) alkyl-, c) CH2 = CH-CH2- or d) CH3-O- (CH2) 2-; R6 is: a) CH3-C (O) -, b) HC (O) -, c) Cl2CH-C (O) -, d) HOCH2-C (O) -, e) CH3SO2-, g) F2CHC ( O) -, i) H3C-C (O) -O-CH2-C (O) -, j) HC (O) -O-CH2-C (O) -, l) HC≡CH-CH2O-CH2- C (O) - or m) phenyl-CH2-O-CH2-C (O) -; R7 is: a) R2O-C (R10) (R11) -C (O) -, b) R3O-C (O) -, c) R8-C (O) -, f) H3C-C (O) - (CH2) 2-C (O) -, g) R9SO2-, i) HO-CH2-C (O) -, j) R16- (CH2) 2-, k) R13-C (O) -O-CH2 -C (O) -, l) (CH3) 2N-CH2-C (O) -NH-, m) NC-CH2- or n) F2-CH-CH2-; R8 is: a) H-, b) (C1-C4) alkyl, c) aryl- (CH2) p, d) ClH2C-, e) Cl2HC-, f) FH2C-, g) F2HC- or h) (C3 -C6) cycloalkyl; R9 is: a) -CH3, b) -CH2Cl, c) -CH2CH = CH2, d) aryl or e) -CH2CN; R10 is H or CH3-, R11 is H or CH3-; R12 is: a) H-, b) CH3O-CH2O-CH2- or c) HOCH2-; R13 is: a) CH3-, b) HOCH2-, c) (CH3) 2N-phenyl, or d) (CH3) 2N-CH2-; R14 is: a) HO-, b) CH3O-, c) H2N-, d) CH3O-C (O) -O-, e) CH3-C (O) -O-CH2-C (O) -O- , f) phenyl-CH2-O-CH2-C (O) -O-, g) HO- (CH2) 2-O-, h) CH3O-CH2-O- (CH2) 2-O-, or i) CH3O -CH2-O-; R15 is: a) H- or b) Cl-; R16 is: a) HO- b) CH2O- or c) F; m is 0 or 1; n is from 1 to 3; p is 0 or 1; aryl is phenyl with substituents zero (0) or one (1) is: a) -F, b) -Cl, c) -OCH3, d) -OH, e) -NH2, f) - (C1-C4 ) alkyl, g) -OC (O) -OCH3, or h) -NO2 and protected forms thereof, comprising (method) reacting a hydroxy compound selected from the group consisting of: a) (S) -, (R) -dihydroxy compound Formula (I): M1-CH2-CH (OH) -CH2-OH, (I) or any mixture thereof where M1 is -Cl, -Br or -O-SO2- φ -CH3, or b) (S) -, (R) -glycidol (IV): C * H2-C * H-CH2-OH, (IV) or any mixture thereof, wherein all the carbon atoms marked with * relate to the same oxygen atom (- O-) to form a three-membered ring, with a carbamate of formula (IIA): R1-NH-CO-O-M2, (IIA) or a trifluoroacetamide of formula (IIB): R1-NH-CO-CF3, (IIB) in the presence of lithium cation and a base whose conjugate acid has a pKa greater than about 8, and where -O-M2 is a base whose conjugate acid has a pKa in the range between the values ​​of about 8 and about 24, and wherein the values ​​of R1 are given above.

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Also disclosed is a method of producing 5-aminomethyl substituted oxazolidinone amines of formula (VII): wherein R1 is as defined above, which (process) comprises (1) contacting 5-hydroxymethyl substituted oxazolidinone alcohols of formula (III): wherein R1 is as defined above with a sulfonylating agent selected from the group consisting of a compound of formula (Va-Vd): O (SO2-F) 2, (Vc) O (SO2-CF3) 2, (Vd) where n1 = 0, 1 or 2; where n2 = 0 - 4 with the proviso that: when n1 = 0, n2 = 2, 3 or 4, if n1 = 1, n2 = 0 or 1, if n1 = 2, n2 = 0; wherein n3 = 5- (n1 + n2); where M3 is Cl- or Br-, to yield the corresponding oksazolidinonsulfonata formula (VIa-VId): and (2) reacting oksazolidinonsulfonata (VIa-VId) with ammonia at a pressure of 2.1 atm smaller.

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DETAILED DESCRIPTION OF THE INVENTION In the process for producing 5-hydroxymethyl substituted oxazolidinone alcohols (III) can use non-cyclic (S) -, (R) -dihydroxy compound of formula (I) or any mixture thereof or (S) -, (R) -glycidol ( IV), or any mixture to couple with the carbamate (IIA) or a trifluoroacetamide of formula (IIB).

5-hydroxymethyl substituted oxazolidinone alcohols (III) are intermediates in the preparation of 5-aminomethyl substituted oxazolidinone amines (VII), which can be acylated to get used for pharmaceutical purposes 5-acylamidomethyl substituted oxazolidinone (VIII) antibacterial agents. Due to the presence of the enantiomeric center may be obtained 5 (R) -, 5 (S) -atsilamidometil substituted oxazolidinones (VIII) and mixtures thereof, (S) -enantiomer of 5-acylamidomethyl substituted oxazolidinone (VIII) has antibacterial activity, while the ( R) -enantiomer does not. Enantiomer 5 (S) aminomethyl substituted oxazolidinone amine (VII) enantiomer is prepared from 5 (R) -hydroxymethyl substituted oxazolidinone alcohol (III), which in turn is derived from (S) -dihydroxy compound (I) or (S ) -glycidol (IV). Accordingly, the desired and preferred enantiomeric sequence is to use enantiomerically pure (S) -dihydroxy compound (I) or (S) -glycidol (IV) to obtain (R) -5-hydroxymethyl substituted oxazolidinone alcohol (III), which was used for preparation of enantiomerically pure (S) -5-aminomethyl substituted oxazolidinone amine (VII), which was converted to enantiomerically pure (S) -5-acylamidomethyl substituted oxazolidinone (VIII). However, those skilled clear that can be easily performed similar to the other stages of the process enantiomeric forms and at any stage of the process to turn the undesired enantiomeric configuration to the desired configuration. Thus, the use of chemical reactions of the process with any of the enantiomeric forms is considered equivalent to the claimed processes.

The dihydroxy compounds, M1-CH2-CH (OH) -CH2-OH, of formula (I) and glycidol compounds C * H2-C * H-CH2-OH Formula (IV), where the asterisk * indicates the carbon atoms bound to the the same oxygen atom - (O) -, forming a three-membered ring, are known to those skilled in the art or can be readily prepared from known components using techniques known to those skilled specified. Preferably, the hydroxy starting material is the dihydroxy compound (I). Preferably, the dihydroxy compound (I) and the glycidol (IV) are (S) -enantiomer. Preferably, M1 represented Cl-; it is preferred that the dihydroxy compound (I) according to claim 5 may be purchased commercially.

Carbamates R1-NH-CO-O-M2 Formula (IIA) and trifluoroacetamide R1-NH-CO-CF3 formula (IIB) are either known to those skilled in the art or can be readily prepared from known compounds by methods known in the art. The nature of the leaving group M2 is not important since this group is lost during the reaction, as is well known in the art. Action M2 (leaving groups) are those for which the -O-M2 is a base whose conjugate acid has a pKa between about 8 and about 24. Preferably M2 includes: C1-C20 alkyl, C3-C7 cycloalkyl, φ - optionally substituted with one or two C1-C3 alkyl or F-, Cl-, Br-, I-.

CH2 = CH-CH2-, CH3-CH = CH-CH2-, (CH3) 2C = CH-CH2-, CH2 = CH-, φ-CH = CH-CH2-, φ-CH2 - optionally substituted on φ with one or two -Cl, C1-C4 alkyl, -NO2, -CN, -CF3, 9-fluorenylmethyl, (Cl) 3C-CH2-, 2-trimethylsilylethyl φ-CH2-CH2-, 1-adamantyl, (φ) 2CH-, CH≡CC (CH3) 2-, 2-furanylmethyl, isobornyl, more preferred leaving groups are C1-C4 alkyl or benzyl. Any other leaving group, working in a similar manner is considered equivalent to the groups identified above. The carbamate (IIA) and trifluoroacetamide (IIB) carry the aromatic / heteroaromatic group (R1-) of 5-hydroxymethyl substituted oxazolidinone alcohol (III). Preferably, R1 is phenyl substituted with one -F and one substituted amino group; more preferably, R1 is a 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl or 3-fluoro-4- (morpholinyl) phenyl. Depending on the particular substituents R1, the group may be protected as is known in the art, the methods prevent undesirable side reactions. For example, if the R1 substituent has a free primary or secondary hydroxy group is not necessary, but preferable to protect it with an alcohol protecting group in the formation of 5-hydroxymethyl substituted oxazolidinone alcohols (III). In general, an unprotected alcohol will not interfere with the reaction of the dihydroxy compound (I) or glycidol (IV) with the carbamate (IIA) or trifluoroacetamide (IIB) in the preparation of 5-hydroxymethyl substituted oxazolidinone alcohols (III). However, an unprotected alcohol will tend to prevent the transformation of the 5-hydroxymethyl substituted oxazolidinone alcohols (III) to the corresponding 5-aminomethyl substituted amines (VII), because it is very difficult or impossible to selectively protect a primary or secondary alcohol on the functional group R1 in the presence of another primary or secondary alcohol. Suitable alcohol protecting groups are well known in the art, and preferred are C1-C5 alkyl, φ-CH2-, CH3-O-CH2-, CH3-, CH3-S-CH2-, φ-CH2-O-CH2-, tetrahydropyranyl, CH3CH (-O-C2H5) -, p-methoxybenzyl, p-methoxyphenyl, p-nitrobenzyl, (φ) 3C-, (CH3) 3Si-, [CH3-CH (CH3)] 3Si-, φ- (CH3) 2Si- . These protective groups are removed by known in the art. For example, when R1 contains a hydroxy substituent, it must be protected during transformation of the 5-hydroxymethyl substituted oxazolidinone alcohol (III) is 5-aminomethyl substituted oxazolidinone amine (VII) or the 5-acylamidomethyl substituted oxazolidinone (VIII). If the R1 substituent contains a free primary or secondary amino as a substituent, in which case it need not be protected during the process of formation of 5-hydroxymethyl substituted oxazolidinone alcohols (III), but must be protected during transformation of the 5-hydroxymethyl substituted oxazolidinone alcohols ( III) to the corresponding 5-aminomethyl substituted oxazolidinone amines (VII) and the 5-acylamidomethyl substituted oxazolidinones (VIII). The reason is that the amino group will generally undergo undesired side reaction during one or more steps of converting the 5-hydroxymethyl substituted oxazolidinone alcohols (III) to the corresponding 5-acylamidomethyl substituted oxazolidinones (VIII). Therefore, it is preferable to protect any amine functional group in the substituent R1 before the reaction of the dihydroxy compound (I) or glycidol (IV) with the carbamate (IIA) or trifluoroacetamide (IIB). Protecting groups for amines are well known to those skilled in the art. Preferred amino-protecting groups are (I) C1-C4 alkyl, (II) φ-CH2-, (III) (φ) 3C-, (IV) Ra-CO-, where Ra is (A) H-, (B) C1 -C4 alkyl, (C) C5-C7 cycloalkyl, (D) (C1-C5 alkyl) -O-, (E) Cl3C-CH2-O-, (F) H2C = CH-CH2O-, (G) φ-CH = CH-CH2-O-, (H) φ-CH2-O-, (I) p-methoxyphenyl-CH2-O-, (J) p-nitrophenyl-CH2-O-, (K) φ-O-, (L) CH3-CO-CH2-, (M) (CH3) 3Si-O-, (V) Rb-SO2-, where Rb is (A) (C1alkil) -, (B) φ-, (C) n -metilfenil- and (D) φ-CH2-. A preferred amino protecting group is benzyloxycarbonyl, which is known in the art, it can be removed by catalytic hydrogenation. There is nothing new to use protecting groups in these reactions or the nature of the individual protecting groups. All this is well known to those skilled in the art. As is known, protective groups may be removed after the last reaction in which the protected substituent to be exposed and stored and removed after subsequent reactions. For example, it may be preferable to retain the protecting group until until the final acylation step is completed. R1 substituent may optionally be modified after the preparation of 5-acylamidomethyl substituted oxazolidinones (VIII) according to what known in the art for this reaction are required.

Reaction of dihydroxy compounds (I) or glycidol (IV) with the carbamate (IIA) or trifluoroacetamide (IIB) leads to the same 5-hydroxymethyl substituted oxazolidinone alcohols (III). Selection use a dihydroxy compound (I) or glycidol (IV) to produce a single 5-hydroxymethyl substituted oxazolidinone alcohol (III) can be made arbitrarily. None of the starting material which would be preferred in all cases; there is no generally preferred way which would be based solely on the laws of chemistry. The solution involves the commercial availability of each source reactant, its chemical and enantiomeric purity, its cost, etc as is well known in the art.

One method of the present invention is a reaction of the dihydroxy compound (I) or glycidol (IV) with the carbamate (IIA) or trifluoroacetamide (IIB) in the presence of lithium cation (Li +) and a base whose conjugate acid has a pKa greater than about 8.

By the method requires about one molar equivalent or dihydroxy compound (I), or glycidol (IV) / equivalent of carbamate (IIA), or trifluoroacetamides (IIB). To the reaction requires a base, the nature of which is not critical, unless the base is strong enough to deprotonate the carbamate (II). Reactive bases are those whose conjugate acid has a pKa greater than about 8. Preferred bases include compounds selected from the group consisting of: alkoxy compounds of one to seven carbon atoms, ct carbonate, methyl, sec-butyl and t-butyl carbanions, tri (alkyl) amines wherein the alkyl groups contain from one to four carbon atoms, conjugate base of the carbamate (II), DBU, DBN, N-methylpiperidine, N-methylmorpholine, 2,2,2-trihloretoksid and Cl3C-CH2-O -; The most preferred base is alkoxy of four or five carbon atoms. Preferably, the alcohol base with four or five carbon atoms are t-amylate or t-butoxide. Sodium or potassium bases in combination with a lithium salt (such as lithium chloride or lithium bromide) can be used for forming the lithium cation and base in situ.

The nature of the solvent is not critical. Suitable solvents include cyclic ethers such as THF, amides such as DMF and DMAC, amines such as triethylamine, acetonitrile, and alcohols such as t-amyl alcohol and tert-butyl alcohol. The choice of solvent depends on the solubility of the carbamate (IIA) or trifluoroacetamide (IIB), is known to those skilled in the art.

If the starting material is the dihydroxy compound (I), the most favorable interaction can be a dihydroxy compound (I) with cyclized agent prior to contacting with the carbamate (IIA) or trifluoroacetamide (IIB). The term "cyclized agent" refers to a base which is cyclized dihydroxy compound (I) to glycidol (IV). Suitable cyclized agents include bases whose conjugate acid has a pKa of greater than about 7; preferred agents are cyclized butoxide, potassium or lithium, sodium or potassium hydroxide, potassium carbonate, DBU, amylate, lithium, sodium and potassium, most preferred is potassium t-butoxide. Preferably the reaction is conducted at a temperature <100 ° C, more preferably at a temperature <70 ° C, more preferably at a temperature <50 ° C and most preferably to carry out the reaction at a temperature of <25 ° C. The reaction can proceed at room temperature (about 20 to 25C). At a temperature of about 20 ° C the reaction requires about 8 hr to completion (in DMAC). If a faster reaction is desired, the reaction can be conducted at a higher temperature. As stated above, a differentiation between primary alcohols and secondary alcohols is difficult. When the cyclization reaction forms a simple alcohol. For instance, benzyl alcohol is formed when benzilkarbonat subjected to cyclization conditions. This alcohol is necessary to successfully remove the alcohol to amine conversion. This is accomplished by crystallization using ethyl acetate / heptane (1/2). The benzyl alcohol stays in solution and the desired oxazolidinone alcohol is isolated as a solid.

Scheme C provides methods for the conversion of 5-hydroxymethyl substituted oxazolidinone alcohols (III) to the corresponding 5-aminomethyl substituted oxazolidinone amines (VII). The protection of the alcohol and / or amine groups on a functional moiety R1 discussed above. 5-hydroxymethyl substituted oxazolidinone alcohols (III) react with a sulfonylating agent (Va-Vd) of four types. This O (SO2-F) 2 (Vc) and O (SO2-CF3) 2 (Vd). M3 is labile group which includes Cl- or Br-; M3 is preferably Cl-. 5-hydroxymethyl substituted oxazolidinones (III) react with a sulfonylating agent (Va-Vd) to form as an intermediate oxazolidinone sulfonate (VIa-VId).

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Conversion of the 5-hydroxymethyl substituted oxazolidinones (III) by sulfonation in respective oksazolidinonsulfonaty (VI) is carried out by reacting the 5-hydroxymethyl substituted oxazolidinones (III) with at least one molar equivalent of the sulfonylating agent (Va-Vd) in the presence of a base in an inert solvent at a temperature of about 0C. Suitable bases include triethylamine, tributylamine, diisopropylethylamine, DABCO, DBU, DBN, n-butyl lithium, ethyl magnesium chloride and the equivalents thereof; preferred is triethylamine. Inert solvents include most organic solvents such as methylene chloride, THF, DMA, DMF, ethyl acetate and their equivalents; preferred is methylene chloride.

Conversion reaction of the oxazolidinone sulfonates (VI) by ammonolysis of the corresponding 5-aminomethyl substituted oxazolidinone amines (VII) are in open conditions or leaking conditions or under sealed conditions although it is preferred to conduct it in a sealed condition.

In either case the ammonolysis reaction is carried out by reacting oksazolidinonsulfonata (VI) with ammonia (preferably aqueous) preferably with a solvent or solvent mixture. Preferred solvents are those that dissolve both the oxazolidinone sulfonates (VI), and the aqueous ammonia because by dissolving both contact between them is ensured. However, the process also passes and solvents that only partially dissolve the oxazolidinone sulfonates (VI); the disadvantage is that the reaction in general is slower. For the case of m-nitrobenzenesulfonate preferred solvent is a mixture of acetonitrile / isopropanol or THF / isopropanol. The system creates a negative pressure. The system is then closed or sealed, was added ammonia (preferably aqueous ammonia) and heated to a temperature below 50 ° C, preferably to a temperature below 40C, preferably to about 38 ° C (about 0.21 atm). At a temperature of about 38-40oS pressure should be in the range from 0 to 0.7 atm, which is far below the limit pressure for standards of general purpose reactors. Under these conditions, a temperature of about 60 ° C when the pressure is the amount of about 1.4 atm. Preferably, the ammoxidation reaction is carried out at a pressure of from 0 to 1.4 atm, preferably from 0 to 0.35 atm and a temperature of about 60C or less. Alternatively, the reaction is conducted in an open system at reflux. In this case the temperature will be slightly lower and the reaction will require slightly longer to fully complete. Ammonia may be aqueous, alcoholic or anhydrous; however, aqueous ammonia is preferred.

In another case, the reaction with aqueous ammonia can be performed in the presence of an aromatic aldehyde (IX, Ar-CHO), preferably salicylaldehyde. 5-aminomethyl substituted oxazolidinone amines (VII) and the aldehyde (IX) form a Schiff base of the formula (oxazolidinone-N = CH-Ar), which is then hydrolyzed in the presence of an aqueous acid solution, as is known in the art, to produce 5-aminomethyl substituted oxazolidinone amine (VII). The aromatic aldehyde (IX) is used to suppress the formation of dimer.

5-aminomethyl substituted oxazolidinone amines (VII) are acylated by known means such as acyl halides or acyl anhydride to form the corresponding 5-acylamidomethyl substituted oxazolidinone (VIII), see. The scheme D. Any protecting groups alcohol or amine can be removed after preparation of 5- acylamidomethyl substituted oxazolidinone (VIII). However, as is known, they can be removed at an earlier stage of the reaction depends on the particular substituents.

It is known that the 5-acylamidomethyl substituted oxazolidinones (VIII) are antibacterial pharmaceutical agents. R2 is selected from the group consisting of -H, C1-C12 alkyl optionally substituted with one or more halogens, (C3-C7) cyclo (C5-C9) alkyl or -O-R2a, where R2a is C1-C6 alkyl. Preferably, R2 is C1alkil.

DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the occurring throughout the description of the terms, including the claims.

Conventions for Formulas and Definitions VARIABLES The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to precisely defined structural features. These variable substituents are identified by a letter or letters with index numbers, such as "Z1" or "Ri", where i is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z1 would represent a bivalent variable if attached to the formula CH3-C (= Z1) H. Groups Ri and Rj would represent monovalent variable substituents if attached to the formula CH3-CH2-C (Ri) (Rj) -H. When chemical formulas are presented in a linear fashion, such as those above, variable substituents are enclosed in parentheses are bonded to, standing just to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded directly to the preceding atom to the left which is not enclosed in parentheses. Thus, in the above formula, Ri and Rj are linked to the preceding carbon atom. Also, for any molecule with a specific system of carbon atom numbering, such as steroids, these carbon atoms are designated as Ci, where "i" is the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by specialists steroid chemistry. Similarly, the designation "R6" represents a variable substituent (either monovalent or bivalent) at the C6-position.

Chemical formulas or their components represented in a linear fashion represent atoms in a linear chain. The symbol "-" in general represents a bond between two atoms in the chain. Thus, the compound of CH3-O-CH2-CH (Ri) -CH3 is referred to as 2-substituted-1-methoxypropane. Likewise, the symbol "=" represents a double bond, e.g., CH2 = C (Ri) -O-CH3, and the symbol "≡" represents a triple bond, e.g., HC≡C-CH (Ri) -CH2-CH3. Carbonyl groups are represented in one of two ways: CO- or -C (= O), wherein the first method is preferable because of its simplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Since the compound 4-chloro-2-methylpyridine can be represented in linear fashion by notation N * = C (CH3) -CH = CCl-CH = C * H with the proviso that the atoms marked with an asterisk (*) are bonded to each other to form a ring. Likewise, the cyclic molecular fragment, 4- (ethyl) -1-piperazinyl can be represented by -N * - (CH2) 2-N (C2H5) -CH2-C * H2.

The rigid cyclic (ring) structure for any compounds herein defines the spatial arrangement relative to the plane of the ring for substituents attached to each carbon atom, a part of the rigid cyclic compound. For saturated compounds which have two substituents bonded to carbon atoms are part of a cyclic system, -C (X1) (X2) - the two substituents may be in axial or equatorial position relative to the ring, and these positions may be exchanged. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of more of the ring (equatorial) rather than above or below the plane (axial position), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X1), located "below" another substituent (X2), is defined as alpha (α) configuration and is indicated by means of broken dashed or dotted lines, connected to a carbon atom, for example, using symbols "---" or ". ..". The corresponding substituent (X2), disposed "above" the other (X1), defined as the beta (β) configuration and is indicated by means of solid lines, connected to a carbon atom.

When a variable substituent is bivalent, the valences may be designated together or separately or both in the variable image. For example, a variable Ri substituent, bound to a carbon atom as a -C (= Ri), might be bivalent and be defined as the "oxo" or "keto" (thus forming a carbonyl group (-CO-), or as two separate monovalent connected variable substituents α -Ri-j and β -Ri-k. When a bivalent variable Ri is defined as consisting of two monovalent variable substituents, abbreviations to describe the bivalent variable is of the form "α-Ri-j: β-Ri-k" or some -So this embodiment. In this case both substituents α-Ri-j and β-Ri-k are connected to a carbon atom to form - C (α-Ri-j) (β-Ri-k). For example, for the case where bivalent variable R6, -C (= R6) - is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R6-1: β-R6-2, ... α-R6-9: β-R6 -10, and so on, which gives a formula -C (α -R6-1) (β -R6-2) -,... -C (α -R6-9) (β-R6-10) - , etc. Similarly, for the bivalent variable R11, -C (= R11) -, two monovalent variable substituents α look like -R11-1: -R11-2 .beta.. For ring substituents for which separate α and β orientations do not exist (e.g. due to the presence of double carbon-carbon bonds in the ring), for a substituent bound to a carbon atom that is not part of the ring, the above symbols are still used, but α and β designations are omitted.

Just as a bivalent variable may be defined as two separate monovalent variable substituents, and two separate monovalent variable substituents may be defined jointly form a bivalent variable. For example, in the formula -C1 (Ri) H-C2 (Rj) H- (C1 and C2 define arbitrarily a first and second carbon atom, respectively) Ri and Rj, taken together form (1) a second bond between C1 and C2 or ( 2) - a divalent group such as oxa (-O-), and the formula thereby describes an epoxide. When Ri and Rj, taken together, form a more complex integral structure, such as the group -XY-, then the orientation of the formation is such that the variable C1 in the above formula is linked to X and C2 is connected with Y. Then, at adopted arrangement definition ".. Ri and Rj, taken together form -CH2-CH2-O-CO -... "means a lactone in which the carbonyl is bound to C2. However, if it is determined that ". .Ri And Rj, taken together form -CO-O-CH2-CH2-", it is meant a lactone in which the carbonyl is bound to C1.

The carbon content of variable substituents is represented by one of two ways. The first method uses a prefix to the full name of the variable such as "C1-C4", where "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is ​​separated from the variable interval. For example, "C1-C4 alkyl" represents an alkyl group having a carbon number of 1 to 4 (including isomeric forms thereof unless a given notation indicating otherwise). If using a single prefix is ​​given, it indicates the total number of carbon atoms contained in the described variable. Thus, the notation C2-C4 alkoxycarbonyl describes a group CH3- (CH2) nO-CO-, where n is zero, one or two. According to the second method the carbon atom content of only each portion of the definition is indicated separately in the parentheses in the expression "Ci-Cj" and by placing it immediately (no intervening interval) before the portion of the above definition. With this optional callout expression (C1-C3) alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because the expression "(C1-C3)" refers only to the carbon atom content of the alkoxy group. Similarly, although C2-C6 alkoxyalkyl and (C1-C3) alkoxy (C1-C3) alkyl represent alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two designations differ since the former definition allows or alkoxy or alkyl radicals individually each contain 4 or 5 carbon atoms while the latter definition limits these groups to 3 carbon atoms.

When the claims contain a complex (cyclic) substituent, at the end of the phrase is / indicates that the substituent to be labeled (in parentheses), which corresponds to the same name / designation substituent in one of the CHARTS which will also provide the chemical structural formula of this Deputy.

Definitions All temperatures are in degrees Celsius.

"TLC" refers to thin layer chromatography.

"THF" means tetrahydrofuran.

"DMF" refers to dimethylformamide.

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

"DBN" denotes 1,5-diazabicyclo [4.3.0] non-5-ene.

"DABCO" denotes 1,4-diazabicyclo [2.2.2] octane.

"DMA" stands for dimethylacetamide.

"Salt (saline)" refers to an aqueous saturated sodium chloride solution.

"Chromatography" (column and flash chromatography) refers to purification / isolation of compounds allocated as (support, eluent). It is understood that the desired fractions were collected and concentrated to give the desired compound (the desired compounds).

"IR" refers to infrared spectroscopy.

"CMP" refers to 13C magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) from TMS (tetramethylsilane).

NMR designates nuclear spectroscopy (proton) is the magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane.

- Φ refers to phenyl (C6H5).

[α] D 25 denotes the angle of the plane polarized light (specific optical rotation) at 25 ° C from the D-line of sodium "MS" refers to mass spectrum, expressed as the ratio m / e, m / z or mass / charge unit. [M + H] + denotes the positive ion source plus a hydrogen atom. "EI" refers to electron capture. "CI" refers to chemical ionization. "FAB" refers to fast atom bombardment.

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"HMRS" refers to mass spectroscopy, high resolution.

"Pharmaceutically acceptable" refers to those properties or compounds which are acceptable to the patient based on a pharmacological / toxicological point of view and to the manufacturer in the pharmaceutical industry with a physicochemical point of view, in regard to the compositions, forms, stability, and bioavailability of a patient perception.

When solvent pairs are used, the ratio of solvents used is given as volume / volume (v / v).

The solubility of a solid in a solvent is determined by the weight ratio of the solid to the solvent as the volume (w / v).

NNNNNN-NN-N refers registration number Chemical Abstracts Service (CAS, Columbus, Ohio), where each "N" is an integer taking values ​​from 0 to 9, but with the absence of leading zeros in the 6-digit portion of the number. Registration numbers are assigned to individual chemical compounds by CAS criteria, provided that the compound has been found and it is characterized by certain. The compounds for which information is published since about 1967 and the present, officially registered and the registration number is the key to finding references in the CAS data base of registered connections. CAS data base open to public access due to several database vendors such as STN International, System Development Corporation (SDC) Orbit Search Service, Lockheed Dialog, Bibliographic Retrieval Systems, Questrel, etc. CAS Registry Number included in the examples of some of registered connections.

Pressure in psig is nanometric (gauge) pressure equal to the absolute pressure in bar minus 1 atm.