MXPA00004244A - Process to produce oxazolidinones - Google Patents

Abstract

The present invention includes a number of novel intermediates such as the (S)-secondary alcohol of formula (VIIIA) X2-CH2-C*H(OH)-CH2-NH-CO-RN and processes for production of pharmacologically useful oxazolidinones.

Description

PROCESS TO PRODUCE OXAZOLIDINONES BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is a process for preparing pharmacologically active oxazolidinones and various intermediates used in the process. 2. Description of the Related Art Various 5-acetamidomethyloxazolidinones are well known to those skilled in the art as pharmacologically useful antibacterials. Various methods are well known to those skilled in the art to prepare these useful therapeutic agents. U.S. Patents 5,164,510, 5,182,403 and 5,225,565 disclose 5'-indolinyloxazolidinones, 3- (5'-indazolyl) oxazolidinones, 3- (their t-times in the fused ring) phenyloxazolidinones, respectively, useful as antibacterial agents. U.S. Patents 5,231,188 and 5,247,090 disclose various fused ring oxazolidinones [6.5.5] and [6.6.5] useful as antibacterial agents.

International Publication WO93 / 09103 discloses oxazolidinone mono- and di-halophenyl antibacterials which are useful as pharmaceutical agents for their antibacterial action. The prior art processes for making oxazolidinones involve the condensation of an aromatic carbamate with a three-carbon reagent that does not contain nitrogen to provide an oxazolidinone intermediate with a hydroxymethyl substituent in the 5-position. The hydroxyl must be replaced by a group acetamido to provide the pharmacologically active 5-acetyl amidomethyl oxazolidinones. Many variants of this essentially two-step process have been developed. U.S. Patents 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773 disclose the synthesis of 5-hydroxymethyloxazolidinones from amines (R-NHXi, where Xi is -H or p-toluenesulfonyl) and R, S-glycidol (C # H2-0-C * H-CH2-OH where the labeled carbon atoms * are joined together, cyclized to form an epoxide). The mixture of enantiomers produced by this process (represented by the formula R-NH-CH 2 -CHOH-CH 2 -OH) is separated by fractional crystallization of the mandelic acid salts. The enantiomerically pure R-diol is then converted to. oxazolidinones substituted with 5R-hydroxymethyl by condensation with diethylcarbonate in the presence of sodium methoxide. These oxazolidinones substituted with 5R-hydroxymethyl should be amined at a later stage. J. Med. Ch em. , 32 1673 (1989), Te t rah edron 45, 1323 (1989) and U.S. Patent 4,948,801 disclose a method for producing oxazolidinones which comprises reacting an isocyanate (RN = C = 0) with (R) -glycidi lbutyrate in the presence of a catalytic amount of lithium bromide-tributylphosphine oxide complex to produce the oxazolidinone substituted with corresponding 5R-butyryloxymethyl. The process is done at 135-145 °. The butyrate ester is then hydrolyzed in a subsequent step to provide the corresponding 5R-hydroxymethyl substituted oxazolidinone. The oxazolidinone substituted with 5R-hydroxymethyl should be amined at a later stage. Abs tra cts of Papers, 206th National Meeting of the American Chemical Society, Chicago, IL, August 1993; American Chemical Society: Washington, DC, 1993; ORGN 089; A Med. Ch em. 39, 673 (1996); J. Med.

Chem. 39, 680 (1996); International Publications WO93 / 09103, WO93 / 09103, WO95 / 07271 and W093 / 23384; PCT applications PCT / US95 / 12751 and PCT / US 95/10992; Abs t ra ct s of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 1995; American Society for Microbiology: Washington, DC, 1995; Extract No. F208; Abs t ra c ts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 1995; American Society for Microbiology; Washington, DC, 1995; Extract No. F207; Abs t ra c t s of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 1995; American Society for Microbiology: Washington, DC, 1995; Extract No. F206; Abs t ra cts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 1995; American Society for Microbiology; Washington, DC, 1995; Excerpt No F227; reveal the reaction of a carbamate with n-butyl-lithium, lithium diisopropylamide or lithium hexamethyldisilazide at a temperature between -78 ° and -40 ° followed by glycidylbutyr or -78 ° followed by heating at 20-25 ° to produce oxazolidinones substituted with 5R-hydroxymethyl where the ester is removed during the reaction. The oxazolidinones substituted with 5R-hydroxymethyl should then be removed at a later stage. International Publication WO95 / 07271 discloses the ammonolysis of oxazolidinones substituted with 5R-methylsulfonyloxymethyl. U.S. Patent 4,476,136 discloses a method for transforming 5-hydroxymethyl substituted oxazolidinones to the corresponding 5 (S) -aminomethyl-substituted oxazolidinones (VII) which involve treatment with methanesulfonyl chloride followed by potassium phthalimide followed by hydrazine. J. Med. Ch em. , 32, 1673 (1989) and Tetrahedron 45, 1323 (1989) disclose a method for transforming 5-hydroxymethyl-substituted oxazolidinones into the corresponding 5S-acetamidomethyl-substituted oxazolidinones which involves treatment with methanesulfonyl chloride or tosyl chloride , followed by sodium azide, followed by trimethylphosphite or platinum / hydrogen dioxide, followed by acetic anhydride or acetyl chloride to provide the desired 5 (S) -acetamidomethyl-substituted oxazolidinone.

US Provisional Application Serial No. 60 / 015,499 discloses a process for preparing oxazolidinone intermediates substituted with 5 (S) -hydroxymethyl which are useful in the preparation of pharmacologically active 5 (S) -acetamidomethyl oxazolidinones. In addition, a process for converting oxazolidinone intermediates substituted with 5-hydroxymethyl to oxazolidinone intermediates substituted with 5-aminomethyl which can be acylated to produce pharmaceutically active 5 (S) -acetamidomethyl-substituted oxazolidinones is disclosed. J. Med. Ch em. , 33, 2569 (1990) discloses the condensation of an isocyanate with racemic glycidyl azide to produce an oxazolidinone substituted with racemic 5-azidomethyl. Two subsequent steps are required to convert racemic azidomethyl-substituted oxazolidinone to racemic substituted 5-acetamidomethyl oxazolidinone, which has antibiotic activity. The present invention converts isocyanates to the (S) -enantiomer of oxazolidinones substituted with acetamidomethyl having a greater antibiotic activity than the racemates, in a single step.

U.S. Patent 5,332,754 discloses (col.2, lines 14-34) that racemic oxazolidinone-CH2-NH-Ac can be synthesized in a single step by the condensation of a carbamate with racemic glycidyl acetamide "in the presence of a base "such as for example an amine," alkali metal hydroxide, an alkali metal alkoxide, and the like ", and which" is preferred to carry out the reaction under heating ... preferably at a temperature between 90 ° C and 110 ° C "(col 4, lines 44-56). The evidence indicates that under these conditions a reordering occurs for an unwanted product. The patent does not provide returns or description of this process in the Examples. Indeed, the EXAMPLES do not reveal a single-step process although multi-step routes involving the mesylation of an oxazolidinone substituted with 5-hydroxymethyl followed by azide displacement, hydrogenation and acetylation are known to those skilled in the art. the amine. In particular, see EXAMPLES 59-63. The present invention differs in that the contact between the carbamate (IX) and the epoxide (VIIIB) is carried out under conditions that compete with the rearrangement so that unwanted by-products are suppressed significantly. Te trahedron Le tt ers, 37, 7937-40 (1996) reveals a sequence for the synthesis of S-glycidylacetamide (R2 = -NHAc) and a process for the condensation of a carbamate with 1.1 equivalents of n-butyllithium (THF) , -78 °) followed by 2 equivalents of S-glycidylacetamide to provide the oxazolidinone substituted with corresponding 5S-acetamidomethyl. The present invention differs in that the contact between the carbamate (IX) and S-glycidylacetamide is carried out in the presence of lithium alkoxide bases or the carbamate (IX) is brought into contact with the S-chlorohydrin-acetamide (VIIIA) or S -chloroacetateacetamide (VIIIC) or an isocyanate (XIV) is contacted with the S-chlorohydrin-acetamide (VIIIA). U.S. Patent 3,654,298 discloses the synthesis of oxazolidinones substituted with 5-alkoxymethyl-3-aryl by sodium ethoxide induced by cyclization of chlorocarbamates. The present invention differs in that the "substituent in the 5-position is acylamino.

BRIEF DESCRIPTION OF THE INVENTION An alcohol (S) -secondary of the formula (VIIIA), an (S) -epoxide of the formula (VIIIB), a (S) -ester of the formula (VIIIC), an alcohol ( S) -protected from the formula (IVA), an alcohol of (S) -phthalimide of the formula (IVC), an epoxide of (S) -phthalimide of the formula (IVD) or a (S) -imine of glycidyl ina of the formula (IVB), an (S) -intermediate of the formula (XV) and an intermediate of (S) -oxazolidinone phthalamide of the formula (XVI). A process for the preparation of an amino alcohol is also revealed of (S) -3-carbon of the formula (V) comprising (1) contacting an adduct without nitrogen of the formula (I) with aqueous ammonia (II) in the presence of an epoxide (S) -protected from the formula (III) and (2) contacting the reaction mixture of step (1) with acid. Furthermore, a process for the preparation of a (S) -3-carbon amino alcohol of the formula (V) comprising (1) contacting a phthalimide of the formula (VI) with an epoxide (S) -protected from formula (III) in the presence of potassium phthalamide in DMF or DMAC to provide an (S) -phthalimide alcohol of the formula (IVC) and (2) contact the product of step (1) with aqueous acid. Further disclosed is a process for the preparation of a secondary alcohol of the formula (VIIIA) comprising (1) contacting a (S) -3-carbon amino alcohol of the formula (V) with an acylating agent and a tri ( alkyl) amine. A process for the production of an (S) -oxazolidinone-CH2-NH-CO-RN of the formula (X) comprising (1) contacting a carbamate of the formula (IX) with an oxygenated amino reagent is disclosed. selected from the group consisting of an alcohol (S) -secondary of the formula (VIIIA), an (S) -epoxide of the formula (VIIIB) or a (S) -ester of the formula (VIIIC) in the presence of a lithium cation and a base whose conjugate acid has a pKa greater than about 8. It is also disclosed a process for the production of a (S) -oxazolidinone-CH2-NH-CO-RN of the formula (X) comprising (1) contracting a carbamate of the formula (IX) with a phthalimide alcohol of the formula (IVC) or a phthalimide epoxide of the formula (IVD), in the presence of a lithium cation and a base whose conjugate acid has a pKa greater than about 8, (2) contacting the product of step (1) with aqueous acid, (3) contacting the reaction mixture of step (2) with an acid anhydride of the formula 0 (CO-RN) 2 or an acid halide of the formula RN-CO-X4 and a tri ( alkyl) amine wherein the alkyl is C1-C5. Furthermore, a process for the production of an (S) -Roxa-RING-CH2-NH-C0-RN of the formula (X) which comprises (1) contacting a carbamate of the formula (IX) with a compound is disclosed. selected from the group consisting of an alcohol (S) -prot egido of the formula (IVA) or an epoxide protected with (S) -3-carbon of the formula (IVB) in the presence of a lithium cation and a base whose acid conjugate has a pKa greater than about 8 to produce an oxazolidinone (S) -protage of formula (XII), (2) contacting the reaction mixture of step (1) with an aqueous acid to produce a free amine of (S) -oxazolidinone of the formula (XIII) and (3) contacting the product of step (2) with an acylating agent selected from the group consisting of an acid anhydride of the formula 0 (CO-RN) 2 or an acid halide of the formula RN-CO-X4 and where RN is as defined above and a tri (alkyl) amine where alkyl is C1-C5 where R0? a is c As it was defined in the above.A process for the production of an (S) -Roxa-RING-CH2-NH-C0-RN of the formula (X) which comprises (1) contacting a carbamate of the formula (IX) in the presence of a lithium cation and a base whose conjugate acid has a pKa greater than about 8 to produce a free (S) -oxazolidinone amine of the formula (XIII), and (2) acylating the free (S) -oxazolidinone amine ( XIII) with an acylating agent selected from the group consisting of an acid anhydride of the formula 0 (CO-R) 2 or an acid halide of the formula RN-CO-X4 and a tri (alkyl) amine where alkyl is C1-C5 .

DETAILED DESCRIPTION OF THE INVENTION The present invention includes both novel intermediates and processes useful in the production of commercially valuable oxazolidinone antibiotics (X). One of the novel processes is established in DIAGRAM D and is the reaction of a carbamate (IX) with either an alcohol (S) -secondary (VIIIA) or (S) -eepioxide (VIIIB) or (S) ester (VIIIC) ) to produce (S) -oxazolidinone-CH2-CO-R? (X) corresponding pharmacologically active. A second process to produce (S) -oxazolidinone-CH2-CO-R? (X) pharmacologically active is established in DIAGRAM H and involves the reaction of an isocyanate (XIV) with an alcohol (S) -secondary (VIII.A) to provide the (S) -intermediate (XV) which is then easily transformed to (S) -oxazolidinone-CH2-CO-R? (X) corresponding pharmacologically active. The fragments of alcohol (S) -secondary (VIIIA), (S) -epoxide (VIIIB) and (S) -ester (VIIIC) containing three carbon-nitrogen atoms can be produced in two different ways. This fragment produces the two adjacent carbon atoms of the oxazolidinone ring, the methylene carbon atom attached thereto as well as the nitrogen atom attached to the methylene group. These fragments of alcohol (S) -secondary (VIIIA), (S) -ephoxide (V'I'IIB) and (S) -ester (VIIIC) containing three carbon-nitrogen atoms are produced according to the processes of DIAGRAM C. DIAGRAM A reveals a process for preparing the aminoalcohol of (S) - 3-carbon (V) from (S) -X2-epoxide (III) using an adduct that does not contain nitrogen (I) and ammonia (II) as the nitrogen source. In the (S) -X2-epoxide (III), and other compounds of this invention # indicates that the atoms marked with a () are joined together resulting in the formation of a ring (epoxide). For (S) -X2-epoxides (III) it is preferred that X2 is -Cl. The (S) -X2-epoxides (III) are either known to those skilled in the art or can be easily prepared from the compounds known to those skilled in the art by methods known to those skilled in the art. For the adduct (I) that does not contain nitrogen it is preferred that Xo is -f; it is preferred that Xo is -f. The reaction of the adduct without nitrogen (I), ammonia (II) and (S) -X2-epoxide (III) is carried out as established in EXAMPLES 1 and 14. It should be noted that if one starts with (S) - Enantiomerically pure x2-epoxide (III), one then obtains alcohol (S) -protected (IVA) enant iomerically pure. The absolute configuration of the carbon atom in the product of (S) -oxazolidinone-CH2-CO-R? (X) pharmacologically useful is "S" and, therefore, it is preferred to start with enantiomerically pure (S) -X2-epoxide (III) and obtain enantiomerically pure (S) -protected alcohol (IVA), see DIAGRAM A. In the DIAGRAMS and CLAIMS the Index "*" as -C * (a) (b) - denotes that the asymmetric carbon atom has the appropriate enantiomeric configuration (S) - so that when this carbon atom becomes part of (S) -oxazolidinone-CH2-CO-R? (X), this is the correct enantiomer. If one begins any of the chemical sequences of the processes of the present invention with an optically impure (racemic) form rather than an enantiomerically pure form, it is evident to one skilled in the art that the products obtained will be optically impure (racemic) forms. ) corresponding. The alcohol (S) -protected (IVA) is then contacted with an acid to form the corresponding aminoalcohol of (S) -3-carbon (V). Nor nature, resistance or the amount of acid is critical. It is preferred that the acid have a pKa less than 4. It does not matter if the acid is organic or inorganic. The aminoalcohol of (S) -3-carbon becomes the cation and the non-proton portion of the acid is the anion. For example, if the mixture is acidified with sulfuric acid, the (S) -3-carbon aminoalcohol (V) is obtained as the sulfate salt. The nature of the anion is not important. DIAGRAM B reveals a way to prepare the desired (S) -3-carbon amino alcohol (V) from it (S) -X2-epoxide (III) although it uses an adduct (VI) containing nitrogen. In this situation, ammonia (II) is not needed. In the final stage of the process, where the product of stage one is contacted with aqueous acid, it is preferred that the acid be hydrochloric, hydrobromic, hydroiodic, sulfuric or p-toluenesulfonic acid. DIAGRAM C reveals the process for converting the aminoalcohol from (S) -3-carbon (V) to the corresponding alcohol (S) -secondary (VIIIA), (S) -epoxide (VIIIB) or (S) -ester (VIIIC) and the conversion of the alcohol (S) -secondary (VIIIA) to the corresponding (S) -ephoxide (VIIIB) and (S) -ester (VIIIC) respectively. To convert the aminoalcohol of (S) -3-carbon (V) to the corresponding corresponding alcohol (S) -secondary (VIIIA), the 3-carbon aminoalcohol (5) is reacted with an appropriate acylating reagent such as for example a Acyl halide or acyl anhydride under acylation reaction conditions well known to those skilled in the art, see EXAMPLE 2. It is preferred that the acylating reagent be selected from the group consisting of an acid anhydride of the formula 0 (CO -RN) 2 wherein RN is C1-C5 alkyl or an acid halide of the formula RN-CO-X4 where X4 is -Cl or -Br and a tri (alkyl) amine where alkyl is C1-C5. It is more preferred that RN is Ci-alkyl and X4 is -Cl. It is more preferred that the acylating reagent be the acyl anhydride and it is preferred that the acyl anhydride is acetic anhydride. Alternatively, (S) -epoxide (VIIIB) can be obtained by reaction of (S) -ester (VIIIC) with bases such as for example sodium methoxide or potassium carbonate / methanol. The aminoalcohol of (S) -3-carbon (V) can also be converted to the corresponding (S) -ester (VIIIC) by reaction with acetic anhydride in pyridine, see EXAMPLE 3. The (S) -ephoxide (VIIIB) can be produced from alcohol (S) -secondary (VIIIA) corresponding by reaction with potassium t-butoxide in THF at -20 °, see EXAMPLE 11. In addition, alcohol (S) -secondary (VIIIA) can be transformed to the corresponding (S) -ester (VIIIC) by reaction with the acylation reagents analyzed in the above. For the (S) -ester (VIIIC), it is preferred that RN is -C0-CH3. DIAGRAM D reveals the process for reacting a carbamate of the formula Roxa-NH-CO-0-CH2-Xi (IX) with either the alcohol (S) -secondary (VIIIA), the (S) -ephoxide (VIIIB) ) or (S) -ester (VIIIC) to produce (S) -oxazolidinone-CH2-CO-R? (X) corresponding. The carbamates (IX) are known to those skilled in the art or can be easily prepared from the known compounds by methods known to those skilled in the art. It is preferred that Xx is -H. Roxa is phenyl substituted with a -F and a substituted amino group. Substituted amino groups include 4- (benzyloxycarbonyl) -1-piperazinyl, 4-morpholinyl and 4-hydroxy-acetyl-piperazinyl. It is preferred that Roxa is 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl or 3-fluoro-4- (4-morpholinyl) phenyl. The carbamate (IX) and the three carbon unit (VIIIA, VLIIb or VIIIC) is reacted by contacting the reactants with a base. The nature of which is not critical as long as it is strong enough to deprotonate the carbamate (IX). Operable bases are those whose conjugated acids have a pKa greater than about 8. Preferred bases include compounds selected from the group consisting of: alkoxy compounds of one to seven carbon atoms, carbonate, methyl, sec-butyl and t-butyl carbanions , tri (alkyl) amines where the alkyl group is from 1 to 4 carbon atoms, base conjugate of carbamate (II), DBU, DBN, N-methyl-piperidine, N-methylmorpholine, 2, 2, 2-t ricloroethoxide and Cl3C-CH2-0", the most preferred bases are wherein the base is four or five carbon atoms.It is preferred that the alcohol bases of four and five carbon atoms are t-amylate or t-butoxide. The sodium or potassium bases in combination with a lithium salt (such as for example lithium chloride or lithium bromide) can be used to form the lithium cation and the base in. The nature of the solvent is not critical. Operable solvents include cyclic ethers such as for example THF, amides such as for example DMF and DMAC, amines such as for example triethylamine, acetonitrile, and alcohols such as for example t-amyl alcohol and t-butyl alcohol. The choice of solvent depends on the solubility of the carbamate (IX) and the three-carbon unit (VIIIA, VlIIb or VIIIC) as known to those skilled in the art. DIAGRAM E reveals the reaction of the carbamate (IX) with either the alcohol (S) -phthalimide (IVC) or the epoxide (S) -phthalimide (IVD) to produce the (S) -nillo-phthalimide (XI) which is then converts the corresponding (S) -oxazolidinone-CH2-NH-CO-RN (X) product having pharmaceutical utility. DIAGRAM F reveals the reaction of carbamate (IX) with either alcohol (S) -protected (IVA) or (S) -glycidylamine imine (IVB) to produce the corresponding compound (S) -oxazolidinone (XII) corresponding to which is then transformed to the free (S) -oxazolidinone amine (XIII) which is then acylated as analyzed in the above to provide the product of (S) -oxazolidinone-CH2-NH-CO-RN (X) having pharmaceutical utility. These processes are the same as those of DIAGRAMS D and E or are well known to those skilled in the art. DIAGRAM G reveals the reaction of the carbamate (IX) directly with the aminoalcohol of (S) -3-carbon (V) to provide the free amine of (S) -oxazolidinone (XIII) which is then acylated to provide the (S) -oxazolidinone-CH2-NH-CO-RN (X).

These processes are carried out in the same way as previously revealed. DIAGRAM H reveals the reaction of isocyanate (XIV) with alcohol (S) -secondary (VIIIA) to provide the (S) -intermediate (XV) which is then transformed to the (S) -oxazolidinone-CH2-NH-CO- RN (X), see EXAMPLES 6, 8 and 9. DIAGRAM I reveals a reaction analogue for that of DIAGRAM E. While the process of DIAGRAM E used a carbamate (IX), the process of DIAGRAM I uses an isocyanate (XIV). The (S) -oxazolidinone-CH2-CO-amines (X) are known to be useful as antibiotic pharmaceuticals.

DEFINITIONS AND CONVENTIONS The following definitions and explanations are for the terms as they are used throughout the entire document that include both the specification and the claims.

. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES Chemical formulas representing various molecular fragment compounds in the specification and claims may contain variable substituents in addition to the structural characteristics expressly defined. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Zi" or "Ri" where "i" is an integer. The variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Zi could represent a bivalent variable if it is linked to the formula CH3-C (= Z?) H. The Ri and Rj groups could represent monovalent variable substituents if they are linked to the formula CH3-CH2-C (R ±) (Rj) -H. When the chemical formulas are represented in a linear form, such as the above, the variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parentheses. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is attached to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the previous formula, both Ri and Rj are linked to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as Cl r where "i" is the integer corresponding to the number of carbon atoms. For example, C e represents the 6-position or the number of carbon atoms in the steroid nucleus as conventionally designated by those skilled in the art of steroid chemistry. Also the term "R6p represents a variable substituent (either monovalent or bivalent) at the C6 position.The chemical formulas or portions thereof shown in a linear form represent atoms in a linear chain.The symbol in general represents a link between two atoms in the chain In this way, CH3-0-CH2-CH (Rx) -CH3 represents a 2-substituted-l-methoxypropane compound In a similar way, the symbol "=" represents a double bond, for example, CH2 = C (Rx) -0-CH3, and the symbol "=" represents a triple bond, for example, HC = C-CH (R;,.) -CH2-CH3 The carbonyl groups are represented either or two forms: -CO- or -C (= 0) -, with the first one preferred for simplicity.

The chemical formulas of the cyclic compounds (ring) or molecular fragments can be represented in a linear fashion. In this way, the 4-chloro-2-methylpyridine compound can be represented in a linear fashion by N * = C (CH3) -CH = CC1-CH = C # H with the convention that atoms marked with an asterisk (#) are linked together resulting in the formation of a ring. Also, the cyclic molecular fragment, 4- (ethyl) -1-piperazinyl can be represented by -N # - (CH2) 2_N (C2H5) -CH2-C # H2. A rigid cyclic structure (ring) for any compounds herein defines an orientation with respect to the plane of the ring for the substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds having two substituents attached to a carbon atom that is part of a cyclic system, -C (X?) (X2) - the two substituents may be either in axial or equatorial position relative to the ring and may be switch between axial / equatorial. However, the position of the two substituents relative to the ring and to each other remains fixed. While any substituent can sometimes be in the plane of the ring (equatorial) instead of being above or below the plane (axial)One substituent is always above the other. In chemical structural formulas representing these compounds, a substituent (Xi) that is "below" another substituent (X2) will be identified to be in the alpha (a) configuration and is identified by a dashed line, dashed or dotted attached to the carbon atom, that is, by the symbol "" or "...". The corresponding substituent attached "above" (X2) to the other (Xi) is identified to be in the beta (ß) configuration and is indicated by a dashed line attached to the carbon atom. When a variable substituent is bivalent, valences can be taken together or separately, or both, in the definition of the variable. For example, a variable R attached to a carbon atom like -C (= R?) - could be bivalent and defined as oxo or keto (thus forming a carbonyl group (-C0-) or as two monovalent variable substituents separately bound to-Ri-j and ß-Ri_. When a bivalent variable, Ri, is defined to consist of two monovalent variable substituents, the convention, used to define the bivalent variable is of the form "a-Ri-j: ß-Ri-k" or some variant thereof.

In this case both a-Ri-j and ß-Ri-k are attached to the carbon atom to provide -C (a-Ri-j) (ßRi-k) - For example, when the bivalent variable R6, -C (= R6) -is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are a-Re-i: ß-Re-2, - • • .a-Rd-gí-R6-? O, etc. , providing -C (a-R6-?) (ßRe-2) -, ....- C (a-R6_9) (ßR6-? o) _A etc. Also, for the bivalent variable Rn, -C (= Rn) -, two monovalent variable substituents are a-Rn_? : ß-Rn-2. For a ring substituent for which there are no orientations a and β separately (for example 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 a ring also, the previous convention is used, although the designations a and ß are omitted. Just as a bivalent variable can be defined as two monovalent variable substituents separately, the two monovalent variable substituents can be defined separately to be taken together to form a bivalent variable. For example, in the formula -Cx (R ±) H-C2 (R) H- (Ci and C2 arbitrarily define a first and second carbon atom, respectively) R¿ and Rj can be defined to be taken together to form ( 1) a second link between Ci and C2 or (2) a bivalent group such as oxa (-0-) and the formula therefore describes an epoxide. When Ri and Rj are taken together to take a more complex entity, such as the group -XY-, then the orientation of the entity is such that Ci in the previous formula is attached to X, and C2 is attached to Y. In this way, by convention the designation "... Ri and Rj taken together to form -CH2-CH2-0-C0- ..." means a lactone in which the carbonyl is attached to C2. However, when designated "... Rj and Ri are taken together to form -CO-O-CH2-CH2-" the convention means a lactone in which the carbonyl is attached to Ci. . The content of carbon atoms of the variable substituents is indicated in one of two ways. The first method uses a prefix for the full name of the variable such as "C? ~ C4", where both "1" and "4" are integers that represent the maximum and minimum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C 1 -C 4 alkyl" represents alkyl of 1 to 4 carbon atoms, (including isomeric forms thereof unless otherwise expressly indicated). As soon as this simple prefix is provided, the prefix indicates the total content of carbon atoms of the variable that will be defined. In this manner C2-C4 alkoxycarbonyl describes a group CH3- (CH2) n_0-C0- where n is zero, one or two. By the second method the content of carbon atoms of only each portion of the definition is indicated separately by enclosing the designation "Ci-C-," between parentheses and placing it immediately (without space) before the portion of the definition that will be defined . By this optional convention (C1-C3) alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because "C1-C3" refers only to the content of carbon atoms of the alkoxy group. In a similar manner while both C2-C6 alkoxyalkyl and (C1-C3) alkoxy (C1-C3) alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the first definition allows any portion of alkoxy or alkyl alone contains 4 or 5 carbon atoms while the latter definition limits any of these groups to 3 carbon atoms. When the claims contain a rather complex (cyclic) substituent, at the end of the phrase appointing / designating this particular substituent, it will be a notation (in parentheses) corresponding to the same name / designation in one of the DIAGRAMS that will also establish the formula chemical structure of that particular substituent.

DEFINITIONS All temperatures are in degrees Celsius. TLC refers to thin layer chromatography. HPLC refers to high pressure liquid chromatography. THF refers to tetrahydrofuran. * indicates that the carbon atom is an enantiomeric carbon in the (S) configuration. # indicates that the atoms marked with a (#) are linked together resulting in the formation of a ring. RING is defined in DIAGRAM J as the oxazolidinone ring, a 2,5-disubstituted oxazolidinone. DMF refers to dimethylformamide. DMAC refers to dimethylacetamide.

Chromatography (column and flash chromatography) refers to the purification / separation of the compounds expressed as (support, eluent). It should be understood that the suitable fractions are combined and concentrated to give the desired compounds. IR refers to infrared spectroscopy. CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) of the descending field of TMS. NMR refers to nuclear magnetic resonance (proton) spectroscopy; chemical shifts are reported in ppm (d) of downfield of tetramethylsilane. TMS refers to trimethylsilyl. -f refers to phenyl (CgH5). [a] D refers to the angle of rotation of the plane polarized light (specific optical rotation) at 25 ° with a D line of sodium (589A). MS refers to mass spectrometry expressed as m / e, m / z or mass / unit load. [M + H] + refers to the positive ion of a precursor plus a hydrogen atom. He refers to electronic impact. Cl refers to chemical ionization. FAB refers to rapid atomic bombing.

Pharmaceutically acceptable refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and to the chemical-pharmaceutical manufacture from a physical / chemical point of view regarding the composition, formulation, stability, acceptance for the patient and bioavailability. When solvent pairs are used, the proportions of the solvents used will be in volume / volume (v / v). When the solubility of a solid in a solvent is used, the ratio of the solid to the solvent is weight / volume (w / v).

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and / or perform the various processes of the invention and should be interpreted only as illustrative, and not as limitations of the preceding description in any form whatsoever. Those skilled in the art will readily recognize appropriate variations of the procedures for both the reagents and the reaction conditions and techniques.

PREPARATION 1 3-Fluoro-4-morpholinyl aniline 3,4-Difluoronitrobenzene (25,196 g, 158.38 mmol) is added to a mixture of morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at -14 °. The mixture is allowed to warm to 10 °, then held at 10-13 ° for 1 hour. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq) in water (365 ml) is added with concomitant exothermic reaction at 28 °. The phases are separated and the aqueous phase is washed with toluene (95 ml). The organic phase is washed with water (315 ml) and concentrated under reduced pressure. Toluene (46 ml) and methanol (60 ml) are added followed by palladium or carbon (humidity in water 5%, 50%, 3.1603 g, 0.7426 mmol, 0.00469 eq) and the mixture is sealed in a Parr stirrer. Hydrogen pressure (40 psi) is applied and maintained while stirring for 42 minutes. The catalyst is then removed by filtration under reduced pressure and washed with toluene (60 ml). Heptane (150 ml) is added to the filtrate and the resulting suspension i is concentrated under reduced pressure. Heptane (300 ml) is added and the precipitate is collected by filtration under reduced pressure and washed with heptane and dried to provide the title compound, HPLC (the stationary phase is column 4.6 ± 250 mm zorbax RX C-8; the mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and enough water to produce 1,000 ml; flow rate = 3.0 ml / min; UV detection at 254 nm) RT = 1.08 min, > area 99.3); NMR (Pyridine-D5) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 d; CMR (Pyridine-D5) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and 157.72 d.

PREPARATION 2 N-Carbomethoxy-3-fluoro-4-morpholinyl aniline (IX) 3,4-Difluoronitrobenzene (PREPARATION 1, 24,967 g, 156.94 mmol) is added to a mixture of morpholine (60.0 ml, 688 mmol, 4.38 eq) in THF (30 mi) a - 6 o. The mixture is allowed to warm to 10 ° for 2 hours then it is maintained at 10 ° for 1/2 hour. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.27 eq) in water (365 ml) is added with concomitant exothermic reaction at 28 °. The phases are separated and the aqueous phase is washed with toluene (95 ml). The organic phases are washed with water (315 ml), the aqueous phase is washed again and extracted with toluene (95 ml) and concentrated under reduced pressure. Toluene (76 ml) and methanol (60 ml) are added followed by palladium or carbon (5% aqueous moisture, 50%, 3.1370 g, 0.7371 mmol, 0.00470 eq) and the mixture is sealed in a Parr stirrer. Hydrogen pressure (40 PSI) is applied and maintained while stirring for 4.5 hours. The catalyst is then removed by filtration under reduced pressure and washed with toluene (100 ml). The mixture is cooled to 2 ° and a mixture of aqueous potassium carbonate (47%, 17.1 ml, 85 mmol, 0.54 eq) and water (150 ml) is added. Methyl chloroformate (16.4 ml, 212 mmol, 1.35 eq) is then added while maintaining the temperature at about 3-3.5 °. The resulting suspension is allowed to warm to 20-25 ° and is stirred for 17 hours. The mixture is heated to 75 ° to provide a solution, then cooled to 46 °, heptane (333 ml) is added, then the mixture is cooled to 0 °, the precipitate is collected by filtration with reduced pressure, washed with heptane (100 ml cooled to 5 °) then with water (230 ml cooled to 5 °) and dried to give the title compound, TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.74 (one stain); NMR (CDC13) 3.03, 3.76, 3.86, 6.75, 6.87, 6.98, 7.27; CMR (CDCI3) 51.18, 52.42, 67.03, 107.81, 114.56, 119.00, 133.25, 135.77, 154.07, 155.70.

PREPARATION 3 3-Fluoro-4-morpholinylphenyl isocyanate (XIV) A mixture of 3-Fluoro-4-morpholinyl aniline (PREPARATION 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) is added to a mixture of phosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) in p-chlorotoluene (60 ml) for 15 minutes, while maintaining the temperature of approximately -12 to 3 °. The material is rinsed in methylene chloride (30 ml). The mixture is then heated to 130 ° under atmospheric pressure with concomitant distillation of methylene chloride, phosgene, toluene and hydrogen chloride gas in a caustic scrubber. The mixture is cooled to 25 ° and filtered. The precipitate is washed with methylene chloride (3x15 ml). The filtrate is concentrated under reduced pressure. Heptane (200 ml) is added to the concentrated filtrate and the resulting suspension is cooled to -32 °. The product is collected by filtration with reduced pressure, washed with heptane cooled to -30 °, and dried in a stream of nitrogen to provide the title compound, HPLC (the stationary phase is a 4.6x250 mm column of zorbax RX. C-8, the mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and enough water to produce 1,000 ml, flow rate = 3.0 ml / min, UV detection at 254 nm ) RT = 1.08 min. Upon dissolution in methanol, the derivatization is carried out as N-carbomethoxy-3-fluoro-4-morpholinyllaniline; NMR (CDC13) 3.05, 3.86 and 6.78-6.89 d; CMR (CDC13) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40 d, MS (El), m / z (relative intensity) 222 (37) and 164 (100).

EXAMPLE 1 (S) -l-Amino-3-chloro-2-propanol (V) Hydrochloride (S) -Epichlorohydrin (III, 44.978 g, 486.1 mmol, 98% enantomeric excess, 99.3% chemical purity) ) to a mixture of benzaldehyde (I, 50.0 ml, 492 mmol, 1012 eq), ethanol (163 ml) and aqueous ammonia (II, 29.8% by weight, 50 ml, 787.4 mmol, 1.62 eq) at 18 ° for 10 minutes with an exothermic reaction at 22 °. The reaction mixture is allowed to react exothermically at 34 ° for 1.5 hours, heat to 42 °, stir at 20-25 ° for 20.5 hours, then heat to 74 ° and allow to cool immediately. The mixture is concentrated under reduced pressure to provide (S) -l-benzalimino-3-chloro-2-propanol (IVA). Water (382 ml) and hydrochloric acid (37.7% by weight, 76.2 ml, 938 mmol, 1.93 eq) are added to the concentrate and the mixture is stirred at 20-25 ° for 2 hours. Toluene (150 ml) is added and the phases are separated. The organic phase is washed with water (15 ml) and the combined aqueous phase is washed with toluene (2 ml 50 ml), extracting each organic extract again with water (15 ml). The combined aqueous extracts are concentrated under reduced pressure. Ethanol (200 ml) is added to the concentrate and the mixture is concentrated under reduced pressure. Ethanol (300 ml) is added to the concentrate and the mixture is heated to reflux. The mixture is cooled to -30 ° and the precipitate is collected by filtration with reduced pressure, washed with ethanol at -30 ° (2? 60 ml) and dried under a stream of nitrogen to provide a white solid, e.g. F. = 132.141 °; NMR (CD3OD) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 d; CMR (CD3OD) 43.52, 46.91 and 68.72 d; MS (Cl, NH3), M / Z (relative intensity) 129 (24), 127 (69), 112 (61), 110 (100); [a] 25D = -22 (c = 1.00, H20).

EXAMPLE 2 (S) -l-Acetamido-2-hydroxy-3-chloropropane (VIIIA) Triethylamine (10.5 ml, 75.3 mmol, 1.11 eq) is added to a suspension of (S) -l-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9.938 g, 68.059 mmol) in THF (80 ml) at -40 ° and the mixture is stirred for 5 minutes at -40 °. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at -40 ° and the mixture is allowed to warm to 20-25 ° for 1.5 hours. The precipitate is removed by filtration with reduced pressure and washed with THF. The filtrate is treated with magnesol (5.69 g), which is removed by filtration with reduced pressure and washed with THF (2? 60 ml). The filtrate is then concentrated under reduced pressure. The concentrate is purified by flash chromatography (silica gel, eluting with gradient of 75-100% ethyl acetate / cyclohexane) to give the title compound, NMR (CDC13) 2.03, 3.32, 3.50-3.57, 3.55, 3.91- 4.13, 5.01 and 7.09 d; CMR (CDC13) 23.00, 43.31, 46.52. 70.65 and 172.40 d; MS (Cl, NH3), M / Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152 (48.1); [a] 25D = -7.44 (c = 1.00, H20).

EXAMPLE 3 (±) -l-Acetamido-2-acetoxy-3-chloropropane (VIIIC) Acetic anhydride (13 ml) is added to a fluid suspension of (±) -l-amino-3-chloro-2-propanol hydrochloride ((±) -V, EXAMPLE 5, 5.0110 g, 34.317 mmol) in pyridine (20 ml) while maintaining the temperature in the range of 20-50 °. The mixture is stirred at 20-25 ° for 18 hours, then water (14 ml) is added with an exothermic reaction at 65 °. The mixture is concentrated under reduced pressure and water (50 ml) is added. The pH is adjusted to 0.89 with hydrochloric acid (37.7%, 1467 g, 15.17 mmol, 0.442 eq) at 0 °. The mixture is extracted with methylene chloride (4? 50 ml), the extracts are dried over sodium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) and heptane (20 ml) are added, the mixture is allowed to age, then heptane (40 ml) is added to the resulting suspension. The precipitate is collected by filtration with reduced pressure, washed with heptane and dried to provide the title compound, e.g. F. = 68.0-69.5 °; TLC (silica gel; ethyl acetate, carbon with iodine) Rf = 0.39 (one spot); NMR 2.00, 2.21, 3.52, 3.62, 3.70, 5.10 and 6.33 d; CMR 20.93, 23.10, 40.47, 43.53, 71.95, 170.45 and 170.71 d; MS (Cl, NH3) m / z (relative intensity) 213 (36), 211 (100), 196 (18) and 194 (53).

EXAMPLE 4 (S) -l-Phthalimido-3-chloro-2-propanol (S) (IVC) (S) -epichlorohydrin (III, enantiomerically pure at 98.9%, 99.3% of chemical purity, 4.9605 g, 53.61 mmol) is added to a suspension of potassium phthalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq) and phthalimide (VI, 11.836 g, 80.45 mmol, 1.5006 eq) in DMF (32 ml) and the mixture is stirred at 50 ° for 4.5 hours. The mixture is added to methylene chloride (50 ml) and water (50 ml) is added. The solids are removed by filtration with reduced pressure and washed with methylene chloride (20 ml). The phases are separated in the filtrate and the aqueous phase is washed with methylene chloride (50 ml). The combined organic phases are washed with water (50 ml) and the aqueous phase is extracted again with methylene chloride (50 ml) after adding water (25 ml). The combined organic phases are dried over sodium sulfate and saturated with hydrogen chloride gas at 6 ° C. Water (100 ml) is added and the phases are separated, the aqueous phase is washed with methylene chloride (2-50 ml). mi) and the combined organic phases are dried over sodium sulfate.The organic phase is concentrated under reduced pressure and toluene (77 ml) is added.The mixture is concentrated under reduced pressure to 31 g net weight and toluene (50 g) is added. mi) and heptane (75 ml) The solids are filtered off and washed with toluene / heptane (1/1, 20 ml) The filtrate is concentrated under reduced pressure to 17 g net weight, heptane (100 g) is added. mi) and the mixture is concentrated under reduced pressure 15 g net weight Heptane (100 ml) and methylene chloride (100 ml) are added and the mixture is concentrated under reduced pressure to 130 g net weight. filtration and washed with heptane / methylene chloride (2/1, 3? 15 mi). The filtrate is concentrated under reduced pressure to 11 g net weight and toluene (90 ml) is added then heptane (400 ml) is added. The resulting suspension is then cooled to -20 ° and the product is collected by filtration under reduced pressure, washed with heptane and dried to give an unpurified solid. Instant chromatography of the unpurified solid (silica gel; eluting with a gradient of ethyl acetate / 15-45% cyclohexane) gives the title compound as an analytical sample, NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14-4.20, 7.70-7.76 and 7.82-7.88 d; CMR 41.61, 47.27, 69.68, 123.53, 131.83, 134.26 and 168.65 d; MS (Cl, NH3), M / Z (relative intensity) 259 (1.4), 257 (17), 242 (0.11), 240 (0.31), 221 (100); [a] 25D = -33 (C = 0.712, CHC13). The NMR of the mosher ester derivative showed that the product has an enantiomeric purity of 96.2% compared to the NMR of the mosher ester of the racemate.

EXAMPLE 5 (±) -l-Amino-3-chloro-2-propanol (±) - (V) Hydrochloride A suspension of (±) - 1-phthalimido-3-chloro-2-propanol (IVC, 40,018 g, 166.98 mmoles) in hydrochloric acid (37.5% by weight, 79 ml, 968 mmol, 5.80 eq) and water (82 ml) is stirred at 109 ° for 5 hours. The mixture is cooled to 22 ° and the precipitate is removed by filtration with reduced pressure and washed with water (40 ml). The filtrate is concentrated under reduced pressure to 26 g net weight and ethanol (100 ml) is added. The mixture is heated to 75 ° to provide a solution, then cooled to -12 ° and the resulting precipitate is collected by filtration under reduced pressure, washed with ethanol cooled to -12 ° and dried to provide the title compound, p. F. = 101-104 °; NMR (CD30D) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 d; CMR (CD3OD) 43.54, 46.95 and 68.71 d; MS (Cl, NH3), M / Z (relative intensity) 129 (12), 127 (39), 112 (56), 110 (100).

EXAMPLE 6 (S) -N-Carbo (1 '-acetamido-3' -chloro-2 '-propoxy) -3-fluoro-4-morpholinyl aniline ((S) -XV) Acetyl chloride (0.3297 g, 4.20 g) is added mmoles, 1019 eq) to a suspension of hydrochloride (S) -l-Amino-3-chloro-2-propanol (V, EXAMPLE 1, 0. 6020 g, 4.12 mmole) and triethylamine (1.26 ml, 9.04 mmole, 2.19 eq) in acetonitrile (70 ml) at -40 °. The mixture is then heated to. 3-6 °, stirring for several hours, warming to 22 ° and 3-fluoro-4-morpholinylphenyl isocyanate (XIV, PREPARATION 3, 1.0152 g, 4.568 mmol, 1108 eq) is added. The mixture is heated to 64 °, stirred 10 minutes, then concentrated under reduced pressure to about 25 ml. 3-Fluoro-4-orpholinylphenyl isocyanate (XIV, 0.0907 g, 0.408 mmol, 0.09887 eq) is then added and the mixture is stirred at 65 ° for 17 hours. Pentanol (1.34 ml, 12.33 mmol, 2 ^ 99 eq) is added and the mixture is stirred at 65 ° during 1. 7 hours. Water (5 ml) is added and the mixture is cooled to -4 °. Water (38 ml) and heptane are added (30 ml) and the mixture is heated to 15 ° and stirred for 1 hour. The resulting precipitate is collected by filtration under reduced pressure and washed with heptane and water and dried to give a solid. The filtrate is concentrated under reduced pressure to 50 ml of total volume and the precipitate is collected by filtration under reduced pressure, washed with water (10 ml) and heptane (10 ml) and dried to give a brown solid. A portion of the first solids (0.9404 g) and second solids (0.4018 g) is dissolved in acetonitrile (15 ml) at 76 °, then cooled to -10 ° and the precipitate is collected by filtration under reduced pressure, washed with acetonitrile cooled to -10 ° and dried to provide the title compound, HPLC (the stationary phase is a 4.6-250 mm column of zorbax RX C-8, the mobile phase is acetonitrile (650 ml), triethylamine (1.85 mi) and acetic acid (1.30 ml) and the amount of water sufficient to produce 1,000 ml, flow rate = 3.0 ml / min, UV detection at 254 nm) = 92.3% area).

EXAMPLE 7 (S) -N-Carbo (1 '-acetapto-3'-chloro-2-propoxy) -3- l oro-4-orpholinyl aniline ((S) -XV) A mixture of (S) -l-acetamido -3-chloro-2-propanol- (VIIIA, EXAMPLE 2, 1024 g, 6,754 mmol, 1.00 eq) and 3-fluoro-4-morpholinylphenyl isocyanate (XIV, PREPARATION 3, 1.6756 g, 7.539 mmol, 1.12 eq) in acetonitrile ( 25 ml) is stirred at 60 ° for 46 hours. The resulting suspension is cooled to -13 °, the precipitate is collected by filtration under reduced pressure, washed with acetonitrile cooled to -13 ° C (20 mL) and dried to provide the title compound, NMR (DMSO-D6) 1.83, 2.93, 3.2-3.5, 3.73, 3.78, 3.88, 4.99, 6.97, 7.20, 7.36, 8.07 and 9.80 d; CMR (DMSO-D6) 22.42, 39.6, 44.71, 50.77, 66.15, 71.81, 106.49, 114.23, 119.21, 134.18, 134.59, 152.57, 154.65 and 169.67 d; MS (Cl, NH3), M / Z (relative intensity) 376 (27.0), 374 (85.9), 339 (12.2), 338 (80.8) and 223 (17.2); [a] 25D = -4.08 (C = 0.930, DMF).

EXAMPLE 8 (S) -N- [[3-Fluoro-4- (4-morpholinyl) phenyl] 2-oxo-5-oxazolidinyl] methyl] cetamide ((S) -X) A solution of sodium t-butoxide (0.0854 g0.889 mmol, 1.05 eq) in ethanol (0.60 ml) is added to a suspension of (S) -N-carbo (1 '-acetamido-3' -chloro-2 '-propoxy) -3-fluoro-4-morpholinyl aniline ((S) - (XV), EXAMPLE 7, 0.3176 g, 0.850 mmol) in ethanol (4.6 ml) at 65 ° and rinse with ethanol (0.50 ml). The mixture is stirred for 28 minutes and cooled to 0 °. Citric acid monohydrate (0.1943 g, 0.925 mmol, 1.09 eq) is added and the resulting suspension is concentrated under reduced pressure to 1.30 g net weight. Water (10 ml) and methylene chloride (10 ml) are added, the phases are separated and the aqueous phase is washed with methylene chloride (2 * 10 ml). The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure to a solid. The solid is dissolved in ethyl acetate (8.4 ml) at 10 °, the solution cooled to 50 °, allowed to age, and further cooled to -28 °, the precipitate is collected by filtration with reduced pressure, washed with ethyl acetate previously cooled to -30 ° and dried to provide the title compound, HPLC (100.7% by weight, 99.9% area; NMR (CDC13) 2.04, 3.04, 3.65, 3.77, 3.86, 4.02, 4.74-4.82, 6.80, 6.91, 7.06 and 7.42 d; CMR (CDC13) 22.99, 41.88, 47.64, 50.96, 66.94, 72.08, 107.55, 113.98, 118.83, 132.93, 136.55, 154.55, 155.44 and 171.40 d; MS (El), M / Z (relative intensity) 337 (16.9), 293 (74.4), 234 (37.5), 209 (100); [a] 25D = -15.8 (C = 0.903, ethanol).

EXAMPLE 9 (S) -N- [[3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] acetamide (IV) Following the general procedure of EXAMPLE 8 and making non-critical variations the title compound, NMR 2.02, 3.04, 3.65, 3.77, 3.86, 4.02, 4.74-4.82, 6.74, 6.91, 7.06 and 7.42 d) is obtained; CMR 23.02, 41.89, 47.65, 50.97, 66.87, 72.06, 107.48, 114.01, 118.76, 132.85, 136.48, 154.52, 155.38 and 171.34 d; MS (Cl, NH3), M / Z (relative intensity) 338 (100), 294 (86 [] 25 = -15.2 (C = 0.783, ethanol).

EXAMPLE 10 (±) -N- (2-Hydroxy-3-chloro) acetamide (VIIIA) To a mixture of (±) -l-Amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 5, 47.71 g , 326.74 mmoles) in THF (381 ml) at -40 ° triethylamine is added (36,496 g, 360.67 mmol, 1104 eq) followed by acetic anhydride (35,007 g, 342.90 mmol, 1049 eq) while maintaining the temperature at < -30 °. The mixture is stirred for 15 minutes at -30 °, then allowed to warm to 20 ° for 1 hour. The mixture is stirred at 20-25 ° for 3 hours, then the precipitate is removed by vacuum filtration through a medium frit and washed with THF (175 ml). The filtrate is concentrated under reduced pressure and toluene (195 ml) is added. The mixture is concentrated under reduced pressure and toluene (250 ml) is added. The mixture is concentrated under reduced pressure and toluene (250 ml), methanol (40 ml) and ethyl acetate (10 ml) are added. The mixture is cooled to -20 °, allowed to age, heptane (200 ml) is added at -30 °, the mixture is cooled to -33 ° and the precipitate is collected by vacuum filtration, washed with heptane (100 ml). ) and it dries. This solid (44818 g) is dissolved- in toluene (250 ml) and methanol (120 ml) and concentrated under reduced pressure. The mixture is cooled to -30 °, allowed to age and heptane (180 ml) is added, the precipitate is collected by vacuum filtration at -30 °, washed with heptane (100-ml) and dried to give a solid, e.g. f. = 50.1-52.3 °; TLC (silica gel; methanol / methylene chloride (5/95); carbon with iodine) Rf = 0.23 (simplest polar spot identified as 1.1% by weight of triethyl ammonium acetate by NMR); NMR (CDC13) 2.03, 3.33, 3.54, 3.95, 4.73 and 6.93 d; CMR (CDC13) 23.01, 43.32, 46.48, 70.72 and 172.37 d; MS (CI, NH3) m / z (relative intensity) 154 (34), 152 (100).

EXAMPLE 11 (1) -Glycidylacetamide (VIIIB) To a solution of (1) 1-acetamido-3-chloro-2-propanol (V, EXAMPLE 10, 10344 g, 68.24 mmol) in tetrahydrofuran (21 ml) at -40 ° a solution of potassium t-butoxide in THF (1.0 M, 65 mL, 65 mmol, 0.95 eq) is added. The mixture is heated to -20 ° and stirred for 15 minutes, then cooled to -37 ° and silica gel (18.5 g) is added. The solids are removed by vacuum filtration and washed with ethyl acetate (1,000 ml). The filtrate is concentrated and the precipitate is removed by vacuum filtration. The filtrate is concentrated and heptane (50 ml) is added. The mixture is allowed to age, sonicate, and the precipitate is collected by vacuum filtration, washed with heptane and dried under a stream of nitrogen to provide the title compound, e.g. F. = 34.6-37.3 °; TLC (silica gel; methanol / methylene chloride (5/95), carbon with iodine) Rf = 0.24; NMR 2.01, 2.59, 2.80, 3.10-3.13, 3.24-3.29, 3.7-3.9, 6.19 d; CMR 23.07, 40.67, 45.19, 50.61 and 170.54 d.

EXAMPLE 12 (+) - N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X) To a solution of (±) -glycidylacet amide (VIIIB, EXAMPLE 11, 0.1571 g, 1.365 mmol) in THF (1.63 ml) at -78 ° N-carbomethoxy-3-fluoro-4-morpholinyl aniline (IX, PREPARATION 2, 0.4358 g, 1.71 mmol, 1.26 eq) and lithium t-butoxide (0.1267 g, 1. 583 mmoles, 1.16 eq). The reaction mixture is then stirred at 0 to 11 ° for 17.5 hours at which point the HPLC shows an 80% yield of (±) -N - [[- (3-fluoro-4-morpholinylphenyl) -2-oxo- 5-oxazolidinyl] methyl] acetamide (retention time = 0.97 min, method B) Stationary phase: column of 4.6x250 mm of Zorbax RX C-8, mobile phase: 650 ml of acetonitrile, 1.85 ml of triethylamine, 1.30 ml of acid acetic, enough water to produce 1000 ml, flow rate: 3.0 ml / min, UV detection at 254 nm). The title compound is isolated by means known in the art.

EXAMPLE 13 (S) -N- [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X) Step A: (S) -N- (2-Hydroxy) 3-chloro) acetamide (VIIIA) Following the general procedure of EXAMPLE 10 and making non-critical variations but starting with (S) -l-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1), the composed of the title.

Step B: (S) -Glididylacetamide (VIIIB) Following the general procedure of EXAMPLE 11 and making non-critical variations but starting with (S) -N- (2-Hydroxy-3-chloro) acetamide (VIIIA, Step A), the title compound is obtained.

Step C: (S) -N- [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] mephyl] acetamide (X) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with (S) -Glycidylacetamide (VIIIB, Step B), the title compound is obtained.

EXAMPLE 14 (S) -l-Acetamido-2-acetoxy-3-chloropropane (VIIIC) Following the general procedure of EXAMPLE 3 and making non-critical variations but starting with (S) -1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1), the title compound is obtained.

EXAMPLE 15 (S) -l-Amino-3-chloro-2-propanol (S) - (V) Hydrochloride Following the general procedure of EXAMPLE 5 and making non-critical variations but using (S) -1-phthalimido-3- chloro-2-propanol (S) - (IVC, EXAMPLE 4) the title compound is obtained.

DIAGRAM A O = CH-XQ (I) NH (ID X2-CH2-C * # H-CH2-O # - (III) -O # -CH2-C * # H-CH2-N = CH-X0 (IVB) DIAGRAM B phthalimide (VI) X2-CH2-C * # H-CH2-O # - (III) DIAGRAM C : -CH2-C * H (OH) -CH2-N? 3+ (V) (vpiA) (VIIIB) X2-CH2-C H (O-CO-RN) -CH2-NH-CO-RN (vmo) DIAGRAM D X2-CH2-C H (OH) -CH2-NH-CO-RN (VIIIA) -O-CH2-C # H-CH2-NH-CO-RN (VIIIB) X2-CH2-CH (O-CO-RN) -CH2-NH-CO-RN (VIIIC) Roxa-ANlLL? -CH2-NH-CO-RN (X) DIAGRAM E R0? A-ANILL0 -CH2-NH-CO-RN (X) DIAGRAM F -O # -CH2-C * # H-CH2-N = CH-X0 (IVB) R ^ -NH-CO-O-C ^ -X! (FORMER) Ro? A-ANILL? -CH2-N = CH-Xn (XII) Ro? A-RING-CH2-NH2 (XIII) R0Xa-ANlLL0 -CH2-NH-CO-RN (X) DIAGRAM G X2-CH2-C * H (OH) -CH2-NH3 + (V) Ro? A-ANILL0-CH2-NH2 (XIII) Ro? A-ANILL0-CH2-NH-CO-RN (X) DIAGRAM H X2-CH2-C H (OH) -CH2-NH-CO-RN (VIIIA) Ro? A-NH-CO-O-C H [-CH2-X2] [- CH2-NH-CO-RN] (XV) Ro? A-ANILL? -CH2-NH-CO-RN (X) DIAGRAM I RoXa-N = c = ° (XIV) or or DIAGRAM J O ~ N RING means A.

Claims (39)

1. RE I INDICATION S An alcohol (S) -secondary of the formula (VIIIA; X2-CH2-C H (OH) -CH2-NH-CO-Rt (VIIIA) where (I) RN is C3-C5 alkyl; (II) X2 is: (A) -Cl, (B) -Br,
2. 2. An alcohol (S) -secondary (VIIIA) according to claim 1 wherein RN is Ci alkyl.
3. 3. An alcohol (S) -secondary (VIIIA) according to claim 1 wherein X2 is -Cl.
4. 4. An alcohol (S) -secondary (VIIIA) according to claim 1 which is selected from the group consisting of (S) -l-acetamido-2-hydroxy-3-chloropropane.
5. 5. A compound selected from the group consisting of: (1) an alcohol (S) -protected from the formula (IVA) X2-CH2-C H (OH) -CH2-N = CH-XC IVA; wherein (1) X is: (A) -f, (B) o-hydroxyphenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl; (II) X2 is: (A) -Cl, (B) -Br, (2) an (S) -phthalimide alcohol of the formula (IVC) where (A) X2 is as defined in the above; (3) an epoxide (S) -phthalimide of the formula (IVD: O where: (A) where # indicates that atoms marked with a (#) are linked together resulting in the formation of a ring; (4) a glycidylamine (S) -imine of the formula (IVB) -Of-CH2-C H-CH2-N = CH-X0 (IVB; where X0 and # are as defined in the above.
6. 6. A (S) -compound according to the claim 5, where XQ is -f or o-hydroxyphenyl and X2 is -Cl.
7. 7. A (S) -compound according to claim 5 which is (S) -l-benzalimino-3-chloro-2-propanol and (S) -1-phthalimido-3-chloro-2-propanol.
8. An (S) -intermediary of the formula (XV) Rr t-NH-CO-0-C H [-CH 2 -X 2] [-CH 2 -NH-CO-RN]: xv) wherein: (I) R0? a is phenyl substituted with a -F and a substituted amino group; (II) RN is C1-C5 alkyl; (III) X2 is: (A) -Cl, (B) -Br,
9. 9. An (S) -intermediary according to claim 8 wherein Roxa is: 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl, 3-fluoro-4- (4-morpholinyl) phenyl and 3-fluoro- 4- (4-Hydroxyacetylpiperazinyl) phenyl.
10. 10. An (S) -intermediary according to claim 8 wherein RN is Ci alkyl.
11. 11. An (S) -intermediary according to claim 8 wherein X2 is -Cl.
12. 12. An (S) -intermediate according to claim 8 wherein the intermediate is (S) -n-carbo (1 '-acetamido-3' -chloro-2 '-propoxy) -3-fluoro-4-morpholinyl aniline.
13. 13. An (S) -oxazolidinone phthalimide intermediate of the formula (XVI) OR wherein: (I) R0? a is phenyl substituted with a -F and a substituted amino group; (II) X2 is: (A) -Cl, (B) -Br, (D) ffl-N02-f-S02-.
14. 14. An oxazolidinone phthalimide intermediate (XVI) according to claim 13 wherein Roxa is: 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl, 3-fluoro-4- (4-morfo1 inyl) phenyl and -fluoro-4- (4-hydroxyacetylpiperazinyl) -phenyl.
15. 15. An oxazolidinone phthalimide intermediate (XVI) according to claim 13 wherein X2 is -Cl.
16. 16. A process for the preparation of a (S) -3-carbon amino alcohol of the formula (V) X2-CH2-C H (OH) -CH2-HN3 (V) where X2 is: (A) -Cl, (B) -Br, (D) m-N02-f-S02- comprising: (1) contacting an adduct without nitrogen of the formula (I) 0 = CH- X (I where Xo is: (A) -f, (B) o-hydroxyphenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl; with aqueous ammonia (II) in the presence of an epoxide (S) -protected of the formula (III) X2-CH2-C * H-CH2-0 '(III) where: (1) # indicates that the atoms marked with a (#) are joined together resulting in the formation of a ring; (II) X2 is as defined in the above, (2) contacting the reaction mixture of step (1) with acid.
17. 17. A process for the preparation of a (S) -3-carbon (V) amino alcohol according to claim 16, wherein X2 is Cl.
18. 18. A process for the preparation of a (S) -3-carbon (V) amino alcohol according to claim 16, wherein the 3-carbon amino alcohol (V) is (S) -l-amino-3-chloro hydrochloride -2-propanol.
19. 19. A process for the preparation of a (S) -3-carbon amino alcohol of the formula (V) X2-CH2-CH (OH) -CH2-NH3J (v; where: (I) X2 is: (A) -Cl, (B) -Br, (D) Bi-N02-f-S02- comprising: (1) contacting phthalimide (VI) with an epoxide (S) -protected from the formula (III) X2-CH2-C fH-CH2-Of- (III in the presence of potassium phthalimide in DMF or DMAC where: (I) # indicates that the atoms marked with a (#) are joined together resulting in the formation of a ring; (II) X2 is as defined in the above; to provide an (S) -phthalimide alcohol of the formula (IVC) where X2 is as defined in the previous and (2) put in contact the product of the stage (1) with aqueous acid.
20. 20. A process for the preparation of a (S) -3-carbon (V) amino alcohol according to claim 19, wherein X2 is Cl.
21. 21. A process for the preparation of a (S) -3-carbon (V) amino alcohol according to claim 19, wherein the (S) -3-carbon amino alcohol is (S) -l-amino-1-hydrochloride. chloro-2-propanol.
22. 22. A process to stop the preparation of a secondary alcohol of the formula (VIIIA) X2-CH2-CH (OH) -CH2-NH-CO-Rt (VIIIA; where: (I) X2 is: (A) -Cl, (B) -Br, (II) RN is C? -C5 alkyl; comprising: (1) counting a (S) 3-carbon amino alcohol of the formula (V) X2-CH2-C * H (OH) -CH2-NH3 + (V) where X2 is as defined above with an acylating agent selected from the group consisting of an acid anhydride of formula 0 (CO-RN) where RN is as defined above or an acid halide of the formula RN-C0 -X4 where X4 is -Cl or -Br and where RN is as defined above and a tri (alkyl) amine where alkyl is C1-C5.
23. 23. A process for the preparation of a secondary alcohol of the formula (VIIIA) according to claim 22 wherein the tri (alkyl) amine is triethylamine.
24. 24. A process for the production of an (S) -oxazolidinone-CH2-NH-CO-RN of the formula (X) R-ILLO-CHs-NH-CO-R, (X) wherein: (I) RN is C? -C5 alkyl; (II) Roxa is phenyl substituted with a -F and a substituted amino group comprising: (1) contacting a carbamate of the formula (IX) Roxa-NH-CO-0-CH2-Xx (IX) where 1) Xi is: (A) C 1 -C 2 alkyl, (B) C 3 -C 7 cycloalkyl, (C) f- optionally substituted with one or two: (1) C 1 -C 3 alkyl, (2) F -, Cl-, Br-, I-, (D) CH2 = CH-CH2-, (E) CH3-CH = CH-CH2-, (F) (CH3) 2C = CH-CH2-, (G) CH2 = CH-, (I) f-CH2- optionally substituted in f-with one or two -Cl, C1-C4 alkyl, -N02, -CN, -CF3, (J) 9-fluorenylmethyl, (L) 2- trimethylsilylethyl, (N) 1-adamantyl, (P) CH = CC (CH 3) 2- (Q) 2-furanylmethyl, (R) isobornyl, (S) -H; (II) R0? A is as defined in the above; with a phthalimide reagent selected from the group consisting of: (1) a phthalimide alcohol of the formula (IVC) wherein (1) X2 is: (A) -Cl, (B) -Br, (2) a phthalimide epoxide of the formula (IVD) where # indicates that the atoms marked with a (*) are joined together resulting in the formation of a ring to provide the ring-phthalimide compound of the formula (XI) where R0? a is as defined above, in the presence of a lithium cation and a base whose acid conjugate has a pKa greater than about (2) contacting the product of step (1) with aqueous acid, (3) contacting the reaction mixture of step (2) with an acid anhydride of formula 0 (CO-RN) 2 where RN is as defined above or an acid halide of the formula RN-CO-X4 where X4 is -Cl or -Br and where RN is as defined above and a tri (alkyl) amine where alkyl is C1-C5 .
25. 25. A process for the production of an (S) oxazolidinone-CH2-NH-CO-RN (X) according to claim 24 wherein Roxa is: 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl, -fluoro-4- (4-morpholinyl) phenyl and 3-fluoro-4- (4-hydroxyacetylpiperazinyl) phenyl.
26. 26. A process for the production of an (S) oxazolidinone-CH2-NH-CO-RN (X) according to claim 24 wherein RN is Ci alkyl.
27. 27. A process for the production of an (S) oxazolidinone-CH2-NH-CO-RN (X) according to claim 24 wherein Xi is -H.
28. 28. A process for the production of an (S) oxazolidinone-CH2-NH-CO-RN (X) according to claim 24 wherein X2 is -Cl.
29. 29. A process for the production of a (S) Roxa-RING-CH2-NH-C0-RN of the formula (X) Roxa-RING-CH2-NH-C0-RN (X) wherein: (I) RN is C? -C5 alkyl; (II) R0? A is phenyl substituted with a -F and a substituted amino group comprising: (1) contacting a carbamate of the formula (IX) Rc • NH-CO-0-X? (IX) wherein: (1) Xi is: (A) C?-C 2 alkyl, (B) C 3 -C 7 cycloalkyl, (C) f- optionally substituted with one or two (1) C 1 -C 3 alkyl, (2) F-, Cl-, Br-, I-, (D) CH2 = CH-CH2-, (E) CH3-CH = CH-CH2-, (F) (CH3) 2C = CH-CH2-, (G) CH2 = CH-, (I) f-CH2- optionally substituted in f-with one or two -Cl, C1-C4 alkyl, -N02, -CN, -CF3, (J) 9-fluorenilmet ilo, (L) 2-trimethylsilylethyl, (N) 1-adamantyl, (O) (f) 2CH-, (P) CH = CC (CH 3) 2- (Q) 2-furanylmethyl, (R) isobornyl, (S) -H; (II) R0Xa is as defined in the above; with a compound selected from the group consisting of an alcohol (S) -protected from the formula (IVA) X2-CH2-C H (OH) -CH2-N = CH-X0 (IVA; wherein (I) Xo is: (A) -f, (B) o-hydroxy phenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl; (II) X2 is: (A) -Cl, (B) -Br, and an epoxide protected with (S) -3-carbon of the formula (IVB) -Of-CH2-C * H-CH2-N = CH-X ((IVB) where: (I) # indicates that the atoms marked with a (*) are joined together resulting in the formation of a ring, (II) Xo is as defined above in the presence of a lithium cation and a base whose acid conjugate has a pKa greater than about 8 to produce an oxazolidinone (S) -protage of the formula (XII) where X0 and Roxa are as defined in the above; (2) contacting the reaction mixture of step (1) with aqueous acid to produce a free (S) -oxazolidinone amine of the formula (XIII) and Rf -AN I LLO- CH2 -NH2 (XIII (3) contacting the product of step (2) with an acylating agent selected from the group consisting of an acid anhydride of formula 0 (C0-RN) 2 where RN is as defined above or an acid halide of the formula RN-C0-X4 where X4 is -Cl or -Br and where RN is as defined above and a tri (alkyl) amine where alkyl is C1-C5 where R0Xa is as defined above.
30. 30. A process for the production of a (S) Roxa-RING-CH2-NH-CO-RN (X) according to claim 43 [sic] where Roxa is: 3-fluoro-4- [4- (benzyloxycarbonyl) -1- piperazinyl] phenyl, 3-fluoro-4- (4-morfo1inyl) phenyl and 3-fluoro-4- (4-hydroxyacetylpiperazinyl) -phenyl.
31. 31. A process for the production of a (S) Roxa-RING-CH2-NH-CO-RN (X) according to claim 30 wherein RN is Ci alkyl.
32. 32. A process for the production of a (S) Roxa-RING-CH2-NH-CO-RN (X) according to claim 30 wherein X0 is -f or o-hydroxyphenyl.
33. 33. A process for the production of a (S) Roxa-RING-CH2-NH-C0-RN (X) according to claim 30 where Xi is -H.
34. 34. A 'process for the production of a (S) Roxa-RING-CH2-NH-CO-RN (X) according to claim 30 wherein X2 is -Cl.
35. 35. A process for the production of a (S) Roxa-RING-CH2-NH-CO-RN of the formula (X) ROXa-A ILLO-CH2-NH-CO-Rt (X) wherein: (I) RN is C1-C5 alkyl; (II) Roxa is phenyl substituted with a -F and a substituted amino group comprising: (1) contacting a carbamate of the formula (IX) Rc ^ NH-CO-O-CHz-Xi IX) where (1) Xx is: (A) C 1 -C 20 alkyl, (B) C 3 -C 7 cycloalkyl, (C) f- optionally substituted with one or two (1) C 1 -C 3 alkyl, (2) F -, Cl-, Br-, I-, (D CH2 = CH-CH2-, (E CH3-CH = CH-CH2-, (F (CH3) 2C = CH-CH2-, (G CH2 = CH-, (I f-CH2- optionally substituted in f-with one or two -Cl, C1-C4 alkyl, -N02, -CN, -CF3, (J) 9-fluorenylmetyl, (L) 2 -trimethylsilylethyl, (N ) 1-adamantyl, (P) CH = CC (CH3) 2- (Q) 2-furanylmethyl, (R) isobornyl, (S) -H; (II) R0? A is as defined above; an amine alcohol of (S) -3-carbon (V) wherein X2 is as defined above in the presence of a lithium cation and a base whose acid conjugate has a pKa greater than about 8 to produce a free amine ( S) -oxazolidinone of the formula (XIII) Roxa-RING-CH2-NH2 (XIII) wherein Roxa is as defined in the foregoing, and (2) acylating the free (S) -oxazolidinone amine (XIII) with an acylating agent selected from the group consisting of an acid anhydride of formula 0 (CO-RN) 2 where RN is as defined above or an acid halide of the formula RN-CO-X4 where X4 is -Cl or -Br and where RN is as defined above and a tr i (alky1) amine where alkyl is C1-C5.
36. 36. A process for the production of a (S) Roxa-RING-CH2-NH-CO-RN (X) according to claim 35 wherein Roxa is: 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl , 3-fluoro-4- (4-morpholinyl) phenyl and 3-fluoro-4- (4-hydroxyacetylpiperazinyl) -phenyl.
37. 37. A process for the production of a Roxa-RING-CH2-NH-C0-RN (X) according to the claim wherein RN is Ci alkyl.
38. 38. A process for the production of a Roxa-RING-CH2-NH-C0-RN (X) according to the claim where Xi is -H.
39. 39. A process for the production of a Roxa-RING-CH2-NH-C0-RN (X) according to the claim wherein X2 is -Cl.