Method of obtaining oxazolydinones

Description of the invention

The present invention relates to a process for the preparation of 5-hydroxymethyl substituted oxazolidinones, a process for the preparation of 5-aminomethyl substituted oxazolidinones, and oxazolidinone sulfonates which are useful in the production of oxazolidinone antibacterial pharmaceuticals (VIII).

U.S. Patent Nos. 5,164,510, 5,182,403, and 5,225,565 disclose 5'-indolinyloxazolidinones, 3- (5'-indazolyl) oxazolidinones, 3- (substituted fused rings) phenyloxazolidinones useful as bactericides, respectively.

US Patent Nos. 5,231,188 and 5,247,090 disclose various tricyclic [6.5.5] and [6.6.5] -fused oxazolidinone rings useful as bactericides.

International publication WO93 / 09103 discloses mono- and di-halogen-phenyl-oxazolidinone bactericides which are useful as pharmaceuticals due to their antibacterial activity.

US patents 4150029, 4250318, 4476136, 4340606 and 4461773 disclose the synthesis of 5-hydroxymethyloxazolidinones from amines (R-NHX1, where X1 is -H or p-toluenesulfonyl) and R, S-glycidol (C * H2-OC * H- CH2-OH, where the carbon atoms marked with * are bound together, cyclized to epoxide). The mixture of enantiomers (represented by the formula R-NH-CH2-CHOH-CH2-OH) thus produced is separated by fractional crystallization of the salt of mandelic acid. Enantiomerically pure R-diols are then converted to the corresponding 5R-hydroxymethyl substituted oxazolidinones (III) by condensation of diethyl carbonates in the presence of sodium methoxide. These 5R-hydroxymethyl substituted oxazolidinones are useful as synthetic precursors to pharmaceutically useful oxazolidinones. The large number of steps makes this process unattractive.

J. Med. Chem., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and U.S. Patent 4,948,801 disclose a method for the preparation of oxazolidinones which involves reacting an isocyanate (RN = C = O) with (R) -glycidyl butyrate in the presence of a catalytic amount of a bromide complex lithium tributylphosphine oxide to produce the corresponding 5R-butyryloxymethyl substituted oxazolidinone. The process is carried out at a temperature of 135-145 °. Then, in a next step, the butyric acid ester is hydrolyzed to the corresponding 5-hydroxymethyl substituted oxazolidinone. The relatively high cost and / or availability of the isocyanate starting material and the high temperature requirement significantly reduce the attractiveness of this method.

In 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 Publications WO93 / 09103, WO93 / 09103, WO95 / 07271 and WO93 / 23384; PCT applications 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 No. 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 No. 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 No. F227 discloses the reaction of carbamate with n-butyl lithium, lithium diisopropylamide or lithium hexamethyldisilazide at -78 ° to -40 ° and then with glycidyl butyrate at -78 ° followed by heating the reaction mixture to 20-25 ° to form 5-hydroxymethyl substituted oxazolidinones (III) where the ester cleaves during the reaction.

US patents 4,062,862 and 4,236,012 disclose a process for the preparation of oxazolidinones which comprises reacting an epoxide with a primary (having no nitrogen substituent) carbamate in the presence of a catalyst. The process is preferably carried out at a temperature of 100 ° to 150 ° for several hours.

Canadian patent 681830 discloses a process for the preparation of oxazolidinones which comprises reacting an aryl glycidol ether with a primary carbamate in the presence of an alkaline catalyst (preferably lithium amide or lithium hydroxide). The method was carried out

PL 192 691 B1 in the "preferred temperature range from 150 ° to 165 °". The products were the aryl ethers of 5-hydroxymethyl substituted oxazolidinones and the yield was low (40-78%).

In J. Am Chem. Soc., 64, 1291 (1942) and U.S. Patent No. 3,547,951 disclose a method of converting primary alcohols to amines which comprises treating with methanesulfonyl chloride to form mesylate followed by contacting the mesylate with anhydrous ammonia at ambient temperature in a sealed high pressure reaction vessel. .

It is also known that primary alcohol mesylates react with aqueous ammonia to form the corresponding primary amines, but high temperature and pressure (687 kPa) are required. Normally this process cannot be used in ordinary general purpose reactors, but should be carried out in special reactors where the reaction is carried out under high pressure.

International publication WO95 / 07271 discloses the ammonolysis of oxazolidinone mesylates.

US Patent No. 4,476,136 discloses a process for converting 5-hydroxymethyl substituted oxazolidinones (III) to the corresponding 5 (S) -aminomethyl substituted oxazolidinones (VII) which involves treatment with methanesulfonyl chloride, then with potassium phthalamide, and finally with hydrazine. This sequence of reactions produces by-products that are difficult to separate from the desired product.

In J. Med. Chem., 32, 1673 (1989) and Tetrahedron 45, 1323 (1989) disclose a method for converting 5-hydroxymethyl substituted oxazolidinones into the corresponding 5S-acetoamidomethyl substituted oxazolidinones which involves treatment with methanesulfonyl chloride or tosyl chloride followed by sodium azide then or trimethylphosphide. platinum hydride / oxide, and finally acetic anhydride or acetyl chloride to give the desired 5 (S) -acetoamidomethyl substituted oxazolidinone. It is known that the use of sodium azide carries an explosion hazard.

US Patent No. 5,210,303 discloses the conversion of various substituted benzyl chlorides to the corresponding benzylamines by heating with aqueous ammonia in the presence of aromatic aldehydes to suppress dialkylation. Dialkylation product impurities are generally difficult to remove, see Chem. Lett., 1057 (1978).

According to the invention, a process for the preparation of 5-hydroxymethyl substituted oxazolidinones of formula (III)

<img file="PL192691B1_D0001.tif" />

wherein R1 is

3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl or

3-fluoro-4- (4-morpholinylphenyl) is contacted by contacting a hydroxy compound selected from the group consisting of: (a) (S) -, (R) - a dihydroxy compound of formula (I)

M1-CH2-CH (OH) -CH2-OH (I) or any mixture thereof, wherein M₁ is -Cl, -Br, or -O-SO₂^ -CH₃, and (b) (S) -, (R) - glycidol of formula (IV)

C * H2-OC * H-CH2-OH (IV) or any mixture thereof, where the carbon atoms marked with * are bonded together to form an epoxy ring, with the carbamate of formula (IIA)

R1-NH-CO-O-M2 (IIA)

In the presence of a lithium cation and a base with which the conjugate acid has a pKa greater than 8, whereby R1 is as defined above and -O-M2 is a base with which the conjugate acid has a pKa in the range 8-24.

In one embodiment, glycidol (IV), especially its (S) enantiomer, is used as the hydroxy compound.

In another embodiment, the hydroxy compound used is a dihydroxy compound of formula (I), especially its (S) enantiomer.

Preferably a dihydroxy compound is used in which M1 is -Cl, in particular (S) - (+) - 3-chloro-1,2-propanediol.

In a preferred embodiment, the dihydroxy compound (I) is contacted with a cyclizing agent prior to contacting the carbamate (IIA).

The preferred cyclizing agent is a base the conjugate acid with which has a pKa of greater than 7, in particular sodium or potassium butoxide, sodium or potassium hydroxide, potassium carbonate, DBU, sodium or potassium amylate.

Preferably, the hydroxy compound is contacted with a carbamate (IIA), wherein M2 is a substituent selected from:

ψ-ΟΗ₂- optionally substituted in φ with one or two substituents selected from the group consisting of:

Cl, C₁-C₄ alkyl, -NO₂, -CN, -CF₃especially benzyl.

Preferably the base is a compound selected from the group consisting of:

C1-7alkoxy compounds of methyl, sec-butyl and t-butyl carbanions, tri (C1-4alkyl) amines, carbamate conjugate bases (IIA),

DBU,

DBN,

N-methyl-piperidine,

N-methyl-morpholine, and more preferably a C4-5alkoxy compound.

According to the invention, a process for the preparation of a 5-aminomethyl substituted oxazolidinone of formula (VII)

O (VII)

L-a-h ch₂- nh₂ where R1 is as defined above is that:

(1) contacting a 5-hydroxymethyl substituted oxazolidinone of formula (III) as defined above with a sulfonating agent selected from compounds of formula (Va-Vb)

M3-SO2-C6Hn3 (NO2) mCln2 (V_and)

O [-SO2-C6Hn3 (NO2) n1Cln2] 2 (Vb) where n1 is 0 and n2 is 2, 3 or 4; n1 is 1 and n2 is 0 or 1; or n1 is 2 and n2 is 0; n3 is 5- (n1 + n2); and M3 is Cl- or Br-; and

(2) contacting the formed oxazolidinone sulfonate of formula (VIa-VIb)

<img file="PL192691B1_D0002.tif" />

wherein R1, n1, n2, n3 are as defined above, with ammonia at a pressure of less than 307 kPa.

Preferably, a compound of formula (Va) is used as the sulfonating agent, in particular a sulfonating agent having a group selected from 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl and 2,5-dichlorobenzenesulfonyl, in particular a sulfonating agent containing 3 -nitrobenzenesulfonyl.

Preferably, step (2) is carried out at a pressure of 0 to 238 kPa, and more preferably 0 to 135 kPa.

The process according to the invention can be carried out at atmospheric pressure.

Preferably, step (2) is conducted at a temperature of about 60 ° C or less.

Preferably step (2) is carried out in the presence of an aromatic aldehyde Ar-CHO, especially an aldehyde where Ar- is phenyl- optionally substituted with F-, Cl-, Br-, C1-C5 alkyl, HO-, O2N-, CH3-O - or C2H5-O-.

Preferably, salicylaldehyde is used as the aldehyde.

Preferably a sulfonating agent of formula (Va) is used, wherein M3 is Cl.

Preferably step (1) is carried out in the presence of water.

According to the invention, the oxazolidinone sulfonate has the formula (VIa or VIb) given above.

In particular, the invention includes the following compounds:

(R) - [N-3- [3-fluoro-4- (N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 2-nitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 2,4-dinitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 4-chlorobenzenesulfonate,

(R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 2,5-dichloro-benzenesulfonate,

(R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 4-nitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 4-nitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2-nitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2,4-dinitrobenzenesulfonate,

(R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 4-chlorobenzenesulfonate,

(R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2,5-dichloro-benzenesulfonate.

Either non-cyclic (S) -, (R) -dihydroxy compounds of formula (I or any mixture thereof or (S) -, (R) -glycidol (IV) or any mixture for coupling to the carbamate of formula (IIA).

5-hydroxymethyl substituted oxazolidinones (III) (alcohols) are useful intermediates for the preparation of 5-aminomethyl substituted oxazolidinones (VII) (amines) that can be acylated to produce pharmaceutically useful 5-acylamidomethyl substituted oxazolidinone (VIII) antibacterial agents. Because of the enantiomeric center, 5 (R) -, 5 (S) -acylamidomethyl-substituted oxazolidinones (VIII) and mixtures thereof can be prepared.

PL 192 691 B1

The (S) enantiomer of the 5-acylamidomethyl substituted oxazolidinone (VIII) has antibacterial activity, the (R) enantiomer does not. The 5 (S) -aminomethyl substituted oxazolidinone (VII) enantiomer (amine) is prepared from the 5 (R) -hydroxymethyl substituted oxazolidinone (alcohol) enantiomer (III), which in turn is prepared from the (S) -dihydroxy compound (I) or (S) ) -glycidol (IV). Therefore, a desired and preferred enantiomeric order is to use the enantiomerically pure (S) -dihydroxy compound (I) or (S) -glycidol (IV) to obtain the (R) -5-hydroxymethyl substituted oxazolidinone (III) (alcohol) which is used to obtain enantiomerically pure (S) -5-aminomethyl substituted oxazolidinone (VII) (amine), which is converted into enantiomerically pure (S) -5-acylamidomethyl substituted oxazolidinone (VIII). However, it is readily foreseen by one skilled in the art that it would be easy to carry out identical process steps with opposite enantiomeric forms and at any point in the process to reverse the undesirable enantiomeric configuration to the desired one. Therefore, applying the chemistry of the claimed process with any enantiomeric forms is considered equivalent to the claimed methods.

Dihydroxy compounds, M1-CH2-CH (OH) -CH2-OH, of formula (I) and glycidol compounds, C * H2-OC * H-CH2-OH, of formula (IV) where the carbon atoms marked with * are bonded together to form epoxy ring are known to those skilled in the art or can be readily prepared from known compounds using methods known to those skilled in the art. The preferably used dihydroxy compound as defined in claim 5 is commercially available.

Carbamates, R1-NH-CO-O-M2, of formula (IIA) are known to those skilled in the art, and can be readily prepared from known compounds using methods known to those skilled in the art. The nature of the leaving group M2 is not important as this group is lost during the course of the reaction, as is known to those skilled in the art. Possible use are M2 groups (leaving groups) such that -O-M2 is the base with which the conjugate acid has a pka in the range 8-24.

Any leaving groups other than the above indicated that function in a similar manner will be considered equivalent to the groups listed. The carbamate (IIA) contains an aromatic / heteroaromatic group (R1-) of the 5-hydroxymethyl substituted oxazolidinone (III).

The R 1 groups may be protected as is generally known to those skilled in the art using means known to those skilled in the art to protect undesired directions of the reaction. For example, when R 1 has free primary or secondary hydroxyl groups, it is not necessary but preferable to protect them with an alcohol protecting group in the preparation of the 5-hydroxymethyl substituted oxazolidinones (III). The unprotected alcohol functionality will generally not affect the reaction of the dihydroxy compound (I) or glycidol (IV) with the carbamate (IIA) to form 5-hydroxymethyl substituted oxazolidinones (III). However, the unprotected functional group of the alcohol will generally affect the conversion of the 5-hydroxymethyl substituted oxazolidinones (III) (alcohols) to the corresponding 5-aminomethyl substituted oxazolidinones (VII) (amines) because it is very difficult or impossible to selectively protect the 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 to those skilled in the art, preferably C₁-C₅ alkyl, &lt;I&gt; -CH₂-, CH₃-O-CH₂-, CH₃-, CH₃-S-CH₂-, &lt;I&gt; -CH₂-O-CH₂-, tetrahydropyranyl, CH₃CH (-OC₂H.₅) -, p-methoxybenzyl, p-methoxyphenyl, p-nitrobenzyl, (Φ) ^ -, (CH₃)₃Si-, [CH₃-CH (CH₃)]₃S._and-, Φ (CH₃)₂Si-. These protecting groups are removed by means known to those skilled in the art. For example, if R1 i contains a hydroxy substituent, it must be protected during the conversion of 5-hydroxymethyl substituted oxazolidinones (III) (alcohols) to 5-aminomethyl substituted oxazolidinones (VII) (amines), or 5-acylamidomethyl substituted oxazolidinones (VIII). If R1 contains a free primary or secondary amino substituent, it does not need to be protected during the formation of the 5-hydroxymethyl substituted oxazolidinones (III) but must be protected during the conversion of the 5-hydroxymethyl substituted oxazolidinones (III) to the corresponding 5-aminomethyl substituted oxazolidinones (VII) and 5-acylamidomethyl substituted oxazolidinones (VIII). This is because the amino group will generally undergo undesirable reactions during one or more of the steps required to convert the 5-hydroxymethyl substituted oxazolidinones (III) to the corresponding 5-acylamidomethyl substituted oxazolidinones (VIII). Therefore, it is preferable to protect each free substituent on the R 1 functional group before reacting the dihydroxy compound (I) or glycidol (IV) with the carbamate (IIA). Amine protecting groups are well known to those skilled in the art.

PL 192 691 B1

Preferred amino protecting groups include:

(I) C1-C4 alkyl, (II) φ-οη₂-, (III) (Φ) 3θ-, (IV) R_and-CO- where R._and is (A) H-, (B) C₁-C₄ alkyl, (O) C₅-C₇ cycloalkyl, (D) (C₁-C₅ alkyl) -O-, (E) C1₃C-CH₂-O-, (F) H.₂C = CH-CH₂-ABOUT-_; (G) φ-ΟΗ = ΟΗ-ΟΗ₂^ -, (H) φ-OH ^ O-, (I) p-methoxyphenyl-OH₂-O-, (J) p-nitrophenyl-OH₂-ABOUT-_; (K) φ-O-, (L) OH₃-OO-OH₂-, (M) (OH₃)₃Si-O-, (V) R_b-SO₂- where R._b is (A) (O₁ alkyl) -, (B) φ, (O) p-methylphenyl- and (D) φ-OHr. A preferred amino protecting group is a benzyloxycarbonyl group which can be removed by catalytic hydrogenation as known to those skilled in the art. There is nothing new about the use of protecting groups in these reactions or the properties of individual protecting groups. All of this is well known to those skilled in the art. The protecting groups may be removed after the last reaction in which the protected substituent would participate and removed by subsequent reactions as is known to those skilled in the art. For example, it may be advantageous to maintain the protecting group until the final acylation step is complete as is known to those skilled in the art. Optionally, the R 1 substituent may be modified after the formation of the 5-acylamidomethyl substituted oxazolidinones (VIII) depending on what chemical reactions are required, which is also known to those skilled in the art.

The reaction of the dihydroxy compounds (I) or glycidol (IV) with carbamates (IIA) leads to the same 5-hydroxymethyl substituted oxazolidinones (III). The choice of whether to use dihydroxy compound (I) or glycidol (IV) to prepare the particular 5-hydroxymethyl substituted oxazolidinone (III) has to be made on a case by case basis. There are no 'win-win' starting substances; there is no advantageous way based on chemistry alone. The decision should depend in each case on the commercial availability of a particular substrate, its chemical and enantiomeric purity, price, etc., which is known to those skilled in the art.

As indicated above, one method of the present invention is to react a dihydroxy compound (I) or glycidol (IV) with a carbamate (IIA) in the presence of a lithium cation (Li⁺) and a base with which the conjugate acid has a pKa greater than 8.

The method requires the use of about one molar equivalent of either the dihydroxy compound (I) or glycidol (IV) / equivalent carbamate (IIA). The reaction requires a base, the nature of which is not critical as long as it is strong enough to deprotonate the carbamate (IIA). Bases are applicable where the pKa of the conjugate acid is greater than 8. The preferred bases have been mentioned above.

They include compounds selected from the group consisting of:

alkoxy compounds having 1-7, especially 4-5 carbon atoms, e.g. 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 to form a lithium cation and base in situ.

The nature of the solvent is also not critical. Suitable solvents include cyclic ethers such as THF, amides such as DMF and DMAO, amines such as triethylamines, acetonitrile, and alcohols such as t-amyl alcohol and t-butyl alcohol.

The choice of solvent depends on the solubility of the carbamate (IIA) as known to those skilled in the art.

When the starting material is the dihydroxy compound (I) as mentioned above, it may be advantageous to react the dihydroxy compound (I) with the cyclizing agent before contacting the carbamate (IIA). The term "cyclining agent" denotes a base that cyclizes the dihydroxy compound (I) to glycidol (IV). Usable cyclizing agents include bases with which the conjugate acid has a pka greater than 7;

Preferably the reaction is performed at a temperature of &lt;100 °, more preferably at a temperature of &lt;70 °, even more preferably at &lt;50 ° and most preferably at &lt;25 °. The reaction can be carried out at room temperature (20-25 ° O). At 20 ° C, the reaction takes about 8 hours to reach a complete conversion (in DMAO). If a faster reaction is required, it can be carried out at a higher temperature. As stated above, it is difficult to distinguish between primary alcohols and secondary alcohols. Simple alcohol is formed in the cyclization reaction.

PL 192 691 B1

For example, when benzyl carbonate is cyclized, benzyl alcohol is formed. Removal of this alcohol is necessary for the successful conversion of the alcohol to amine. This is done by crystallization using ethyl acetate / heptane (1/2). The benzyl alcohol remains in solution and the desired oxazolidinone alcohol is isolated as a solid.

SCHEME C discloses methods to convert 5-hydroxymethyl substituted oxazolidinones (III) (alcohols) to the corresponding 5-aminomethyl substituted oxazolidinones (VII) (amines). The situation of protecting the alcohol and / or amino groups on the R 1 function was discussed above. The 5-hydroxymethyl substituted oxazolidinones (III) (alcohols) are contacted with a sulfonating agent (Va-Vb) of two types, namely M3-SO2-C6Hn3 (NO2) n1Cln2 (Va), O [-SO2-C6Hn3 (NO2) n1Cln2] 2 (Vb). M3 is a leaving group that includes Cl- or Br-; preferably Cl-. The 5-hydroxymethyl substituted oxazolidinones (III) are contacted with a sulfonating agent (Va-Vb) to form the oxazolidinone sulfonate intermediate (VIa-VIb).

The sulfonation reaction to convert the 5-hydroxymethyl substituted oxazolidinones (III) to the corresponding oxazolidinone sulfonates (VI) is carried out by contacting the 5-hydroxymethyl substituted oxazolidinones (III) with at least one molar equivalent of the sulfonating agent (Va-Vb) in the presence of a base in an inert solvent at a temperature of about 0 ° C. Usable bases include triethylamine, tributylamine, diisopropylethylamine, DABCO, DBU, DBN, n-butyllithium, ethylmagnesium chloride, and their equivalents; triethylamine is preferred. The inert solvents include, at best, organic solvents such as methylene chloride, THF, DMA, DMF, ethyl acetate, and their equivalents; methylene chloride is preferable.

The ammonolysis reaction to convert the oxazolidinone sulfonates (VI) to the corresponding 5-aminomethyl substituted oxazolidinones (VII) (amines) is carried out under open conditions without sealing, although it is preferably carried out under sealing conditions.

In any case, the ammonolysis reaction is carried out as mentioned above by contacting the oxazolidinone sulfonates (VI) with ammonia (preferably an aqueous solution), preferably in a solvent or solvent mixture. Solvents which dissolve both the oxazolidinone sulfonates (VI) and the aqueous ammonia solution are preferred, since by dissolving the two substances contact between them is ensured. However, the process is also applicable with solvents that only partially dissolve the oxazolidinone sulfonates (VI); the disadvantage is that the reaction is generally slower. In the case of the m-nitrobenzenesulfonates, the preferred solvent is acetonitrile / isopropanol or THF / isopropanol. The system is placed under reduced pressure.

The system is then closed or sealed, and ammonia (preferably aqueous ammonia) is added and heated to a temperature of less than 50 ° C, preferably less than 40 ° C, more preferably 38 ° C (121 kPa). At 38-40 ° C, the pressure is 0-169 kPa, which is below the upper pressure limit for general purpose reactors. Under these conditions, at a temperature of about 60 ° C, the pressure is about 238 kPa. Preferably the ammonolysis reaction is carried out at a pressure of 0 - 238 kPa, preferably 0 - 135 kPa and a temperature of 60 ° C or less. Alternatively, the reaction is carried out in an open system at reflux temperature. In this case, the temperature will be slightly lower and the reaction will take a little longer to reach complete conversion. The ammonia can be in the form of an aqueous, alcoholic or anhydrous solution; however, an aqueous ammonia solution is preferable.

Alternatively, as indicated above, the contact with the aqueous ammonia solution may be carried out in the presence of an aromatic aldehyde (IX, Ar-CHO), preferably salicylaldehyde. The 5-aminomethyl substituted oxazolidinones (VII) (amines) and the aldehyde (IX) form a SchifTa base of formula (oxazolidinone-N = CH-Ar) which is then hydrolyzed with an aqueous acid solution as known to those skilled in the art to produce the desired 5-aminomethyl substituted oxazolidinones (VII). Aromatic aldehyde (IX) is useful in inhibiting the formation of dimers.

The 5-aminomethyl substituted oxazolidinones (VII) (amines) are acylated using known agents such as acyl halides or acyl anhydrides to give the corresponding 5-acylamidomethyl substituted oxazolidinones (VIII), see SCHEME D. Any alcohol or amine protecting groups must be removed after the formation of the 5-acylamidomethyl substituted oxazolidinones (VIII). However, they may be removed earlier in the run

The reaction depends on the particular substituents indicated as known to those skilled in the art.

The 5-acylamidomethyl substituted oxazolidinones (VIII) are known as pharmaceutical antibacterial agents.

The following definitions and symbols are used throughout the text of the document, including both the specification and the claims.

The chemical formulas in the specification and claims for various compounds and molecular fragments may contain various substituents in addition to the clearly marked structural features. The various substituents are defined by letters or letters followed by a numeric subscript, for example, Z1 or Ri where i is an integer. These heterogeneous substituents are either monovalent or bivalent, that is, they represent a group linked to the formula through one or two chemical bonds. For example, a group Z1 can represent a bivalent substituent when bound to the formula CH3-C (= Z1) H. The RI and Rj groups may be different monovalent substituents when bound to the formula CH3-CH2-C (Ri) (Rj) H. When chemical formulas are drawn linearly, such as those above, the variable substituents enclosed in the parentheses are attached to the atom immediately to the left of the variable substituent enclosed in the parentheses. When two or more consecutive different substituents are inside parentheses, each of the consecutive different substituents is bonded to the left-most atom that preceded it that is not included in parenthesis. Thus, in the above formula, RI and Rj are both bonded to the preceding carbon atom. Also, for each molecule with a stabilized carbon numbering system, such as steroids, these carbon atoms are denoted as Ci, where "i is an integer corresponding to the carbon number. For example, C6 represents the 6-position or the carbon number of the steroid molecule as is conventionally used by those skilled in the art of steroid chemistry. Similarly, "R6" represents a variable substituent (either monovalent or bivalent) at the C6 position.

Linearly drawn chemical formulas or their fragments denote atoms in a linear chain. Symbol - usually denotes a bond between two atoms in the chain.

Thus CH3-O-CH2 - CH (Ri) -CH3 is 2-substituted-1-methoxypropane. Similarly, the symbol = represents a double bond, e.g. CH₂= C (Rj) -O-CH₃and the symbol '= represents a triple bond, e.g. HC C-CH (R) -CH₂-CH₃. Carbonyl groups are represented in one of these two ways: -CO- or -C (= O) - with the first notation being preferred for its simplicity.

Chemical formulas of cyclic (ring) compounds or fragments of their molecules can be presented in a linear fashion. Thus, 4-chloro-2-methylpyridine can be represented linearly N * = C (CH3) -CH = CCl-CH = C * H according to the agreement that the atoms marked with an asterisk (*) are bonded together causing ring formation . Similarly, cyclic molecular fragments 4- (ethyl) -1-piperazinyl can be represented as -N * - (CH2) 2-N (C2H5) -CH2-C * H2.

The rigid cyclic (ring) structure for any compound presented herein determines the orientation with respect to the ring plane of the substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds that have two substituents attached to a carbon atom that is part of a cyclic system, -C (X1) (X2) -, the two substituents can be either axial or equatorial with respect to the ring and transition between axial / equatorial. However, the position of the two substituents relative to the ring and each other remains constant.

Although each substituent may sometimes lie in the plane of the ring (equatorial position) rather than above or below the plane (axial position), one substituent is always above the other. In chemical structural formulas representing such compounds, the substituent (X1) which is "downstream of another substituent (X2) will be referred to as being in the alpha (α) configuration, which is indicated by a broken, dashed or dotted line of attachment to the carbon atom, i.e. . symbol - - - or .... A suitable substituent linked upstream (X2) to another (X1) is referred to as a beta (β) substituent as denoted by an uninterrupted bond to the carbon atom.

When a variable substituent is bivalent, the valences may be taken together or separately, or both in the definition of the substituent. For example, Ri attached to a carbon atom as -C (= Ri) - may be bivalent and may be defined as oxo or keto (forming a carbonyl (-CO-) group or as two separately attached monovalent a-Rj and β- substituents. Rk .. When the bivalent substituent R | is defined as consisting of two monovalent substituents, the conventional notation used to denote a bivalent substituent

The PL 192 691 B1 has the form a-Rj eR_ik or some variant of it. In this case, both aR and eR_ik are attached to a carbon atom to give -C (aR_and-j) (pR_ik)-.

For example, when a bivalent substituent R6, -C (= R6) - is defined as consisting of two monovalent substituents, the two monovalent substituents are a-R6- i: e-Rg-2, aR1: pR2o, etc. to give -C (a-R6-i) (PR₆-2) - -C (a-R6-g) (β-Ra-io) -, etc. Similarly, for the bivalent substituent R11, -C (= R11) -, the two monovalent substituents are aR₁₁.₁ : eR₁₁.₂. For a ring substituent for which separate a and β orientations do not exist (e.g., due to the presence of a carbon-carbon double bond in the ring), and for a substituent attached to a carbon atom that is not part of the ring, the conventional notations above apply, with which omits the notations a and β.

Just as a bivalent substituent can be defined as two separate monovalent substituents, also two separate monovalent substituents can be defined as taken together to form a bivalent substituent.

For example, in the formula -C1 (Ri) H-C2 (Ri) H- (C1 and C2 are arbitrarily the first and second carbon atoms, respectively) Ri and Rj can be determined to form (1) an additional bond between C1 and C2 or (2) a divalent group such as oxa (-O-), then the formula represents an epoxy. When RI and Rj are taken together to form a more complex moiety, such as the group -XY-, then the orientation of the moiety is such that C1 in the above formula is linked to X and C2 is linked to Y.

Thus, the term ... Ri and Rj taken together form -CH2-CH2-O-CO- means a lactone wherein the carbonyl is bound to C2. However, for the definition of ... Rj and Ri taken together form -CO-O-CH2-CH2- the term denotes a lactone in which the carbonyl group is attached to C1.

The carbon content of the various substituents is indicated in two ways. The first uses a prefix such as C1-C4 in front of the entire name of the substituent, where 1 and 4 are both integers representing the minimum and maximum number of carbon atoms in the substituent. The prefix is ​​separated by a space from the substituent. For example, C1-C4 alkyl is an alkyl group of 1 to 4 carbon atoms (including its isomeric forms, unless otherwise expressly indicated). Whenever this single prefix is ​​given it indicates the total carbon content of the substituent being specified. Thus, C2-C4 alkoxycarbonyl describes the group CH3- (CH2) nO-CO- where n is zero, one or two.

In a second method, the carbon content of each part of the term is separately indicated by placing the notation Ci-Cj in parentheses immediately (with no space) before the defined part of the term. In this alternative notation, (C1-C3) alkoxycarbonyl has the same meaning as C2-C4alkoxycarbonyl because C1-C3 only refers to the number of carbon atoms in the alkoxy group. Likewise, although both C2-C6alkoxyalkyl and (C1-C3) alkoxy (C1-C3) alkyl are alkoxyalkyl groups containing 2 to 6 carbon atoms, the two definitions differ because the former allows either the alkoxy or the alkyl portion to be itself contains 4 or 5 carbon atoms, while the latter definition limits each of these groups to 3 carbon atoms.

When the claims contain a very complex (cyclic) substituent, at the end of the phrase relating to the name / designation of that particular substituent there will be a conventional designation (in parentheses) corresponding to the same name / designation on one of the SCHEME sheets, which also gives the chemical structural formulas of that particular substituent.

All temperatures are expressed in degrees Celsius.

TLC means thin layer chromatography.

THF means tetrahydrofuran.

DMF means dimethylformamide.

DBU is 1,8-diazabicyclo [5,40] undec-7-ene.

DBN is 1,5-diazabicyclo [4.3.o] non-5-ene.

DABCO is 1,4-diazabicyclo [2.2.2] octane.

DMA means dimethylacetamide.

Saline is a saturated aqueous sodium chloride solution.

Chromatography (column chromatography or flash chromatography) means purification / separation of compounds identified as (carrier / eluent). It is understood that the appropriate fractions are diluted and concentrated to obtain the desired compound (s).

PL 192 691 B1

LR stands for Infrared Spectroscopy.

CMR stands for Magnetic Resonance Spectroscopy ¹³C, the chemical shift is expressed in ppm (δ) with respect to tetramethylsilane.

NMR means (proton) magnetic resonance spectroscopy, the chemical shift is expressed in ppm (δ) with respect to tetramethylsilane.

φ is phenyl (C6H5).

[and]_D²⁵ is the rotation angle of the plane of light polarization (specific optical rotation) at 25 ° using the D line of sodium light (589A).

MS means mass spectrometry expressed as m / e or mass / charge. [M + H]⁺ refers to the positive ion of the parent molecule plus a hydrogen atom. EI stands for electron bombardment. CI stands for Chemical Ionization. FAB stands for Fast Atom Bombardment.

HRMS stands for High Resolution Mass Spectrometry.

"Pharmaceutically acceptable means those properties and / or substances which are acceptable to the patient from a pharmacological / toxicological point of view and to the producing chemist from a physical / chemical point of view in terms of composition, form, stability, patient acceptance and bioavailability."

When a pair of solvents is used, the ratio of these solvents is expressed as volume / volume (v / v).

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

NNNNNN-NN-N refers to the Chemical Abstracts Service Registry Number (CAS, Columbus, Ohio) where each N represents an integer from 0 to 9 but by deleting the preceding zeros in the six-membered number. Registration numbers are assigned to a specific chemical on the basis of CAS criteria, provided that the compound has been identified as existing and has been identified in some way. Compounds published approximately from 1967 to the present are openly registered and the registration number is the key to finding references in the CAS database for a registered compound. The CAS database is widely available from several database vendors such as STN International, System Development Corporation (SDC) Orbit Search Service, Lockheed Dialog, Bibliographic Retrieval Systems, Qestrel, etc. CAS registration numbers are included in the examples for those compounds that have been registered.

EXAMPLES

Example 1. (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III)

A mixture of N-carbobenzoxy-3-fluoro-4- (N-carbobenzoxypiperazinyl) aniline (II, J. Med. Chem., 39 (3), 673 (1996)), 100 g 98.4% pure substance, 0.2133 moles) in DMAC (300 ml) cooled to 0 °. In a separate vessel, a mixture of t-amyl alcohol (75 mL, 60.37 g, 0.0685 mol, 3.23 eq.) And heptane (75 mL) was cooled to -10 ° and treated with n-butyllithium in heptane (290 mL , 203 g 14.4% w / v a solution, containing 29.2 g or 0.456 moles = 2/15 eq. of n-butyllithium, keeping the temperature below 10 °. The lithium t-amylate mixture was then added to the N-carbobenzoxy-3-fluoro-4- (N-carbobenzoxypiperazinyl) aniline (II) keeping the temperature below 10 °.

Neat S - (+) - 3-chloro-1,2-propanediol (I, CAS # 60827-45-4, 22 mL, 29.1 g, 0.263 mol, 1.24 eq.) Was then added, rinsing with a small amount of heptane. The reaction mixture was then stirred at 20-25 ° and monitored by TLC (methanol / methylene chloride; 5/95) until the reaction was complete. The reaction mixture was then added to a mixture of acetic acid (40 ml, 42.0 g, 0.699 mol, 3.29 eq) in methanol (700 ml) and water (700 ml). The resulting suspension was stirred at 20-25 ° for 30 min, cooled to 0 °, stirred at 0 ° for 30 min, and filtered. The filter cake was washed with methanol / water (50/50) and dried in vacuo to afford the title compound, TLC (methylene chloride / methanol, 95/5) Rf = 0.43.

Example 2. (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III)

T-Amyl alcohol (0.967 g, 10.97 mmol, 2.571 eq.) Was cooled to -10 °. Butyllithium (4.3 mL, 2.5 M in hexane, 10.8 mmol, 2.5 eq.) Was added while stirring and keeping the temperature below 5 °.

N-carbobenzoxy-3-fluoro-4- (N-carbobenzoxypiperazinyl) aniline (II, 1.9780 g, 4.267 mmol, 1.000 eq.) And dimethylacetamide (6.2 ml) were mixed and cooled to -25 ° to give a rare suspension. Then to the mixture of N-benzyloxycarbonyl-3-fluoro-4 - ((4-benzyloxycar12

A mixture of lithium t-amylate was added to the bonyl) -1-piperazinyl) aniline (II) keeping the temperature below -20 °. The resulting mixture was warmed to 0 ° and S - (+) - 3-chloro-1,2-propanediol (I, 0.5672 g, 5.131 mmol, 1.20 eq.) Was added. The resulting mixture was heated to 21 ° and stirred for 7.5 h.

The reaction mixture was added to a mixture of methanol (28 ml) and glacial acetic acid (0.73 ml, 12.75 mmol) at 20-22 °. The resulting slurry was then cooled to -30 ° and the product collected by vacuum filtration and washed with methanol at -30 °. The solid was dried under a stream of nitrogen to give the title compound, TLC (eluent chloroform / methanol, 90/10), Rf = 0.67;

CMR (CDCl3) 43.91, 46.39, 50.58, 62.60, 67.29, 72.89, 107.21, 107.56, 113.85, 119.36, 127.92, 128, 09, 128.52, 133.51, 133.65, 136.05, 136.17, 136.57, 153.91, 154.80, 155.25 and 157.17 δ;

NMR (CDCl3) 7.43, 7.31-7.37, 7.09, 6.88, 5.15, 4.67-4.90, 3.89-3.99, 3.67-3, 74, 3.66, 3.25 and 2.98 δ;

MS (Cl, m / e) = 430 (100%, P + 1).

Example 3. (R) - [N-3- (3-Fluoro-4- (4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methanol (III)

Tetrahydrofuran (3.0 mL) and amyl alcohol (0.66 mL, 6.03 mmol, 2.00 eq.) Were mixed. Butyllithium (1.8 ml, 2.5 M in hexane, 4.55 mmol, 1.5 eq.) Was added while stirring and keeping the temperature below 2.5 °.

A mixture of N-carbobenzoxy-3-fluoro-4-morpholinylaniline II, J. Med. Chem., 39 (3), 673 (1996), 0.9942 g, 3.009 mmol, 1.000 eq.) And tetrahydrofuran 3.5 ml) stirred and cooled. The t-amylate mixture was then added to the carbamate mixture (II) keeping the temperature below 8 ° and washed with tetrahydrofuran (1 ml).

Tetrahydrofuran (3.2 mL) and S - (+) - 3-chloro-1,2-propanediol (I, 0.299 mL, 3.58 mmol, 1.19 eq.) Were mixed. The mixture was cooled to -16 ° and t-butoxide (3.2 mL, 1.0 M in tetrahydrofuran, 3.2 mmol, 1.07 eq.) Was added keeping the temperature below -10 °. The resulting suspension was stirred at -14 to 0 ° for 1 h, then a lithium anion mixture was added keeping both mixtures at 0 °, then washed with THF (2 mL). The resulting suspension was stirred at 20-23 ° for 2 h. then cooled to 6 ° and a mixture of acetic acid monohydrate (0.4459 g, 2.122 mmol, 0.705 eq.) in water (10 ml) was added. The resulting liquid phases were separated and the lower aqueous phase was washed with ethyl acetate (12 ml). The organic layers were combined and the solvent was removed under reduced pressure until the weight of the residue was 9.73 g. Heptane (10 ml) and water (5 ml) were added and the solvent was removed under reduced pressure until a total residual volume of 5 ml. The precipitated product was collected by vacuum filtration and washed with water (7 ml). The solid was dried under a stream of nitrogen to afford the title compound, TLC (chloroform / methanol, 95/5) Rf = 0.23;

CMR (CDCl3) 46.42, 51.01, 62.58, 73.07, 107.29, 107.64, 113.94, 118.80, 118.85, 128.28, 128.61, 133, 15, 133.29, 136.26, 136.38, 153.82, 154.92 and 157.08 δ;

NMR (CDCl3) 7.42, 7.32-7.37, 7.10, 4.67-4.75, 3.90-4.00, 3.86, 3.70-3.73, 3, 44 and 3.03 δ;

MS (EI, m / e) = 296.

Alternatively, the crude product can be extracted with methylene chloride. The solvent was removed under reduced pressure. The solid was redissolved in hot ethyl acetate, heptane was added, and the mixture was cooled to provide the title compound.

Example 4. (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III)

A solution of amyl alcohol (75 ml, 60.3 g, 0.68 m) and heptane (75 ml) was stirred and cooled to -10 ° C. The mixture was treated with n-butyllithium in heptane (1.6 M, 0.46 m, 290 ml) for a period of 30 min, keeping the temperature &lt;10 ° C. After 30 min, a mixture of lithium t-amylate was added at 0 ° C to a mixture of N-carbobenzoxy-3-fluoro-4- (N-carbobenzoxypiperazinyl) aniline (II, 100 g, 0.22 m) and dimethylacetamide (300 ml) at 0 ° C. temp. &lt;10 ° C. The mixture was stirred for 30 min and then treated with S - (+) - 3-chloro-1,2-propanediol (1.22 mL, 0.26 m). Cooling was eliminated, and the mixture was allowed to warm to 20-25 °. The reaction was monitored by TLC and the reaction was found to be complete after about 8 hours. The reaction mixture was poured into a mixture of methanol (700 ml), water (700 ml) and acetic acid (40 ml) and stirred for 30 min at 20-25 °, then stirred for 30 min with cooling to 0 ° C. The mixture was filtered, washed with aqueous methanol (50/50) and dried under reduced pressure at 45 ° C to give the title compound, TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.5 ( yield 90.3%).

PL 192 691 B1

Example 5. (R) - [N-3- [3-fluoro-4- (N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate (VI)

A mixture of (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III, example 1, 43 g, 0.1 m) and methylene chloride (500 ml) was treated with triethylamine (32 ml, 0.23 m) and cooled to -5 ° C. To this mixture was added a mixture of 3-nitrobenzenesulfonyl chloride (CAS # 121-51-7, 32 g, 0.14 ml) in methylene chloride (60 ml) maintaining the temperature &lt;10 ° C for more than 1 h.

The reaction was monitored by TLC and the reaction was found to be complete after 45 min. The mixture was diluted with methylene chloride (500 ml) and then washed with water (2 x 600 ml). The organic phase was then washed with chloroacetic acid (IN, 400 ml) and concentrated to a thick residue. The residue was diluted with methanol (200 ml) and stirred for 1.5 h. The solid was filtered off, washed with methanol and dried in vacuo at 40 ° C overnight to provide the title compound, TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.75.

Example 6. (S) -N - [[3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (VII)

A suspension of (R) - [N-3- [3-fluoro-4- (N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate (VI, example 5, 50 g, 0.081 ml), isopropanol (250 ml), acetonitrile (400 ml) and an aqueous ammonium hydroxide solution (29% w / w ammonia, 500 ml) at 40 ° C for 3.5 h. Then the mixture was treated with an aqueous solution ammonia with higher water content (100 ml) and stirred for 20 h. The reaction was monitored by TLC and was found to be complete within this time. The mixture was concentrated under reduced pressure with heating and suspended in methylene chloride / water (1250 ml / 750 ml). The phases were separated and the organic phase was concentrated to a residue.

The residue was dissolved in methylene chloride (2 L) and treated with triethylamine (20 mL, 0.14 m). The mixture was then treated with acetic anhydride (10 ml, 0.11 m) at 20-25 ° for 10 min. The acetylation was monitored by TLC and the reaction was found to be complete after 15 min. The organic mixture was washed with water (2 x 400 ml) then concentrated to a solid. The solid was recrystallized from ethanol (400 ml), filtered and dried in vacuo to give the title compound, TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.6.

Example 7 (S) -N - [[3- [3-Fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride (intermediate)

A mixture of (S) -N - [[3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (VII, example 6 , 35 kg, 74.5 mol), palladium on carbon (5%, 10 kg, 50% w / w water), methanol (550 L) and tetrahydrofuran (250 L) shaken at 22 to 42 ° C under a pressure of 290 - 345 kPa of hydrogen. After 31 hours, TLC analysis showed that the reaction was complete and the hydrogen atmosphere was replaced with nitrogen. The catalyst was removed by filtration and the filtrate concentrated in vacuo to 100 L. To the remaining mixture, cooled to 2 ° C, methanol (50 L) was added followed by a mixture of methanol (100 L) and acetyl chloride (6.04 kg, 77 mol) at -2 ° C to 6 ° C. The resulting mixture was stirred 90 minutes then concentrated in vacuo to 60L, diluted with acetone (100L) and further concentrated to 100L. The resulting suspension was diluted with acetone (200L) and stirred 15h. at 16 ° C. The solid was collected on a filter, washed with acetone (50 L) and dried in vacuo at 20-25 ° to give the desired product. It was dissolved in methanol (56 L) at 53 ° C, diluted with acetone (150 L), stirred for 30 minutes at 48 ° C, then cooled to 15 ° C and stirred 18 h. The solid was collected on a filter, washed with acetone (50 L) and dried in vacuo at 20-25 ° to give the title compound,

NMR (CDCl3) 7.56-7.45, 7.31, 7.12-6.86, 4.79, 4.09-4.0, 3.81, 3.62, 3.40-3, 11 and 2.01 δ.

Example 8 (S) -N - [[3- [3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - sesquihydrate acetamide (VIII).

To a stirred mixture of (S) -N - [[3- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride (example 7, 16.2 kg, 43 , 5 moles), tetrahydrofuran (205 kg), and triethylamine (10.1 kg, 100 moles) were added acetoxyacetyl chloride (6.5 kg, 47.8 moles) in tetrahydrofuran (11.1 kg) over 35 minutes, keeping the temperature at 22 -23 ° C. After 40 minutes, when TLC and HPLC analyzes indicated complete formation of acetoxyacetamide intermediate, the mixture was concentrated in vacuo to 30L, diluted with methanol (100L and concentrated to 30L. Methanol (25L) and aqueous potassium carbonate (5L) were added to the residue. 6 kg in 56 L) The remaining mixture was stirred for 20 h at 22-25 ° C after which time TLC and HPLC analysis indicated complete conversion.

Exaggeration. The pH was adjusted to 7-7.5 with chloroacetic acid (4 N, 14.3 L). The mixture was stirred for 18 h. at 15-22 ° C, and then for 3 hours. at 2-5 ° C. The solid was collected on a filter, washed with water (68 L) and dried at 20-25 ° with nitrogen purge to give the desired product. The crude product was dissolved in water (225 L) at 60-70 ° C, clarified through a 0.6 micron filter, diluted with water, washed (55 L) and stirred for 17 h. at 15 ° C. The solid was collected on a filter, washed with water at 15 ° C and dried at 45 ° C under nitrogen purge to a water content of 0.33%. This solid was dissolved in a solution of ethyl acetate (143 L), methanol (65 L) and water (1.95 L) at 60-65 ° C. The solution was cooled to 15-25 ° C and stirred for 16 h. in order to crystallize. The solid was collected on a filter, washed with ethyl acetate (75 L) and dried with nitrogen at 45 ° C to give the desired product. The product was recrystallized twice from water (147 L then 133 L) at 60-70 ° C, clarified each time through a 0.6 micron filter and washed with water (40 L 30 L). The solid was dried on a filter at 30 ° C with a nitrogen purge to give the title compound as a sesquihydrate (6.45% water) after deagglomeration in a mill. TLC (silica gel; methanol / methylene chloride, 5/95) R_f = 0.45; [and]_D = -20 ° (c = 1.0, ethanol).

Example 9. (R) - [N-3- [3-fluoro-4- (N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate (VI)

To a suspension of (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III, example 1, 5.086 g , 11.86 mmol) in methylene chloride (50 ml) and triethylamine (2.0 ml, 14.38 mmol) at 0 ° C were added dropwise over 6 minutes a solution of 3-nitrobenzenesulfonyl chloride (V) in methylene chloride (0.356 M, 33.4 ml, 11.89 mmol). After stirring for 3.25 h, an additional 3.4 ml (1.21 mmol) of a 0.356 M solution of 3-nitrobenzenesulfonyl chloride (V) was added. After stirring for 1.75 h, hydrochloric acid (IN, 50 ml) was added. The phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The concentrate was crystallized from hot methylene chloride / methanol to give the title compound, mp = 155-157 °;

NMR (CDCl3, 400 MHz) 8.72, 8.51, 8.23, 7.81, 7.35, 7.01, 6.91, 5.17, 4.85, 4.44, 4.39 , 4.09, 3.85, 3.68 and 3.01 δ;

CMR (CDCl3, 100 MHz) 44.26, 46.81, 50.91, 67.64, 69.54, 69.91, 107.85, 114.32, 119.85, 123.55, 128.30 , 128.47, 128.91, 129.15, 131.51, 133.71, 136.99, 137.70, 148.71, 153.62, 155.57 and 155.88 δ; LR (mineral oil suspension test) 1744, 1703, 1528, 1520, 1367, 1347 and 1192 cm^-1;

MS (EI, M / Z) 614,411, 107, 91, 79, 65 and 56; [α] D = -78 ° (c = 0.9812, CHCl3); TLC (ethyl acetate / hexane, 3/1) R f = 0.43.

Example 10. (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 2-nitrobenzenesulfonate ( VI)

Following the general procedure of example 5 (for (VI) 3-nitrobenzenesulfonyl ester) and making minor changes, (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III, Example 1, 1.106 g, 2.578 mmol) was treated with triethylamine (0.54 ml, 3.882 mmol) and commercial grade 2-nitrobenzenesulfonyl chloride (V, 679 mg, 3.064 mmol) to give the title compound,

NMR (CDCl3, 400 MHz) 8.15, 7.82, 7.37, 7.06, 6.94, 5.17, 4.89, 4.59, 4.50, 4.10, 3.98 , 3.69 and 3.03 δ; IR (mineral oil suspension test) 1757, 1697, 1517, 1445, 1423, 1376, 1237 and 1188 cm^-1;

MS (EL, M / Z; averaged): 614 (18.3, M⁺), 91 (100), 69 (23.8) and 56 (52.9); TLC (ethyl acetate / hexane, 3/1) R f = 0.31.

Example 11 (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2,4-dinitrobenzenesulfonate ( VI)

Following the general procedure in Example 5 (for 3-nitrobenzenesulfonyl) and making minor changes to (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2- oxo-5-oxazolidinyl] methanol (III, Example 1, 1.094 g, 2.550 mmol) was treated with triethylamine (0.55 mL, 3.950 mmol) commercially grade 2,4-dinitrobenzenesulfonyl chloride (833 mg, 3.124 mmol) to give the title compound ,

NMR (CDCl3, 400 MHz) 8.59, 8.38, 7.35, 7.02, 5.17, 4.88, 4.74, 4.58, 4.10, 3.98, 3.71 , and 3.05 δ; IR (mineral oil suspension test) 1756, 1697, 1554, 1541, 1517, 1351, 1237 and 1189 cm^-1;

MS (FAB, M / Z, averages) 660 (21.3, [M + H]⁺), 659 (24.2, M.⁺), 102 (76.5) and 91 (100); TLC (ethyl acetate / hexane, 3/1) R f = 0.41.

PL 192 691 B1

Example 12 (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 4-chlorobenzenesulfonate ( VI)

To a suspension of (R) - [N-3- [3-fluoro-4- [N-1- (4-carbo-benzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III, example 1, 3.450 g, 8.034 mmol) in methylene chloride (40 ml) and triethylamine (2.55 ml, 18.3 mmol) 4-chlorobenzenesulfonyl chloride (V, Aldrich Ohemical Oo - commercial, 2.298 g, 10, 88 mmol) as a solid as a whole. The mixture was stirred in a 0 ° bath for 2.5 h, then washed with water (2 X 35 ml) and 1N hydrochloric acid (35 ml). The organic extracts were concentrated to 20 mL total volume and methanol (50 mL) was added. The precipitate was collected by vacuum filtration, washed with methanol, dried and redissolved in methylene chloride (55 ml). The mixture was concentrated to a 32 g suspension and methanol (11 ml) was added. The precipitate was collected by vacuum filtration, washed with methanol and dried. The solid was then dissolved in methylene chloride (58 ml) and passed through a chromatographic column (silica column, 93 g 40-63 µ; eluted with 450 ml of each of the following 25/75 ethyl acetate / cyclohexane; 35/65; 45/55; 55/45; 50% eluent finally collected). The collected eluent was concentrated to 200 ml and 200 ml of heptane was added. The precipitate was collected by vacuum filtration and dried to afford the title compound; TLO (silica gel; methanol / chloroform 5/95) Rf = 0.53;

MS (FAB, M / Z) = 604.7 (100%, [P + H]⁺);

NMR (DMSO-d6, 300 MHz) 7.93, 6.7, 7.75, 7.48-7.32, 7.12-7.03, 5.12, 4.93-4.92.4 , 40, 4.09, 3.69, 3.57 and 2.96 δ;

OMR (DMSO-d6, 75 MHz) 43.51, 45.84, 50.22, 66.33, 69.75, 70.75, 106.63, 114.08, 119.83, 127.59, 127 , 87, 128.43, 129.62, 130.00, 133.31, 133.63, 135.52, 136.84, 139.63, 153.54, 154.40 and 154.62 δ.

Example 13. (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] 2,5-dichloro-benzenesulfonate] methyl (VI)

To a suspension of (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III, example 1, 3.439 g , 8.008 mmol) in methylene chloride (40 ml) and triethylamine (2.55 ml, 18.3 mmol) at -8 ° added 2,5-di-chlorobenzenesulfonyl chloride (V, Aldrich Ohemical O.- commercial, 2.675 g, 10.90 mmol) as a solid as a whole. The mixture was stirred in a 0 ° bath for 2.5 h, then washed with water (2 X 35 mL), and 1N hydrochloric acid (35 mL). The organic extracts were then concentrated to 12.0 g by column chromatography (silica column, 108 g, 40-63 μ; eluted with 450 ml of each of the following 10/90, 20/80, 30/70, 40/60 mixtures of ethyl acetate / cyclohexane) and 60/40 finally collecting 20% ​​eluent). The collected eluent was concentrated and 300 ml of methanol was added. The precipitate was collected by vacuum filtration, washed with methanol and dried to give the title compound, TLO (silica gel; methanol / chloroform 5/95) Rf = 0.66;

MS (FAB, M / Z) = 638.6 (100%, [P + H]⁺);

NMR (ODO13, 300 MHz) 8.04, 7.57-7.32, 7.06, 6.91, 5.16, 4.89-4.47, 4.42, 4.08, 3.93 , 3.67 and 3.01 δ;

OMR (ODOl3, 75 MHz) 43.93, 45.51, 50.56, 67.26, 69.16, 69.46, 107.55, 113.98, 119.41, 127.92, 128.10 , 128.54, 131.21, 131.46, 132.97, 133.44, 133.50, 134.68, 135.15, 136.45, 136.61, 153.36, 155.22 and 155 , 53 δ.

Example 14 (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 4-nitrobenzenesulfonate ( VI)

To a suspension of (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (III, example 1, 3.437 g , 8.003 mmol) and 4-nitro-benzenesulfonyl chloride (V, 75% technically pure substance, Ohemical Oo - commercial, 3.077 g, 10.41 mmol) in methylene chloride (32 ml) at 0 ° triethylamine (2 , 23 mL, 16.0 mmol). The mixture was stirred in a 0 ° bath for 1 h, then water (1 ml) was added and the mixture was stirred at 20-25 ° for 30 min. Methylene chloride (75 ml) was added and the mixture was washed with hydrochloric acid (5%, 50 ml) then sodium carbonate (5%, 50 ml) and dried over magnesium sulfate. The organic extracts were then concentrated and the concentrate placed in boiling ethyl acetate / cyclohexane (1/1, 10 mL) and passed through a column chromatography (silica gel, 4 cm X 6, 40-63 μ; eluting with about 400 mL of each ethyl acetate / cyclohexane 20/80, 30/70, 40/60, 50/50, 60/40 and 70:30 finally collecting about 45% eluent). The appropriate fractions were combined and concentrated to a solid which was dissolved in 70 mL of methylene chloride and 50 mL of ethyl acetate. The mixture was concentrated to 50 ml twice and cyclohexane (50 ml) was added after each concentration. The sediment was collected by vacuum filtration,

Washed with cyclohexane and dried to afford the title compound, TLC (silica gel; ethyl acetate / cyclohexane 60/40) Rf = 0.37;

NMR (CDCl3, 300 MHz) 8.36, 8.07, 7.38-7.29, 7.03, 6.89, 5.15, 4.86-4.80, 4.39, 4.07 , 3.80, 3.67 and 3.00 δ;

CMR (CDCl3, 75 MHz) 43.85, 46.34, 50.45, 67.20, 69.17, 69.57, 107.64, 113.88, 119.34, 124.63, 127.85 , 128.05, 128.49, 129.26, 132.67, 136.48, 136.57, 140.75, 150.95, 153.29, 155.14 and 155.40 δ.

Example 15. (S) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methylamine (VII)

(R) - [N-3- [3-fluoro-4- (N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate (R) - [N-3- [3-fluoro-4- (N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl was stirred under nitrogen at 40 ° C. VI, Example 5, 1.0099 g, 1.643 mol), isopropanol (5.6 ml), acetonitrile (9.0 ml), benzaldehyde (0.50 ml, 4.92 mmol) and aqueous ammonia (29.8 wt% 9.5 ml, 148.6 mmol) The mixture was stirred at 40 ° for 21.5 h, then concentrated under reduced pressure Toluene (13.3 ml) and ethanol (6.0 ml) were added and the mixture was heated in a 70 ° bath. Then citric acid monohydrate (2.433 g, 11.58 mmol) was added over 3.5 hours. and the phases were separated at 64 °. The organic phase was washed with water (2.5 ml) at 64 °. The combined aqueous layers were washed with toluene (10 ml) at 64 °. Then toluene (10 ml) was added to water and the mixture was cooled to 0 °. The precipitate was collected by vacuum filtration, washed with 0 ° toluene (10 ml) and 0 ° water (10 ml) and dried to a solid. A portion of this solid (0.7301 g) was suspended in water (10 ml) and methylene chloride (10 ml) and the pH was adjusted to a value in the range 2.78-13.92 with an aqueous sodium hydroxide solution (50%, 0.12). 3915 g, 4.90 mmol) at -4 to -2 °. The mixture was warmed to 20-25 ° and sonicated with stirring for 0.5 h. Methylene chloride (55 ml), saturated aqueous sodium chloride solution (5 ml) and water (35 ml) were added and the phases were separated. The aqueous phase was washed twice with methylene chloride (25 ml) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Toluene (5 ml) was added followed by slow addition of heptane (25 ml). The resulting precipitate was collected by vacuum filtration, washed with heptane (20 ml) and dried to give the title compound, TLC (silica gel; methanol / chloroform 10/90) Rf = 0.32;

MS (EI), M / Z (relative intensity) = 428 (28%, M +), 252 (15%), 92 (32%), 91 (100%);

NMR (CDCl3, 300 MHz) 7.46, 7.38-7.27, 7.12, 6.90, 5.16, 4.69-4.60, 3.98, 3.80, 3.67 , 3.09, 3.00-2.92 and 1.30 δ;

CMR (CDCl3, 75 MHz) 43.94, 44.89, 47.60, 50.63, 67.23, 73.84, 107.29, 113.72, 119.37, 127.92, 128.07 , 128.52, 133.79, 136.05, 136.64, 154.57, 155.19 and 155.61 δ.

Example 16 (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 4-nitrobenzenesulfonate (VI)

To a suspension of (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methanol (III, example 3, 43.0 g, 145 mmol) and triethylamine (36 g, 355 mmol) in methylene chloride (450 ml) at 0 ° C a mixture of 4-nitrobenzenesulfonyl chloride (V, 32 g, 145 mmol) in methylene chloride (55 ml) was added. The mixture was stirred in a 0 ° bath for 30 min and then quenched with hydrochloric acid (10%, 200 ml). The organic phase was separated and the aqueous phase was extracted again with methylene chloride (200 ml). The combined organic extracts were concentrated again by column chromatography (silica gel, 4 cm X 6, 40-63 µ; methanol / methylene chloride 1-2 / 98-99, approx. 8 L). The appropriate fractions were combined and concentrated to give the title compound, Rf = 0.2;

NMR (CDCl3, 300 MHz) 8.73, 8.54, 8.23, 7.82, 7.33, 7.04, 6.91, 4.86, 4.42, 4.12, 3.86 , and 3.05 δ;

CMR (CDCl3, 75 MHz) 46.42, 50.89, 66.87, 69.09, 69.45, 107.45, 113.95, 118.84, 123.14, 128.73, 131.08 , 133.28 and 137.27 δ.

Example 17 condensation product of (S) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methylamine and salicylaldehyde (imine)

A mixture of (R) - [N-3- (3-fluoro-4- (4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl 3-nitrobenzenesulfonate (VI, example 16, 20.608 g, 42.803 mmol), isopropanol ( 149 ml), acetonitrile (245 ml), salicylaldehyde (13.7 ml, 129 mmol) and aqueous ammonia solution (30%, 257 ml, 4.02 mol), heated to 40 ° and stirred at 39-42 ° for 24 hours

The mixture was then cooled to -22 ° and the precipitate was collected by vacuum filtration, washed with water (10 ml) and dried to give the title compound, TLC (silica gel; methanol / chloroform 5/95) Rf = 0.79;

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EIMS (m / z, relative intensity) = 399 (M +, 51) 234 (11), 196 (11), 149 (22), 135 (100), 134 (47);

NMR (300 MHz, CDCl3) 8.44, 7.41, 7.33-6.87, 4.96-4.88, 4.12, 3.94-3.84 and 3.04 δ;

CMR (CDCl3, 75 MHz) 48.21, 50.99, 61.94, 66.95, 71.30, 107.68, 114.12, 117.02, 118.43, 118.82, 119.01 , 131.93, 133.04, 136.51, 154.24, 155.47, 160.78 and 168.87 δ.

Example 18. (S) -N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (VIII)

The imine-product from the previous example (example 17, 1.0068 g, 2.521 mmol) was suspended in water (10 ml) and 37% aqueous hydrochloric acid (0.417 ml, 5.04 mmol) and stirred at 20-25 ° C for 15 hours Toluene (10 ml) was added and the phases were separated; then, the organic phase was washed with hydrochloric acid (1M, 5 ml) and the combined aqueous phases were washed with toluene (10 ml). The resulting toluene wash was extracted with hydrochloric acid (1M, 5 mL). The combined aqueous phases were then adjusted to pH 13.0 with aqueous sodium hydroxide solution (50%, 1.83 g, 22.9 mmol). Methylene chloride (10 ml) and sodium chloride (1 g) were then added to the resulting suspension and the phases were separated. The aqueous phase was then washed with methylene chloride (10 ml). Acetic anhydride (0.472 mL, 5.00 mmol) was added to the combined organic phases while maintaining the temperature at 24-27 °. The mixture was stirred 40 min, then water (5 ml) was added. The phases were separated and the aqueous phase was washed with methylene chloride (5 ml). The combined organic phases were concentrated and ethyl acetate (25 ml) was added. The mixture was heated to 70 ° C and then the resulting mixture was slowly cooled to -25 ° C. The precipitate was collected by vacuum filtration, washed with -25 ° ethyl acetate (5 ml) and dried to give the title compound, HPLC major component (99.93 area percent when detected at 254 nm) retention time = 0.97 min, column = Zorbax RX-C8, 250 X 4.6 mm, mobile phase = 650 ml of acetonitrile, 1.85 ml of triethylamine, 1.30 ml of acetic acid, and enough water to obtain 1000 ml; flow rate = 3ml / min.

Example 19. (R) - [N-3- [3-fluoro-4- [N-1- (4-carbobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl} methanol (III)

A mixture of N-carbobenzoxy-3-fluoro-4- (N-carbobenzoxypiperazinyl) aniline (II, 2.014 g, 4.345 mmol) and THF (10 ml) was cooled to -20 °. In a separate vessel, a solution of amyl alcohol (0.71 mL, 6.48 mmol) in THF (10 mL) at -33 ° was treated with n-butyl lithium in heptane (13.65 wt%, 2.53 g, 5.38 mmol) ), keeping the mixture at a temperature lower than -20 °. The resulting lithium t-amylate solution was then added to the mixture of N-carbobenzoxy-3-fluoro-4- (N-carbobenzoxypiperazinyl) aniline keeping the temperature below -20 ° and washed with THF (4 ml). S-glycidol (IV, 0.3360 g, 4.536 mmol) was then added to the resulting mixture at -28 °. The mixture was then stirred at -20 ° for 1.5 hours, then at -16 ° for 17 hours, at -11 ° for 4 hours and finally at -1 ° for 2 hours. HPLC analysis then showed that the major component has a retention time corresponding to the title compound (90.4 area percent when detected at 254 nm; retention time = 1.30 min; Column = Zorbax RX-C8, 250 X 4.6 mm ; mobile phase = 650 ml acetonitrile, 1.85 ml triethylamine, 1.30 ml acetic acid and addition of sufficient water to obtain 1000 ml; flow rate = 3 ml / min), such as by TLC analysis (silica gel; methanol / chloroform 10/90) Rf = 0.60.

Example 20. (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 4-nitrobenzenesulfonate (VI)

Following the general procedure in Example 16 making minor changes but starting from 4-nitrobenzenesulfonyl chloride to give the title compound.

Example 21 (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2-nitrobenzenesulfonate (VI)

Following the general procedure in Example 16 making minor changes but starting from 2-nitrobenzenesulfonyl chloride to give the title compound.

Example 22 (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2,4-dinitrobenzenesulfonate (VI)

Following the general procedure in Example 16 making minor changes but starting from 2,4-dinitrobenzenesulfonyl chloride to give the title compound.

Example 23 (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 4-chlorobenzenesulfonate (VI)

Following the general procedure in Example 16 making minor changes but starting from 2,4-dinitrobenzenesulfonyl chloride to give the title compound.

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Example 24 (R) - [N-3- [3-fluoro-4-morpholinylphenyl] -2-oxo-5-oxazolidinyl] methyl 2,5-dichloro-benzenesulfonate (VI)

Following the general procedure of Example 16 and making minor modifications but starting from 2,5-dinitro-benzenesulfonyl chloride, the title compound was obtained.

SCHEME A

M._rCH₂-CH (OH) -CH2-OH (I)

R₁-NH-CO-OM₂ (HA)

ABOUT ¹ (HI)

I — Qh

CHg-OH

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SCHEME B c * h₂-oc * h-ch₂-oh (IV) where the carbon atoms marked with * are bonded together to form an epoxy ring +

R₁-NH-CO-OM₂ (HA)

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