US 20080045707A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0045707 A1 Fine et al. (43) Pub. Date: Feb. 21, 2008

(54) PROCESSES FOR THE PREPARATION OF (60) Provisional application No. 60/656,778, filed on Feb. LINEZOLD INTERMEDIATE 24, 2005. Provisional application No. 60/656,646, filed on Feb. 24, 2005. Provisional application No. (75) Inventors: Serguei Fine, Qiriat-Arbaa (IL); Tamar 60/690,822, filed on Jun. 14, 2005. Nidam, Yehud (IL); Viviana Braude, Kadima (IL) Publication Classification Correspondence Address: (51) Int. Cl. KENYON & KENYON LLP C07D 43/10 (2006.01) ONE BROADWAY (52) U.S. Cl...... 544/137 NEW YORK, NY 10004 (US) (73) Assignees: Teva Pharmaceutical Industries Ltd.: (57) ABSTRACT Teva Pharmaceuticals USA, Inc. for The present invention provides improved methods of con Barbados verting R N-(4-morpholiyl-3-fluorophenyl)-2-oxo-5-ox azolidinyl-methyl azide (III) to the intermediate S N-(4- (21) Appl. No.: 11/977,344 morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl (22) Filed: Oct. 23, 2007 amine (II) that involve the production of fewer by-products than previous methods. The amine (II) may then be con Related U.S. Application Data verted into linezolid (I) of high chemical purity with respect to the inactive R-enantiomer and bis-linezolid (IV), and is in (62) Division of application No. 1 1/361,457, filed on Feb. high yield, without the need for tedious, complicated puri 23, 2006, now Pat. No. 7,291,614. fication steps, such as chromatography. US 2008/0045707 A1 Feb. 21, 2008

PROCESSES FOR THE PREPARATION OF LINEZOLD INTERMEDIATE

CROSS-REFERENCE TO RELATED APPLICATIONS 0001. This application is a divisional of U.S. patent application Ser. No. 1 1/361,457, filed Feb. 23, 2006, claims the benefit of priority to U.S. provisional application Ser. Nos. 60/656,778, filed Feb. 24, 2005, 60/656,646, filed Feb. 24, 2005, as well as 60/690,822, filed Jun. 14, 2005 which are incorporated herein by reference.

FIELD OF THE INVENTION 0004) Linezolid is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 0002 The present invention relates to improved methods 165800-03-3) as white crystals, with a melting point of of converting the intermediate R-N-(4-morpholinyl-3- 181.5-182.5° C. Linezolid, as well as a process for its fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide to the preparation, is disclosed in U.S. Pat. No. 5,688,792 intermediate S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo (Example 5), European Patent No. 717738, Israeli Patent No. 110,802, Canadian Patent No. 2,168,560, and Interna 5-oxazolidinyl-methyl amine, and the use of Such methods tional Patent Publication WO95/07271. in the preparation of linezolid. 0005. This oxazolidinone is marketed in the United States by Pfizer, Inc. as an injection, tablet, and oral Suspension BACKGROUND OF THE INVENTION under the name ZYVOXR). It is mainly used to treat nosocomial pneumonia, skin and skin-structure infections, 0003) Linezolid (S)- N-3-(3-Fluoro-4-morpholi and Vancomycin-resistant Enterococcus faecium infections. nyl)phenyl)-2-oxo-5-oxazolidinylmethylacetamide is an 0006 U.S. Pat. No. 5,688,792, hereinafter the 792 antimicrobial agent. Linezolid is an oxazolidinone, having patent, claims lineZolid and its use for the treatment of the empirical formula ClFIFNO and the following struc microbial infections. This patent also discloses, but does not ture (I): claim, the following method of preparation:

NO F NH2 98% 1.10% crude

CICOCHPh NaHCO;| || O

O~ O~ O OI O N- N N- N is CHOCCH, N F Ol -.O F Ol N -( F DOl NOCH.Ph Sk (R) Sk O CHOH CHOCCH 93% >80% >96% ee so EtN US 2008/0045707 A1 Feb. 21, 2008

-continued

N NaN N H N He- -as F N-( F N-( F N-( O (R) CHOSOMe cateso

O F -( O (S) CH-NHAc

0007. This method of preparation was also disclosed in Bricker, et al., J. Med. Chem., 39 673-679 (1996), where it was stated that the above route avoids the use of phosgene III to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use of NaNs can be N avoided by using potassium phthalimide, followed by deblocking of the phthalimide with aqueous methyl amine. O 0008. In the above-described synthesis, the intermediate F N amine, S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-ox O aZolidinyl-methylamine, having the following structure (II): (R) CHN

II is reduced to its corresponding amine, S-N-(4-morpholi nyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methylamine (II) N through catalytic hydrogenation in the presence of a palla O dium/carbon catalyst in the solvent ethyl acetate. These reaction conditions lead to the production of an undesirable F -(O level of reaction by-products, and thereby, following the acetylation of the intermediate amine (II) to linezolid (I), to SK undesirably high levels of bis-linezolid (IV). CH-NH2 is reacted without isolation with acetic anhydride as an oily product or in Solution to produce the acetamide, lineZolid (I). This is followed by procedures for isolating the linezolid such as those described in the 792 patent (col. 15, 11. 22-28) wherein a method of chromatography and separation of the desired fraction is described, followed by evaporation and trituration of the product to obtain pure linezolid. Due to the necessary treatment required for recovery, lineZolid is derived in low yields. 0009. In the above-described syntheses, the intermediate azide, R N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-ox azolidinyl-methyl azide (III) US 2008/0045707 A1 Feb. 21, 2008

0010. It would be desirable to have a simple, efficient, 0022. In yet another embodiment, the present invention industrial process for producing pure intermediate amine (II) provides a process for reducing R-N-(4-morpholinyl-3- used to then prepare linezolid (I) without the need of fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) to applying complicated and time consuming purification treat S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidi ments, such as column chromatography, before the last nyl-methyl amine (II). This process comprises: trituration or recrystallization. The present invention pro 0023 (a) combining R N-(4-morpholinyl-3-fluo vides such a method. rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and SUMMARY OF THE INVENTION C-C linear or branched-chain aliphatic alcohols, mono-, di-, or tri-C-C alkyl Substituted or unsubsti 0011. In one embodiment of the present invention, the tuted benzenes, or C to C alkyl esters; and reduction process is performed by catalytic hydrogenation in a process comprising: 0024 (b) reduction using a triethyl phosphite as a reducing agent to obtain S—N-(4-morpholinyl-3-fluo 0012 (a) combining R N-(4-morpholinyl-3-fluo rophenyl)-2-oxo-5-oxazolidinyl-methyl amine (ID. rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) with an organic solvent other than ethyl acetate selected 0025. In another aspect of the present invention, provided from the group consisting of C-C linear or branched are methods of preparing lineZolid (I), that comprise one of chain aliphatic alcohols, C-C aromatic hydrocar the methods described above of reducing the azide (III) to bons, mono-di-, or tri-C-C alkyl Substituted or the amine (II), and further the reducing the amine (II) to unsubstituted benzenes, C to C alkyl esters excluding linezolid by methods known in the art. The linezolid ethyl acetate, and chlorinated aromatic hydrocarbons to obtained is of high chemical purity, with respect to the obtain a mixture; inactive R-enantiomer and bis-linezolid (IV), and is in high yield, without the need for tedious, complicated purification 0013 (b) inducing catalytic hydrogenation of the azide steps, such as chromatography. (III) mixture to obtain S N-(4-morpholinyl-3-fluo rophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II). 0026. By the process of the present invention, linezolid (1) can be produced with a content of less than about 3.2% 0014. In a another embodiment of the present invention, a process is provided wherein R-N-(4-morpholinyl-3-fluo of the bis-linezolid (IV) impurity, preferably less than about rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) is 1%, more preferably less than about 0. 10%, and most reduced to S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- preferably less than about 0.05%. oxazolidinyl-methyl amine (II) by a process comprising: 0027. In addition, by the methods of the present inven tion, linezolid (I) of high purity can be produced without the 0015 (a) combining R N-(4-morpholinyl-3-fluo need for chromatographic purification procedures. Linezolid rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and (1) having a purity of more than about 95%, preferably more a linear or branched-chain aliphatic C to Cs alcohol or than about 98%, and most preferably more than about 99% a biphasic solvent system to obtain a reaction mixture; with respect to reaction by-product impurities can be and obtained by employing the methods disclosed herein. 0016 (b) reduction using a reducing agent selected 0028. The present invention further provides a process from the group of formic acid and salts thereof to obtain for preparing a pharmaceutical formulation comprising lin S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazo eZolid (1) having less than about 3.2% area by HPLC of lidinyl-methyl amine (II). bis-lineZolid (IV), comprising: 0017. In yet another embodiment, the present invention provides a process for reducing R-N-(4-morpholinyl-3- 0029 a) obtaining one or more samples of one or more fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) to batches of linezolid (I); S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidi 0030 b) measuring the level of bis-linezolid (IV) in nyl-methyl amine (II). This process comprises: each of the samples; 0018 (a) combining R N-(4-morpholinyl-3-fluo 0031 c) selecting a batch of linezolid (I) having a level rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and of bis-linezolid (IV) of less than about 3.2% area by a C to C alkyl ester; HPLC, based on the measurement of the samples from 0019 (b) reduction using a reducing agent selected the batches; and from the group of borohydrides and complexes thereof 0032 d) using the selected batch to prepare a formu in the presence of an alkaline metal base to obtain lation comprising lineZolid (I) having less than about S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazo 3.2% area by HPLC of bis-linezolid (IV). lidinyl-methyl amine (II). 0020. In a particularly preferred embodiment, the ester DETAILED DESCRIPTION OF THE used is ethyl acetate. Preferably, the reducing agent is INVENTION sodium or potassium borohydride. Preferably, the base used 0033. As used herein, room temperature and is meant to is alkaline earth hydroxides, more preferably sodium indicate a temperature of about 18 to about 25°C., prefer hydroxide. ably about 20 to about 22°C. 0021 Preferably, the reduction is carried out to comple 0034. As used herein, a biphasic solvent system can be a tion by using periodic TLC or HPLC analysis to measure mixture of an organic solvent and an aqueous solvent. when the reaction has been carried out to completion. Preferably, the aqueous solvent is water. The ratio of organic US 2008/0045707 A1 Feb. 21, 2008

solvent: water can be from about 0.1:1 to about 10:1, with a 0044) This reduction reaction is conducted in the pres ratio of about 1:1 being preferred. The phase transfer agent ence of a catalyst. Catalysts used are noble metal catalysts, can be selected from a wide variety of known phase transfer such as platinum, palladium. Preferably the noble metal agents, including tetrabutylammonium bromide (TBAB). catalyst is palladium. The noble metal catalyst may be 0035. The present invention relates to novel and provided on an inert Support such as carbon, activated improved methods for the reduction of R N-(4-morpholi carbon or alumina. Preferably, the noble metal catalyst is nyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide palladium on carbon (“Pd/C). Preferably, the noble metal (III), to its corresponding amine, S-N-(4-morpholinyl-3- catalyst is an amount of about 2-20% compared to the azide. fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II). 0045 Preferably, the catalytic hydrogenation reaction is conducted in the presence of any form of ammonium, 0036) As used herein, the conversion of the azide ( N) including aqueous and gaseous form, water, a C to C. group to the amine (-NH2) group is by a reduction reaction. In this context, the reduction reaction can comprise catalytic alcohol, water or sodium hydroxide which is added to the hydrogenation, for example, see Sheradsky, T. in The Chem reaction mixture in step (a). Preferably, ammonia gas is istry of the Azido Group, Patai, S. Ed., Interscience Press bubbled or ammonium hydroxide is admixed into the reac (1971), Chapter 6, p. 331, or use of another reducing agent. tion mixture in step (a). 0046) Once obtaining the S N-(4-morpholinyl-3-fluo 0037 Disclosed in the 792 patent, Example 5 therein, is rophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) in step a procedure for the preparation of linezolid, wherein reduc (b), recovery may be performed by any method known in the tion of the corresponding azide (III) to the corresponding art. amine (II) is by hydrogenation, using ethyl acetate as the Solvent. In contradistinction, the present invention discloses 0047 Preferably, the recovery is performed by filtering, a process for reduction wherein hydrogenation is carried out more preferably through a celite filter and removal of the in the absence the solvent ethyl acetate, or using ammonium solvent. formate as a reducing agent in a variety of Solvents or 0048. In a another embodiment of the present invention, Solvent systems. a process is provided wherein R-N-(4-morpholinyl-3-fluo 0038. In one embodiment of the present invention, the rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) is reduction process is performed by catalytic hydrogenation in reduced to S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- a process comprising: oxazolidinyl-methyl amine by a process comprising: 0039 (a) combining R N-(4-morpholinyl-3-fluo 0049 (a) combining R N-(4-morpholinyl-3-fluo rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) with rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and an organic solvent other than ethyl acetate selected a linear or branched-chain aliphatic C to Cs alcohol or from the group consisting of C-C linear or branched a biphasic solvent system to obtain a reaction mixture; chain aliphatic alcohols, C-C aromatic hydrocar and bons, and mono-di-, tri-C -C alkyl Substituted or 0050 (b) reduction using a reducing agent selected unsubstituted benzenes, C to C alkyl esters excluding from the group of formic acid and salts thereof to obtain ethyl acetate and chlorinated aromatic hydrocarbons to S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazo obtain a mixture; lidinyl-methyl amine (II). 0040 (b) inducing catalytic hydrogenation of the said 0051 Preferably, the organic solvent is in an amount of azide (III) mixture to obtain S—N-(4-morpholinyl-3- about 10 to about 25 volumes, more preferably about 15 fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II). Volumes (g/mL). In known prior art processes, larger amounts of solvents are used in order to obtain complete 0041. In this process, ethyl acetate is not present in such dissolution. an amount as to function as a solvent or co-solvent. The absence of ethyl acetate is not intended to include situations 0052 The most preferred solvent in step (a) is ethanol or where ethyl acetate is present in trace amounts or in amounts butanol. Preferably, the reducing agent is ammonium for Small enough to be insignificant in terms of functioning as mate. a solvent. The most preferred organic solvent in step (a) is 0053. This reduction reaction is conducted in the pres toluene. Preferably, the organic solvent is in an amount of ence of a catalyst. Catalysts used are Zinc or noble metal about 28 to about 40 volumes, more preferably about 35 catalysts, such as platinum, palladium. Preferably the noble Volumes (g/mL) in order to obtain complete dissolution. metal catalyst is palladium. The noble metal catalyst may be These volumes are less than those mentioned in the 792 provided on an inert Support such as carbon, activated patent and thus provide an advantage. carbon or alumina. Preferably, the noble metal catalyst is palladium on carbon (“Pd/C). Preferably, the noble metal 0.042 Preferably, when combining the azide with the catalyst is in an amount of about 2-20% compared to the organic solvent in step (a), complete dissolution is obtained. azide while the zinc is in an amount of about 1 to 2 0.043 Catalytic hydrogenation of azides in general are equivalents, relative to the azide. known in the art and is typically performed by flushing the reaction mixture 3 times with nitrogen and 3 times with 0054 Preferably, the reduction is carried out to comple hydrogen at 1.5 atm, while maintaining a temperature of tion, as judged using periodic TLC or HPLC analysis. about -5°C. to about 35°C., preferably room temperature. 0055 Once obtaining the S N-(4-morpholinyl-3-fluo The catalytic hydrogenation is preferably carried out to rophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) in step completion by using periodic TLC or HPLC analysis. (b), recovery may be performed by any method known in the US 2008/0045707 A1 Feb. 21, 2008 art. Preferably, the recovery is performed by filtering, more rities so as not to require purification by Such means as preferably through a celite filter and removal of the solvent. chromatography, can be produced. 0056. In yet another embodiment, the present invention 0068. When linezolid (I) is produced by the process of provides a process for reducing R-N-(4-morpholinyl-3- the present invention, it is in high purity and Substantially fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (II) to free of by-products and undesirable levels of impurities such S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidi as bis-linezolid. In addition, the ability to produce pure nyl-methyl amine (II). This process comprises: intermediate amine (II) by the methods of the present invention avoids the need for tedious, expensive, and time 0057 (a) combining R N-(4-morpholinyl-3-fluo consuming purification steps. In published procedures of rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and preparing lineZolid, purification steps are needed after the a C to C alkyl ester; acetylation step that converts the amine to linezolid. This 0058 (b) reduction using a reducing agent selected requires a tedious chromatography procedure and separation from the group of borohydrides and complexes thereof of the desired fraction, followed by evaporation and tritu in the presence of an alkaline metal base to obtain ration of the product to obtain pure lineZolid (see, e.g., U.S. S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazo Pat. No. 5,688,792, at col. 15, 11. 22-28). Such manipula lidinyl-methyl amine (II). tions are time consuming, expensive, and inevitably decrease yield. 0059. In a particularly preferred embodiment, the ester used is ethyl acetate. Preferably, the reducing agent is 0069. By the process of the present invention, linezolid sodium or potassium borohydride. Preferably, the base used (I) can be produced with a content of less than about 3.2% is alkaline earth hydroxides, more preferably sodium of the bis-linezolid impurity, preferably less than about 1%, hydroxide. more preferably less than about 0.10%, and most preferably less than about 0.05%. 0060 Preferably, the reduction is carried out to comple tion by using periodic TLC or HPLC analysis to measure 0070. In addition, by the methods of the present inven tion, linezolid (I) of high purity can be produced without the when the reaction has been carried out to completion. need for chromatographic purification procedures. Linezolid 0061. In yet another embodiment, the present invention (I) having a purity of more than about 95%, preferably more provides a process for reducing R-N-(4-morpholinyl-3- than about 98%, and most preferably more than about 99% fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) to with respect to reaction by-product impurities can be S N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidi obtained by employing the methods disclosed herein. nyl-methyl amine (II). This process comprises: 0071. The present invention further provides a process 0062 (a) combining R N-(4-morpholinyl-3-fluo for preparing a pharmaceutical formulation comprising lin rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and eZolid (I) having less than about 3.2% area by HPLC of a C-C linear, mono-di-, tri-C-C alkyl Substituted or bis-lineZolid (IV), comprising: unsubstituted benzenes, C to C alkyl esters or branched-chain aliphatic alcohol. 0072 (a) obtaining one or more samples of one or more batches of linezolid (I); 0063 (b) reduction using a triethyl phosphite as a reducing agent to obtain S—N-(4-morpholinyl-3-fluo 0073 (b) measuring the level of the compound of rophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II). bis-linezolid (IV) in each of the samples; 0064 Preferably R N-(4-morpholinyl-3-fluorophenyl)- 0074 (c) selecting a batch of linezolid (I) having a 2-oxo-5-oxazolidinyl-methyl azide (III) is combined with a level of bis-linezolid (IV) of less than about 3.2% area toluene, benzene or ethyl acetate while toluene is more by HPLC, based on the measurement of the samples preferable. from the batches; and 0065 Preferably, the reduction is carried out to comple 0075 (d) using the selected batch to prepare a formu tion by using periodic TLC or HPLC analysis to measure lation comprising lineZolid (I) having less than about when the reaction has been carried out to completion. 3.2% area by HPLC of bis-linezolid (IV). 0066. In another aspect of the present invention, provided 0076 Preferably, the bis-linezolid content is less than are methods of preparing lineZolid, that comprise one of the about 0.25% area by HPLC. More preferably, less than about methods described above of reducing the azide (III) to the 0.10%, and most preferably less than about 0.05%. amine (II), and further reducing the amine (II) to linezolid by 0077. If the level of the bis-linezolid measured in step b) methods known in the art. The linezolid obtained is of high is higher than about 3.2% area by HPLC, it may be reduced chemical purity, with respect to the inactive R-enantiomer by crystallization from ethyl acetate. and bis-linezolid, and is in high yield, without the need for tedious, complicated purification steps, such as chromatog 0078 Having described the invention with reference to raphy. certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration 0067. In a preferred embodiment of this process, a one of the specification. The invention is further defined by pot process is provided wherein the amine (II) is not reference to the following examples describing in detail the precipitated from the reduction reaction mixture but rather is preparation of the composition and methods of use of the converted directly in the solution to linezolid by acetylation. invention. It will be apparent to those skilled in the art that Even without precipitation and/or further purification of the many modifications, both to materials and methods, may be amine (II), linezolid (I) free of undesirable levels of impu practiced without departing from the scope of the invention. US 2008/0045707 A1 Feb. 21, 2008

EXAMPLES Example 4 Example 1 Preparation of Linezolid Free the (R)-Linezolid Enantiomer from AZide (III) Intermediate by Comparative Example, Based on U.S. Pat. No. Catalytic Hydrogenation and Ammonium Gas 5,688,792 Preparation of Linezolid from Azide (III) 0083. In a 10L reactor, 150 g R N-(4-morpholinyl-3- Intermediate by Catalytic Hydrogenation fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged with 5L toluene, followed by 15 g Pd/C (10% Pd/C 0079. In a 1L reactor, 6 g R-N-(4-morpholinyl-3-fluo containing 52% water). The system was bubbled with rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was ammonia (gas) during 2 h, then flushed 3 times with nitrogen charged with 150 ml ethyl acetate, followed by 0.6 g Pd/C. and 3 times with hydrogen. The pressure of hydrogen was The system was flushed 3 times with nitrogen and 3 times set to 1.5 atm. The reaction mixture was stirred at RT and the with hydrogen. The pressure of hydrogen was set to 1.5 atm. reaction followed until completion. The reaction mixture The reaction mixture was stirred at RT and the reaction was filtered through celite and the solution was treated with followed by TLC or HPLC until completion. The reaction 60 ml acetic anhydride at RT. The precipitate was filtered mixture was filtered through celite and the solution was and dried to obtain linezolid (I) crystalline Form IV (purity: treated with acetic anhydride in the presence of triethyl 99.5%, yield: 91%). amine at RT. The precipitate was filtered and dried to obtain linezolid (I) crystalline Form IV with a 3.2% content of Example 5 bis-linezolid (IV). Preparation of Intermediate Amine (II) by Catalytic Example 2 Hydrogenation 0084. In a 10L reactor, 150 g R N-(4-morpholinyl-3- Preparation of Linezolid from AZide (III) fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was Intermediate by Catalytic Hydrogenation charged, followed by 15 g Pd/C in 5L toluene. Finally 500 ml ammonium hydroxide was added. The system was 0080. In a 1L reactor, 9 g R-N-(4-morpholinyl-3-fluo flushed 3 times with nitrogen and 3 times with hydrogen. rophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was The pressure of hydrogen was set to 1.5 atm. The reaction charged with 150 ml toluene, followed by 0.6 g Pd/C and 20 mixture was stirred at RT and the reaction followed by TLC ml ammonium hydroxide. The system was flushed 3 times or HPLC until completion. The reaction mixture was filtered with nitrogen and 3 times with hydrogen. The pressure of through celite. S. N-(4-morpholinyl-3-fluorophenyl)-2- hydrogen was set to 1.5 atm. The reaction mixture was oXo-5-oxazolidinyl-methylamine (II) precipitated on stand stirred at RT and the reaction followed by TLC or HPLC ing and/or cooling as a white solid, was filtered, and dried at until completion. The reaction mixture was filtered through 50° C. overnight. (Form C, 98.6% total purity by HPLC). celite and the solution was treated with 1.5 to 5 equivalents of acetic anhydride at RT. The precipitate formed was Example 6 filtered and dried to obtain linezolid (I) No traces of bis linezolid (4) were detected, indicating not more than 0.01% Preparation of Linezolid from AZide (III) (w/w) bis-linezolid (4). Intermediate by Catalytic Hydrogenation Example 3 0085. In a 10L reactor, 150 g R N-(4-morpholinyl-3- fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was Preparation of Linezolid Free of the (R)-Linezolid charged with 5L toluene, followed by 15 g Pd/C (10% Pd/C Enantiomer from AZide (III) Intermediate by containing 52% water). The system was bubbled with Catalytic Hydrogenation and Ammonium ammonia (gas) during 2 h, then flushed 3 times with nitrogen Hydroxide and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT and the 0081. In a 10L reactor, 150 g R-N-(4-morpholinyl-3- reaction followed by TLC or HPLC until completion. The fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was reaction mixture was filtered through celite and the solution charged, followed by 15 g Pd/C in 5L toluene. Finally, 500 was treated with 60 ml acetic anhydride at RT. The precipi ml ammonium hydroxide was added. The system was tate was filtered and dried to obtain crystalline linezolid (D flushed 3 times with nitrogen and 3 times with hydrogen. (purity: 99.5%, yield: 91%). The pressure of hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT and the reaction followed by TLC Example 7 or HPLC until completion. The reaction mixture was filtered through celite. Preparation of Linezolid from AZide (III) Intermediate by Catalytic Hydrogenation 0082 To the solution containing the obtained (S)-N-(4- morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methy 0086. In a 10L reactor, 150 g R N-(4-morpholinyl-3- lamine (II) formed above, acetic anhydride was added drop fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide were wise (2 equivalents). The reaction mixture was stirred during charged followed by 7.5 g Pd/C in 5.25L toluene. Finally, 4 hours at RT. During this period, linezolid (I) crystals were ammonia was bubbled for 1 hr. The system was flushed three precipitated. The crystals were filtered and dried. (% times with nitrogen and 3 times with hydrogen. The pressure R-enantiomer of linezolid: 0.6% (w/w). of hydrogen was set to 1.7 atm. The reaction mixture was US 2008/0045707 A1 Feb. 21, 2008

stirred at RT and the reaction followed up until completion. Example 11 The reaction mixture was filtered. The toluene was distill Preparation of Linezolid from AZide (III) lated out to dryness. Intermediate Using Reducing Agent: Sodium 0087. 4.5L ethyl acetate were added to the residual (S)- Borohydride N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl 0091. In a three necked flask, 10 g R N-(4-morpholinyl methylamine The mixture was heated until dissolution and 3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) filtered. To the solution, acetic anhydride was added drop was charged, followed by 1 g TBAB, 2 g NaBH, 1 g NaOH wise (at least 2.5 equivalents). The reaction mixture was pellets, and 100 ml ethyl acetate under a nitrogen atmo stirred over 2 hours at RT (until completion, if needed more sphere. The reaction mixture was maintained at 55° C. acetic anhydride is added). During this period, lineZolid was overnight. Water was added and the phases were separated. precipitated. The crystals wore filtered and dried (Form IV). The aqueous phase was washed twice with ethyl acetate. The No further purification is needed. organic phases were combined. Triethyl amine (10 ml) was Example 8 added to the solution, followed by 10 ml of acetic anhydride. The solution was stirred overnight. 30 ml petroleum ether Preparation of Intermediate Amine (II) using was added, inducing precipitation of crystalline lineZolid (I). Ammonium Formate 2.6 g white crystals were obtained (purity: 96.2% yield: 0088. In a three necked flask, 6.4 g R N-(4-morpholi 35%). nyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) Example 12 was charged, followed by 2.5 g ammonium formate, 23 ml ethanol, and 2.6 g Zinc powder. The reaction mixture was Preparation of Linezolid from Amine (II) stirred at RT and the reaction followed by TLC or HPLC Intermediate Using Acetic Anhydride until completion. 60 ml acetone was then added. The reac 0092) 200 ml toluene at 25° C. was added to a flask tion mixture was filtered and by evaporation S N-(4- containing 29 g of crystalline (S) N-(4-morpholinyl-3- morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl fluorophenyl)-2-oxo-5-oxazolidinyl-methylamine (II). Ace amine (II) was obtained as a solid. (Form A, 96.5% total tic anhydride (2.5 equivalents) was added dropwise. The purity by HPLC). reaction mixture was stirred overnight. Linezolid (I) that precipitated from the reaction mixture was filtered. The Example 9 precipitate was dried at 50° C. in an oven overnight. The crystals obtained were analyzed by PXRD and showed Preparation of Linezolid Free of the (R)-Linezolid linezolid (I) Form IV. The yield was 84.9% and the (R)- Enantiomer and bis-linezolid (4) from Azide (III) linezolid enantiomer content found was 0.03%. Further Intermediate using Reducing Agent: Ammonium more, no traces of bis-linezolid (IV) were detected, indicat Formate (and Ammonium Hydroxide) ing not more than 0.01% (w/w) bis-linezolid (IV). 0089. In a three-necked flask, 6.4 g R N-(4-morpholi nyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) Example 13 was charged, followed by 100 ml butanol, 2.5 g ammonium Preparation of Linezolid Form IV Free of formate, and 1.3 g 10% palladium over charcoal. The Bis-Linezolid (IV) and the (R)-Linezolid reaction mixture was stirred at 80° C. during 6 h. The Enantiomer from Amine (II) Intermediate Using reaction mixture was filtered. To the organic solution, 4 ml Acetic Anhydride triethyl amine was added and the mixture was cooled to 0° 0093. To the solution containing the obtained (S)-N-(4- C. 4.7 ml acetic anhydride was added dropwise. Linezolid morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methy (I) precipitated from the reaction mixture and was filtered lamine (II), acetic anhydride was added drop wise (2 equiva off. 2.45 g dry linezolid (I) Form IV was obtained (purity: lents). The reaction mixture was stirred during 4 hours at RT. 93.2%; 50% yield). During this period, crude linezolid (I) was precipitated. The crystals were filtered and dried (% R-enantiomer of lin Example 10 eZolid: 0.6% (w/w). Preparation of Linezolid from AZide (III) Example 14 Intermediate Using Reducing Agent: Ammonium Formate Preparation of Linezolid from Amine (II) Intermediate Using Ethyl Acetate 0090. In a three necked flask, 6.4 g R N-(4-morpholi nyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) 0094) 3 g of S N-(4-morpholinyl-3-fluorophenyl)-2- was charged, followed by 2.5 g ammonium formate, 2.6 g. oxo-5-oxazolidinyl-methylamine (II) was mixed with 50 ml Zinc powder, 0.6 g TBAB, and 100 ml of a 1:1 mixture ethyl ethyl acetate. 3 ml triethyl amine was added and the mixture acetate: water. The reaction mixture was stirred at RT during was cooled to 0°C. 2.5 ml acetic anhydride was added drop 2 h, and then heated to reflux for 10 h. The reaction mixture wise. The reaction mixture was stirred overnight. 2.5 g dry was filtered. The phases were separated; the aqueous phase linezolid (I) Form IV was obtained (purity: 98.3% yield: was extracted twice with ethyl acetate. All the organic 70%). phases were combined, 4 ml triethyl amine was added and Example 15 the mixture was cooled to 0°C. 4.7 ml acetic anhydride was added drop wise. The reaction mixture was stirred overnight. Batch Method 3.6 g dry linezolid (I) were obtained (purity: 98.7%, 54% 0095 Linezolid (1.7 g, containing 3.15% bis-linezolid) yield). was mixed with ethyl acetate (110 ml, 66V) and heated to US 2008/0045707 A1 Feb. 21, 2008

reflux. The turbid solution was filtered while hot to obtain a 6. The process of claim 1, wherein the organic solvent of clear Solution. By cooling until room temperature, the crys the biphasic solvent is ethylacetate. tals were filtered and dried. 1.22 g (71.3% yield) were 7. The process of claim 1, wherein the ratio of organic obtained and analyzed for their bis-linezolid content. bis solvent: water of the biphasic solvent is from about 0.1:1 to linezolid was 0.02%. about 10:1 8. The process of claim 7, wherein the ratio of organic 0.096 Linezolid (15 g, containing 0.16% bis-linezolid) solvent: water of the biphasic solvent is about 1:1. was mixed with ethyl acetate (450 ml, 30V) and heated to 9. The process of claim 1, wherein the process comprises reflux. The turbid solution was filtered while hot to obtain a a phase transfer agent and the phase transfer agent is clear Solution. By cooling until room temperature, the crys tetrabutylammonium bromide (TBAB) or Aliquot 336. tals were filtered and dried. 12.5 g (83.3% yield) were 10. The process of claim 1, wherein the reducing agent is obtained and analyzed for their bis-linezolid content. bis ammonium formate. linezolid was not detected. 11. The process of claim 1, wherein reduction conducted 0097 HPLC method in the presence of Zinc or a noble metal catalyst on an inert Support Such as carbon, activated carbon, alumina or zinc. 0098 Column Hypersil Gold 150x4.6, 5u 12. The process in claim 11, wherein the noble metal 0099) Detection limit: 0.1% catalyst is palladium on carbon (“Pd/C). 13. The process in claim 11, wherein the noble metal 0100 Eluents: 0.01M KHPO:MeOHA: 80:20 B: 50:50 catalyst is in an amount of about 2-20% compared to the azide. TABLE 1. 14. The process in claim 11, wherein the Zinc is in an Time A. B Flow amount of about 1 to 2 equivalents, relative to the azide. O 100 O 1.5 15. The process in claim 11, wherein the reduction is 15 57 43 2 carried out to completion as judged by using periodic TLC 25 35 65 2 or HPLC analysis. 16. The process in claim 1 further comprising converting the said amine (II) into linezolid. We claim: 17. The process of claim 16, wherein the linezolid (I) 1. A process for preparation of S-N-(4-morpholinyl-3- produced comprises less than about 3.2% of bis-linezolid fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) from (IV). R N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidi 18. The process of claim 17, wherein the linezolid (I) nyl-methyl azide (III) by catalytic hydrogenation compris produced comprises less than about 1% of bis-linezolid (IV). ing: combining R-N-(4-morpholinyl-3-fluorophenyl)-2- 19. The process of claim 18, wherein the linezolid (I) oxo-5-oxazolidinyl-methyl azide (III) and a linear or produced comprises less than about 0.1% of bis-linezolid branched-chain aliphatic C to Cs alcohol or a biphasic (IV). Solvent system to obtain a reaction mixture; and reducing the 20. The process of claim 16, wherein the linezolid (I) said azide (III) using a reducing agent selected from the produced comprises less than about 0.05% of bis-linezolid group of formic acid and salts thereof to obtain S N-(4- (IV). morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl 21. The process of claim 16, wherein pure linezolid (I) is amine (II). produced having a purity of more than about 95% with 2. The process of claim 1, wherein the alcohol is ethanol respect to reaction by-product impurities. or butanol. 22. The process of claim 16, wherein pure linezolid (I) is 3. The process of claim 1, wherein the amount of alcohol produced having a purity of more than about 98% with is about 10 volumes to about 25 volumes relative to the said respect to reaction by-product impurities. azide. 23. The process of claim 22, wherein pure linezolid (I) is 4. The process of claim 1, wherein the amount of alcohol produced having a purity of more than about 99% with is about 15 volumes (g/mL) relative the said azide. respect to reaction by-product impurities. 5. The process of claim 1, wherein the aqueous solvent of the biphasic solvent is water. k k k k k