Process to prepare oxazolidinones

Description: TECHNICAL FIELD [Detailed description of the invention]

Manufacturing method of oxazolidinone Background of the invention 1. Field of invention The present invention relates to a 5-hydroxymethyl substituted oxazolidinone alcohol (III). Regarding the manufacturing method. Also, 5-hydroxymethyl-substituted oxazolidinone alcohol (I) II), the corresponding 5-ami, useful for the production of oxazolidinone antibacterial drug (VIII) A method for converting to a nomethyl-substituted oxazolidinone amine (VII) is disclosed. 2. Explanation of related technology U.S. Pat. Nos. 5,164,510, 5,182,403 and 5,225,565, respectively, , 5'-Indrinyl oxazolidinone, useful as an antibacterial agent, 3- (5'-in Dazolyl) oxazolidinone, 3- (condensation ring substitution) phenyloxazolidinone It is disclosed. U.S. Pat. Nos. 5,231,188 and 5,247,090 are useful as antibacterial agents. The tricyclics [6.5.5] and [6.6.5] -condensed ring oxazolidinone of. International publication WO93 / 09103 is useful as a medicinal agent due to its antibacterial activity. -And the-Halo A phenyloxazolidinone antibacterial agent is disclosed. U.S. Pat. Nos. 4,150,029, 4,250,318, 4,476,136, 4,340,606 No. and No. 4,461,773 are amines (R-NHX).₁, Here X₁Is -H or p-True (Sulfonyl) and R, S-glycidol (C * H)₂-OC * H-CH₂-OH, here The carbon atoms marked with * bond with each other and cyclize to form an epoxide) The synthesis of 5-hydroxymethyloxazolidinone is disclosed. (Formula R-NH-CH₂-CHOH-CH₂Mix of enantiomers produced by this method (represented by -OH) The substance is separated by a fractional crystallization of mandelic acid salt. Then, as an enantiomer Pure R-diol is condensed with diethyl carbonate in the presence of sodium methoxide. By doing so, the corresponding 5R-hydroxymethyl substituted oxazolidinone (III) Convert to. These 5R-hydroxymethyl substituted oxazolidinones are pharmaceutically It is useful as a useful synthetic precursor of oxazolidinone. A huge number of processes Makes the method unattractive. J.Med.Chem., 32,1673 (1989), Tetrahedron 45,1323 (1989) and US Patent No. 4,948,801 is a catalytic amount of lithium bromide-tributylphosphine oxide complex. Isocyanate (RN = C = O) is reacted with (R) -glycidyl butyric acid in the presence of the body. From producing the corresponding 5R-butyryloxymethyl substituted oxazolidinone Discloses a method for producing oxazolidinone. The method is carried out at 135-145 ° C. The butyrate is then hydrolyzed in subsequent steps to the corresponding 5-hydroxy. Obtain a methyl-substituted oxazolidinone. Relatively high cost and / or isocyanate The availability of nat starting materials as well as the high temperature requirements greatly undermine the attractiveness of this method. ing. 206th National Meeting of the held in Chicago, Illinois in August 1993 American Chemical Society; American Chemical Society: Washington, DC, 1993 A collection of abstracts of ORGN089; J.Med.Chem.39,673 (1996); J.Med.Chem.39,680 (1996); International publication WO93 / 09103, WO93 / 09103, WO95 / 07271 and WO93 / 23384; PCT application PCT / US95 / 12751 and PCT / US95 / 10992; Califo in September 1995 35th Interscience Conference on Anti in San Francisco, Lunia microbial Agents and ChemotheraPy; held in Washington in 1995 Abstracts of the American Society for Microbiology; Abstract No. F208; 35th Interscience Conference o in San Francisco, Lifonia n Antimicrobial Agents and Chemotherapy; held in Washington in 1995 American Society for Microbiology; Abstract No. F206; Califor in September 1995 35th Interscience on Antimicrobial held in San Francisco, Nia Abstracts of Agents and Chemotherapy; American held in Washington, 1995 Society for Microbiology; abstract number F227; is carbamate and n-butyllithi Umm, lithium diisopropylamide or lithium hexamethyldisiradi Reaction with glycidyl butyric acid at -78 ° C to -40 ° C, followed by reaction with glycidyl butyric acid at -78 ° C. Then warm to 20-25 ° C and the ester was cleaved during the reaction 5-hid It discloses that it produces a loxymethyl-substituted oxazolidinone (III). U.S. Pat. Nos. 4,062,862 and 4,236,012 are with epoxies in the presence of catalysts. React with primary carbamate (lacking any substituent on the nitrogen atom) It discloses a method for producing oxazolidinone. The manufacturing method is "preferably For several hours at a temperature of 100-150 ° C. " Canadian Patent No. 681,830 states that it is an alkaline catalyst (preferably lithium amide). Or lithium hydroxide) in the presence of glycidol aryl ether and primary cal It discloses a method for producing oxazolidinone, which comprises reacting with Bamart. The production method was carried out in a "preferably a temperature range of 150 ° C to 165 ° C". Its product is 5 -Hydroxymethyl substituted oxazolidinone aryl ether, yield Low (40-78%). J.Am.Chem.Soc., 64,1291 (1942) and US Pat. No. 3,547,951 are chloride. Treated with methanesulfonyl to produce mesylate, followed by this mesylate and nothing First, including contacting with water ammonia under pressure in a closed reaction vessel at room temperature. It discloses a method for converting primary alcohols to amines. In addition, the primary alcohol is reacted with aqueous ammonia to obtain the corresponding primary amine. It is also known to be obtained, but this requires high temperature and high pressure (85 psig). Connoisseur Normally, this process cannot be used in normal general purpose reactors and is graded for high pressure. Must be done in a special reactor. International release WO 95/07271 presents oxazolidinone mesylate ammonolesis It is disclosed. U.S. Pat. No. 4,476,136 states that methanesulfonyl chloride, followed by phthalamide. 5-Hydroxymethyl substitution, including potassium followed by treatment with hydrazine 5 (S) -aminomethyl-substituted oxazolidinone (V) corresponding to oxazolidinone (III) The method of converting to II) is disclosed. This reaction sequence is isolated from the product of interest Produces by-products that are difficult to produce. J.Med.Chem., 32,1673 (1989) and Tetrahedron 45,1323 (1989) Methanesulfonyl or tosyl chloride, followed by sodium azide, followed by sub-li Trimethylate or platinum dioxide / hydrogen, followed by acetic anhydride or acetyl chloride To obtain the desired 5 (S) -acetamide methyl substituted oxazolidinone by treatment with 5S-acetami corresponding to 5-hydroxymethyl substituted oxazolidinone, including It discloses a method for converting to a domethyl-substituted oxazolidinone. Natriu Azide Mu is known to be an explosive hazard. U.S. Pat. No. 5,210,303 is co-located with aqueous ammonia in the presence of aromatic aldehydes. Various substituted benzyl chloride pairs by heating to suppress dialkylation The conversion to the corresponding benzylamine is disclosed. Dialkylated impurities are removed Is generally difficult to do. See Chem. Lett., 1057 (1978). Outline of the invention Lithium cation and its conjugate acid exceed about 8 pK_aPresence of bases with In the presence Equation (a): M₁-CH₂-CH (OH) -CH₂-OH (I) (In the formula, M₁Is -Cl, -Br or -O-SO₂-φ-CH₃Is) (S)-, (R) -dihydroxy compounds indicated by or a mixture thereof Things, and Equation (b) (IV): C * H₂-C * H-CH₂-OH (IV) (In the formula, the carbon atoms marked with * are each bonded to the same oxygen atom (-O-). Form a 3-membered ring) From (S)-, (R) -glycidol or a mixture of any of them Hydroxy compounds selected from the group and formula (IIA): R₁-NH-CO-OM₂ (IIA) Carbamate represented by, or formula (IIB): R₁-NH-CO-CF₃ (IIB) (In the formula, -OM₂The acid is about 8 to about 24 pK_aIs a base with R₁Is the same as the definition below) It is characterized by contacting with trifluoroacetamide represented by. Equation (III):<img file="JP2000508312A_D0001.tif" />[In the formula, R₁Is<img file="JP2000508312A_D0002.tif" />Is; Here, X¹Is -H or -F; X²Is -H or -F; Q¹Ha: a)<img file="JP2000508312A_D0003.tif" /> b)<img file="JP2000508312A_D0004.tif" />c)<img file="JP2000508312A_D0005.tif" />d)<img file="JP2000508312A_D0006.tif" />f)<img file="JP2000508312A_D0007.tif" />g)<img file="JP2000508312A_D0008.tif" />h)<img file="JP2000508312A_D0009.tif" /> i)<img file="JP2000508312A_D0010.tif" /> j)<img file="JP2000508312A_D0011.tif" /> k)<img file="JP2000508312A_D0012.tif" />Or m)<img file="JP2000508312A_D0013.tif" />Is; Q¹And X²Together:<img file="JP2000508312A_D0014.tif" />Next; Here, Z¹Ha: a)-CH₂-, b)-CH (R)⁴)-CH₂-, c) -C (O)-or d)-CH₂CH₂CH₂-And; Z²Ha: a) -O₂S-, b) -O-, c)-N (R)⁷)-, d) -OS-, or e) -S- is; Z³Ha: a) -O₂S-, b) -O-, c) -OS-, or d) -S- is; A¹Ha: a) H-, or b) CH₃Is; A²Ha: a) H-, b) HO-, c) CH₃-, d) CH₃O-, e) R²O-CH₂-C (O) -NH-, f) R³OC (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-, m)<img file="JP2000508312A_D0015.tif" />Or n)<img file="JP2000508312A_D0016.tif" />Is; A¹And A²Together: a)<img file="JP2000508312A_D0017.tif" /> b) O = c)<img file="JP2000508312A_D0018.tif" />Next; R¹Ha: a)-CHO, b)-COCH₃, c)-COCHCl₂, d)-COCHF₂, e)-CO₂CH₃, f)-SO₂CH₃, Or g)-COCH₂OH; R²Ha: a) H-, b) CH₃-, c) Phenyl-CH₂-Or d) CH₃C (O)-is; R³Ha: a) (C₁-C₃) Alkyl-, or b) Phenyl-is; R⁴Ha: a) H-, or b) HO-is; R⁵Ha: a) H-, b) (C₁-C₃) Alkylation-, c) CH₂= CH-CH₂-Or d) CH₃-O- (CH₂)₂-And; R⁶Ha: a) CH₃-C (O)-, b) HC (0)-, c) Cl₂CH-C (0)-, d) HOCH₂-C (O)-, e) CH₃SO₂-, f)<img file="JP2000508312A_D0019.tif" /> g) F₂CHC (O)-, h)<img file="JP2000508312A_D0020.tif" /> i) H₃CC (O) -O-CH₂-C (O)-, j) HC (O)-0-CH₂-C (O)-, k)<img file="JP2000508312A_D0021.tif" /> l) HCCH-CH₂O-CH₂-C (O)-or m) Phenyl-CH₂-O-CH₂-C (O)-is; R⁷Ha: a) R²OC (R¹⁰) (R¹¹) -C (O)-, b) R³OC (O)-, c) R⁸-C (O)-, d)<img file="JP2000508312A_D0022.tif" /> e)<img file="JP2000508312A_D0023.tif" /> f) H₃CC (O)-(CH₂)₂-C (O)-, g) R⁹-SO₂-, h)<img file="JP2000508312A_D0024.tif" /> 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-And; R⁸Ha: a) H-, b) (C₁-C₄) Alkyl, c) Aryl- (CH₂)_p, d) ClH₂C-, e) Cl₂HC-, f) FH₂C-, g) F₂HC-, or h) (C₃-C₆) Cycloalkyl; R⁹Ha: a)-CH₃, b)-CH₂Cl, c)-CH₂CH = CH₂, d) Aryl, or e)-CH₂CN; R¹⁰Is H- or CH₃-And; R¹¹Is H- or CH₃-And; R¹²Ha: a) H-, b) CH₃O-CH₂O-CH₂-Or c) HOCH₂-And; R¹³Ha: a) CH₃-, b) HOCH₂-, c) (CH₃)₂N-Phenyl, or d) (CH₃)₂N-CH₂-And; R¹⁴Ha: a) HO-, b) CH₃O-, c) H₂N-, d) CH₃OC (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- is; R¹⁵Ha: a) H-, or b) Cl-is; R¹⁶Ha: a) HO-, b) CH₃O-, or c) is F; m is 0 or 1; n is 1-3; p is 0 or 1; Aryl is unsubstituted or one of the following groups: a) -F, b)-Cl, c)-OCH₃, d) -OH, e)-NH₂, f)-(C₁-C₄) Alkyl, g) -OC (O) -OCH₃, Or h)-NO₂And phenyl substituted with their protective form] Discloses the method for producing a 5-hydroxymethyl-substituted oxazolidinone represented by. Also, Equation (1) (III):<img file="JP2000508312A_D0025.tif" />(In the formula, R₁Is the same as the above definition) 5-Hydroxymethyl-substituted oxazolidinone alcohol, indicated by Expression (V_a-V_d): M₃-SO₂-C₆H_n3(NO₂)_n1Cl_n2 (V_a) O [-SO₂-C₆H_n3(NO₂)_n1Cl_n2]₂ (V_b) O (SO)₂-F)₂ (V_c),and O (SO)₂-CF₃)₂ (V_d) (During the ceremony,_n1Is 0, 1 or 2; _n2Is 0 to 4, however _n1If is 0_n2Is 2, 3 or 4 _n1If is 1,_n2Is 0 or 1 _n1If is 2,_n2Is 0; _n3Is 5-(_n1+_n2) And; M₃Is C1- or Br-) Contact with a sulfonylating agent selected from the group consisting of the compounds indicated by Expression (VI_a-VI_d): <img file="JP2000508312A_D0026.tif" />Produces the corresponding oxazolidinone sulfonate indicated by; (2) At a pressure of less than about 30 psig, the oxazolidinone sulfonate (VI)_a--- VI_d) And ammonia. Equation (VII):<img file="JP2000508312A_D0027.tif" />(In the formula, R₁Is the same as the above definition) Also disclosed is a method for producing a 5-aminomethyl-substituted oxazolidinone amine represented by. Detailed description of the invention The method for producing the 5-hydroxymethyl-substituted oxazolidinone alcohol (III) is formula (I). ) Is a non-cyclic (S), (R) -dihydroxy compound or any of them. Mixtures or (S), (R) -glycidol represented by formula (IV) or them Carbamate represented by formula (IIA) using any of the mixtures of Or it can be coupled with trifluoroacetamide represented by formula (IIB). it can. 5-Hydroxymethyl substituted oxazolidinone alcohol (III) is acylated 5-Acylamide Methyl Substituted Oxazolidinone (VIII) Antibacterial Agent 5-Aminomethyl Substituted Oxazolidinone Amine (VII) Is a useful intermediate for producing. Because the enantiome center ric center), 5 (R)-, 5 (S) -acylamide methyl substituted oxazolidinone (VI) II) and their mixtures can be produced. 5-Acylami Domethyl-substituted oxazolidinone (VIII) (S) -enantiomer has antibacterial activity Has, but does not have (R) -enantiomer. 5 (S) -aminomethyl substituted oxa Zolidinoneamine (VII) enantiomer is also a (S) -dihydroxy compound (I) Is a 5 (R) -hydroxymethyl-substituted oxa produced from (S) -glycidol (IV) Zolidinone Alcohol (III) Produced from enanthiomers. Therefore, for the purpose Yes and preferred enantiomeric sequences are enantiomerically pure (S) -di (R) -5-Hide with hydroxy compound (I) or (S) -glycidol (IV) Roxyme A chill-substituted oxazolidinone alcohol (III) was obtained and used as an enantiomer. Obtained a pure (S) -5-aminomethyl-substituted oxazolidinone amine (VII). Enantiomerically pure (S) -5-acylamide methyl substituted oxazolidi Convert to non (VIII). However, the same production using the reverse enantiomer form The process can be carried out easily and is desirable at any time of the process. Those skilled in the art will be able to convert the enantiomer configuration to the desired one. It is clear. However, the chemistry of the manufacturing method claimed for patent in one of the enantiomeric forms It is considered that the use corresponds to the manufacturing method for which a patent is claimed. Dihydroxy compound represented by the formula (I), M₁-CH₂-CH (OH) -CH₂-OH, and the glycidol compound C * H represented by formula (IV)₂-C * HC H₂-OH (Here, each carbon atom marked with * is the same oxygen atom (-O- ) To form a three-membered ring) is known to those skilled in the art or known to those skilled in the art. It can be easily prepared from known compounds by the methods described. Hydro The xy starting material is preferably dihydroxy compound (I). Dihydroxy Compound (I) and glycidol (IV) must be (S) -enantiomer Is preferable. M₁Is preferably Cl-; the dihydroxy compound (I) is It is preferably the one described in claim 5, which is commercially available. Carbamate represented by formula (IIA), R₁-NH-CO-OM₂And formula (I Trifluoroacetamide, represented by IB), R₁, -NH-CO-CF₃Is a business Is it a compound known to one of ordinary skill in the art or known by a method known to those skilled in the art? Either can be easily prepared. Leaving group M₂The nature of There is no. Because, as is known to those skilled in the art, it desorbs during the reaction process. Because it does. Operable M₂(Leaving group) is -OM₂But the acid is about 8 ~ It is a base having 24 pKa. Preferred M₂To C₁-C₂₀Alkyl, C₃-C₇Cycloalkyl, 1 or 2 Cs, if desired₁-C₃Alkyl or F-Cl-, Br-, I May be replaced with-, φ-, CH₂= CH-CH₂--- CH₃-CH = CH-CH₂-, (CH₃)₂C = CH-CH₂-, CH₂= CH-, φ-CH = CH-CH₂-, If desired, one or two -Cl, C on the φ-₁-C₄Alkyl, -NO₂, -CN, or -CF₃May be replaced with φ-CH₂-, 9-Fluorenylmethyl, (Cl)₃C-CH₂-, 2-trimethylsilylethyl, φ-CH₂-CH₂-, 1-Adamantane, (φ)₂CH-, CH = CC (CH₃) 2-, 2-Franylmethyl, and A more preferred leaving group containing isobornyl is C₁-C₄Alkyl or Ben Jill. Any other leaving group operating in a similar fashion corresponds to the above. It is thought that. Carbamate (IIA) and trifluoroacetamide (I) IB) is a 5-hydroxymethyl-substituted oxazolidinone alcohol (III) Aromatic / complex aromatic groups (R)₁-) Is being carried. R₁Is one -F and one permutation Preferably phenyl substituted with an amino group; R₁Is 3-fluoro-4 -[4- (benzyloxycarbonyl) -1-piperazinyl] phenyl or 3- More preferably, it is fluoro-4- (4-morpholinyl) phenyl. R₁Known to those skilled in the art to prevent unwanted side reactions, depending on the particular substituents in The group must be protected as known to those skilled in the art by means of use. It can happen. For example, R₁Primary or secondary hydroxy with free substituents If it has a group, it does not have to be, but it is preferably 5-hydro. Alcohols in the formation of xymethyl-substituted oxazolidine alcohols (III) Protect It is preferable to protect it with a protective base. Unprotected alcohol is generally 5-hi Dihydro to obtain droxymethyl-substituted oxazolidinone alcohol (III) Roxy compound (I) or glycidol (IV) and carbamate (IIA) Will not interfere with the reaction with trifluoroacetamide (IIB). However However, unprotected alcohols are generally the corresponding 5-aminomethyl-substituted oxas. 5-Hydroxymethyl Substitution with Zolidinone Amin (VII) Oxazolidinone It will interfere with the conversion of Lucor (III). Because other first-class or R in the presence of secondary alcohol₁Primary or secondary alcohols on functional groups This is because selective protection is very difficult or impossible. Suitable alcohol protecting groups are well known to those of skill in the art and are preferably C.₁-C₅Al Kill, φ-CH₂-, CH₃-O-CH₂-, CH₃-, CH₃-S-CH₂-, φ- CH₂-O-CH₂-, Tetrahydropyranyl, CH₃CH (-OC₂H₅)-, p -Methoxybenzyl, p-methoxyphenyl, p-nitrobenzyl, (φ)₃C- , (CH₃)₃Si-, [CH₃-CH (CH)₃)]₃Si- or φ (CH₃)₂Si- is there. These protecting groups are removed by methods known to those of skill in the art. example For example, R₁5-Hydroxymethyl Substituent Oxazoli 5-Aminomethyl Substitution of Dinone Alcohol (III) Oxazolidinone Amine (V) II) or 5-acylamide methyl substituted oxazolidinone (Vlll) You have to protect it in the meantime. R₁Primary or free substituent 5-Hydroxymethyl substituted oxazolidi, if containing a secondary amino substituent It is not necessary to protect it while forming non-alcoholic (III), but 5-hi 5-Amino Corresponding to Droxymethyl Substituted Oxazolidinone Alcohol (III) Methyl Substituted Oxazolidinone Amine (VII) and 5-Acylamide Methyl Station It must be protected during conversion to oxazolidinone (VIII). Why The amino group is generally a 5-hydroxymethyl-substituted oxazolidinone. 5-Acylamide Methyl Substituted Oxazolidinone (V) Corresponding to Lucor (III) Desirable during one or more steps involved in converting to III) This is because it will cause a side reaction. Therefore, the dihydroxy compound (I) Or Lysidol (IV) and Carbamate (IIA) or Trifluoroacetamide (I) Before reacting with IB), R₁Protects any free amino substituent in the functional group Is preferable. Amino protecting groups are very well known to those of skill in the art. Prefer For amino protecting groups: (I C₁-C₄Alkyl, (II) φ-CH₂-, (III) (φ)₃C-or (IV) R_a-CO-Here, R_aIs (A) H- (B) C₁-C₄Alkyl, (C) C₅-C₇Cycloalkyl, (D) (C₁-C₅Alkyl) -O-, (E) Cl₃C -CH₂-O-, (F) H₂C = CH-CH₂-O-, (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-CH₃-, ( M) (CH₃)₃Si-O-or (V) R_b-SO₂-(Here, R_bIs: (A) (C₁A Lucille)-, (B) φ-, (C) p-methylphenyl-, or (D) φ-CH₂-And ) Is included. Preferred amino protecting groups are contact waters such as those known to those of skill in the art. It is benzyloxycarbonyl that can be removed by dehydrogenation. these Nothing new about the use of protecting groups in the reaction or the nature of specific protecting groups I. All of these are well known to those skilled in the art. The protecting group can be used by those skilled in the art. As is known, protective substituents are affected or carried together, after subsequent reactions. It can be removed after the last reaction that will be removed. For example, to those skilled in the art As is known, protection before removal until the final acylation step is complete. It is preferable to carry the groups together. If desired, R₁Substituents known to those skilled in the art 5-Acylamide methyl station, depending on which chemical reaction is required It can be modified after producing a oxazolidinone (VIII). Carba with either dihydroxy compound (I) or glycidol (IV) Anti-Mart (IIA) or Trifluoroacetamide (IIB) Depending on the response, the same 5-hydroxymethyl-substituted oxazolidinone alcohol (II) I) get. Either dihydroxy compound (I) or glycidol (IV) Specific 5-hydroxymethyl substituted oxazolidinone alcohol (III) used The choice of whether to generate must be made on a case-by-case basis .. There is no preferred starting material in all cases; generally in chemistry alone There is also no preferred method on which to base it. The decision is specific, as known to those skilled in the art. Market availability of starting materials, their chemistry and enantiomer purity, their co Includes strikes and others. The production method of 1 of the present invention is a lithium cation (Li).⁺), And its conjugate acid is about 8 Dihydroxy compound (I) or g. Lysidol (IV) and Carbamate (IIA) or Trifluoroacetamide It is a reaction with (IIB). The process includes approximately 1 molar equivalent of dihydroxy compound (I) or glycidol ( IV) / equivalent of carbamate (IIA) or trifluoroacetamide (II) B) is required. In the reaction, the base deprotonates carbamate (II). As long as it is strong enough, its properties require bases that are not important. The operable base is The conjugate acid has a pKa of more than about 8. Preferred bases include Alkoxy compounds with 1 to 7 carbon atoms, Carbonate, Methyl, sec-butyl and t-butyl carbanion, Tri (alkyl) amine (where the alkyl group has 1 to 4 carbon atoms) , Carbamate (II) conjugate base, DBU, DBN, N-methyl-piperidine, N-methylmorpholine, 2,2,2-trichloroethoxydo, and Cl₃C-CH₂-O^-Contains compounds selected from the group consisting of, the most preferred base is if the base is 4. Or it is an alkoxy of 5 carbon atoms. 4 and 5 carbon al The col base is preferably t-amyl acetate or t-butoxide. (salt Sodium combined with lithium salt (such as lithium bromide or lithium bromide) Or potassium bases form lithium cations and bases in situ Can be used to The nature of the solvent is not important. Operable solvents include cyclic ethers such as THF. Amides such as le, DMF and DMAC, triethylamine, acetonitrile Of amines, as well as t-amyl alcohol and t-butyl alcohol Alcohol is included. Solvent selection is known to those skilled in the art. Depends on the solubility of rubamate (IIA) or trifluoroacetamide (IIB) To. If the starting material is dihydroxy compound (I), carbamate (IIA) or Before contacting with trifluoroacetamide (IIB), dihydroxy compounds It may be advantageous to react (I) with the cyclizing agent. The word "ringing agent" is dihid A base that cyclizes a loxy compound (I) to glycidol (IV). Operable Ringing agents include bases whose acid has a pKa greater than about 7; preferred rings. Agents include sodium, potassium or lithium butoxide, sodium hydroxide Or potassium, potassium carbonate, DBU, lithium amylate, amyl Sodium acid salt and potassium amylate salt; most preferred is potassium t -Butoxide. The reaction is preferably &lt;100 ° C, more preferably &lt;70 ° C. At ° C, even more preferably &lt;50 ° C, most preferably &lt;25 ° C. The reaction Can be performed at room temperature (about 20 to about 25 ° C). At about 20 ° C, the reaction is (D It takes about 8 hours to reach completion (in MAC). A faster reaction is desirable In some cases, the reaction can be carried out at a higher temperature. As mentioned above, first-class Alco The distinction between alcohol and secondary alcohol is difficult. In the cyclization reaction, simple Alcohol is formed. For example, when benzyl carbonate is applied to the cyclization condition, Benzyl alcohol is formed. Successful conversion of alcohol to amines It is necessary to remove this alcohol in order to get rid of it. This means ethyl acetate / f Butane (1 This is done by cyclization using / 2). Benzyl alcohol stays in solution and aims The oxazolidinone alcohol is isolated as a solid. Chart C shows a 5-hydroxymethyl-substituted oxazolidinone alcohol (II). Convert I) to the corresponding 5-aminomethyl-substituted oxazolidinone amine (VII) It discloses the method of making it. R₁Alcohol and / or amino groups on functional groups The situation to protect is discussed earlier. 5-Hydroxymethyl Substituted Oxazolidinone Al Cole (III), four types of sulfonylating agents (V)_a-V_d) .. These are M₃-SO₂-C₆H_n3(NO₂)_n1Cl_n2(V_a), O [-SO₂-C₆H_n3(NO₂)_n1Cl_n2]₂(V_b), O (SO)₂-F)₂(V_c) And O (SO)₂-CF₃)₂(V_d). M₃Is a leaving group and contains Cl- or Br-; M₃Is Cl- Is preferable. 5-Hydroxymethyl substituted oxazolidinone (III) Honyl agent (V_a-V_d) In contact with oxazolidinone sulfonate (VI)_a-V I_d) Form an intermediate. Corresponding oxazolidione with 5-hydroxymethyl substituted oxazolidinone (III) The sulfonate reaction to convert to non-sulfonate (VI) is carried out in an inert solvent at about 0 ° C. , 5-Hydroxymethyl substituted oxazolidinone (III) in the presence of base At least 1 molar equivalent of sulfonylating agent (V)_a-V_d) By contacting U. Activable bases include triethylamine, tributylamine, diisopropi Ethylamine, DABCO, DBU, DBN, n-Butyllithium, Ethylamine Includes magnesium chloride and their equivalents; preferably triethyla Min. The inert solvent includes methylene chloride, THF, DMA, DMF, acetic acid d. Contains most organic solvents such as chill and their equivalents; preferably chloride It is methylene. Corresponding 5-aminomethyl substituted oxy from oxazolidinone sulfonate (VI) The ammonolysis reaction of conversion to sazolidinone amine (VII) is open or non-open -Performs under airtight conditions or under airtight conditions, but is preferably performed under airtight conditions .. In either case, the ammonolesis reaction is oxazolidinone sulfona. To (VI) and ammonia (preferably aqueous ammonia), preferably a solvent or it. Et al. This is done by contacting with the mixture of. The preferred solvent is oxazolidinones It dissolves both Luhonate (VI) and aqueous ammonia. because By dissolving both, the contact between them is guaranteed. .. However, the process partially comprises oxazolidinone sulfonate (VI). It can be operated with an insoluble solvent, and the disadvantage is that the reaction is generally slow. And. In the case of m-nitrobenzene sulfonic acid, the preferred solvent is a A mixture of acetonitrile / isopropanol or THF / isopropanol. To. The system is placed under reduced pressure. The system is then closed or sealed with ammonia (preferably). (Or ammonia water) is added, less than 50 ° C, preferably less than 40 ° C, more preferred Or heat to about 38 ° C (about 3 psig). At about 38-40 ° C, the pressure is about 0 to about 10 It is psig, which is well below the critical pressure rating of a general purpose reactor. Under these conditions, the psig is about 20 at about 60 ° C. Ammonorisis reaction , About 0 to about 20 psig, preferably about 0 to about 5 psig and at about 60 ° C or less. Is preferable. Alternatively, the reaction is carried out in an open system at reflux temperature. In this case The temperature is slightly lower, and the reaction takes a slightly longer time to complete. Will be. Ammonia can be aqueous, alcoholic or anhydrous Ammonia water is preferable. Alternatively, contact with aqueous ammonia is an aromatic aldehyde (IX, Ar-CH). O), preferably in the presence of salicylaldehyde. 5-Ami The nomethyl-substituted oxazolidinone amines (VII) and aldehydes (IX) are of the formula It forms the Schiff base represented by (oxazolidinone-N = CH-Ar) and then , Hydrolyzed with an aqueous acid, as known to those skilled in the art, to the desired 5-amino Obtain a methyl-substituted oxazolidinone amine (VII). Aromatic aldehyde (IX ) Is useful for suppressing dimer formation. Acyl halide of 5-aminomethyl substituted oxazolidinone amine (VII) Alternatively, acylate by known means such as acyl anhydride to the corresponding 5-a. Form silamide methyl substituted oxazolidinone (VIII). Chart D It was referenced. Produces 5-acylamide methyl-substituted oxazolidinone (VIII) After formation, any alcohol or amino protecting group must be removed .. However, it is a particular replacement in question, as is known to those skilled in the art. Depending on the group, it can be removed earlier in the reaction sequence. 5-Acylamide Methyl Substituted Oxazolidinone (VIII) is an Antibacterial Pharmaceutical Agent Is known to be. R₂-H, one or more haloges if desired May be replaced with C₁-C₁₂Alkyl, (C₃-C₇) Cyclo (C₅-C₉) A Rukil or -OR_2a(Here, R_2aIs C₁-C₆Group consisting of (alkyl) Is selected from. R₂Is C₁It is preferably alkyl. Definitions and promises The following definitions and descriptions cover both the specification and the claims. It is about words and phrases used throughout. I. Expression promises and variable definitions Represents various compounds or molecular fragments within the specification and claims Chemical formulas may include variable substituents in addition to the specified structural features. these The variable substituent is a letter or a number following the letter, for example "Z"₁Or "R_i(This Here, i is an integer). These variable substituents are monovalent or They are either divalent, i.e. they are by one or two chemical bonds Represents a group that binds to the equation. For example, base Z₁Is the expression CH₃-C (= Z₁) A place to combine with H In that case, it will represent a divalent variable. Group R_iAnd R_jIs the expression CH₃-CH₂-C (R)_i) (R_j) Will represent a monovalent variable substituent when bound to H. The chemical formula is above When shown in linear form, the variable substituents contained in parentheses are in parentheses. It is attached to the atom just to the left of the variable substituent that is closed inside. 2 or 3 If the above consecutive variable substituents are closed in parentheses, each continuous variable substitution The group binds to the atom immediately ahead on the left, which is not closed in parentheses. Obey In the above equation, R_iAnd R_jBoth are bonded to the preceding carbon atom There is. It also has an established system of carbon atomic numbering, such as steroids. For any molecule, these carbon atoms are C_iIs shown, and here the "i" is It is an integer corresponding to the number of carbon atoms. For example, C₆Is traditionally shown by those skilled in the art of steroid chemistry It represents the 6th position of the Lloyd's nucleus or the number of carbon atoms. Similarly, "R₆Is the word , C (either monovalent or divalent)₆Represents a variable substituent at the position. The chemical formula shown in linear form or a part thereof represents an atom of a linear chain. The "-" symbol represents the bond between two atoms in the chain. Therefore, CH₃-O-CH₂-CH (R)_i)-CH₃Is 2-substituted-1-methoxypropanation It represents a combination. In a similar fashion, the "=" symbol is a double bond, eg CH₂= = C (R_i)-O-CH₃And the symbol "three" is a triple bond, for example HC = C-CH (R_i)-CH₂-CH₃Represents. Carbonyl groups can be used in two ways: -CO- Is expressed by any one of -C (= O)-, but the former is preferable because it is simple. Good. The chemical formula of a cyclic (cyclic) compound or molecular fragment shall be expressed in a linear fashion. Can be done. Thus, the compound 4-chloro-2-methylpyridine is an asterisk. N * = C with the promise that the atoms marked with (*) will combine with each other to form a ring. (CH₃)-CH = CCl-CH = C * H can be expressed in a linear fashion. Similarly, the cyclic molecular fragment 4- (ethyl) -1-piperazinyl -N *-(CH₂)₂-N (C₂H₅)-CH₂-C * H₂Can be represented by. For any of the compounds herein, the rigid cyclic structure is a rigid ring. Defines the orientation of the ring with respect to the substituents attached to each carbon atom of the compound. .. A saturated compound with two substituents attached to a carbon atom that is part of the ring system,- C (X₁) (X₂For)-, the two substituents are axial or equix to the ring. Can exist in any of the atrial positions, axial / equiatrial It can also change between. However, the ring and the two placements relative to each other The position of the replacement group remains fixed. At some point, one of the substituents is on the surface of the ring Can exist in the plane of the ring (equatorial) rather than above or below (axial) However, one substituent is always above the other. Chemical structure showing such a compound formula In the other substituent (X₂Substituent (X) present "below"₁) Is Alf Identified to exist in the (α) configuration, dashed lines and dash lines that bond to carbon atoms Or it is identified by a dotted line, that is, the symbol "-" or "...". On the other hand (X₁) Corresponding substituent (X) attached to "above"₂) Exists in beta (β) configuration Is identified and indicated by a straight line that binds to the carbon atom. If the variable substituent is divalent, the valences are together or separately in the definition of the variable. , Or both. For example, -C (= R)_i)-Binds to a carbon atom as Variable R_iCan be divalent and can be oxo or keto (hence the carbonyl group (-CO) -) Can be specified as), or separately for monovalent variable substituents Two α-Rs to combine_ijAnd β-R_ikCan be specified as. Divalent variable R_iIf is specified to consist of two monovalent variable substituents, then using that promise, The divalent variable is "α-R"_ij: β-R_ikOr some kind of variant thereof. In such a case, α-R_ijAnd β-R_ikBoth are bonded to the carbon atom , -C (α-R)_ij) (Β-R_ik)-. For example, the divalent variable R₆, -C (= R)₆) Is 2 If specified to consist of monovalent variable substituents, the two monovalent variable substituents are α- R_6-1: β-R_6-2, .... α-R_6-9: β-R_6-10Other, -C (α-R)_6-1) (Β-R6-2 )-, ....- C (α-R)_6-9) (Β-R_6-10)-, Other. Similarly, the divalent variable R₁₁, -C ( = R₁₁For)-, the two monovalent variable substituents are α-R_11-1: β-R_11-2Is. ( Separate α for it (due to the presence of carbon-carbon double bonds in the ring, for example) And for ring substituents that do not have a β direction, and carbons that are not part of the ring For substituents attached to atoms, the above promises are still used, but α and β The symbol of is omitted. Two separate monovalent variables, just as we could define a divalent variable as two separate monovalent variables Substituents can be specified to form a divalent variable together. For example, Equation-C₁( R_i) HC₂(R_i) H- (C₁And C₂Tracks the first and second carbon atoms, respectively In (regulated morally), R_iAnd R_jTogether (1) C₁And C₂With It forms a second bond between them; or (2) a divalent group such as oxa (-O-); In the case of (2), the equation thereby describes the epoxide. To. R_iAnd R_jTogether form a more complex group such as the group -XY- In the case, the direction of the group is C in the above formula.₁Joins X and C₂To join Y It is a thing. Therefore, by promise, "... R_iAnd R_jTogether -CH₂-CH₂The statement "forms -O-CO- ..." states that the carbonyl is C.₂Combine to Means the lactone that is However, "... R_jAnd R_iTogether -CO-O-CH₂-CH₂-Forming ", the promise is Carboni Le is C₁Means a lactone bound to. The carbon element content of the variable substituent is indicated by one of two methods. 1st person The law is "C₁-C₄(In the equation, both "1" and "4" are the smallest carbon atoms in the variable. And use a prefix for the whole name of the variable, such as (representing the maximum number). The prefix Is separated from the variable by a space. For example, "C₁-C₄What is "alkyl"? Alkyl of four carbon atoms (unless otherwise indicated, enclose its isomer form Includes). In any case if this single prefix is listed Even so, the prefix indicates the total carbon atom content of the specified variable. Therefore, C₂-C₄Alkoxycarbonyl is the group CH₃-(CH₂)_n-O-CO- (where n is 0 , 1 or 2). According to the second method, carbon only in each part of the definition Atomic content is in parentheses "C_i-C_jShown separately by closing the "symbol" It is placed just before the part of the defined definition (there is no intervening space). This responsibility According to my promise, (C₁-C₃) Alkoxycarbonyl is C₂-C₄Alkoxycal It has the same meaning as Bonil. Because, "C₁-C₃Is an alkoxy-based charcoal This is because it shows only the elementary atom content. Similarly, C₂-C₆Alkoxyalkyl And (C₁-C₃) Alkoxy (C₁-C₃) Both alkyls have 2-6 carbon atoms The alkoxyalkyl group contained is specified, but the former definition is alkoxy or a. Only the Lucil part allows to contain 4 or 5 carbon atoms, whereas The latter definition limits these groups to any of up to three carbon atoms, so there are two The definition of is different. If the claims include fairly complex (cyclic) substituents, then that particular substituent. There is a name in (parentheses) at the end of the phrase that names / indicates that particular Same name / symbol in one of the charts that also describes the chemical structural formula of the substituent Corresponds to. II. Definition All temperatures are at ° C. TLC refers to thin layer chromatography. THF means tetrahydrofuran. DMF refers to dimethylformamide. DBU refers to 1,8-diazabicyclo [5.4.0] undec-7-ene. DBN refers to 1,5-diazabicyclo [4.3.0] nona-5-ene. DABCO refers to 1,4-diazabicyclo [2.2.0] octane. DMA means dimethylacetamide. The salt solution refers to a saturated aqueous solution of sodium chloride. What is chromatography (column and flash chromatography)? A method for purifying / separating a compound represented as a support (support, eluate). Appropriate flak It is understood that the compounds of interest are pooled and concentrated to obtain the desired compound (group). IR refers to infrared spectroscopic analysis. What is CMR¹³C nuclear magnetic resonance analysis, the chemical shift from TMS to the low magnetic field side Report in ppm (δ). NMR refers to nuclear (proton) magnetic resonance analysis, and the chemical shift is tetramethylsis. Report in ppm (δ) from the run to the low magnetic field side. -φ is phenyl (C₆H₅). [α]_D²⁵Is the swirl of plane polarized light at 25 ° C on the sodium D line (589A). Angle (specific optical rotation). MS refers to mass spectrometry expressed as m / e, m / z or mass / charge.

[ M + H]⁺Means the cation of the parent + hydrogen atom. EI means electronic shock. CI Means chemical ionization. FAB is a fast atom bombardment. HRMS refers to high-resolution mass spectrometry. Pharmaceutically acceptable means patient-acceptable from a pharmacological / toxicological point of view, composition, Physical / chemical perspectives on formulation, stability, patient tolerance and bioavailability A property and / or substance that is more acceptable to a pharmaceutical chemist. When using a solvent pair, the ratio of the solvent used is volume / volume (v / v). When using the solubility of solids in a solvent, the ratio of solids to solvent is weight / volume. (wt / v). NNNNNN-NN-N is the Chemical Abstracts Service (CAS, Columbus) , Ohio) Refers to the registration number, where each "N" is an integer from 0 to 9, but the 6-digit part of the number The leading 0 in the minute is omitted. Registration numbers are specific chemical compounds according to CAS standards Assigned, however, the compound has been found to already exist and is of some sort. Characterized by the method. Approximately announced from 1967 to the present The compound is publicly registered and the registration number is C for such registered compound. The key to finding a reference in the AS database. CAS database is STN International, System Development Corporation (SDC) Orbit Search Service , Lockheed Dialog, Bibliographic Retrieval Systems, Questrel, etc. It is publicly available from several database vendors such as. CAS Registry Number Are included in the examples for some of the compounds already registered There is. A "psig" is a "gauge" pressure equal to (psi) pressure-1 atmosphere (14.7 psi). pressure) ". Example Needless to say, those skilled in the art will use the above description to describe the present invention. It is considered that it can be carried out in the maximum range of. In the detailed example below, the seed How to prepare the compounds and / or how to use the various methods of the invention. It explains what to do, it is just for the purpose of explanation, and in any case before It is not intended to be limited to the disclosure of the description. If you are a person skilled in the art, the reactants Immediate recognition of suitable variants from methods and techniques both as and reaction conditions Ru Will. Example 1 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbobe) Nzoxy) piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] methanol Le (III) N-Carbobenzoxyl 3-fluoro-4- (N-) in DMAC (300 ml) Carbobenzoxibiperazinyl) Aniline (II, J.Med.Chem., (3), 673 (1996)), A mixture of 100 g (0.2133 mol) of 98.4% pure material was cooled to 0 ° C. Minutes T-amyl alcohol (75 ml, 60.37 g, 0.685 mol) in a liquid flask , 3.23 eq) and heptane (75 ml) are cooled to -10 ° C and warmed. Keeping the degree below 10 ° C (29.2 g or 0.456 mol = 2/15 equivalent) Heptane (containing n-butyllithium) (14.4% wt / v solution 290 ml , 203g). Then t-amyl, keeping the temperature below 10 ° C. Lithium acid salt mixture N-carbobenzoxi-3-fluoro-4- (N-carbo) Benzodiazepine rajinyl) was added to aniline (II). Then, while rinsing with a small amount of heptane, net S- (+)-3-chloro-1,2-p Lopandiol (I, CAS # 60827-45-4, 22ml) 29.1g, 0.263 mol , 1.24 equivalents) was added. The reaction mixture is then stirred at 20-25 ° C. And by TLC (methanol / methylene chloride; 5/95) until the reaction is complete I monitored it. The reaction mixture is then mixed with methanol (700 ml) and water ( Acetic acid in 700 ml) (40 ml, 42.0 g, 0.699 mol, 3.29 equivalents) Was added to the mixture of. Stir the formed slurry at 20-25 ° C for 30 minutes to 0 The mixture was cooled to ° C, stirred at 0 ° C for 30 minutes and filtered. Methanol / water for the cake The mixture was washed with (50/50) and dried under reduced pressure to give the title compound. TLC (Methylene Chloride / Methanol, 95/5) Rf = 0.43 Example 2 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbo Benoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] meta Knoll (III) t-amyl alcohol (0.967 g, 10.97 mmol, 2.571 equivalent) Was cooled to -10 ° C. N-Butyllithium (2.5M in 4.3mL hexane, 10 Add .8 mmol, 2.5 eq) with stirring while maintaining temperature below 5 ° C. Ta. N-Carbobenzoxi-3-fluoro-4- (N-Carbobenzoxiperadi) Nil) Aniline (II, 1.9780 g, 4.267 mmol, 1.000 equivalent) And dimethylacetamide (6.2 ml) were mixed, stirred and cooled to -25 ° C. To obtain a dilute slurry. Then, while maintaining the temperature below -20 ° C, t-ami Lithium acid acid salt mixture was added to N-benzyloxycarbonyl-3-fluoro-4-((( In 4-benzyloxycarbonyl) -1-piperazinyl) aniline (II) mixture Added. The resulting mixture was warmed to 0 ° C and S- (+)-3-chloro-1,2- Propanediol (I, 0.5672 g, 5.131 mmol, 1.20 equivalent) Added. The resulting mixture was warmed to 21 ° C and stirred for 7.5 hours. The reaction mixture Mix the mixture with methanol (28 ml) at 20-22 ° C and glacial acetic acid (0.73 ml, 12.75 mmol) was added to the mixture. The resulting slurry was then placed at -30 ° C. Cool to, collect product by vacuum filtration and wash with -30 ° C methanol Ta. The solid was dried in nitrogen vapor to give the title compound. TLC (developing solution; chloroform / methanol, 90/10) Rf = 0.67; CMR (CDCl)₃) 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 157.17δ; 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 2.98δ; MS (CI, m / e) = 430 (100%, P + 1) Example 3 (R)-[N-3- [3-Fluoro-4- (4-morpholinylph) Enyl) -2-oxo-5-oxazolidinyl] methanol (III) Tetrahydrofuran (3.0 ml) and t-amyl alcohol (0.66 ml) ) 6.03 mmol, 2.00 eq) were mixed. Keeping the temperature below 2.5 ° C With stirring, butyllithium (1.8 ml, 2.5 M in hexanes, 4.55 ml) Limol (1.5 eq) was added. N-Carbobenzoxyl-3-fluoro-4-morpholinylaniline (II) J. Med.Chem., 39 (3), 673 (1996), 0.9942g, 3.009 mmol, 1.000 Equivalent) and tetrahydrofuran (3.5 ml) were mixed, stirred and cooled. Next Carbamate t-lithium amylate mixture while keeping the temperature below 8 ° C. (II) It was added to the mixture and rinsed with tetrahydrofuran (1 ml). Tetrahydrofuran (3.2 ml) and S- (+)-3-chloro-1,2-p Mix lopandiol (I, 0.299 ml, 3.58 mmol, 1.19 eq) did. Cool the mixture to -16 ° C and keep the temperature below -10 ° C. Rium t-butoxide (3.2 ml, 1.0 M in tetrahydrofuran, 3.2 ml) Limol (1.07 eq) was added. The obtained slurry is placed at -14 to 0 ° C at 1 o'clock. Stir for a while, then the lithium anion mixture, keeping both mixtures at 0 ° C. And then rinsed with THF (2 ml). The resulting slurry is 20-23 ° C Stir for 2 hours, then cool to 6 ° C and monohydrate citric acid in water (10 ml). A mixture of products (0.4459 g, 2.122 mmol, 0.705 eq) was added. .. The obtained liquid phase was separated, and the sewage phase was washed with ethyl acetate (12 ml). Organic The layers were combined and the solvent was removed under reduced pressure until the net weight remained at 9.73 g. Cheb Add tongue (10 ml) and water (5 ml) and reduce until total volume stays at 5 ml The solvent was removed under pressure. Precipitation products are collected by vacuum filtration and water (7 ml) Washed with. The solid was dried in nitrogen vapor to give the title compound. TLC (chloroform / methanol, 95/5) Rf = 0.23; CMR (CDCl)₃) 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 157.08δ; NMR (CDC1₃) 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 3.03δ; MS (EI, m / e) = 296 Alternatively, the crude product can also be extracted with methylene chloride. Under reduced pressure The solvent was removed with. The solid was redissolved in hot ethyl acetate, heptane was added, and then The mixture was cooled to recover the title compound. Example 4 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbo) Benoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Tanol (III) t-amyl alcohol (75 ml, 60.3 g, 0.68 mmol) and hepta The solution was stirred and cooled to -10 ° C. Keep the temperature below 10 ° C While holding the mixture, n-Butyllithium (1.6M, 0.46mi) in heptane Limol, 290 ml) was treated for 30 minutes. After 30 minutes, t-amyl acid A mixture of lithium salts at 0 ° C N-carboben while maintaining the temperature below 10 ° C. Zoxy-3-fluoro-4- (N-carbobenzoxiperadinyl) aniline ( II, 100g, 0.22m) and dimethylacetamide (300ml) Added to the mixture. The mixture is stirred for 30 minutes, then S-(+)-3-chloro- Treated with 1,2-propanediol (I, 22 ml, 0.26 m). Take a cooling bath The mixture was removed and left to warm to 20-25 ° C. Moni reaction by TLC After about 8 hours, it was judged to be completed. Methanol (700 m) of the reaction mixture l), inject into a mixture of water (700 ml) and acetic acid (40 ml), 20-25 The mixture was stirred at ° C for 30 minutes and then cooled to 0 ° C for 30 minutes. That mixture Filter, wash with aqueous methanol (50/50) and dry at 45 ° C under reduced pressure The title compound was obtained. TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.5 (90.3% yield) Example 5 3-Nitrobenzene Sulfonate (R)-[N-3- [3] -Fluoro-4- (N-1- (4-Carboxoxoxy) Piperazinyl] Phenyl] -2-oxo-5-oxazolidinyl] methanol (VI) (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carboxoxoxy)) Piperazinyl] Phenyl] -2-oxo-5-oxazolidinyl] Methanol (II I, Example 1, 43 g, 0.1 m) and methylene chloride (500 ml) mixture It was treated with triethylamine (32 ml) 0.23 m) and cooled to -5 ° C. 1 Methylene chloride (6) in this mixture, keeping the temperature below 10 ° C over time. 3-Nitrobenzenesulfonyl Chloride (CAS # 121-51-7, 32) in 0 ml) g, 0.14 ml) mixture was added. The reaction is monitored by TLC and It was judged to be completed after 45 minutes. Dilute the mixture with methylene chloride (500 ml) Then washed with water (2 x 600 ml). Then the organic phase is hydrochloric acid (1N, 40). Washed with 0 ml) and concentrated to give a viscous residue. The residue is methanol (200) It was diluted with ml) and stirred for 1.5 hours. The solid matter is filtered off, and the pressure is reduced to 40 ° C. It was dried in the evening to give 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-Cal) Bobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Chill] acetamide (VII) 3-Nitrobenzene Sulfonic Acid Ester (R)-[N-3- [3-Fluoro- 4- (N-1- (4-Carboxoxoxy) Piperazinyl) Phenyl] -2-Oki So-5-oxazolidinyl] methanol (VI, Example 5, 50 g, 0.081 m) l), isopropanol (250 ml), ayatoa nitrile (400 ml) and Slurry of aqueous ammonium hydroxide solution (29% by weight ammonia, 500 ml) Heated at 40 ° C for 3.5 hours. The mixture is then added to aqueous ammonia ( It was treated with 100 ml) and stirred for 20 hours. The reaction is monitored by TLC However, it was judged to be completed at this point. The mixture is concentrated under reduced pressure while heating and salted. Suspended in methylene carbonate / water (1250 ml / 750 ml). Separate the phases and that The organic phase was concentrated to give a residue. The residue is dissolved in methylene chloride (2L) and triethylamine (20ml, 0). Processed with .14m). The mixture is then mixed with acetic anhydride (10 m) at 20-25 ° C. l, 0.11 m) for 10 minutes. Acetylation by TLC It was monitored and judged to be complete after 15 minutes. Water the organic mixture (2 x 400 ml) ), And then concentrated to make a solid. Ethanol (400m) the solid It was recrystallized from l), filtered, and dried under reduced pressure 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) (S) -N-[[3- [3-Fluoro-4- [N-1- (4-Carboxoxoxy)) Piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] methyl] acet Amide (VII, Example 6, 35 kg, 74.5 mol), carbon palladium (5%, 10 kg, 50% water content), methanol (550 L) and tetrahydrofuran (2) The mixture of 50 L) was stirred at 22-42 ° C under a 42-50 psi hydrogen atmosphere. After 31 hours TLC analysis showed that the reaction was complete, replacing the hydrogen atmosphere with nitrogen did. The catalyst was removed by filtration and the filtrate was concentrated to 100 L under vacuum. Cool to 2 ° C To the resulting mixture, methanol (50 L) was added, followed by a meter of -2 ° C to 6 ° C. Mixture of tanol (100 L) and acetyl chloride (6.04 kg, 77 mol) Was added. The resulting mixture is stirred for 90 minutes and then concentrated to 60 L under vacuum. It was shrunk, diluted with acetone (100 L) and further concentrated to 100 L. Obtained The slurry was diluted with acetone (200 L) and stirred at 16 ° C for 15 hours. solid Collect things on a filter, wash with acetone (50L), under reduced pressure, 20-25 The desired product was obtained by drying at ° C. Convert it to methanol (56L) at 53 ° C Dissolve, dilute with acetone (150 L), stir at 48 ° C for 30 minutes, up to 15 ° C The mixture was cooled with and stirred for 18 hours. Collect the solids on a filter and acetone (50) The mixture was washed with L) and dried under reduced pressure at 20-25 ° C to give the title compound. NMR (CDCl₃) 7.56-7.45,7.31,4.12-6.86,4.79,4.09-4.0,3.81,3 .62,3.40-3.11 and 2.01δ Example 8 (S) -N-[[3- [3-Fluoro-4- [4- (Hydroxyace) Chill) -1-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] Methyl] -acetamide sesquihydrate (VIII) (S) -N-[[3- [3-Fluoro-4- (1-piperazinyl) phenyl] -2 -Oxo-5-oxazolidinyl] methyl] acetamide hydrochloride (Examples 7, 16. 2 kg, 43.5 mol), tetrahydrofuran (205 kg) and triethyla Maintain a temperature of 22-23 ° C in a stirred mixture of min (10.1 kg, 100 mol) While doing so, acetoxyacetyl chloride in tetrahydrofuran (11.1 kg) (6. 5 kg, 47.8 mol) was added over 35 minutes. 40 minutes later, at that point TLC and HPLC analysis showed that the formation of acetamide acetamide intermediate was completed. And the mixture was concentrated to 30 L under reduced pressure and methanol (100 L). Diluted with, and concentrated to 30 L. Methanol (25 L) and carbonic acid in the residue An aqueous potassium solution (5.6 kg in 56 L) was added. 22- Stir at 25 ° C for 20 hours, at which point TLC and HPLC analysis complete the reaction I showed that I did. The pH was adjusted to 7-7.5 with hydrochloric acid (4N, 14.3L). That The mixture was stirred at 15-22 ° C for 18 hours and then at 2-5 ° C for 3 hours. That Collect solids on a filter, wash with water (68L) and circulate nitrogen 2 The desired product was obtained by drying at 0-25 ° C. The crude product at 60-70 ° C Dissolve in water (225L), clarify through 0.6μ filter, rinse with water (55) It was diluted with L) and stirred at 15 ° C for 17 hours. Collect solids on a filter and Wash with water at 15 ° C and dry at 45 ° C with circulating nitrogen to a water content of 0.3. It was set to 3%. These solids were mixed with ethyl acetate (143L) at 60-65 ° C, methanol. It was dissolved in a solution of le (65 L) and water (1.95 L). 15-25 the solution It was cooled to ° C and stirred for 16 hours for crystallization. Collect the solid on the filter Take, wash with ethyl acetate (75L) and dry with nitrogen at 45 ° C to obtain the desired product. Obtained. That Reconnect the product from 60-70 ° C water (147L, then 133L) two more times Crystallize and clarify through a 0.6μ filter at each point in time with water (4OL and 3) Rinse with 0L). The solid material is dried on a filter at 30 ° C while circulating nitrogen. The title compound was sesquihydrate (6.45% water) after being allowed to and deaggregate through a mill. Content). TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.45 ; [α]_D= -20 ° (c = 1.0, ethanol) Example 9 3-Nitrobenzene Sulfonate (R)-[N-3- [3] -Fluoro-4- (N-1- (4-Carboxoxoxy) piperazinyl] -Phenyl] -2-oxo-5-oxazolidinyl] methanol (VI) Methylene chloride (50 mL) and triethylamine (2.0 mL, 14.) at 0 ° C. (R)-[N-3- [3-fluoro-4- [N-1- (4-cal)) in 38 mmol) Bobenzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] Slurry of methanol (III, Example 1, 5.086 g, 11.86 mmol) In addition, a solution of 3-nitrobenzenesulfonyl chloride (V) in methylene chloride (0.3) 56 M, 33.4 ml, 11.89 mmol) was added dropwise over 6 minutes. 3. After stirring for 25 hours, 0.356 of 3-nitrobenzenesulfonyl chloride (V) An additional 3.4 ml (1.21 mmol) of M solution was added. Stir for 1.75 hours Later, hydrochloric acid (1N, 50 mL) was added. The phases are separated and the aqueous phase is chlorided. Extracted with chillen. The combined organic phases are washed with salt solution and dried over magnesium sulphate. And concentrated. Crystallize the concentrate from hot methylene chloride / methanol to mark The title compound was obtained. Melting point = 155-157 ° C; NMR (CDCl₃, 400MHz) 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 3.01δ; CMR (CDCl)₃, 100MHz) 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 155.88δ; IR (mineral oil mull) 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 (c = 0.9812, CHCl₃); TLC (Ethyl Acetate / Hexane, 3/1) Rf = 0.43 Example 10 2-Nitrobenzene Sulfonate (R)-[N-3- [3] -Fluoro-4- [N-1- (4-Carboxoxoxy) Piperazinyl] Phenyl] -2-oxo-5-oxazolidinyl] methanol (VI) With respect to (3-nitrobenzenesulfonyl ester) without significant modification According to the general method of Example 5, (R)-[N-3- [3-Fluoro-4] -[N-1- (4-Carboxoxoxy) piperazinyl] phenyl] -2-oxo- 5-Oxazolidinyl] Methanol (III, Example 1, 1.106 g, 2.57 8 mmol) to triethylamine (0.54 ml, 3.882 mmol) and city Sales grade 2-nitrobenzene sulfonyl chloride (V, 679 mg, 3.064 mm) The title compound was obtained by treatment with (molar). NMR (CDCl₃, 400MHz) 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 3.03δ; IR (mineral oil mull) 1757,1697,1517,1445,1423,1376,1237 and 1188cm- , MS (EI, M / Z; relative absorption): 614 (18.3, M)⁺), 91 (100), 69 (23.8) and 56 (52.9); TLC (ethyl acetate / hexane, 3/1) Rf = 0.31 Example 11 2,4-Dinitrobenzene Sulfonate (R)-[N-3 -[3-Fluoro-4- [N-1- (4-Carboxoxoxy) piperazinyl] pheni Le] -2-oxo-5-oxazolidinyl] methanol (VI) With respect to (1-nitrobenzenesulfonyl ester) without significant modification According to the general method of Example 5, (R)-[N-3- [3-Fluoro-4] --- [N-1- (4-Carboxoxoxy) piperazinyl] Phenyl] -2-oxo-5 -Oxazolidinyl] Methanol (III, Example 1, 1.094 g, 2.550 Millimole) with triethylamine (0.55 ml, 3.950 mmol) and commercially available Grade 2,4-dinitrobenzenesulfonyl chloride (833 mg, 3.124 mm) The title compound was obtained by treatment with (molar). NMR (CDCl₃, 400MHz) 8.59,8.38,7.35,7.02,5.17,4.88,4 .74,4.58,4.10,3.98,3.71 and 3.05δ; IR (mineral oil mull) 1756,1697,1554,1541,1517,1351,1237 and 1189cm- ; MS (FAB, M / Z; relative absorption): 660 (21.3, [M + H]⁺), 659 (24.2, M₊) , 102 (76.5) and 91 (100); TLC (ethyl acetate / hexane, 3/1) Rf = 0.41 Example 12 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbobe) Nzoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] metano 4-Chlorobenzene Sulfonic Acid Ester (VI) -12 ° C methylene chloride (40 ml) and triethylamine (2.55 ml, (R)-[N-3- [3-Funoleoro-4- [N-1- (4)) in 18.3 mmol) -Carbobenzoxi) piperazinyl] phenyl] -2-oxo-5-oxazolidi Nil] Methanol (III, Example 1, 3.450 g, 8.034 mmol) Lee, 4-chlorobenzenesulfonyl chloride (V, Aldrich Chemical Co., Inc.) Sale, 2.298 g, 10.88 mmol) was added at one time as a solid. That The mixture is stirred in a 0 ° C bath for 2.5 hours, then water (2 x 35 ml) and IN. Washed with hydrochloric acid (35 ml). Concentrate the organic extract to a total volume of 20 ml, Tanol (50 ml) was added. Precipitate is collected by vacuum filtration and methanol It was washed with water, dried and redissolved in methylene chloride (55 ml). That mixture The slurry was concentrated to a weight of -32 g, and methanol (llml) was added. sediment Was collected by vacuum filtration, washed with methanol and dried. Then that solid Shape Dissolve in methylene chloride (58 ml) and perform column chromatography (silica column) , 93g, 40-63μ; Ethyl Acetate / Cyclohexane Mixture 25/75; 35 / 65; 45/55; 55/45 Elute with 450 ml each; Take 50% of the final eluate Attached to). Concentrate the collected eluate to 200 ml and add 200 ml of heptane. Added. The precipitate was collected by vacuum filtration and dried to give the title compound. .. TLC (silica gel; methanol / chloroform 5/95) Rf = 0.53; MS (FAB, M / Z) = 604.7 (100%, [P + H]⁺); NMR (DMSO-d₆, 300MHz) 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 2.96δ; CMR (DMSO-d₆, 75MHz) 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 154.62δ Example 13 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbo) Benoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] meta Nord 2,5-dichlorobenzenesulfonic acid ester (VI) -8 ° C methylene chloride (40 ml) and triethylamine (2.55 mL 18) (R)-[N-3- [3-Fluoro-4- [N-1- (4-Canole)) in .3 mmol) Bobenzoxi) Piperazine] Phenyl] -2-oxo-5-oxazolidinyl] Meta In a slurry of Noor (III, Example 1, 3.439 g, 8.008 mmol), 2,5-Dichlorobenzenesulfonyl Chloride (V, Aldrich Chemical Co., Inc.-City Sale, 2.675 g, 10.90 mmol) was added at one time as a solid. That mixture Stir the mixture in a 0 ° C bath for 2.5 hours, then water (2 x 35 ml) and IN salt. Washed with acid (35 ml). The organic extract was then concentrated to 12.0 g and Column chromatography it (silica column, 108g, 40-63μ; vinegar Ethyl acid / cyclohexane mixture 10/90, 20/80, 30/70, 40 / Elute with 450 ml each of 60 and 60/40, and collect the last 20% of the eluate) Attached. The collected eluate was concentrated and 300 ml of methanol was added. Its precipitation Vacuum filtration of things Was collected, washed with methanol and dried to give the title compound. TLC (silica gel; methanol / chloroform, 5/95) Rf = 0.66 ; MS (FAB, M / Z) = 638.6 (100%, [P + H]⁺); NMR (CDCl₃, 300MHz) 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 3.01δ; CMR (CDCl)₃, 75MHz) 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 15 5.53δ Example 14 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbo) Benoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] meta Nord 4-nitrobenzene sulfonic acid ester (VI) (R)-[N-3- [3-Fluoro-4-) in methylene chloride (32 ml) at 0 ° C [N-1- (4-Carboxoxoxy) piperazinyl] Phenyl] -2-oxo-5 -Oxazolidinyl] Methanol (III, Example 1, 3.437 g, 8.003 Mmol) and 4-nitrobenzenesulfonyl chloride (V, 75% purity technical material, Aldrich Chemical Co.-Commercially available, 3.077 g, 10.41 mmol) slurry -Triethylamine (2.23 ml, 16.0 mmol) was added. That mixture The mixture is stirred in a 0 ° C bath for 1 hour, then water (1 ml) is added and the mixture is 2 The mixture was stirred at 0-25 ° C for 30 minutes. Add methylene chloride (75 ml) and mix Wash the mixture with hydrochloric acid (5%, 50 ml) and then sodium bicarbonate (5%, 50 ml) It was purified and dried over magnesium sulfate. The organic extract is then concentrated and then Concentrate in boiling ethyl acetate / cyclohexane (1/1, 10 ml) Lamb chromatography (silica gel, 4 cm x 6 , 40-63 μ; ethiacetate Le / cyclohexane mixture 20/80, 30/70, 40/60, 50/50, Elute at about 400 ml each on 60/40 and 70/30, nearly 45 at the end of the eluate % Was collected). Combine the appropriate fractions and concentrate to make a solid, which Chloride methyle Dissolved in 70 ml of ethyl acetate and 50 ml of ethyl acetate. 2 up to 50 ml of the mixture It was concentrated once and cyclohexane (50 ml) was added after each concentration. Vacuum the precipitate It was collected by filtration, washed with cyclohexane and dried to give the title compound. TLC (silica gel; ethyl acetate / cyclohexane 60/40) Rf = 0.37 ; NMR (CDCl₃, 300MHz) 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 3.00δ; CMR (CDCl)₃, 75MHz) 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 155.40δ Example 15 (S)-[N-3- [3-Fluoro-4- [N-1- (4-Carbo) Benoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] meth Luamine (VII) 3-Nitrobenzene Sulfonate (R)-[N-] at 40 ° C under Nitrogen 3- [3-Fluoro-4- (N-1- (4-Carboxoxoxy) piperazinyl)] -Phenyl] -2-oxo-5-oxazolidinyl] methanol (VI, Example 5) , 1.0099 g, 1.634 mmol), isopropanol (5.6 ml), aceto Nitrile (9.0 ml), benzaldehyde (0.50 ml, 4.92 mmol) and Ammonia water (29.8% by weight, 9.5 ml, 148.6 mmol) was mixed. .. The mixture was stirred at 40 ° C. for 21.5 hours and then concentrated under reduced pressure. To Add ruen (13.3 ml) and ethanol (6.0 ml) and mix Warmed in a 70 ° C bath. Then citric acid monohydrate (2.433 g, 11.58 mm) Mol) was added over 3.5 hours and the phases were separated at 64 ° C. Its organic phase Was washed with water (2.5 ml) at 64 ° C. Combined aqueous layer with 64 ° C toluene (1) Washed with 0 ml). Then, toluene (10 ml) is added to the aqueous solution and mixed. The mixture was cooled to 0 ° C. The precipitate is collected by vacuum filtration and toluene at 0 ° C. It was washed with (10 ml) and 0 ° C water (10 ml) and dried to a solid. Part of this solid (0.7301 g) with water (10 ml) and methylene chloride (0.7301 g) In 10 ml) Slurry and sodium hydroxide aqueous solution (50%, 0.39) at -4 ° C to -2 ° C The pH was adjusted from 2.78 to 13.92 at 15 g, 4.90 mmol). That mixture The mixture was warmed to 20-25 ° C and sonicated for 2.5 hours with stirring. Mechi chloride Len (55 ml), saturated aqueous sodium chloride solution (5 ml) and water (35 ml) It was added and the phases were separated. The aqueous phase was washed twice with methylene chloride (25 ml). The combined organic matter was dried over sodium sulfate, filtered and concentrated under reduced pressure. Toluene (5 ml) was added, followed by gradual addition of heptane (25 ml). The resulting precipitate is collected by vacuum filtration, washed with heptane (20 ml) and dried. It was dried to give the title compound. TLC (silica gel; methanol / chloroform 10/90) Rf = 0.3 2; MS (EI), M / Z (relative strength) = 428 (28%, M)⁺), 252 (15%), 92 (32%), 91 (100%) ; NMR (CDCl₃, 300MHz) 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 1.30δ; CMR (CDCl)₃, 75MHz) 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 155.61δ Example 16 (R)-[N-3- [3-Fluoro-4-morpholinylphenyl) ] -2-oxo-5-oxazolidinyl] methanol 4-nitrobenzene sulfo Nate ester (VI) (R)-[N-3- [3-Fluoro-4) in methylene chloride (450 ml) at 0 ° C -Morphorinyl phenyl] -2-oxo-5-oxazolidinyl] Methanol (I II, Example 3, 43.0 g, 145 mmol) and triethylamine (36) In a slurry of g, 355 mmol), 4-dichloride in methylene chloride (55 ml) A mixture of trobenzenesulfonyl (V, 32 g, 145 mmol) was added. The mixture is stirred in a 0 ° C bath for 30 minutes, then hydrochloric acid (10%, 200 ml). Quenched with. Separate the organic phase and re-do the aqueous phase with methylene chloride (200 ml) Extracted. The combined organic extracts are then concentrated and column chromatographed. Rika Gel, 4 cm x 6 ", 40-63 μ; Methanol / Methylene Chloride 1-2/98 -99, about 8L). Combine the appropriate fractions and concentrate to give the title compound Obtained. Rf = 0.2; NMR (CDCl₃, 300MHz) 8.73,8.54,8.23,7.82,7.33,7.04,6 .91,4.86,4.42,4.12,3.86 and 3.05δ; CMR (CDCl)₃, 75MHz, partial) 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 137.27δ Example 17 (S)-[N-3- [3-Fluoro-4-morpholinylphenyl] ] -2-oxo-5-oxazolidinyl] Methylamine salicylaldehyde imi N (R)-[N-3- (3-Fluoro-4- (4-morpholinylphenyl) -2- Oxo-5-oxazolidinyl] methanol 3-nitrobenzene sulfonic acid d Steal (VI, Example 16, 20.608 g, 42.803 mmol), Isopro Panol (149 ml), acetonitrile (245 ml), salicylaldehyde (1) 3.7 ml, 129 mmol) and aqueous ammonia (30%, 257 ml, 4.0) The 2 mmol) mixture was heated to 40 ° C and stirred at 39-42 ° C for 24 hours. .. The mixture is then cooled to -22 ° C and the precipitate is 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 ; EIMS (m / z, relative strength) = 399 (M⁺, 51), 234 (11), 196 (11), 149 (22), 1 35 (100), 134 (47); NMR (300MHz, CDCl₃) 8.44,7.41,7.33-6.87,4.96-4.88,4.1 2,3.94-3.84 and 3.04δ; CMR (CDCl)₃, 75MHz) 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 168.87δ Example 18 (S) -N-[[3- (3-Fluoro-4-morpholinylphenyl) ) -2-oxo-5-oxazolidinyl] methyl] acetamide (VIII) (S)-[N-3- [3-Fluoro-4-morpholinylphenyl] -2-oxo -5-oxazolidinyl] Methylamine Salicylaldehyde imine (Example 17) , 1.0068 g, 2.521 mmol) in water (10 ml) and 37% dilute hydrochloric acid (0. Slurry in 417 ml, 5.04 mmol) at 20-25 ° C for 15 hours Stirred. Toluene (10 ml) is added to separate the phases; then the organic phase Was washed with hydrochloric acid (1M, 5 ml), and the combined organic phase was washed with toluene (10 ml). Purified. The toluene cleaning solution was re-extracted with hydrochloric acid (1M, 5 ml). Then go Aqueous sodium hydroxide solution (50%, 1.83 g, 22.9 mmol) Adjusted to pH 13.0. Then, methylene chloride (10 m) was added to the obtained slurry. l) and sodium chloride (1 g) were added and the phases were separated. Then that water The phase was washed with methylene chloride (10 ml). Then maintain at 24-27 ° C Acetic anhydride (0.472 ml, 5.00 mmol) was added to the combined organic phases. The mixture was stirred for 40 minutes and then water (5 ml) was added. Separate the phases, The aqueous phase was washed with methylene chloride (5 ml). Concentrate the combined organic phase and acetic acid Ethyl (25 ml) was added. The mixture is warmed to 70 ° C and then obtained The mixture was gradually cooled to -25 ° C. The precipitate is collected by vacuum filtration and- The mixture was washed with ethyl acetate (5 ml) at 25 ° C. and dried to give the title compound. HPLC main component (99.93 area% at 254 nm detection) Retention time = 0.97 Minutes, column = Zorbax RX-C8, 250 x 4.6 mm, mobile phase = acetonitrile 6 50 ml, triethylamine 1.85 ml, acetic acid 1.30 ml and 1000 in total ml of water; flow rate = 3 ml / min Example 19 (R)-[N-3- [3-Fluoro-4- [N-1- (4-Carbo) Benoxy) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] meta Knoll (III) N-Carbobenzoxi-3-fluoro-4- (N-Carbobenzoxiperadi) Nil) Aniline (II, 2.014 g, 4.345 mmol) and THF (10) The mixture of ml) was cooled to -20 ° C. In a separatory flask, THF at -33 ° C Dissolution of t-amyl alcohol (0.71 ml, 6.48 mmol) in (10 ml) The liquid, n-butyllithium in heptane, keeping the mixture below -20 ° C Treated with (13.65 wt%, 2.53 g, 5.38 mmol). Then get N-Carboben while maintaining the resulting lithium amyl acetate solution below -20 ° C Zoxy-3-fluoro-4- (N-carbobenzoxiperadinyl) aniline blend It was added to the mixture and rinsed with THF (4 ml). The resulting mixture at -28 ° C was then obtained. S-glycidol (IV, 0.3360 g, 4.536 mmol) was added to the mixture. .. The mixture is then placed at -20 ° C for 1.5 hours and then at -16 ° C for 17 hours. , -11 ° C for 4 hours, then -1 ° C for 2 hours. Then, HPLC a Sussie is TLC (silica gel; methanol / chloroform 10/90) Rf As with = 0.60, that the major component has a retention time consistent with the title compound Shown (90.4 area% at 254 nm detection; retention time = 1.30 minutes; column = Zorb ax RX-C8, 250 x 4.6 mm; mobile phase = acetonitrile 650 ml) Triethyl Luamine 1.85 ml) 1.30 ml acetic acid and 1000 ml total water; flow rate = 3 ml / min). Example 20 (R)-[N-3- [3-Fluoro-4-morpholinylphenyl) ] -2-oxo-5-oxazolidinyl] methanol 4-Nitrobenzene sulfo Acid ester (VI) With non-significant modifications other than starting with 4-nitrobenzenesulfonyl chloride, The title compound was obtained according to the general method of Example 16. Example 21 (R)-[N-3- [3-Fluoro-4-morpholinylphenyl) ] -2-oxo-5-oxazolidinyl] methanol 2-nitrobenzene sulfo Acid ester (VI) With non-significant modifications other than starting with 2-nitrobenzenesulfonyl chloride, The title compound was obtained according to the general method of Example 16. Example 22 (R)-[N-3- [3-Fluoro-4-morpholinylphenyl) ] -2-oxo-5-oxazolidinyl] Methanol 2,4-dinitrobenzene Sulfonic acid ester (VI) Deformations that are not significant except starting with 2,4-dinitrobenzenesulfonyl chloride The title compound was obtained according to the general method of Example 16. Example 23 (R)-[N-3- [3-Fluoro-4-morpholinylphenyl) ] -2-oxo-5-oxazolidinyl] Methanol 4-Chlorobenzene sulfo Acid ester (VI) With non-significant modifications other than starting with 4-chlorobenzenesulfonyl chloride, The title compound was obtained according to the general method of Example 16. Example 24 (R)-[N-3- [3-Fluoro-4-morpholinylphenyl) ] -2-oxo-5-oxazolidinyl] Methanol 2,5-dichlorobenzene Sulfonic acid ester (VI) Non-significant variants other than starting with 2,5-dichlorobenzenesulfonyl chloride The title compound was obtained according to the general method of Example 16. Chart A<img file="JP2000508312A_D0028.tif" />Or<img file="JP2000508312A_D0029.tif" /> Chart B C * H₂-C * H-CH₂-OH (IV) (Here, the carbon atoms marked with * are each bonded to the same oxygen atom (-O-). To form a 3-membered ring or epoxide)<img file="JP2000508312A_D0030.tif" /> Or<img file="JP2000508312A_D0031.tif" />Chart C<img file="JP2000508312A_D0032.tif" />Chart D<img file="JP2000508312A_D0033.tif" />