Method of obtaining axazolydinones

Description of the invention

The present invention relates to a secondary (S) -alcohol and a method of its preparation and a method of producing the (S) -3-carbamino alcohol. These compounds serve as intermediates in a process for the preparation of pharmacologically active oxazolidinones.

Various 5-acetamidomethyloxazolidinones are well known to those skilled in the art to be pharmacologically useful antibacterial agents. Various methods are well known to those skilled in the art for the preparation of these therapeutically useful agents.

Nos. 5,164,510, 5,182,403 and 5,225,565 disclose 5-indolinyl oxazolidinones, 3- (5'-indazolyl) oxazolidinones, 3- (fused-ring substituted) phenyloxazolidinones useful as antibacterial agents.

US Patent Nos. 5,231,188 and 5,247,090 disclose various ring-linked tricyclic oxazolidinones [6.5.5] and [6.6.5] useful as antibacterial agents.

International publication WO 93/09103 discloses mono- and dihalophenyloxazolidinone antibacterial agents which are useful as pharmaceuticals due to their antibacterial activity.

The prior art process for the preparation of oxazolidinones comprises the condensation of an aromatic carbamate with a nitrogen-free three-carbon reagent to obtain an oxazolidinone intermediate with a hydroxymethyl substituent at the 5th position. The hydroxyl must then be replaced with an acetamide group to obtain pharmacologically active 5-acetamidomethyloxazolidinones. Many variants of this essentially two-step process have been investigated.

Documents US 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773 disclose the synthesis of 5-hydroxymethyl oxazolidinones from amines (R-NHX1, where X1 is -H or p-toluenesulfonyl) and R, S-glycidol (C^#H2-OC^#H-CH2-OH where the carbon atoms are marked^# are bound together to cyclize to form an epoxide). The enantiomeric mixture obtained by this process (represented by the formula R-NH-CH2-CHOH-CH2-OH) is separated by fractional crystallization of the salt of mandelic acid. The enantiomerically pure R-diol is then converted to the corresponding 5R-hydroxymethyl substituted oxazolidinones by condensation with ethyl carbonate in the presence of sodium methoxide. These 5R-hydroxymethyl substituted oxazolidinones have to be aminated in the next step.

J. Med. Chem., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and U.S. Patent 4,948,801 disclose a method for the preparation of oxazolidinones which involves reacting an isocyanate (RN = C = O) with (R) -glycidyl butyrate in the presence of a catalytic amount of a complex lithium bromide tributylphosphine oxide, yielding the corresponding 5R-butyryloxymethyl substituted oxazolidinone. The process is carried out at a temperature of 135-145 °. The butyrate is then hydrolyzed in a further step to give the corresponding 5R-hydroxymethyl substituted oxazolidinone. The 5R-hydroxymethyl substituted oxazolidinone has to be aminated in the next step.

Abstracts of Papers, 206th National Meeting of the American Chemical Society, Chicago, IL, August, 1993; American Chemical Society: Washington, DC, 1993; ORGN 089; J. Med. Chem. 39, 673 (1996); J. Med. Chem. 39, 680 (1996); international publications WO 93/09103, WO 93/09103, WO 95/07271 and WO 93/23384; PCT applications: PCT / US95 / 12751 and PCT / U595 / 10992; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract No. F208; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract No. F207; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract No. F206; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September, 1995; American Society for Microbiology: Washington, DC, 1995; Abstract No. F227; disclose the reaction of carbamate with n-butyl lithium, lithium diisopropylamide or lithium hexamethyldisilazide at -78 ° to -40 ° followed by reaction with glycidyl butyrate at -78 ° followed by heating to 20-25 °. These reactions give 5R-hydroxymethyl substituted oxazolidinones in which the ester decomposes during the course of the reaction. The 5R-hydroxymethyl substituted oxazolidinones therefore have to be aminated in the next step.

International publication WO 95/07271 discloses the ammonolysis of 5R-methylsulfonyloxymethyl substituted oxazolidinones.

PL 199 355 B1

US Patent 4,476,136 discloses a method for converting 5-hydroxymethyl substituted oxazolidinones to the corresponding 5 (S) -aminomethyl substituted oxazolidinones (VII) which involves treatment with methanesulfonyl chloride followed by potassium phthalimide followed by hydrazine.

J. Med. Chem., 32, 1673 (1989) and Tetrahedron 45, 1323 (1989) disclose a method for converting 5-hydroxymethyl substituted oxazolidinones to the corresponding 5S-acetamidomethyl substituted oxazolidinones which involves treatment with methanesulfonyl chloride or tosyl chloride followed by sodium azide after being methyl phosphate or PtO2 / hydrogen, then acetic anhydride or acetyl chloride; the desired 5 (S) -acetamidomethyl substituted oxazolidinone is obtained.

US Provisional Application Serial No. 60 / 015,499 discloses a process for the preparation of 5 (S) -hydroxymethyl substituted oxazolidinone intermediates that are useful in the preparation of pharmacologically active 5 (S) -acetamidomethyloxazolidinones. It also discloses a process for converting 5-hydroxymethyl substituted oxazolidinone intermediates into 5-aminomethyl substituted oxazolidinone intermediates that can be acylated to provide pharmacologically active 5 (S) -acetamidomethyl substituted oxazolidinones.

J. Med. Chem., 33, 2569 (1990) discloses the condensation of an isocyanate with racemic glycidyl azide to yield racemic 5-azidomethyl substituted oxazolidinone. Two consecutive steps are required to convert racemic azidomethyl substituted oxazolidinone to racemic 5-acetamidomethyl substituted oxazolidinone which has antibiotic activity. In an embodiment of the present invention, the isocyanates are converted into the (S) -enantiomer of acetamidomethyl substituted oxazolidinones in one step, which has greater antibiotic activity than the racemates.

U.S. Patent 5,332,754 (col. 2, lines 14-34) discloses that racemic oxazolidinone-CH2-NH-Ac can be synthesized in one step by condensation of carbamate with racemic glycidyl acetamide in the presence of a base such as an amine, alkali metal hydroxide, alcoholate alkali metal, and the like, and that it is preferable to carry out the reaction with heating ... preferably at temperatures between 90 ° C and 110 ° C (col. 4, lines 44-56). Experimental data show that rearrangement to undesirable products takes place under these conditions. The examples of this patent do not specify yields or provide a detailed description of the process. Indeed, the examples disclose not a one-step process, but multi-step procedures that are known to those skilled in the art, including mesylation of 5-hydroxymethyl substituted oxazolidinone followed by azide displacement, hydrogenation and acetylation of the amine (especially see examples 59-63). The invention is distinguished in that the contacting between carbamate (IX) and epoxide (VIIIB) is carried out under such conditions that competitive rearrangement to undesired by-products is largely eliminated.

Tetrahedron Letters, 37, 7937-40 (1996) discloses a route to synthesize S-glycidylacetamide (R² = -NHAc) and a carbamate condensation process with 1.1 equivalents of n-butyl lithium (THF, -78 °) followed by 2 equivalents of S-glycidylacetamide to obtain the corresponding 5S-acetamidomethyl substituted oxazolidinone. The solution according to the invention is distinguished by the fact that the contact between carbamate (IX) and S-glycidyl acetamide is carried out in the presence of bases - lithium alkoxides, or the carbamate (IX) is contacted with S-chlorohydrin acetamide (VIIIA) or S-chloroacetate acetamide (VIIIC ), or the isocyanate (XIV) is contacted with S-chlorohydrin acetamide (VIIIA).

US Patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl substituted oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates. The embodiment of the invention differs in that the substituent in the 5-position is an acylamino group.

The secondary (S) -alcohol according to the invention is characterized in that it is represented by the formula (VIIIA)

X2-CH2-C * H (OH) -CH2-NH-CO-RN (VIIIA) where (I) RN is C1-C5 alkyl, (II) X2 is (A) -Cl, (B) -Br.

Preferably, in formula (VIIIA), RN is C1alkyl.

PL 199 355 B1

Preferably, in formula (VIIIA), X2 is -Cl.

Preferably, the secondary (S) alcohol is selected from the group consisting of (S) -1-acetamido-2-hydroxy-3-chloropropane.

A method of producing an (S) -3-carbamino alcohol of formula (V) or its salt X2-CH2-C * H (OH) -CH2-NH3⁺ (V) wherein X2 is (A) -Cl, (B) -Br, the invention is characterized in that it comprises (1) the reaction of a compound of formula (I)

O = CH-X0 (I) where X0 is (A) -φ, (B) o-hydroxyphenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl, with an aqueous ammonia solution (II) in the presence of the protected (S ) -epoxide of formula (III)

X2-CH2-C *^#H-CH2-O^#- (III) where (I) # indicates that atoms marked with (^#) are bonded to each other, resulting in a ring, (II) X2 is as defined above, (2) reacting the mixture of step (1) with an acid.

Preferably, a substrate of formula (III) in which X2 is -Cl is used.

Preferably, the 3-carbamino alcohol (V) is (S) -1-amino-3-chloro-2-propanol hydrochloride. The method of producing (S) -3-carbamino alcohol of formula (V)

X2-CH2-C * H (OH) -CH2-NH3⁺ (V) wherein (I) X2 is (A) -Cl, (B) -Br, according to the invention is also characterized in that it comprises (1) reacting a phthalimide (VI) with a protected (S) -epoxide of formula (III) )

X2-CH2-C *^#H-CH2-O^#- (III) in the presence of potassium phthalamide in DMF or DMAC, where (I) # indicates that atoms marked with (^#) are interconnected to give a ring, (II) X2 is as defined above to give the (S) -phthalimide alcohol of formula (IVC)

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wherein X2 is as defined above and (2) reacting the product of step (1) with an aqueous acid solution.

Preferably, a substrate of formula (III) in which X2 is -Cl is used.

Preferably, the (S) -3-carbamino alcohol is (S) -1-amino-3-chloro-2-propanol hydrochloride. A method for producing a secondary alcohol of formula (VIIIA) X2-CH2-C * H (OH) -CH2-NH-CO-RN (VIIIA) where (I) X2 is

(A) -Cl, (B) -Br, (II) RN is C1-C5 alkyl, according to the invention it is characterized in that it comprises (1) a reaction of (S) -3-carbamino alcohol of 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 O (CO-RN) 2 where RN is as defined above or an acid halide of formula RN-CO-X4 where X4 is - Cl or -Br, and where RN is as defined above, in a tri (alkyl) amine environment, wherein the alkyl is C1-C5 alkyl.

Preferably, triethylamine is used as the tri (alkyl) amine.

Disclosed is a secondary (S) -alcohol of formula (VIIIA), (S) -epoxide of formula (VIIIB), (S) -ester of formula (VIIIC), protected (S) -alcohol of formula (IVA), (S) -phthalimide alcohol of formula (IVC), (S) -phthalimide epoxide of formula (IVD), (S) -glycidylamine of formula (IVB), (S) -intermediate of formula (XV) and (S) -phthalimide the oxazolidinone intermediate of formula (XVI).

A method of producing an (S) -oxazolidinone-CH2-NH-CO-RN of formula (X) is disclosed which comprises (1) contacting a carbamate of formula (IX) with an oxidized aminoreagent selected from the group consisting of a secondary (S) -alcohol of formula (X). of formula (VIIIA), the (S) -epoxide of formula (VIIIB), or the (S) -ester of formula (VIIIC) in the presence of a lithium cation and a base whose conjugated acid has a pKa greater than about 8.

Further disclosed is a method for preparing an (S) -oxazolidinone-CH2-NH-CO-RN of formula (X) which comprises (1) contacting a carbamate of formula (IX) with a phthalimide alcohol of formula (IVC) or a phthalimide epoxide of formula (IVD) ), in the presence of a lithium cation and a base whose conjugated acid has a pKa greater than about 8, (2) contacting the product of step (1) with the aqueous acid solution, (3) contacting the reaction mixture of step (2) with an acid anhydride of formula O (CO-RN) 2 or an acid halide of formula RN-CO-X4 and a tri (alkyl) amine, wherein the alkyl is C1-C5.

Thereafter, a method for producing an (S) -Roxa-RING -CH2-NH-CO-RN of formula (X) is disclosed which comprises (1) contacting a carbamate of formula (IX) with a compound selected from the group consisting of the protected (S) - an alcohol of formula (IVA) or a protected (S) -3-carbon epoxide of formula (IVB) in the presence of a lithium cation and a base whose conjugated acid has a pKa of greater than about 8 to provide the protected (S) -oxazolidinone of formula (XII) ), (2) contacting the reaction mixture of step (1) with an aqueous acid solution to yield the free (S) -oxazolidinone amine of formula (XIII) and (3) contacting the product of step (2) with an acylating agent selected from the group consisting of the acid anhydride of the formula O (CO-RN) 2 or an acid halide of the formula RN-CO-X4 where RN is as defined above, and tri (alkyl) amines where the alkyl is C1-C5 where Roxa is as defined above.

Additionally disclosed is a method for producing (S) -Roxa-RING-CH2-NH-CO-RN of formula (X) which comprises (1) contacting a carbamate of formula (IX) in the presence of a lithium cation and a base whose conjugated acid has a pKa greater than than about 8 to give the (S) -oxazolidinone free amine of formula (XIII), and (2) acylating the free amine (S) -oxazolidinone (XIII) with an acylating agent selected from the group consisting of an acid anhydride of formula O (CO-RN) 2 or an acid halide of formula RN-CO-X4 and a tri (alkyl) amine where the alkyl is C1-C5.

The present invention includes both novel intermediates and methods useful in the production of oxazolidinone antibiotics (X). One of the new processes is in Scheme D and is the reaction of carbamate (IX) with a secondary (S) alcohol (VIIIA) or with an (S) epoxide (VIIIB) or (S) ester (VIIIC) to give the corresponding pharmacologically active (S) -oxazolidinone-CH2-CO-R1 (X). A second method for the preparation of pharmacologically active (S) -oxazolidinone-CH2-CO-R1 (X) is given in Scheme H and involves the reaction of an isocyanate (XIV) with a secondary (S) -alcohol (VIIIA) to give the (S) -intermediate (XV) which is then readily transformed into the corresponding pharmacologically active (S) -oxazolidinone-CH2-CO-R1 (X).

The three carbon and nitrogen containing fragments in the secondary (S) -alcohol (VIIIA), (S) -epoxide (VIIIB) and (S) -ester (VIIIC) can be obtained in two different ways. This fragment forms two adjacent carbon atoms in the oxazolidinone ring, a methylene carbon atom attached thereto, as well as a nitrogen atom attached to the methylene group. Those containing tri-carbon nitrogen fragments of secondary (S) -alcohol (VIIIA), (S) -epoxide (VIIIB), and (S) -ester (VIIIC) are prepared according to the process described in Scheme C.

PL 199 355 B1

SCHEME A discloses a process for the preparation of (S) -3-carbamino alcohol (V) from (S) -X2-epoxide (III) using non-nitrogen containing adduct (I) and ammonia (II) as nitrogen source. In (S) -X2-epoxide (III), and other compounds of the present invention, # indicates that the atoms labeled (^#) are bonded to each other as a result of ring (epoxide) formation. For the (S) -X2-epoxides (III) it is preferred that X2 is -Cl. (S) -X2-epoxides (III) are either known to those skilled in the art or can be readily prepared from compounds known to those skilled in the art by methods known to those skilled in the art. For the non-nitrogen containing adduct (I) it is preferred that X0 is -φ; more preferably X0 is -φ. The reaction of the non-nitrogen containing adduct (I), ammonia (II) and (S) -X2-epoxide (III) is performed as set out in Examples 1 and 14. Note that when starting from enantiomerically pure (S) -X2- epoxide (III), an enantiomerically pure protected (S) alcohol (IVA) is obtained. The absolute configuration of the carbon atom in the pharmacologically useful (S) -oxazolidinone-CH2-CO-R1 product (X) is S and hence it is preferred to start with enantiomerically pure (S) -X2-epoxide (III) to obtain an enantiomerically pure protected (S) -alcohol (IVA), see SCHEME A. In the schemes and claims, the override * in -C * (a) (b) - means that the asymmetric carbon atom has the correct enantiomeric configuration (S) - such that when this carbon atom becomes part of the (S) -oxazolidinone-CH2-CO -R1 (X) is the correct enantiomer. It is apparent to the skilled person that if any chemical sequence of the processes of the present invention is started with an optically impure (racemic) form instead of an enantiomerically pure form, the resulting products will exist in a suitably optically impure (racemic) form.

The protected (S) -alcohol (IVA) is then contacted with the acid to form the corresponding (S) -3-carbamino alcohol (V). Neither the type, strength nor amount of acid are critical. It is preferred that the acid has a pKa of less than 4. It does not matter whether the acid is organic or inorganic. The (S) -3-carbamino alcohol becomes the cation and the non-proton portion of the acid becomes the anion. For example, if the mixture is acidified with sulfuric acid, the (S) -3-carbamino alcohol (V) is obtained as the sulfate salt. The type of anion is not important.

SCHEME B discloses a route to prepare the desired (S) -3-carbamino alcohol (V) from the same (S) -X2-epoxide (III) but using a nitrogen containing adduct (VI). In this case, ammonia (II) is not needed. In the final step of this process, when the product of the first step is contacted with the aqueous acid solution, it is preferable that the acid is hydrochloric, hydrobromic, hydroiodic, sulfuric or p-toluenesulfonic acid.

SCHEME C discloses the process of converting (S) -3-carbamino alcohol (V) into the corresponding secondary (S) -alcohol (VIIIA), (S) -epoxide (VIIIB) or (S) -ester (VIIIC) and converting the secondary (S) an alcohol (VIIIA) to the corresponding (S) -epoxide (VIIIB) and (S) -ester (VIIIC). To convert (S) -3-carbamino alcohol (V) into the corresponding secondary (S) -alcohol (VIIIA), the 3-carbamino alcohol (V) is reacted with an appropriate acylating reagent such as an acyl halide or acyl anhydride under acylating reaction conditions well known. to those skilled in the art, see example 2. It is preferred that the acylating reagent is selected from the group consisting of an acid anhydride of formula O (CO-RN) 2 where RN is C1-C5 alkyl, or an acid halide of formula RN-CO-X4 where X4 is -Cl or -Br. and tri (alkyl) amine, wherein the alkyl is C1-C5. More preferably, RN is C1 alkyl and X4 is chlorine. More preferably, the acylating agent is an acyl anhydride, and it is preferred that the acyl anhydride is acetic anhydride.

Alternatively, (S) -epoxide (VIIIB) can be obtained by reacting the (S) -ester (VIIIC) with bases such as sodium methoxide or potassium carbonate / methanol. Also (S) -3-carbamino alcohol (V) can be converted to the corresponding (S) -ester (VIIIC) by reaction with acetic anhydride in pyridine, see example 3. (S) -epoxide (VIIIB) can be obtained from the corresponding secondary (S) ) alcohol (VIIIA) by reaction with potassium t-butoxide in THF at -20 °, see example 11. Thereafter, the secondary (S) -alcohol (VIIIA) can be converted into the corresponding (S) -ester (VIIIC) by reaction with the acylating reagents discussed above. For the (S) -ester (VIIIC), RN is preferably -CO-CH3.

SCHEME D discloses the process of reacting a carbamate of formula Roxa-NH-CO-O-CH2-X1 (IX) with a secondary (S) -alcohol (VIIIA), or (S) -epoxide (VIIIB) or (S) -ester (VIIIC) ) to give the corresponding (S) -oxazolidinone-CH2-CO-R1 (X). Carbamates (IX) are known to those skilled in the art or can be readily prepared from compounds known to those skilled in the art by methods known to those skilled in the art. Preferably X1 is -H. Roksa is phenyl substituted with one -F and one substituted amino group. Substituted amino groups include 4- (benzyloxycarbonyl)

-1-piperazinyl, 4-morpholinyl and 4-hydroxyacetylpiperazinyl. Preferably Roksa is 3-fluoro-4- [4- (benzyloxycarbonyl) -1-piperazinyl] phenyl or 3-fluoro-4- (4-morpholinyl) phenyl. The carbamate (IX) and the three-carbon unit from (VIIIA, VIIIB or VIIIC) react by contacting the reactants with a base. Its type is not important as long as it is strong enough to deprotonate the carbamate (IX). Suitable bases for use in this process have a conjugated acid having a pKa greater than about 8.

Preferred bases include compounds selected from the group consisting of:

alkoxy compounds with one to seven carbon atoms;

carbonates, methyl, sec-butyl and t-butyl carbanions, tri (alkyl) amines in which the alkyl group has from 1 to 4 carbon atoms, conjugated with carbamates (II) bases,

DBU,

DBN,

N-methyl-piperidine,

N-methyl-morpholine,

2,2,2-trichloroethoxide and

Cl3C-CH2-O^-.

Bases in which the base is an alkoxy radical of four or five carbon atoms are most preferred. It is preferred that the four and five carbon alcohol bases be t-amylate or t-butoxide. Sodium or potassium bases in combination with a lithium salt (such as lithium chloride or lithium bromide) can be used to form the lithium cation and base in situ. The nature of the solvent is not critical. Solvents that can be used include cyclic ethers such as THF, amides such as DMF and DMAC, amines such as triethylamine, acetonitrile, and alcohols such as t-amyl alcohol and t-butyl alcohol. The choice of solvent depends on the solubility of the carbamate (IX) and the three-carbon unit (VIIIA, VIIIB or VIIIC) as known to those skilled in the art.

SCHEME E discloses the reaction of carbamate (IX) with either a phthalimide (S) -alcohol (IVC) or a phthalimide (S) -epoxide (IVD), resulting in an (S) -cytoid phthalimide (XI) which is then converted to a suitable product (S) -oxazolidinone-CH2-NH-CO-RN (X) which has pharmaceutical utility.

SCHEME F discloses the reaction of carbamate (IX) with protected (S) -alcohol (IVA) or with (S) -imine glycidylamine (IVB) to yield the corresponding (S) -oxazolidinone protected compound (XII) which is then converted to the free (S) -oxazolidinone amine (XIII) which is then acylated in the manner discussed above to give the product (S) -oxazolidinone-CH2-NH-CO-RN (X) which is pharmaceutically useful. These processes are the same as those for Schemes D and E or are well known to those skilled in the art.

SCHEME G discloses the reaction of carbamate (IX) directly with (S) -3-carbamino alcohol (V) to give the free amine (S) -oxazolidinone (XIII) which is then acylated to give (S) -oxazolidinone-CH2-NH- CO-RN (X). These processes are carried out in the same way as described previously.

SCHEME H discloses the reaction of an isocyanate (XIV) with a secondary (S) -alcohol (VIIIA) to give an (S) -intermediate (XV) which is then converted to (S) -oxazolidinone-CH2-NH-CO-RN ( X), see examples 6, 8 and 9.

SCHEME I discloses a reaction analogous to that of Scheme E. While the process of Scheme E uses a carbamate (IX), the process of Scheme I uses an isocyanate (XIV).

The (S) -Oxazolidinone-CH2-CO-amines (X) are known and useful as antibiotics.

The definitions and explanations given below apply to the terms used in both the specification and the claims.

The chemical formulas representing the various chemical compounds or molecular fragments in the specification and claims may contain variable substituents in addition to directly expressed structural features. These variable substituents are identified by a letter or a letter followed by a numerical index, for example, "Z1 or" Ri, where "i is an integer. These substituents are either monovalent or divalent, that is, they represent groups attached to the structure by one or two chemical bonds. For example, a group Z1 can represent a bivalent variable if attached to a CH3-C (= Z1) H structure. The groups Ri and Rj will represent monovalent variable substituents if attached to the structure CH3-CH2-C8

PL 199 355 B1 (Ri) (Ri) -H. When chemical formulas are drawn in a linear fashion, such as above, the parenthetical variable substituents are attached to the atom immediately to the left of the parenthetical variable substituents. When two or more consecutive variable substituents are enclosed in parentheses, each of the successive variable substituents is bound to an atom immediately to the left that is not enclosed in parentheses. Thus, in the formula above, Ri and Rj are both bonded to the preceding carbon atom. Moreover, for any molecule with an established carbon numbering system, such as for steroids, these carbon atoms are listed as Ci, where i is an integer corresponding to the carbon number. For example, C6 is the 6th position or carbon number of the steroid backbone according to the customary designations of one skilled in the art of steroid chemistry. Similarly, the term R6 represents a variable substituent (both monovalent and bivalent) at the C6 position.

Linearly drawn chemical formulas or parts thereof represent atoms in a linear chain. The symbol - in general, means a bond between two atoms in a chain. Hence CH3-O-CH2-CH (Ri) -CH3 is a 2-substituted-1-methoxypropane compound. Similarly, the symbol = represents a double bond, e.g., CH₂= C (R 1) - O-CH₃, and the symbol 'W represents a triple bond, e.g., HC C-CH (Ri) -CH2-CH3. Carbonyl groups are represented in one of two ways: -CO- or -C (= O) -, of which the first form is preferred because of its simplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented linearly. Thus, the compound of 4-chloro-2-methylpyridine can be represented linearly as follows: N^#= C (CH3) -CH = CCl-CH = C^#H in the convention in which the atoms marked with an asterisk (#) are bonded to form a ring. Similarly, the cyclic moiety, 4- (ethyl) -1-piperazinyl can be represented as -N^#- (CH2) 2-N (C2H5) -CH2-C^#H2.

The rigid cyclic (ring) structure of the compounds described herein defines the orientation with respect to the ring plane for the substituents attached to each carbon atom of the rigid cyclic chemical compound. For saturated compounds that have two substituents attached to a carbon atom that is part of a cyclic structure, -C (X1) (X2) - these two substituents can be either axial or equatorial with respect to the ring and can vary between axial position / equatorial. Nevertheless, the position of the two substituents with respect to the ring and their mutual remains constant. While each substituent temporarily may lie in the ring plane (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In the chemical structural formulas representing such compounds, the substituent (X1) which is 'downstream' of the second substituent (X2) will be identified as occurring in the alpha (α) configuration and its connection to a carbon atom will be indicated by a broken, dashed or dotted line, i.e., by the symbols '----' or '...'. A suitable substituent attached 'upstream' (X2) of the second (X1) will be identified as being in the beta (β) configuration and its connection to carbon will be denoted by a solid line.

When a variable substituent is bivalent, the valence valences may be taken together or separately or both in the definition of the variables. For example, a variable Ri attached to a carbon atom as -C (= Ri) - may be bivalent and defined as oxo or keto (then forms a carbonyl (-CO-) group) or as two separate monovalently attached variable substituents aR_and-j and eR_and._k. When a bivalent variable R ,, is defined as consisting of two monovalent substituent variables, the convention used to define bivalent variables defines it in the form aR_and.j: pR_and._k or the like. In that case, both aR_ij and eR_ikare attached to a carbon atom to give -C (aR_ij) (eR_ik) -. For example, when a bivalent variable R6, -C (= R6) - is defined as consisting of two monovalent variable substituents, the two monovalent variable substituents are aR_6-1: eR_6-2, .... aR_6-9: eR_6-10, etc., giving -C (aR_6-1) (eR_6-2) -, ...- C (aR_6-9) (eR_6-10) etc. Similarly, for the bivalent variable R.₁₁, -C (= R₁₁) -, the two monovalent variable substituents are: aR_11-1: eR_11-2. For a ring substituent for which a separate orientation of a and β does not exist (e.g., due to the presence of a carbon-carbon double bond in the ring), and for a substituent attached to a carbon atom that is not part of the ring, the above convention is also used, but the terms ai β are ignored.

Just as a bivalent variable can be defined as two separate monovalent variable substituents, so two separate monovalent variable substituents can be defined as taken together to form a bivalent variable. For example, in the formula -C1 (Ri) H-C2 (Rj) H- (C1 and C2 arbitrarily define the first and second carbon atoms, respectively) Ri and Rj may be defined as taken together and forming (1) a second bond between C1 and C2, or (2) divalent

A group such as oxa (-O -) - and the formula then describes the epoxide. When Ri and Rj are taken together to form a more complex form, such as the group -XY-, then the orientation of this embodiment is such that C1 in the formula above relates to X and C2 binds to Y. ... Ri and Rj taken together form -CH2-CH2-O-CO- ... is a lactone in which the carbonyl is bound to C2. Nevertheless, the term ... Ri and Rj taken together form -CO-O-CH2-CH2- ... by convention it is a lactone in which the carbonyl is linked to C1.

The number of carbon atoms in variable substituents is indicated in one of two ways. The first method uses a prefix in front of the entire variable name, such as C1-C4, where both 1 and 4 are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is ​​separated from the variable by a gap. For example, C1-C4 alkyl is alkyl of 1 to 4 carbon atoms (including the isomeric forms, unless expressly indicated otherwise). Whenever this single prefix is ​​given, it indicates the total carbon content of the variable being defined. Thus, C2-C4 alkoxycarbonyl describes a CH3- (CH2) nO-CO- group, where n is zero, one or two. According to the second method, the number of carbon atoms included for each part of the definition is indicated separately by enclosing the term Ci-Cj in parentheses and placing them immediately (without a separating gap) before the defined part of the definition. Under this optional convention, (C1-C3) alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl since C1-C3 only refers to the carbon content of the alkoxy group. While both the definitions of C2-C6 alkoxyalkyl and (C1-C3) alkoxy (C1-C3) alkyl define an alkoxyalkyl group similarly as having from 2 to 6 carbon atoms, the two definitions differ in that while the former allows alkoxy or alkyl individually have 4 or 5 carbon atoms, the latter definition limits each group to 3 carbon atoms.

When the claims contain a complete complex (cyclic) substituent, at the end of an expression naming / denoting that particular substituent there will be a designation in (parentheses) which will correspond to the same name / designation in one of the SCHEMES, which will also cite the structural chemical formula of that particular substituent.

All temperatures are stated in ° C.

TLC means thin layer chromatography.

HPLC stands for High Performance Liquid Chromatography.

THF means tetrahydrofuran.

* means that the carbon atom so marked is an enantiomeric carbon of the S configuration).

# indicates that atoms marked with (^#) are bound to each other to form a ring.

RING is defined in SCHEME J as an oxazolidinone ring, 2,5-substituted-oxazolidinone.

DMF means dimethylformamide.

DMAC means dimethylacetamide.

Chromatography (column and flash chromatography) means purification / separation of compounds; expressed through (vehicle, eluent). It is understood that the appropriate fractions are combined and concentrated to give the desired compound (s).

IR stands for Infrared Spectroscopy.

CMR stands for C-13 Magnetic Resonance Spectroscopy, chemical shifts are expressed in ppm (δ) versus TMS.

NMR means nuclear (proton) magnetic resonance spectroscopy, chemical shifts are expressed in ppm (δ) relative to tetramethylsilane.

TMS means tetramethylsilane.

-φ is phenyl (C6H5).

[a] D²⁵ is the rotation angle of the plane of polarized light (specific rotation) at 25 ° for the sodium D line (589A).

MS means mass spectroscopy, expressed as m / e, m / z or in mass / charge units. [M + H]⁺ represents positive parent ion plus hydrogen. El means electron shock. CI stands for Chemical Ionization. FAB stands for Fast Atoms Bombardment.

The term "pharmaceutically acceptable" means those properties and / or substances that are acceptable to the patient from a pharmacological-toxicological point of view and to a chemist-pharmacist technologist from a physicochemical point of view with regard to composition, formulation, stability, patient acceptance and bioavailability.

PL 199 355 B1

When mixtures of two solvents are used, the ratio is given in volume / volume (v / v).

When solubilization of solids in solvents takes place, the solid to liquid ratio is expressed in weight / volume (w / v).

Based on the disclosure in the specification, one skilled in the art may carry out the present invention. Rather, the specific examples describe how to prepare the various compounds and / or set forth the various processes of the invention, and are intended to be merely illustrative and not in any way limiting the above disclosure. One skilled in the art will immediately recognize suitable variations for the procedures for both the reagents and the reaction conditions and techniques.

Preparatory example 1

3-Fluoro-4-morpholinylaniline

3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) was added to a mixture of morpholine (60.0 mL, 688 mmol, 4.34 eq.) In THF (30 mL) at -14 °. The mixture was allowed to warm to 10 ° and 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) was added under the conditions of an exothermic reaction to 28 ° C. The phases were separated and the aqueous phase was washed with toluene (95 ml). The organic phase was washed with water (315 ml) and concentrated under reduced pressure. Toluene (46 ml) and methanol (60 ml) were added followed by palladium on carbon (5%, 50% wetted with water, 3.1603 g, 0.7426 mmol, 0.00469 eq.) And the mixture was sealed in a Parr shaker. 'and. Hydrogen pressure (40 psi) was applied and held with shaking for 42 min. The catalyst was then removed by filtration under reduced pressure and washed with toluene (60 ml). Heptane (150 mL) was added to the filtrate and the resulting suspension was concentrated in vacuo. Heptane (300 ml) was added and the precipitate was collected by filtration under reduced pressure, washed with heptane and dried to give the title compound, HPLC (stationary phase was 4.6 x 250 mm zorbax RX C-8 column; mobile phase was acetonitrile (650 ml ), triethylamine (1.85 ml), acetic acid (1.30 ml) and water up to 1.000 ml; flow rate = 3.0 ml / min; UV detection at 254 nm) RT = 1.08 min, &gt; 99.3 areas); NMR (Pyridine-D5) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 δ; CMR (Pyridine-D5) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and 157.72 δ.

Preparatory example 2

N-Carbomethoxy-3-fluoro-4-morpholinylaniline (IX)

3,4-Difluoronitrobenzene (Preparation 1, 24.967 g, 156.94 mmol) was added to a mixture of morpholine (60.0 ml, 688 mmol, 4.38 eq.) In THF (30 ml) at -6 °. The mixture was allowed to warm to 10 ° over 2 hours and then held at 10 ° for 1/2 hour. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq.) In water (365 ml) was added under the conditions of an exothermic reaction to 28 ° C. The phases were separated and the aqueous phase was washed with toluene (95 ml). The organic phase was washed with water and concentrated under reduced pressure. The organic phase was washed with water (315 ml), the washes were extracted with toluene (95 ml) and concentrated under reduced pressure. Toluene (76 ml) and methanol (60 ml) were added followed by palladium on carbon (5%, 50% wetted with water, 3.1370 g, 0.7371 mmol, 0.00470 eq.) And the mixture was sealed in a Parr 'shaker and. Hydrogen pressure (40 psi) was applied and held with agitation for 4.5 hours. The catalyst was removed by filtration under reduced pressure and washed with toluene (100 ml). The mixture was cooled to 2 ° and a mixture of aqueous potassium carbonate (47%, 17.1 ml, 85 mmol, 0.54 eq.) And water (150 ml) was added. Methyl chloroformate (16.4 mL, 212 mmol, 1.35 eq.) Was added while maintaining the temperature at about 3-3.5 °. The resulting suspension was allowed to warm to 20-25 ° and stirred for 17 hours. The mixture was heated to 75 ° to obtain a solution, then cooled to 46 °, heptane (333 ml) was added, then the mixture was cooled to 0 °, the precipitate was collected by filtration under reduced pressure, washed with heptane (100 ml cooled to 5 °) , water (230 mL cooled to 5 °) and dried to afford the title compound, TLC (silica gel; methanol / methylene chloride, 5/95) Rf = 0.74 (one spot); NMR (CDCl3) 3.03, 3.76, 3.86, 6.75, 6.87, 6.98, 7.27; CMR. (CDCl3) 51.18, 52.42, 67.03, 107.81, 114.56, 119.00, 133.25, 135.77, 154.07, 155.70,

Preparatory example 3

3-Fluoro-4-morpholinylphenylisocyanate (XIV)

A mixture of 3-fluoro-4-morpholinylaniline (Preparation 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) was 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 min, keeping the temperature from about -12 to 3 °. The material was rinsed with methylene chloride (30 ml). The mixture was then heated to 130 ° under pressure

Atmospheric distillation with methylene chloride, phosgene, toluene and hydrogen chloride gas distillation in a caustic scrubber. The mixture was cooled to 25 ° and filtered. The precipitate was washed with methylene chloride (3 x 15 ml). The filtrate was concentrated under reduced pressure. Heptane (200 ml) was added to the concentrated filtrate and the resulting suspension was cooled to -32 °. The product was collected by filtration under reduced pressure, washed with heptane cooled to -30 °, and dried under a stream of nitrogen to give the title compound, HPLC (stationary phase was 4.6 x 250 mm zorbax RX C-8 column; mobile phase was acetonitrile (650 ml ), triethylamine (1.85 ml), acetic acid (1.30 ml) and water up to 1.000 ml; flow rate = 3.0 ml / min; UV detection at 254 nm) RT = 1.08 min. During differentiation from N-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol; NMR (CDCl3) 3.05, 3.86 and 6.78-6.89 δ; CMR (CDCl3) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155, 40 δ; MS (EI), m / z (relative intensity) 222 (37) and 164 (100).

Example 1

(S) -1-Amino-3-chloro-2-propanol (V) (S) -Epichlorohydrin hydrochloride (III, 44.978 g, 486.1 mmol, 98.9% enantiomeric excess, 99.3% chemical purity) was added to a mixture of benzaldehyde (I, 50.0 ml, 492 mmol, 1.012 eq.), ethanol (163 ml) and aqueous ammonia solution (II, 29.8 wt.%, 50 ml, 787.4 mmol, 1.62 eq. .) at 18 ° C for 10 min under the conditions of an exothermic reaction accompanying to 22 ° C. The reaction mixture was allowed to exotherm to 34 ° over 1.5 hours, heated to 42 °, stirred at 20-25 ° for 20.5 hours then heated to 74 ° and allowed to cool. The mixture was concentrated under reduced pressure to give (S) -1-benzylideneimino-3-chloro-2-propanol (IVA). Water (382 ml) and hydrochloric acid (37.7 wt%, 76.2 ml, 938 mmol, 1.93 equiv) were added to the concentrate and the mixture was stirred at 20-25 ° for 2 hours. Toluene (150 ml) was added and the phases were separated. The organic phase was washed with water (15 ml) and the combined aqueous washes washed with toluene (2 X 150 ml), back-extracted each organic extract with water (15 ml). The combined aqueous extracts were concentrated under reduced pressure. Ethanol (200 ml) was added to the concentrate, and the mixture was concentrated under reduced pressure. Ethanol (300 ml) was added to the concentrate and the mixture was heated to reflux. The mixture was cooled to -30 ° and the precipitate was collected by filtration under reduced pressure, washed with ethanol at -30 ° (2 x 60 ml) and dried under a stream of nitrogen to give a white solid, Mp = 132-141 °; NMR (CD3OD)

2.96, 3.21, 3.57-3.64 and 4.03-4.09 δ; CMR (CD3OD) 43.52, 46.91 and 68.72 δ; MS (Cl, NH 3), M / Z (relative intensity) 129 (24), 127 (69), 112 (61), 110 (100); [ab²⁵ = -22 (c = 1.00, H2O).

Example 2 (S) -1-Acetamido-2-hydroxy-3-chloropropane (VIIIA)

Triethylamine (10.5 mL, 75.3 mmol, 1.11 eq.) Was added to a suspension of (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1, 9.938 g, 68.059 mmol) in THF (80 ml) at -40 ° and the reaction medium was stirred for 5 min at -40 °. Then acetic anhydride (6.78 mL, 71.86 mmol, 1.056 eq.) Was added at -40 ° and the mixture was allowed to warm to 20-25 ° over 1.5 hours. The deposited solid was collected by filtration under reduced pressure and washed with THF. The filtrate was treated with magnetol (5.69 g) which was removed by filtration under reduced pressure and washed with THF (2 x 60 ml). The filtrate was then concentrated under reduced pressure. The concentrate was purified by flash chromatography (silica gel; 75-100% ethyl acetate / cyclohexane gradient elution) to provide the title compound, NMR (CDCl3) 2.03, 3.32, 3.50-3.57, 3.55, 3, 91-4.13, 5.01 and 7.09 δ; CMR (CDCl3) 23.00, 43.31, 46.52, 70.65 and 172.40 δ; MS (Cl, NH 3), M / Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152 (48.1); [ab²⁵ = -7.44 (c = 1.00, H.₃ABOUT).

Example 3 (±) -1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

Acetic anhydride (13 ml) was added to a thin suspension of (±) -1-amino-3-chloro-2-propanol hydrochloride ((±) -V, example 5, 5.0110 g, 34.317 mmol) in pyridine (20 ml) keeping the temperature in the range of 20-50 °. The reaction medium was stirred at 20-25 ° C for 18 hours, then water (14 ml) was added under an exothermic reaction to 65 ° C. The mixture was concentrated under reduced pressure then water (50 mL) was added. The pH was adjusted to 0.89 with hydrochloric acid (37.7%, 1.467 g, 15.17 mmol, 0.442 eq.) at 0 °. The mixture was extracted with methylene chloride (4 x 50 mL), and the extracts were dried over sodium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) and heptane (20 ml) were added, the mixture was nucleated, then heptane (40 ml) was added to the resulting suspension. The precipitated solid was collected by filtration under reduced pressure, washed with heptane and dried to obtain the title compound, Tt = 68.0-69.5 °; TLC (silica12

Gel; ethyl acetate, iodine char) Rf = 0.39 (one spot); NMR 2.00, 2.21, 3.52, 3.62, 3.70, 5.10 and 6.33 δ; CMR 20.93, 23.10, 40.47, 43.53, 71.95, 170.45 and 170.71 δ; MS (Cl, NH 3) m / z (relative intensity) 213 (36), 211 (100), 196 (18) and 194 (53).

Example 4 (S) -1-Phthalimido-3-chloro-2-propanol (S) - (IVC) (S) -Epichlorohydrin (III, 98.9% enantiomeric purity, 99.3% chemical purity, 4 , 9605 g, 53.61 mmol) was 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 reaction medium was stirred at 50 ° for 4.5 hours. The mixture was added to methylene chloride (50 ml) and water (50 ml) was added. The precipitates were removed by filtration under reduced pressure and washed with methylene chloride (20 ml). The phases in the filtrate were separated and the aqueous phase was washed with methylene chloride (50 ml). The combined organic solutions were washed with water (50 ml) and the aqueous was back-extracted with methylene chloride (50 ml) after the addition of water (25 ml). The combined organic solutions were dried over sodium sulfate and saturated with hydrogen chloride gas at 6 °. Water (100 ml) was added and the phases were separated. The aqueous phase was washed with methylene chloride (2 x 50 ml) and the combined organic phases were dried over sodium sulfate. The organic phases were concentrated under reduced pressure, and toluene (77 ml) was added. The mixture was concentrated under reduced pressure to 31 g net weight and toluene (50 ml) and heptane (75 ml) were added. The precipitates were filtered off and washed with toluene / heptane (1/1, 20 ml). The filtrate was concentrated under reduced pressure to 11 g net weight, heptane (100 ml) was added and the mixture was concentrated under reduced pressure to 15 g net weight. Heptane (100 ml) and methylene chloride (100 ml) were added and the mixture was concentrated under reduced pressure to 130 g net weight. The precipitates were filtered off and washed with heptane / methylene chloride (2/1, 3 x 15 ml). The filtrate was concentrated under reduced pressure to 11 g net weight and toluene (90 ml) was added followed by heptane (400 ml). The resulting slurry was then cooled to -20 ° and the product collected by filtration under reduced pressure, washed with heptane and dried to give a crude solid. Flash chromatography of the crude product (silica gel; eluting with a gradient of 15-45% ethyl acetate / cyclohexane) gave 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 δ; CMR 41.61, 47.27, 69.68, 123.53, 131.83, 134.26 and 168.65 δ;

MS (Cl, NH3), M / Z (relative intensities) 259 (1.4), 257 (17), 242 (0.11), 240 (0.31), 221 (100);

[a] D²⁵ = -33 (C = 0.712, CHCl₃). NMR of the Mosher ester of this compound showed the product to be 96.2% enantiomerically pure compared to the NMR of the Mosher ester of the racemate.

Example 5

Hydrochloride (±) -1-amino-3-chloro-2-propanol (±) - (V)

Suspension of (±) -1-phthalimido-3-chloro-2-propanol (IVC, 40.018 g, 166.98 mmol) in hydrochloric acid (37.5 wt%, 79 mL, 968 mmol, 5.80 eq.) and water (82 ml) were stirred at 109 ° for 5 hours. The mixture was cooled to 22 ° and the precipitate was collected by filtration under reduced pressure and washed with water (40 ml). The filtrate was concentrated under reduced pressure to 26 g net weight and ethanol (100 ml) was added. The mixture was heated to 75 ° and a solution was obtained, which was cooled to -12 ° and the precipitate was collected by filtration under reduced pressure, washed with ethanol cooled to -12 ° and dried to give the title compound, Mp = 101-104 °; NMR (CD3OD) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 δ; CMR (CD3OD) 43.54, 46.95 and 68.71 δ; MS (Cl, NH3), M / Z (relative intensities) 129 (12), 127 (39), 112 (56), 110 (100).

Example 6 (S) -N-carb (1'-acetamido-3'-chloro-2'-propoxy) -3-fluoro-4-morpholinylaniline ((S) -XV)

Acetyl chloride (0.3297 g, 4.20 mmol, 1.019 eq.) Was added to a suspension of (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1, 0.6020g, 4.12 mmol ) and triethylamine (1.26 mL, 9.04 mmol, 2.19 eq.) in acetonitrile (70 mL) at -40 °.

The mixture was then warmed to 3-6 °, stirred for several hours, warmed to 22 ° and 3-fluoro-4-morpholinylphenyl isocyanate (XIV, Preparation 3, 1.0152 g, 4.568 mmol, 1.108 eq.) Was added. The mixture was heated to 64 °, stirred 10 minutes and concentrated in vacuo to about 25 mL. Then 3-fluoro-4-morpholinylphenylisocyanate (XIV, 0.0907 g, 0.408 mmol, 0.09887 eq.) Was added and the reaction medium was stirred at 65 ° for 17 hours. Pentanol (1.34 ml, 12.33 mmol, 2.99 eq.) Was added and the reaction medium was stirred at 65 ° for 1.7 hours. Water (5 ml) was added and the mixture was cooled to -4 °. Water (38 ml) and heptane (30 ml) were added, the mixture was heated to 15 ° and stirred for 1 hour, the precipitate was collected by filtration under reduced pressure, washed with heptane and water and dried to give a solid. The filtrate was concentrated under reduced pressure to 50 ml in total volume, and the precipitate was collected by filtration under reduced pressure, washed with

Water (10 ml) and heptane (10 ml) and dried to give a brown solid. Portions of the first solid (0.9404 g) and the second solid (0.4018 g) were dissolved in acetonitrile (15 ml) at 76 °, then cooled to -10 °, and the precipitate deposited was collected by filtration under reduced pressure, washed with acetonitrile cooled to -10 ° and dried to give the title compound, HPLC (stationary phase was 4.6 x 250 mm zorbax RX C-8 column; mobile phase was acetonitrile (650 ml), triethylamine (1.85 ml), acetic acid (1.30 ml) and water up to 1,000 ml; flow rate = 3.0 ml / min; UV detection at 254 nm) = 92.3 area%).

Example 7 (S) -N-carb (1'-acetamido-3'-chloro-2'-propoxy) -3-fluoro-4-morpholinylaniline ((S) -XV)

A mixture of (S) -1-Acetamido-3-chloro-2-propanol (VIIIA, example 2, 1.024 g, 6.754 mmol, 1.00 eq.) And 3-fluoro-4-morpholinylphenylisocyanate (XIV, preparation example 3, 1 , 6756 g, 7.539 mmol, 1.12 eq.) In acetonitrile (25 mL) was stirred at 60 ° for 46 hours. The resulting suspension was cooled to -13 °, the precipitate was collected by filtration under reduced pressure, washed with acetonitrile cooled to -13 ° (20 ml) and dried to give the title compound, NMR (DMSO-D6) 1.83, 2.93, 3, 2-3.5, 3.73, 3.78, 3.88, 4.99, 6.97, 7.2, 7.36, 8.07 and 9.80 δ; CMR (DMSO-D6) 22.42, 39.6,

44.71, 50.77, 66.15, 71.81, 106.49, 114.23, 119.21, 134.59, 152.57, 154.65 and 169.67 δ; MS (CI, NH3)

M / Z (relative intensities) 376 (27.0), 374 (85.9), 339 (12.2), 338 (80.8) and 223 (17.2; [a] D²⁵ = -4.08 (C = 0.930, DMF).

Example 8 (S) -N - [[3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide ((S) -X)

A solution of sodium t-butoxide (0.0854 g, 0.889 mmol, 1.05 eq.) In ethanol (0.60 ml) was added to the suspension of (S) -N-carbon (1'-acetamido-3'-chloro-2). '-propoxy) -3-fluoro-4-morpholinylaniline ((S) -XV), example 7, 0.3176 g, 0.850 mmol) in ethanol (4.6 ml) at 65 ° and rinsed with ethanol (0.50 ml ). The reaction medium was stirred for 28 min and cooled to 0 °. Citric acid monohydrate (0.1943 g, 0.925 mmol, 1.09 eq.) Was added, and the resulting suspension was concentrated under reduced pressure to 1.30 g net weight. Water (10 ml) and methylene chloride (10 ml) were added, the phases were separated and the aqueous phase was washed with methylene chloride (2 x 10 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to a solid. The precipitate was dissolved in ethyl acetate (8.4 ml) at 70 °, the solution was cooled to 50 °, seeded, cooled again to -28 °, the precipitate was collected by filtration under reduced pressure, washed with ethyl acetate cooled to -30 ° and dried affording the title compound, HPLC (100.7 wt, 99.9 area%); NMR (CDCl3) 2.04, 3.04, 3.65, 3.77, 3.86, 4.02, 4.74-4.82, 6.8, 6.91, 7.06 and 7, 42 δ; CMR (CDCl3) 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 δ; MS (EI), M / Z (relative intensities) 337 (16.9), 293 (74.4), 234 (37.5), 209 (100); [ab²⁵ = -15.8 (C = 0.903, ethanol).

Example 9 (S) -N - [[3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (IV)

Following the general procedure of Example 8 with non-critical changes provided the title compound, NMR 2.04, 3.04, 3.65, 3.77, 3.86, 4.02, 4.74-4.82, 6.74, 6.91, 7.06 and 7.42 δ; CMR 23.0241.89, 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 δ; MS (CI, NH₃), M / Z (relative intensities) 338 (100), 294 (86.8); [and]_D²⁵ = -15.2 (C = 0.783, ethanol).

Example 10 (+) - n- (2-Hydroxy-3-chloro) acetamide (VIIIA)

To a suspension of (±) -1-amino-3-chloro-2-propanol hydrochloride (V, example 5, 47.71 g, 326.74 mmol) in THF (381 ml) at -40 °, was added triethylamine (36.496 g, 360.67 mmol, 1.104 eq.) Followed by acetic anhydride (35.007 g, 342.90 mmol, 1.049 eq.) Keeping the temperature &lt;-30 °. The reaction medium was stirred for 15 min at -30 °, after which the mixture was allowed to warm to 20 ° over 1 hour. The reaction medium was stirred at 20-25 ° for 3 hours, then the precipitate was removed by vacuum filtration through a medium frit and washed with THF (175 ml). The filtrate was concentrated under reduced pressure and toluene (195 ml) was added. The mixture was concentrated under reduced pressure and toluene (250 ml) was added. The mixture was concentrated under reduced pressure and toluene (250 ml), methanol (40 ml) and ethyl acetate (10 ml) were added. The mixture was cooled to -20 °, seeded, heptane (200 ml) was added at -30 °, the mixture was cooled to -33 ° and the precipitate was collected by vacuum filtration, washed with heptane (100 ml) and dried. This solid (44.818 g) was dissolved in toluene (250 ml) and methanol (120 ml) and concentrated under reduced pressure. The mixture was cooled to -30 °, seeded and heptane (180 ml) was added. The precipitated solid was collected by filtration under vacuum at -30 °, washed with hep14

With tan (100 ml) and dried to give a solid, Mp = 50.1-52.3 °; TLC (silica gel; methanol / methylene chloride (5/95), iodine char) Rf = 0.23 (one more polar spot identified as 1.1 wt% triethylammonium acetate by NMR); NMR (CDCl3) 2.03, 3.33, 3.54, 3.95, 4.73 and 6.93 δ; CMR (CDCl3) 23.01, 43.32, 46.48, 70.72 and 172.37 δ; MS (Cl, NH3), M / Z (relative intensities) 154 (34), 152 (100).

Example 11 (±) -glycidyl acetamide (VIIIB)

To a solution of (±) 1-acetamido-3-chloro-2-propanol (V, example 10, 10.344 g, 68.24 mmol) in THF (21 ml) at -40 ° a solution of potassium t-butoxide in THF (1 (0.0M, 65 mL, 0.95 eq.). The mixture was warmed to -20 ° and stirred for 15 min, then cooled to -37 ° and silica gel (18.5 g) was added. The precipitates were removed by vacuum filtration and washed with ethyl acetate (1,000 ml). The filtrate was concentrated and the deposited solid was removed by vacuum filtration. The filtrate was concentrated and heptane (50 ml) was added. The mixture was seeded, treated with ultrasound, and the precipitate was collected by vacuum filtration, washed with heptane and dried under a stream of nitrogen to afford the title compound, Mp = 34.6-37.3 °; TLC (silica gel; methanol / methylene chloride (5/95), iodine char) Rf 0.24; NMR 2.01, 2.59, 2.80, 3.10-3.13, 3.24-3.29, 3.7-3.9, 6.19 δ; CMR 23.07, 40.67, 45.19, 50.61 and 170.54 δ.

Example 12 (±) -N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X)

To a solution of (±) -glycidylacetamide (VIIIB, example 11, 0.1571 g, 1.365 mmol) in THF (1.63 ml) at -78 ° was added N-carbomethoxy-3-fluoro-4-morpholinylaniline (IX, preparatory example 2, 0.4358 g, 1.71 mmol, 1.26 eq.) And lithium t-butoxide (0.1267 g, 1.583 mmol, 1.16 eq.). The reaction medium was then stirred at 0 to 11 ° for 17.5 hours at which time HPLC showed 80% yield of (±) -N - [[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (retention time = 0.97 min; method B; stationary phase: 4.6 x 250 mm zorbax RX C-8 column; mobile phase: 650 ml acetonitrile, 1.85 ml triethylamine, 1.30 ml acetic acid and water in up to 1,000 ml; flow rate = 3.0 ml / min; UV detection at 254 nm). The title compound was isolated by means known to those skilled 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 with non-critical changes starting from (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1) gave the title compound.

Step B: (S) -Glycidylacetamide (VIIIB)

Following the general procedure of Example 11 with non-critical changes but starting with (S) -N- (2-hydroxy-3-chloro) acetamide (VIIIA, Step A), the title compound was obtained.

Step C: (S) -N - [[3- (3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (X)

Following the general procedure of Example 12 and making non-critical changes starting with (S) -glycidylacetamide (VIII, Step B), provided the title compound.

Example 14 (S) -1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

Following the general procedure of Example 3 and making non-critical changes starting from (S) -1-amino-3-chloro-2-propanol hydrochloride (V, Example 1) gave the title compound.

Example 15

(S) -1-Amino-3-chloro-2-propanol hydrochloride

Following the general procedure of Example 5 with non-critical changes except using (S) -1-phthalimido-3-chloro-2-propanol (S) - (IVC, Example 4) gave the title compound.

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SCHEME G

X₂-CH₂-C * H (OH) -CH₂-NH₃⁺ (V) + '

RoKSA-NH-CO-O-CHz-Ki (IX)

Roksa-PIERŚCIEŃ-CH₂-NH₂ (XIII)

Roksa-PIERŚCIEŃ-CH₂-NH-CO-R_n (X)

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SCHEME Η

Roksa-N = C = O (XIV) + '

X₂-CH₂-C * H (OH) -CH₂-NH-CO-R_n (VIIIA)

Roksa-NH-C0-0-C * H [-CH₂-X₂] [-CH₂-NH-CO-R_n] (XV)

Roksa-PIERŚCIEŃ-CH₂-NH-CO-Rn (X)

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