(12) Patent Application Publication (10) Pub. No.: US 2016/0102064 A1 DODDA Et Al

US 201601 02064A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0102064 A1 DODDA et al. (43) Pub. Date: Apr. 14, 2016

(54) IMPROVED PROCESSES FOR THE Publication Classification PREPARATION OF LINEZOLD USING (51) Int. Cl. NOVELINTERMEDIATES C07D 263/24 (2006.01) C07D 295/135 (2006.01) (71) Applicant: SYMED LABS LIMITED, Hyderabad C07D 209/248 (2006.01) (IN) (52) U.S. Cl. CPC ...... C07D 263/24 (2013.01); C07D 209/48 (72) Inventors: Mohan Rao DODDA, Hyderabad (IN); (2013.01); C07D 295/135 (2013.01) Venkat Reddy BUTHUKURI, (57) ABSTRACT Hyderabad (IN) Provided herein are improved, commercially viable and industrially advantageous processes for the preparation of Linezolid, in high yield and purity, using novel intermediates. (21) Appl. No.: 14/785,960 In one aspect, provided herein are efficient, industrially advantageous and environmentally friendly processes for the (22) PCT Filed: Apr. 25, 2013 preparation of lineZolid, in high yield and with high purity, using novel intermediates. The processes disclosed herein (86). PCT No.: PCT/N2013/000278 avoid the tedious and cumbersome procedures of the prior processes, thereby resolving the problems associated with the S371 (c)(1), processes described in the prior art, which is more convenient (2) Date: Oct. 21, 2015 to operate at lab scale and in commercial scale operations. US 2016/01 02064 A1 Apr. 14, 2016

IMPROVED PROCESSES FOR THE cocci, Vancomycin-resistant enterococci (VRE), and methi PREPARATION OF LINEZOLD USING cillin-resistant Staphylococcus aureus (MRSA). Linezolid is NOVELINTERMEDIATES represented by the following structural formula I: FIELD OF THE INVENTION 0001. The present invention relates to improved, commer cially viable and industrially advantageous processes for the preparation of Linezolid, in high yield and purity, using novel N intermediates. O BACKGROUND OF THE INVENTION F -, 0002 U.S. Pat. No. 5,688,792 (hereinafter referred to as H the US 792 patent), assigned to Pharmacia & Upjohn Com Q- CH pany, discloses a variety of oxazine and thiazine oxazolidi none derivatives and their Stereochemically isomeric forms, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are useful antimicrobial agents, effective against 0003. The main indications of linezolid are infections of a number of human and Veterinary pathogens, particularly the skin and Soft tissues and pneumonia (particularly hospi gram-positive aerobic bacteria Such as multiply-resistant sta tal-acquired pneumonia). Linezolid is marketed by Pfizer phylococci, streptococci and enterococcias well as anaerobic under the trade names ZyVox (in the United States, United organisms and acid-fast organisms. Among them, Linezolid, Kingdom, Australia, and several other countries), Zyvoxid (in a member of the oxazolidinone class of drugs and chemically Europe), and ZyVoxam (in Canada and Mexico). named as N-(5S)-3-3-fluoro-4-(4-morpholinyl)phenyl-2- 0004. The synthesis of Linezolid was first described in the oXo-5-oxazolidinylmethylacetamide, is active against most US 792 patent. According to the US 792 patent, the Lin Gram-positive bacteria that cause disease, including strepto eZolid is prepared by a process as depicted in Scheme 1:

Scheme-1: n-Butyl Lithium in hexane NaHCO3/Acetone, H2O (R)-Glycidylbutyrate O N NH2 -e- O N NHCOOCH2Ph -e- Benzyl chloroformate Tetrahydrofuran, N2 \ / \ / -78° C. F 3-Fluoro-4-morpholinyl N-Carbobenzyloxy-3-fluoro aniline 4-morpholinyl aniline

O Methanesulfonyl Ethyl chloride / V acetate l -e- O N N O -e- Q N N O Triethylamine? O-SOCH HO F \-Q-ol methylenechloride F N (R)-N-(3-3-Fluoro-4-morpholinyl (R)-N-3-3-Fluoro-4-morpholinylphenyl)-2-oxo phenyl)-2-oxo-5-oxazazolidinyl 5-oxazazolidinyl-methyl methanesulfonate methanol O

KN Acetonitrile US 2016/01 02064 A1 Apr. 14, 2016

-continued / \, -, / \, 1s, O \ / -)- Q

O (R)-N-3-3-Fluoro-4-4- (S)-N-3-3-Fluoro-4-morpholinyl morpholinylphenyl-2-oxo phenyl)-2-oxo-5-oxazolidinyl)methyl 5-oxazolidinyl-methylazide phthalimide

10% Pol/C, H2 Ethanol s CH3NH2. Acetic anhydride

Acetic anhydride Acetylchloride se C-\ / -y\-Q-Nicoch, Pyridine C-\ / -yQ-Ns (S)-N-3-3-Fluoro-4-morpholinylphenyl (S)-N-3-3-fluoro-4-morpholinyl 2-oxo-5-oxazolidinyl)methyl)acetamide phenyl)-2-oxo-5-oxazazolidinyl)methyl (Linezolid) amine

0005. The synthesis of Linezolid as described in the morpholinyl)phenyl-2-oxo-5-oxazolidinyl-methyl amine; US 792 patent involves the following main reaction steps: a) and f) the (S)-N-3-fluoro-4-(4-morpholinyl)phenyl-2-oxo 3-Fluoro-4-morpholinyl aniline is reacted with benzyl chlo 5-oxazolidinyl-methyl amine intermediate is then subjected roformate in the presence of sodium bicarbonate to produce to acetylation with acetic anhydride to produce Linezolid. N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline; b) the N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline is reacted 0006. The processes for the preparation of Linezolid as described in the aforementioned prior art suffer from several with a solution of (R)-glycidylbutyrate in tetrahydrofuran in disadvantages and limitations. The main disadvantage of the the presence of n-butyl lithium/hexane at a temperature of prior art processes is that the reaction between N-carboben -78° C. under nitrogen atmosphere, followed by tedious Zyloxy-3-fluoro-4-morpholinyl aniline and (R)-glycidyl work-up and isolation methods to produce the (5R)-5-(hy butyrate intetrahydrofuran in the presence of n-butyl lithium/ droxymethyl)-3-3-fluoro-4-(4-morpholinyl)phenyl)-2-ox hexane should be performed at extremely low temperatures azolidinone; c) the (5R)-5-(Hydroxymethyl)-3-3-fluoro-4- (-78° C.) under very strict control of reaction conditions: (4-morpholinyl)phenyl-2-oxazolidinone is reacted with processes involving extreme low temperatures are undesir methanesulfonyl chloride in the presence of triethylamine in able for large-scale operations since they require special methylene chloride solvent under nitrogen atmosphere to equipment and an additional reactor, adding to the cost, produce (5R)-3-3-fluoro-4-(4-morpholinyl)phenyl-2- thereby making the processes commercially unfeasible. oxo-5-oxazolidinyl)methyl methane sulfonate; d) (i) the (5R)-3-3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-ox 0007 Various processes for the preparation of Linezolid, azolidinyl)methyl methane sulfonate is reacted with sodium its intermediates, and related compounds are described in azide to produce (5R)-3-3-fluoro-4-(4-morpholinyl)phe U.S. Pat. No. 5,837,870, U.S. Pat. No. 5,880,118, U.S. Pat. nyl)-2-oxo-5-oxazolidinylmethyl azide, or alternatively (ii) No. 6,107,519, U.S. Pat. No. 6,362,334, U.S. Pat. No. 6,887, the (5R)-3-3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5- 995, U.S. Pat. No. 7,429,661, U.S. Pat. No. 7,307,163 and oxazolidinylmethyl methane sulfonate intermediate is U.S. Pat. No. 7,291,614; PCT Publication Nos. WO reacted with potassium phthalimide to produce (S)-N-3-3- 99/24393, WO 2007/116284, WO 2009/063505, WO 2010/ Fluoro-4-4-morpholinylphenyl)-2-oxo-5-oxazolidinylme 031769, WO 2010/081404, WO 2010/084514, WO 2011/ thylphthalimide; e) (i) the (5R)-3-3-fluoro-4-(4-mor 077,310, WO 2011/137222 and WO 2012/114355; Chinese pholinyl)phenyl-2-oxo-5-oxazolidinylmethyl azide Patent Application Publication No. CN 1772750; and Journal intermediate is hydrogenated in the presence of 10% palla Articles: J. Med. Chem. 39(3), 673-679, 1996: Tetrahedron dium/carbon to produce (S)-N-3-3-Fluoro-4-4-morpholi Lett., 40(26), 4855, 1999; and Organic Letters 2003, 5,963 nylphenyl-2-oxo-5-oxazolidinylmethylamine, or (ii) the 965. (S)-N-3-3-Fluoro-4-4-morpholinylphenyl)-2-oxo-5-ox 0008. According to the U.S. Pat. No. 5,837,870 (hereinaf azolidinyl)methylphthalimide intermediate is then reacted ter referred to as the US 870 patent), the Linezolid is prepared with aqueous methylamine to produce (S)-N-3-fluoro-4-(4- by a process as depicted in scheme 2: US 2016/01 02064 A1 Apr. 14, 2016

Scheme-2: THF t-amylalcohol NaHCO3/Acetone, H2O BuLihexane O N NH2 Hos NHCOOCH2Ph Hos Benzylchloroformate (S)-(+)-3-chloro \ / 1,2-propanediol F 3-Fluoro-4-morpholinyl N-Carbobenzyloxy-3-fluoro aniline 4-morpholinyl aniline

Triethylamine? methylenechloride -e- 4-Nitrobenzene C-\ / -yQuoi Sulfonylchloride (R)-N-3-(3-Fluoro-4-(4-morpholinyl phenyl)-2-oxo-5-oxazolidinyl methanol

/ / \ , Salyciladehyde Isopropanol -- \ / - Q--( )-so aq. ammonia (R)-N-3-3-Fluoro-4-morpholinylphenyl 2-oxo-5-oxazazolidinyl-methanol 4-nitrobenzenesulfonate ester

H2O 37% aq. HCI He C-\ / -y\-N-N=l OH Acetic anhydride (S)-(N-3-3-Fluoro-4-morpholinylphenyl 2-oxo-5-oxazolidinylmethaylamine Salicyladehyde imine

O-)-.'F Q- r

Linezolid

0009. As stated in the preceding paragraphs, the processes tetrahydrofuran while maintaining the temperature at less for the preparation of Linezolid as disclosed in the prior art than -10°C. The resulting slurry is then stirred at -14°C. to were tedious and cumbersome for example, U.S. Pat. No. 0° C. for 1 hour and then added to the lithium anion mixture 5.837,870 describes a process for the preparation of (5R)-5- while maintaining both mixtures at 0°C., then rinsed in with (hydroxymethyl)-3-3-fluoro-4-(4-morpholinyl)phenyl-2- tetrahydrofuran. The resulting slurry is stirred for 2 hours at oxazolidinone intermediate wherein, tetrahydrofuran is 20-23°C. and then cooled to 6°C., followed by the addition mixed with t-amyl alcohol, followed by the addition of butyl ofa mixture of citric acid monohydrate in water. The resultant lithium in hexanes with agitation to produce a lithium t-amy liquid phases are separated and the lower aqueous phase is late mixture, which is then added to solution of N-carboben washed with ethyl acetate. The organic layers are combined Zyloxy-3-fluoro-4-morpholinyl aniline obtained as per the and solvent is removed under reduced pressure. Heptane and process described in J. Med. Chem., 39(3), 673 (1996) in water are added to the resulting mass and the solvent is tetrahydrofuran while maintaining the temperature at less removed by reduced pressure until a total volume of 5 ml than 8° C. and rinsed in with tetrahydrofuran to produce a remains. The precipitated product is collected by vacuum lithium anion mixture. Tetrahydrofuran is mixed with S-(+)- filtration and washed with water and then dried in a stream of 3-chloro-1,2-propanediol, the resulting mixture is cooled to nitrogen to produce (5R)-5-(hydroxymethyl)-3-3-fluoro-4- -16°C., followed by the addition of potassium t-butoxide in (4-morpholinyl)phenyl-2-oxazolidinone. US 2016/01 02064 A1 Apr. 14, 2016

0010. Organic Letters 2003, 5, 963-965 describes a pro cess for the preparation of Linezolid as depicted in Scheme 3:

Scheme-3: O O M V HONO M V -l PPTS O N NH2 -- O N Br HN O a V M 47%.CuBr HBir N M \ QuotHP Dihydropyran HN O F F 5-(Tetrahydropyran-2- OH 3-Fluoro-4-morpholinyl 3-Fluoro-4-morpholinyl yloxymethyl)-oxazolidin- 5-Hydroxymethyl aniline bromo benzene 2-one oxazolidin-2-one

Dioxane, K2CO3 CuI, (+)-trans-1,2-diamino cyclohexane

O O CHSOCl, / V PPTS / V Triethyalmine O N N O - O N N O Dichloromethane \ / \-Quoni 8O \ / -Q-oil ClOOCl3e. F F (R)-N-3-(3-Fluoro-4-(4-morpholinyl (R)-N-3-(3-Fluoro-4-(4-morpholinyl phenyl)-5-[(tetrahydropyran-2-yloxy phenyl)-2-oxo-5-oxazolidinyl)methanol methyl)-oxazolidin-2-one

O O O N ls, NaNs of N -, CH3COSH V / Q- -SOCH DMF V / Q- N F F (R)-N-3-(3-Fluoro-4-morpholinylphenyl- (R)-N-3-(3-Fluoro-4-morpholinyl 2-oxo-5-oxazazolidinyl- phenyl)-2-oxo-5-oxazolidinyl methyl methanesulfonate methylazide

Linezolid

0011 U.S. Pat. No. 6,107,519 (hereinafter referred to as the US 519 patent) describes various processes for the prepa ration of Linezolid as depicted in schemes 4 & 5:

Scheme-4: O Aq. NH3 A \ C -- CHO -e- '1 (S)-Epichlorohydrin Benzaldehyde

C OH OH Acetic anhydride? Aq. HCI Acetyl Chloride N Hos Nulu-N. oHCI HeTriethylamine N (S)-1-Benzalimino-3-chloro- (S)-1-Amino-3-chloro-2- 2-propanol propanol hydrochloride US 2016/01 02064 A1 Apr. 14, 2016

-continued OH v V Methylene chloride H -- O N NCO -a- claulus " V / COCl2(Phosgene) O\ /N NH2 O F (S)-1-Acetamido-2-hydroxy 3-Fluoro-4-morpholinyl 3-Fluoro-4-morpholinyl 3-chloropropane phenylisocyanate aniline

-1.Heptane

H r N CH N O r Citric acid monohydrate O ls O HeSodium tert-butoxide l N O Ethanol F N O H H C N CH

O (S)-N-Carbo (1'-acetamido-3'-chloro-2'- Linezolid propoxy)-3-fluoro-4-morpholinylaniline

Scheme-5: O Aq. NH3 A -- CHO -e- w '1 C (S)-Epichlorohydrin Benzaldehyde

C OH OH Acetic anhydride? Aq. HCI Acetyl Chloride N He Nulu-N. oHCI HeTriethylamine N (S)-1-Benzalimino-3-chloro (S)-1-Amino-3-chloro-2- 2-propanol propanol hydrochloride

OH O H H O N NH2 C N." He- N." \ / O O (S)-1-Acetamido-2-hydroxy- (S)-Glycidyl acetamide 3-Fluoro-4-morpholinyl 3-chloropropane aniline

- A v H Lithium tert-butoxide O N N Methyl chloroformate Linezolid -H -78° C. y-OMe Potassium carbonate Heptane F O N-Carbomethoxy-3-fluoro-4- morpholinyl aniline US 2016/01 02064 A1 Apr. 14, 2016

0012. PCT Publication No. WO 2012/114355 describes a -continued process for the preparation of LineZolidas depicted in scheme O 6: O KN O/ \N N l O

Scheme 6: \ / \-Q-O-SOCH, O F A. v (R)-Epichlorohydrin (R)-N-3-3-Fluoro-4-morpholinylphenyl O N NH -> 2-oxo-5-oxazazolidinyl-methyl methanesulfonate O F 3-Fluoro-4-morpholinyl O / \N N - O Q Hydrazine aniline V W Q- N Hehydrate F r O Nu HeCDI (S)-N-3-3-Fluoro-4-morpholinyl phenyl)-2-oxo-5-oxazolidinyl-methyl phthalimide F 1N1\e O Acetic anhydride? M V -l Acetyl chloride OH O N N O -- N-3-Chloro-2-(R)-hydroxypropyl-3- fluoro-4-morpholinyl aniline \ / Q-Ni. F (S)-N-3-Fluoro-4-(4-morpholinyl)phenyl 2-oxo-5-oxazolidinyl)-methylamine r Nu O DOJ -e- C-\ / -y\-Q-Nicoch, Q Linezolid (5R)-5-(Chloromethyl)-3-3-fluoro 4-morpholinyl)phenyl-2- 0013 The processes for the preparation of Linezolid as oxazolidinone described in the aforementioned prior art suffer from the following disadvantages and limitations: 0014) a) the prior art processes involve the use of highly r flammable and dangerous reagents like n-butyl lithium in Nu O hexanes; 00.15 b) handling of n-butyl lithium is very difficult at lab scale and in commercial scale operations; 0016 c) the reaction between N-carbobenzyloxy-3- fluoro-4-morpholinyl aniline and (R)-glycidylbutyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane S-- should be performed at extremely low temperatures (-78° (5R)-3-3-Fluoro-4-(4-morpholinyl)phenyl C. to -16°C.) under very strict control of reaction condi 2-oxazolidinylmethyl acetate tions; processes involving extremely low temperatures are undesirable for large-scale operations since they require special equipment and an additional reactor, adding to the r cost, thereby making the processes commercially unfea Nu Methanesulfonyl sible; Chloride Ho 0017 d) the processes require longer reaction times and F Ol 1,O the yields and purity of the product obtained is very low: 0018 e) the processes involve the use of expensive Q H reagents including noble metal catalysts such as palladium (5R)-5-(Hydroxymethyl)-3-3-fluoro-4- on charcoal; and expensive chiral reagents such as (E)- morpholinyl)phenyl-2-oxazolidinone trans-1,2-diaminocyclohexane, in excess amounts, for pre paring the starting material 5-(tetrahydro-pyran-2- yloxymethyl)-2-oxazolidinone which is difficult to synthesize; US 2016/01 02064 A1 Apr. 14, 2016

0019 f) the processes involve the use of tedious and cum 0024. The major drawback of the processes for the prepa berSome procedures like prolonged reaction time periods, ration of linezolid described in the aforementioned prior art is multiple process steps, column chromatographic purifica that the processes involve the use of highly flammable, cor tions, multiple isolation/re-crystallizations—methods rosive and pyrophoric reagents like n-butyl lithium in hex involving column chromatographic purifications are gen anes, thereby requiring very strict control of reaction condi erally undesirable for large-scale operations, thereby mak tions at low temperatures (-78°C. to -16°C.). Handling of ing the process commercially unfeasible; n-butyl lithium is very difficult at lab scale and in commercial 0020 g) the processes involve the use of multiple and scale operations. Moreover, the yields and purities of the excess amounts of hazardous solvents like n-hexane, hep product obtained according to the prior art processes are very tanes, dioxane and tetrahydrofuran: low. 0025 Based on the aforementioned drawbacks, the prior 0021 h) the processes involve the use of highly toxic art processes have been found to be unsuitable for the prepa reagents like phosgene, triphosgene, pyridinium p-tolu ration of (5R)-5-(hydroxymethyl)-3-3-fluoro-4-(4-mor enesulfonate, pyridine and sodium azide; pholinyl)phenyl-2-oxazolidinone at lab scale and in com 0022 i) methods involving column chromatographic puri mercial scale operations. fications are generally undesirable for large-scale opera (0026 U.S. Pat. No. 7,307,163 B2 (hereinafter referred to tions, thereby making the process commercially unfea as the US 163 patent), assigned to Symed Labs Limited (the sible; present applicant), discloses a novel and commercially viable 0023) ) the overall processes generate a large quantity of process for the preparation of Linezolidas depicted in scheme chemical waste which is difficult to treat. 7. US 2016/01 02064 A1 Apr. 14, 2016

H IO US 2016/01 02064 A1 Apr. 14, 2016

0027 U.S. Pat. No. 7,429,661 B2 (hereinafter referred to as the US 661 patent), assigned to Symed Labs Limited (the present applicant), discloses a novel and commercially viable process for the preparation of LineZolidas depicted in scheme

Scheme-8:

r O N N O + K. N. -3- F N1\1\e F 1n 1 H i O OH OH O N-3-Chloro-2-(R)-hydroxypropyl-3- Potassium phthalimide N-3-Phthalimido-2-(R)-hydroxypropyl fluoro-4-morpholinyl aniline 3-fluoro-4-(4-morpholinyl)aniline -

Carbonylating agent Aprotic Solvent

F NH2 3-Fluoro-4-morpholinyl (2)-N-2,3-epoxypropyl aniline phthalimide r r N O Hydrazine hydratef N--N Aq. Methylamine Linezolid st F s a DOJ, O Q H Q

O (S)-N-3-Fluoro-4-(4-morpholinyl)phenyl (S)-N-3-3-Fluoro-4-4-morpholinylphenyl 2-oxo-5-oxazolidinyl)methylamine 2-oxo-5-oxazolidinyl)methylphthalimide

0028. However, a need remains for an improved, commer 2-(R)-hydroxypropyl-N-3-fluoro-4-(4-morpholinyl)phe cially viable, cost effective and environmentally friendly pro nyl-carbamate intermediate, which is then reacted with an cess of preparing Linezolid with high yield and purity, to acetylating agent to produce an alkyl/aryl N-3-phthalimido resolve the problems associated with the processes described 2-(R)-acetyloxypropyl-N-3-fluoro-4-(4-morpholinyl)phe in the prior art, and that will be suitable for large-scale prepa nyl-carbamate, followed by deprotection with a suitable ration. Desirable process properties include non-hazardous reagent in the presence of a base to produce lineZolid. conditions, environmentally friendly and easy to handle 0030. In one aspect, provided herein are efficient, indus reagents, reduced cost, greater simplicity, increased purity, trially advantageous and environmentally friendly processes and increased yield of the product, thereby enabling the pro for the preparation of linezolid, in high yield and with high duction of Linezolid, in high purity and with high yield. purity, using novel intermediates. The processes disclosed herein avoid the tedious and cumbersome procedures of the SUMMARY OF THE INVENTION prior processes, thereby resolving the problems associated 0029. The present inventors have surprisingly and unex with the processes described in the prior art, which is more pectedly found that LineZolid can be prepared in high purity convenient to operate at lab scale and in commercial scale and with high yield, by reacting N-3-phthalimido-2-(R)- operations. hydroxypropyl-3-fluoro-4-(4-morpholinyl)aniline with an 0031. In another aspect, provided herein is a novel (R)- alkyl or aryl chloroformate, or a dicarbonate reagent, in the phthalimido-2-acetyloxypropyl-carbamate compound of for presence of a base to produce an alkyl/aryl N-3-phthalimido mula III: US 2016/01 02064 A1 Apr. 14, 2016 10

cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or III substituted or unsubstituted aralkyl; and Ac' represents an acetyl group. 0034. In another aspect, provided herein is a novel (R)- amino-2-hydroxypropyl-carbamate compound of formula VI:

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, s^n, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or OH substituted or unsubstituted aralkyl; and Ac' represents an 1sO acetyl group. 0032. In another aspect, provided herein is a novel (R)- or an enantiomeric form or a mixture of enantiomeric forms phthalimido-2-hydroxypropyl-carbamate compound of for thereof, wherein R is C straight or branched chain alkyl, mula IV: cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. 0035. In another aspect, provided herein is a novel (R)-2- hydroxypropyl-carbamate compound of formula VII:

IV VII

or an enantiomeric form or a mixture of enantiomeric forms or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted aralkyl; and Y is a leaving group substituted or unsubstituted aralkyl. Such as a halogen or a Sulfonyloxy group. 0033. In another aspect, provided herein is a novel (R)- 0036. In another aspect, provided herein is a novel (R)-2- amino-2-acetyloxypropyl-carbamate compound of formula acetyloxypropyl-carbamate compound of formula VIII: V:

VIII

OAc or an enantiomeric form or a mixture of enantiomeric forms RO thereof, wherein R is C straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted aralkyl;Y is a leaving group Such or an enantiomeric form or a mixture of enantiomeric forms as a halogen or a Sulfonyloxy group, and Ac’ represents an thereof, wherein R is C. Straight or branched chain alkyl, acetyl group. US 2016/01 02064 A1 Apr. 14, 2016

0037. In another aspect, provided herein is a novel (R)-2, 0040. In another aspect, provided herein is a novel (R)- 3-epoxypropyl-carbamate compound of formula IX: acetamido-2-acetyloxypropyl-carbamate compound of for mula XII:

XII IX

eY. Y.O RO revO or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, or an enantiomeric form or a mixture of enantiomeric forms cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or thereof, wherein R is C. Straight or branched chain alkyl, substituted or unsubstituted aralkyl; and Ac' represents an cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or acetyl group. substituted or unsubstituted aralkyl. 0041. In another aspect, the present invention also encom 0038. In another aspect, provided herein is a novel N-2 passes the use of the novel compounds of formula III, IV, V. (R)-2,3-epoxypropyl-3-fluoro-4-(4-morpholinyl)aniline of VI, VII, VIII, IX, X, XI and XII disclosed herein for preparing formula X: Linezolid. 0042. The processes for the preparation of Linezolid dis closed herein have the following advantages over the pro cesses described in the prior art: 0043 i) the processes involve the use of novel intermedi ate compounds; 0044) ii) the overall process involves a reduced number of process steps, shorter reactions times and less expensive reagents thereby making the process cost effective; 0045 iii) the overall yield of the Linezolid product is increased and the purity of the product is increased without additional purifications such as multiple isolations and re eY. Y.O crystallizations or column chromatographic purifications; 0046 iv) the processes avoid the use of highly inflam mable, dangerous and difficult to handle reagents like n-bu or an enantiomeric form or a mixture of enantiomeric forms tyl lithium; thereof, or a salt thereof. 0047 v) the processes avoid the use of highly inflammable 0039. In another aspect, provided herein is a novel (R)- and toxic solvents like hexane, dioxane and heptanes; acetamido-2-hydroxypropyl-carbamate compound of for 0048 vi) the processes avoid the use of additional and mula XI: excess amounts of solvents, multiple isolation steps, col umn chromatographic purifications; 0049 vii) the processes avoid the use of expensive reagents including noble metal catalysts, e.g., palladium on charcoal, chiral reagents like (E)-trans-1,2-diaminocyclo XI hexane and 5-(tetrahydro-pyran-2-yloxymethyl)-2-oxazo lidinone; 0050 viii) the process avoids the use of tedious and cum berSome procedures like prolonged reaction time periods, O extremely low temperatures (-78°C. to -16°C.), multiple process steps, column chromatographic purifications, mul tiple isolations, additional and excess amounts of solvents; F r’sH and RO lsO OH 0051 ix) the process involves easy work-up methods and simple isolation processes, and there is a reduction in chemical waste. or an enantiomeric form or a mixture of enantiomeric forms 0052. In a preferred embodiment, the radical R in the thereof, wherein R is C. Straight or branched chain alkyl, compounds of formulae III, IV, V, VI, VII, VIII, IX, XI and cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or XII is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, substituted or unsubstituted aralkyl. chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibro US 2016/01 02064 A1 Apr. 14, 2016 mophenyl or p-methoxybenzyl; and most specifically R is group Y is C1 or toluenesulfonyloxy; and a most specific methyl, ethyl, benzyl or tert-butyl. leaving group is Cl. 0053. In another preferred embodiment, the leaving group 0054 The processes for the preparation of Linezolid using Y in the compound of formula VII & VIII is a halogen, or an novel intermediates disclosed herein may be represented by a alkyl or aryl Sulfonyloxy group. Specifically, the leaving schematic diagram as depicted in scheme-9: group Y is selected from the group consisting of Cl, Br, I, methanesulfonyloxy, toluenesulfonyloxy and trifluo Schematic Representation: romethanesulfonyloxy group; more specifically the leaving 0055

Nu1 F 1N1-y O O H RO -NO 6H RO ullsO OR (or) (XV) (VII) (XIVa) (or) O

ON .. (XIVb) F N1-7 F 1Y 7 6 ls % (X) (IX) rein Phthalimide | Potassium Phthalimide

O O --- Nu1. (XIVa) OR (or) Ol O F N1\1\s 5. ls 5 H O RO C so-so O (XIII) (XIVb) (IV)

Hydrazine hydrate (or) Methylamine esting Agent Base US 2016/01 02064 A1 Apr. 14, 2016 13

r -continued r Nu O Nu O F -, F 11N

Q-Ni. RO -NO ÖAc O (II) (III) Acetylating Agent Flyyists (or)

Base r N O F 1s, H

Q-listO (I) Linezolid

DETAILED DESCRIPTION OF THE INVENTION 0.058 or an enantiomeric form or a mixture of enantio meric forms thereof, wherein R is C. Straight or (0056. According to one aspect, there is provided an branched chain alkyl, cycloalkyl, haloalkyl, substituted improved and cost effective process for the preparation of or unsubstituted aryl, or substituted or unsubstituted Linezolid of formula I: aralkyl: I 0059 with an acetylating agent optionally in the pres r ence of a base to produce an (R)-phthalimido-2-acety Nu loxypropyl-carbamate compound of formula III: O III

or an enantiomeric form or a mixture of enantiomeric forms thereof, which comprises: 0057 a) acetylating (R)-phthalimido-2-hydroxypropyl carbamate compound of formula IV: 0060 or an enantiomeric form or a mixture of enantio meric forms thereof, wherein R is as defined informula IV IV, and Ac' represents an acetyl group; and O 0061 b) reacting the (R)-phthalimido-2-acetyloxypropyl N carbamate compound of formula III with a suitable O reagent, optionally in the presence of a base, to produce the Linezolid of formula I. F 1N1 SN 0062. The structural formulae of novel intermediate com i pounds disclosed herein contain one chiral centre and thus ls OH exist as two optical isomers, i.e. enantiomers (R & S-iso RO O mers). The process disclosed herein encompasses the prepa ration of both enantiomers and mixtures thereof in all propor tions. US 2016/01 02064 A1 Apr. 14, 2016

0063. In one embodiment, the radical R in the compounds 0074 Base addition salts may be derived from an organic of formulae III and IV is methyl, ethyl, propyl, isopropyl. or an inorganic base. For example, the base addition salts are isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-ni derived from alkali or alkaline earth metals such as Sodium, trobenzyl, dibromophenyl or p-methoxybenzyl; and most calcium, potassium and magnesium, ammonium salt, organic specifically R is methyl, ethyl, benzyl or tert-butyl. amines such as ethylamine, tert-butylamine, diethylamine, diisopropylamine, and the like. Exemplary acetylating agents 0064. Unless otherwise specified, the term “alkyl', as used used in step-(a) include, but are not limited to, acetyl halide herein, denotes an aliphatic hydrocarbon group which may be Such as acetyl chloride, acetyl bromide, acetyl iodide; acetic straight or branched having 1 to 12 carbonatoms in the chain. anhydride, Sodium acetate, and the like, or a combination Preferred alkyl groups have 1 to 6 carbon atoms in the chain. thereof. A most specific acetylating agent is acetic anhydride. The alkyl may be substituted with one or more “cycloalkyl 0075. The reaction in step-(a) can be carried out in the groups”. Exemplary alkyl groups include methyl, ethyl, presence or absence of a reaction inert Solvent. In one n-propyl, iso-propyl. n-butyl, iso-butyl, t-butyl, and n-pentyl. embodiment, the reaction in step-(a) is carried out in the 0065. The term “cycloalkyl, as used herein, denotes a absence of a solvent. In another embodiment, the reaction in non-aromatic mono- or multicyclic ring system of 3 to 10 step-(a) is optionally carried out in the presence of a first carbonatoms, preferably of about 5 to about 10 carbonatoms. solvent. The term solvent also includes mixture of solvents. Exemplary monocyclic cycloalkyl groups include cyclopen 0076 Exemplary first solvents used in step-(a) include, tyl, cyclohexyl, cycloheptyl and the like. but are not limited to, water, an alcohol, a hydrocarbon Sol 0066. The term “aralkyl, as used herein, denotes an aryl vent, an ester, a ketone, an ether, a nitrile, a polar aprotic alkyl group wherein the aryland alkyl are as herein described. Solvent, a halogenated hydrocarbon solvent, and mixtures Preferred aralkyls contain a lower alkyl moiety. Exemplary thereof. aralkyl groups include benzyl, 2-phenethyl and naphthalen 0077 Specifically, the first solvent used in step-(a) is emethyl. selected from the group consisting of water, methanol, etha 0067. The term “aryl', as used herein, denotes an aromatic nol, isopropanol, n-butanol, ethyl acetate, methyl acetate, monocyclic or multicyclic ring system of 6 to 10 carbon isopropyl acetate, tert-butyl methyl acetate, ethyl formate, atoms. The aryl is optionally substituted with one or more acetone, n-pentane, n-hexane, n-heptane, cyclohexane, tolu “ring system substituents’ which may be the same or differ ene, Xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran, ent, and are as defined herein. Exemplary aryl groups include dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl phenyl, tolyl or naphthyl. ether, monoglyme, diglyme, acetonitrile, propionitrile, N.N- dimethylformamide, N,N-dimethylacetamide, dimethylsul 0068. The compounds of formulae III & IV disclosed foxide, dichloromethane, dichloroethane, and mixtures herein are novel and constitute another aspect of the present thereof. Most specific first solvents are methanol, ethanol, invention. isopropanol, and mixtures thereof. 0069. The use of the novel intermediate compounds of 0078. In one embodiment, the acetylating agent in step-(a) formulae III & IV in the preparation of Linezolid of formula is used in a ratio of about 1 to 6 equivalents, specifically about I is novel and forms further aspect of the present invention. 3 to 5 equivalents, with respect to (R)-phthalimido-2-hydrox 0070 Advantageously, the novel intermediate compounds ypropyl-carbamate compound of formula IV in order to of Linezolid disclosed herein are obtained as solid state forms ensure a proper course of the reaction. in Substantially pure form. 0079. In another embodiment, the acetylation in step-(a)is 0071. The term “substantially pure' as used herein refers optionally carried out in the presence of a base. Specifically, to the solid state form of linezolid intermediates, disclosed the base is an organic base or inorganic base, and most spe herein, having a purity of greater than about 90 wt %, specifi cifically an inorganic base. cally greater than about 95 wt %, more specifically greater 0080 Exemplary bases include, but are not limited to, than about 98 wt %, and still more specifically greater than hydroxides, alkoxides, bicarbonates, phosphates and carbon about 99 wt %. The purity is preferably measured by High ates of alkali or alkaline earth metals; ammonia, collidine, Performance. Liquid Chromatography (HPLC). For trimethylamine, triethylamine, tributylamine, diisopropyl example, the purity of solid state form of linezolid interme ethylamine, N-methylmorpholine, 1-alkylimidazole and 1.8- diates obtained by the processes disclosed hereincan be about diazabicyclo5.4.0]undec-7-ene (DBU). Specific bases are 95% to about 99%, or about 98% to about 99.9%, as measured aqueous ammonia, potassium phosphate, sodium hydroxide, by HPLC. calcium hydroxide, magnesium hydroxide, potassium hydroxide, Sodium carbonate, potassium carbonate, sodium 0072 Unless otherwise specified, the term salt as used bicarbonate, potassium bicarbonate, sodium tert-butoxide, herein may include acid addition salts and base addition salts. Sodium isopropoxide, potassium tert-butoxide, or a combina 0.073 Acid addition salts, as used herein, include the salts tion thereof, and most specifically potassium carbonate, that are derived from organic and inorganic acids. For Sodium hydroxide and potassium hydroxide. example, the acid addition salts are derived from a therapeu tically acceptable acid such as hydrochloric acid, hydrobro I0081. The reaction temperature and time period will ordi mic acid, Sulfuric acid, nitric acid, oxalic acid, acetic acid, narily depend on the starting compounds and the solvent/ propionic acid, phosphoric acid, Succinic acid, maleic acid, reagent employed in the reaction. fumaric acid, citric acid, glutaric acid, tartaric acid, benzene I0082 In one embodiment, the acetylation reaction in step Sulfonic acid, toluenesulfonic acid, di-p-toluoyl-L-(+)-tar (a) is carried out at a temperature of about 0°C. to the reflux taric acid, malic acid, ascorbic acid, and the like. temperature of the Solvent used, specifically at a temperature US 2016/01 02064 A1 Apr. 14, 2016

of about 25°C. to the reflux temperature of the solvent used, and more specifically at about 30° C. to about 60° C. The IIIb. reaction time may vary between about 1 hour to about 10 hours, specifically about 2 hours to about 7 hours, and more specifically about 4 hours to about 6 hours. N 0083. The reaction mass containing the (R)-phthalimido O 2-acetyloxypropyl-carbamate compound of formula III obtained in step-(a) may be subjected to usual work up Such as F 1N1. a washing, an extraction, a pH adjustment, an evaporation, a HC layer separation, a decolorization, or a combination thereof. 3 1s 5Ac The reaction mass may be used directly in the next step to HC O O O produce the Linezolid of formula I, or the compound of HC formula III may be isolated and/or recrystallized and then used in the next step. After completion of the reaction, the or an enantiomeric form or a mixture of enantiomeric forms excess acetic anhydride may be removed by distillation. thereof. 0084. In one embodiment, the (R)-phthalimido-2-acety I0088. In another embodiment, a most specific (R)-phthal loxypropyl-carbamate compound of formula III is isolated imido-2-acetyloxypropyl-carbamate compound of formula and/or re-crystallized from a suitable solvent by conventional III prepared by the process described herein is N-3-phthal methods such as cooling, seeding, partial removal of the imido-2-(R)-acetyloxypropyl-N-3-fluoro-4-(4-morpholi Solvent from the Solution, by adding an anti-solvent to the nyl)phenyl-carbamic acid benzyl ester of formula IIIc (for Solution, evaporation, vacuum distillation, or a combination mula III, wherein R is benzyl): thereof. 0085. The solvent used for isolating and/or recrystallizing the (R)-phthalimido-2-acetyloxypropyl-carbamate com IIIc pound of formula III is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon Solvent, a halogenated hydrocarbon, and mixtures thereof. ON Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diiso F N propyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, Xylene, dichlo p1No 1sO iAc O romethane, dichloroethane, chloroform, and mixtures thereof. I0086. In one embodiment, a most specific (R)-phthal or an enantiomeric form or a mixture of enantiomeric forms imido-2-acetyloxypropyl-carbamate compound of formula thereof. III prepared by the process described herein is N-3-phthal I0089. The reagent used in step-(b) is a primary amine imido-2-(R)-acetyloxypropyl-N-3-fluoro-4-(4-morpholi formation agent. Exemplary primary amine formation agents nyl)phenyl-carbamic acid ethyl ester of formula IIIa (for used in step-(b) include, but are not limited to, hydrazine mula III, wherein R is ethyl): hydrate, methylamine, and the like. A most specific reagent is hydrazine hydrate or aqueous methylamine. 0090. In another embodiment, the reaction in step-(b) is IIIa optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base, selected from the group as described here inabove. 0091 Specific bases are aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potas sium hydroxide, Sodium carbonate, potassium carbonate, Sodium bicarbonate, potassium bicarbonate, sodium tert-bu toxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium carbonate. 0092. In one embodiment, the reaction in step-(b) is car ried out in the presence of a second solvent. or an enantiomeric form or a mixture of enantiomeric forms 0093 Exemplary second solvents used in step-(b) include, thereof. but are not limited to, water, an alcohol, a hydrocarbon Sol 0087. In another embodiment, a most specific (R)-phthal vent, an ester, a ketone, an ether, a nitrile, a polar aprotic imido-2-acetyloxypropyl-carbamate compound of formula Solvent, a halogenated hydrocarbon solvent, and mixtures III prepared by the process described herein is N-3-phthal thereof. imido-2-(R)-acetyloxypropyl-N-3-fluoro-4-(4-morpholi 0094 Specifically, the second solvent used in step-(b) is nyl)phenyl-carbamic acid tert-butyl ester of formula IIIb selected from the group consisting of water, methanol, etha (formula III, wherein R is tert-butyl): nol, isopropanol, n-butanol, ethyl acetate, methyl acetate, US 2016/01 02064 A1 Apr. 14, 2016

isopropyl acetate, tert-butyl methyl acetate, ethyl formate, V and XI. For example, use of mild reaction conditions (e.g. acetone, n-pentane, n-hexane, n-heptane, cyclohexane, tolu low temperatures and mild base) may permit isolation of the ene, Xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran, compound of formula V. Application of heat to the compound dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl of formula V optionally in the presence of a base may permit ether, monoglyme, diglyme, acetonitrile, propionitrile, N.N- the isolation of the compound of formula XI. In one embodi dimethylformamide, N,N-dimethylacetamide, dimethylsul ment, the reaction time may vary between about 30 minutes to foxide, dichloromethane, dichloroethane, and mixtures about 10 hours and specifically about 1 hour to about 3 hours. thereof. Most specific second solvents are methanol, ethanol, The isolated novel intermediate compounds of formulae V isopropanol, acetone, and mixtures thereof. and XI may be further converted into linezolid of formula I 0095. In one embodiment, the reagent in step-(b) is used in using the methods described herein. a ratio of about 1 to 5 equivalents, specifically about 3 to 5 0100. The solvent used for washing, extracting, isolating equivalents, with respect to the (R)-phthalimido-2-acetylox and/or recrystallizing the pure Linezolid of formula I is ypropyl-carbamate compound of formula III in order to selected from the group as described herein above. Specifi ensure a proper course of the reaction. cally, the solvent is selected from the group consisting of 0096. In one embodiment, the reaction in step-(b) is car water, methanol, ethanol, n-propanol, isopropyl alcohol, ried out at a temperature of about 0°C. to the reflux tempera acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diiso ture of the solvent used, specifically at a temperature of about propyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, 20°C. to the reflux temperature of the solvent used, and most n-hexane, n-heptane, cyclohexane, toluene, Xylene, dichlo specifically at the reflux temperature of the solvent used. The romethane, dichloroethane, chloroform, and mixtures reaction time may vary between about 3 hours to about 10 thereof. Most specifically, the solvent is selected from the hours, and specifically about 4 hours to about 6 hours. group consisting of water, methanol, ethanol, n-propanol, 0097. The reaction mass containing the Linezolid of for isopropyl alcohol, acetone, ethyl acetate, dichloromethane, mula I obtained may be subjected to usual work up Such as a and mixtures thereof. In one embodiment, the isolation is washing, an extraction, an evaporation, a pH adjustment etc., carried out by cooling the reaction mass at a temperature of followed by isolation and/or recrystallization from a suitable below about 35° C., followed by the addition of water at a Solvent by conventional methods such as cooling, seeding, temperature of about 10° C. to about 35°C., and more spe partial removal of the solvent from the Solution, by adding an cifically at a temperature of about 20°C. to about 30°C. After anti-solvent to the solution, evaporation, vacuum distillation, completion of addition process, the resulting mass is option or a combination thereof. ally stirred at a temperature of about 10°C. to about 35°C. for 0098. It has been found that two novel intermediate com at least 10 minutes, and most specifically at a temperature of pounds, namely (R)-amino-2-acetyloxypropyl-carbamate about 20° C. to about 30° C. for about 15 minutes to about 2 compound of formula V and (R)-acetamido-2-hydroxypro hours. pyl-carbamate compound of formula XI, are formed when 0101. In another embodiment, the isolation is carried out reacting the (R)-phthalimido-2-acetyloxypropyl-carbamate by cooling the reaction mass while stirring at a temperature compound of formula III with the primary amine formation below about 30° C. and more specifically at about 20° C. to agent and these novel compounds may be isolated using the about 30° C. methods described herein. The novel compounds of formula 0102 The solid obtained is collected by filtration, filtra V and formula XI are characterized by having the following tion under vacuum, decantation, centrifugation, filtration structural formulae: employing a filtration media of a silica gel or celite, or a combination thereof. 0103) The novel (R)-phthalimido-2-hydroxypropyl-car V bamate compound of formula IV employed as intermediate in the process for manufacture of Linezolid disclosed herein r allows the product to be easily isolated and purified, thereby Nu producing a product with 70-80% overall yield. 0104. According to another aspect, there is provided a process for the preparation of Linezolid of formula I, or an F r^ NH2 enantiomeric form or a mixture of enantiomeric forms -N OAc thereof, comprising reacting the (R)-phthalimido-2-acety RO O loxypropyl-carbamate compound of formula III: XI

III

F r H RO -NO OH

0099 Particular variations of reaction conditions and parameters (e.g., temperature, time, reagent, base, solvent, etc.) may permit the isolation of the compounds of formulae US 2016/01 02064 A1 Apr. 14, 2016 17 or an enantiomeric form or a mixture of enantiomeric forms 0111. The process for the preparation of (R)-phthalimido thereof, wherein R is C. Straight or branched chain alkyl, 2-acetyloxypropyl-carbamate compound of formula III dis cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or closed herein is carried out by using the methods, reagents substituted or unsubstituted aralkyl; and Ac' represents an and parameters as described hereinabove. acetyl group: 0105 with a suitable reagent, optionally in the presence of 0112 According to another aspect, there is provided an a base, to produce the Linezolid of formula I. improved and cost effective process for the preparation of 0106. In one embodiment, the radical R in the compounds Linezolid of formula I, or an enantiomeric form or a mixture of formula III is methyl, ethyl, propyl, isopropyl, isobutyl, of enantiomeric forms thereof, which comprises: tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, 0113 a) reacting (R)-phthalimido-2-hydroxypropyl-car dibromophenyl or p-methoxybenzyl; and most specifically bamate compound of formula IV: R is methyl, ethyl, benzyl or tert-butyl. 0107 The process for the preparation of linezolid of for mula I disclosed herein is carried out by using the methods, IV reagents and Parameters as described hereinabove. 0108. According to another aspect, there is provided a process for the preparation of (R)-phthalimido-2-acetylox ypropyl-carbamate compound of formula III:

III

0114 or an enantiomeric form or a mixture of enantio meric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl, with a suitable reagent, optionally in the pres ence of a base, to produce (S)-N-3-fluoro-4-(4-mor or an enantiomeric form or a mixture of enantiomeric forms pholinyl)phenyl-2-oxo-5-oxazolidinyl-methyl amine thereof, wherein R is C straight or branched chain alkyl, of formula II: cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and Ac' represents an acetyl group: II 0109 comprising acetylating (R)-phthalimido-2-hydrox ypropyl-carbamate compound of formula IV:

0115 or an enantiomeric form or a mixture of enantio meric forms thereof, or a salt thereof, and 0116 b) acetylating the amine compound of formula II with a suitable acetylating agent to produce the Linezolid of formula I. or an enantiomeric form or a mixture of enantiomeric forms 0117. In one embodiment, the radical R in the compounds thereof, wherein R is as defined above; with an acetylating of formula IV is methyl, ethyl, propyl, isopropyl, isobutyl, agent optionally in the presence of a base to produce an tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, (R)-phthalimido-2-acetyloxypropyl-carbamate compound of dibromophenyl or p-methoxybenzyl; and most specifically formula III or an enantiomeric form or a mixture of enantio meric forms thereof. R is methyl, ethyl, benzyl or tert-butyl. 0110. In one embodiment, the radical R in the compounds 0118. The reagent used in step-(a) is a primary amine of formulae III & IV is methyl, ethyl, propyl, isopropyl. formation agent. Exemplary primary amine formation agents isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-ni used in step-(a) include, but are not limited to, hydrazine trobenzyl, dibromophenyl or p-methoxybenzyl; and most hydrate, methylamine, and the like. A most specific reagent is specifically R is methyl, ethyl, benzyl or tert-butyl. hydrazine hydrate or aqueous methylamine. US 2016/01 02064 A1 Apr. 14, 2016

0119. In another embodiment, the reaction in step-(a) is carried out in the presence of a base. Specifically, the base is VI an organic or inorganic base, and most specifically an inor ganic base, selected from the group as described hereinabove. 0120 Specific bases are aqueous ammonia, Sodium hydroxide, calcium hydroxide, magnesium hydroxide, potas sium hydroxide, sodium carbonate, potassium carbonate, Sodium bicarbonate, potassium bicarbonate, sodium tert-bu toxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium carbonate. RO 0121. In one embodiment, the reaction in step-(a) is car ried out in the presence of a solvent. Exemplary solvents used 0127 Particular variations of reaction conditions and in step-(a) include, but are not limited to, water, an alcohol, a parameters (e.g., temperature, time, reagent, base, solvent, hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a etc.) may permit the isolation of the compound of formula VI. polar aprotic solvent, a halogenated hydrocarbon solvent, and For example, use of mild reaction conditions (e.g. low tem mixtures thereof. peratures and mild base) may permit isolation of the com 0122) Specifically, the solvent used in step-(a) is selected pound of formula VI. The isolated novel intermediate com from the group consisting of water, methanol, ethanol, iso pound of formulae VI may be further converted into linezolid propanol, n-butanol, ethyl acetate, methyl acetate, isopropyl of formula I using the methods described herein. acetate, tert-butyl methyl acetate, ethyl formate, acetone, I0128. The solvent used for isolating and/or recrystallizing n-pentane, n-hexane, n-heptane, cyclohexane, toluene, the (S)-N-3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-ox Xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, azolidinyl-methyl amine of formula II is selected from the diethyl ether, diisopropyl ether, methyl tert-butyl ether, mono group as described above for Such purpose. Specifically, the glyme, diglyme, acetonitrile, propionitrile, N,N-dimethylfor Solvent is selected from the group consisting of water, metha mamide, N,N-dimethylacetamide, dimethylsulfoxide, nol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahy dichloromethane, dichloroethane, and mixtures thereof. Most drofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, specifically, the solvent is selected from the group consisting methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, of methanol, ethanol, isopropanol, acetone, and mixtures n-heptane, cyclohexane, toluene, Xylene, dichloromethane, thereof. dichloroethane, chloroform, and mixtures thereof. 0123. In one embodiment, the reagent in step-(a) is used in I0129. The acetylation reaction in step-(b) is carried out by a ratio of about 1 to 5 equivalents, specifically about 3 to 5 the methods known in the art. Exemplary acetylating agents equivalents, with respect to the (R)-phthalimido-2-hydrox used in step-(b) include, but are not limited to, acetyl halide ypropyl-carbamate compound of formula IV in order to Such as acetyl chloride, acetyl bromide, acetyl iodide; acetic ensure a proper course of the reaction. anhydride, Sodium acetate, and the like, or a combination 0.124. In one embodiment, the reaction in step-(a) is car thereof A most specific acetylating agent is acetic anhydride. ried out at a temperature of about 0°C. to the reflux tempera ture of the solvent used, specifically at a temperature of about 0.130. The reaction mass containing the linezolid of for 20°C. to the reflux temperature of the solvent used, and most mula I obtained in step-(b) may be subjected to usual work up, specifically at the reflux temperature of the solvent used. The followed by isolation and/or recrystallization from a suitable reaction time may vary between about 2 hours to about 8 solvent using the methods as described herein above. hours, and specifically about 3 hours to about 4 hours. The I0131. According to another aspect, there is provided an reaction mass containing the (S)-N-3-fluoro-4-(4-morpholi improved process for the preparation of (S)-N-3-fluoro-4- nyl)phenyl)-2-oxo-5-oxazolidinyl-methyl amine of formula (4-morpholinyl)phenyl-2-oxo-5-oxazolidinyl-methylamine II obtained in step-(a) may be subjected to usual work up of formula II: methods as described hereinabove. The reaction mass may be used directly in the next step to produce the Linezolid of formula I, or the compound of formula II may be isolated and/or recrystallized and then used in the next step. II 0.125. In one embodiment, the (S)-N-3-fluoro-4-(4-mor pholinyl)phenyl)-2-oxo-5-oxazolidinyl-methylamine of for mula II is isolated and/or re-crystallized from a suitable sol vent by the methods as described hereinabove. 0126. It has been found that a novel intermediate com pound, (R)-amino-2-hydroxypropyl-carbamate compound, of formula VI is formed when reacting the (R)-phthalimido 2-hydroxypropyl-carbamate compound of formula IV with the primary amine formation agent and it may be isolated using the methods described herein. The novel compound of formula VI is characterized by having the following structural or an enantiomeric form or a mixture of enantiomeric forms formula: thereof, or a salt thereof US 2016/01 02064 A1 Apr. 14, 2016 19

0132) comprising reacting (R)-phthalimido-2-hydrox N-3-phthalimido-2-(R)-hydroxypropyl-3-fluoro-4-(4- ypropyl-carbamate compound of formula IV: morpholinyl)aniline of formula XIII:

XIII

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof 0.137 with a suitable activating agent, optionally in the 0133 or an enantiomeric form or a mixture of enantio presence of a base, wherein the activating agent is a car meric forms thereof, wherein R is C straight or bonate compound of formula XIVa, or a chloroformate branched chain alkyl, cycloalkyl, haloalkyl, substituted or compound of formula XIVb: unsubstituted aryl, or substituted or unsubstituted aralkyl: with a Suitable reagent, optionally in the presence of a base, to produce the aminomethyl compound of formula II, oran XIVa. enantiomeric form or a mixture of enantiomeric forms O O thereof, or a salt thereof. I0134) In one embodiment, the radical R in the compounds ---. (or) of formulae IV is methyl, ethyl, propyl, isopropyl, isobutyl, XIVb tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl; and most specifically R is methyl, ethyl, benzyl or tert-butyl. RO l C 0135 The process for the preparation of (S)-N-3-fluoro 4-(4-morpholinyl)phenyl-2-oxo-5-oxazolidinyl-methyl wherein the radical R is as defined in Formula IV; to produce amine of formula II disclosed herein is carried out by using the (R)-phthalimido-2-hydroxypropyl-carbamate compound the methods, reagents and parameters as described herein of formula IV or an enantiomeric form or a mixture of enan above. tiomeric forms thereof. 0.138. In one embodiment, the radical R in the compounds 0136. According to another aspect, there is provided a of formulae IV. XIVa & XIVb is methyl, ethyl, propyl, iso process for the preparation of (R)-phthalimido-2-hydrox propyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, ben ypropyl-carbamate compound of formula IV: Zyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl; and most specifically R is methyl, ethyl, benzyl or tert-butyl. 0.139. Unless otherwise specified, the N-3-phthalimido 2-(R)-hydroxypropyl-3-fluoro-4-(4-morpholinyl)aniline of formula XIII as used herein as starting material is a known IV compound and can be obtained by the processes described in the prior art, for example, the processes described in the U.S. Pat. No. 7,429,661 B2 assigned to Symed Labs Limited (the present applicant). 0140. In one embodiment, the reaction between the com pounds of formula XIII and XIVa or XIVb is carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an organic base. 01.41 Exemplary bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals; ammonia, collidine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-me thylmorpholine, and 1-alkylimidazole. 0.142 Specific bases are trimethylamine, tributylamine, or an enantiomeric form or a mixture of enantiomeric forms triethylamine, diisopropylethylamine and N-methylmorpho thereof, wherein R is C. Straight or branched chain alkyl, line; and most specifically diisopropylethylamine. cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or 0143. In one embodiment, the reaction between the com Substituted or unsubstituted aralkyl, comprising reacting pounds of formula XIII and XIVa or XIVb is carried out in the US 2016/01 02064 A1 Apr. 14, 2016 20 presence of a solvent. Exemplary solvents used herein include, but are not limited to, water, an alcohol, a hydrocar IVb bon Solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon Solvent, and mix tures thereof. A most specific solvent is dichloromethane. 0144. In one embodiment, the activating agent of formula XIVa or XIVb is used in a ratio of about 1 to 3 equivalents, specifically about 1.1 to 1.5 equivalents, with respect to the N-3-phthalimido-2-(R)-hydroxypropyl-3-fluoro-4-(4- H3C S OH morpholinyl)aniline of formula XIII in order to ensure a H3C O O O proper course of the reaction. 0145. In one embodiment, the reaction between the com pounds of formula XIII and the activating agent is carried out at a temperature of about 0°C. to the reflux temperature of the or an enantiomeric form or a mixture of enantiomeric forms solvent used, specifically at a temperature of about 10° C. to thereof. the reflux temperature of the solvent used, and most specifi 0150. In another embodiment, a most specific (R)-phthal cally at a temperature of about 20° C. to about 40°C. The imido-2-hydroxypropyl-carbamate compound of formula IV prepared by the process described, herein is N-3-phthal reaction time may vary between about 30 minutes to about 8 imido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4-morpholi hours, specifically about 1 hour to about 5 hours, and more nyl)phenyl-carbamic acid benzyl ester of formula IVc (for specifically about 1 hour to about 2 hours. mula IV, wherein R is benzyl): 0146 The reaction mass containing the (R)-phthalimido 2-hydroxypropyl-carbamate compound of formula IV obtained may be subjected to usual work up, followed by isolation and/or recrystallization from a suitable solvent using the methods as described herein above. IVc 0147 The solvent used for isolating and/or recrystallizing the (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV is selected from the group as described herein ON above. 0148. In one embodiment, a most specific (R)-phthal F N imido-2-hydroxypropyl-carbamate compound of formula IV 5 prepared by the process described herein is N-3-phthal p1No O O imido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4-morpholi ls, in nyl)phenyl-carbamic acid ethyl ester of formula IVa (for mula IV, wherein R is ethyl): or an enantiomeric form or a mixture of enantiomeric forms thereof. 0151. According to another aspect, there is provided a process for the preparation of (R)-phthalimido-2-hydrox IV a ypropyl-carbamate compound of formula IV:

or an enantiomeric form or a mixture of enantiomeric forms thereof. RO 1. O OH O 0149. In another embodiment, a most specific (R)-phthal imido-2-hydroxypropyl-carbamate compound of formula IV prepared by the process described herein is N-3-phthal or an enantiomeric form or a mixture of enantiomeric forms imido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4-morpholi thereof, wherein R is C. Straight or branched chain alkyl, nyl)phenyl-carbamic acid tert-butyl ester of formula IVb cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or (formula IV, wherein R is tert-butyl): substituted or unsubstituted aralkyl; which comprises: US 2016/01 02064 A1 Apr. 14, 2016 21

0152 a) reacting a (R)-2-hydroxypropyl-aniline com -continued pound of formula XV or N-2(R)-2,3-epoxypropyl-3- IX fluoro-4-(4-morpholinyl)aniline of formula X:

s r Y.Y. lu O O

F 11y 0156 or an enantiomeric form or a mixture of enantio 6H meric forms thereof, wherein R and Y are as defined above; and 0157 b) reacting the (R)-2-hydroxypropyl-carbamate compound of formula VII or the (R)-2,3-epoxypropyl-car X bamate compound of formula IX obtained in step-(a) with potassium phthalimide, optionally in the presence of a r base, to produce the (R)-phthalimido-2-hydroxypropyl N carbamate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof. 0158. In one embodiment, the radical R in the compounds F N e of formulae IV, VII, IX, XIVa & XIVb is methyl, ethyl, Y H 1Y a.O 7 propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxy benzyl; and most specifically R is methyl, ethyl, benzyl or 0153 or an enantiomeric form or a mixture of enantio tert-butyl. meric forms thereof, or a salt thereof, wherein Y is a 0159. In another embodiment, the leaving group Y in the leaving group Such as a halogen or a Sulfonyloxy group; compounds of formulae VII and XV is a halogen, or an alkyl oraryl Sulfonyloxy group. Specifically, the leaving group Yis 0154 with a suitable activating agent, optionally in the selected from the group consisting of Cl, Br, I, methanesulfo presence of a base, wherein the activating agent is a nyloxy, toluenesulfonyloxy and trifluoromethanesulfonyloxy carbonate compound of formula XIVa, or a chlorofor group; more specifically the leaving group Y is C1 or toluene mate compound of formula XIVb: Sulfonyloxy; and a most specific leaving group is C1. (0160. The compounds of formulae IV, VII, IX & X dis closed herein are novel and constitute another aspect of the XIVa. present invention. O O 0.161 The use of the novel intermediate compounds of formulae IV, VII, IX & X in the preparation of Linezolid of ---. (or) formula I is novel and forms further aspect of the present XIVb invention. O 0162 Unless otherwise specified, the (R)-2-hydroxypro pyl-aniline compound of formula XV as used herein as start ing material is a known compound and can be obtained by the 1. processes described in the prior art, for example, the pro cesses described in the U.S. Pat. No. 7.307,163 B2 assigned to Symed Labs Limited (the present applicant). 0155 wherein the radical R is as defined in Formula 0163. In one embodiment, the reaction in step-(a) is car IV; to produce an (R)-2-hydroxypropyl-carbamate com ried out in the presence of a base. Specifically, the base is an pound of formula VII or an (R)-2,3-epoxypropyl-car organic or inorganic base, and most specifically an organic bamate compound of formula IX: base, selected from the group as described herein above. 0164. Exemplary bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali VII or alkaline earth metals; ammonia, collidine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-me thylmorpholine, and 1-alkylimidazole. 0.165 Specific bases are trimethylamine, tributylamine, triethylamine, diisopropylethylamine and N-methylmorpho line; and most specifically diisopropylethylamine. 0166 In one embodiment, the reaction in step-(a) is car ried out in the presence of a solvent. Exemplary solvents used herein include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a US 2016/01 02064 A1 Apr. 14, 2016 22 polar aprotic solvent, a halogenated hydrocarbon solvent, and specifically at the reflux temperature of the solvent used. The mixtures thereof. A most specific solvent is dichloromethane. reaction time may vary between about 1 hour to about 10 0167. In one embodiment, the activating agent of formula hours, and specifically about 4 hours to about 6 hours. XIVa or XIVb is used in a ratio of about 1 to 3 equivalents, 0177. The reaction mass containing the (R)-phthalimido specifically about 1.1 to 1.5 equivalents, with respect to the 2-hydroxypropyl-carbamate compound of formula IV (R)-2-hydroxypropyl-aniline compound of formula XV, or obtained may be subjected to usual work up, followed by N-2(R)-2,3-epoxypropyl-3-fluoro-4-(4-morpholinyl) isolation and/or recrystallization from a suitable solvent by aniline of formula X, in order to ensure a proper course of the the methods as described herein above. reaction. 0.168. In one embodiment, the reaction in step-(a) is car 0.178 The solvent used for washing, extracting, isolating ried out at a temperature of about 0°C. to the reflux tempera and/or recrystallizing the (R)-phthalimido-2-hydroxypropyl ture of the solvent used, specifically at a temperature of about carbamate compound of formula IV is selected from the 10°C. to the reflux temperature of the solvent used, and most group as described herein above. specifically at a temperature of about 20°C. to about 40°C. (0179 The solid obtained in step-(b) is collected by filtra The reaction time may vary between about 30 minutes to tion, filtration under vacuum, decantation, centrifugation, fil about 8 hours, specifically about 1 hour to about 5 hours, and tration employing a filtration media of a silica gel or celite, or more specifically about 1 hour to about 2 hours. a combination thereof. 0169. The reaction mass containing the (R)-2-hydrox ypropyl-carbamate compound of formula VII or an (R)-2,3- 0180. In one embodiment, a most specific (R)-2-hydrox epoxypropyl-carbamate compound of formula IX obtained in ypropyl-carbamate compound of formula VII prepared by the step-(a) may be subjected to usual work up Such as a washing, process described herein is N-3-Chloro-2-(R)-hydroxypro an extraction, a pH adjustment, an evaporation, a layer sepa pyl-N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ration, a decolorization, or a combination thereof. The reac ethyl ester of formula VIIa (formula VII, wherein R is ethyl tion mass may be used directly in the next step to produce the and Y is Cl): (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV, or the compound of formula VII or IX may be isolated and/or recrystallized and then used in the next step. 0170 In one embodiment, the (R)-2-hydroxypropyl-car bamate compound of formula VII oran (R)-2,3-epoxypropyl VIIa carbamate compound of formula IX is isolated and/or re crystallized from a suitable solvent by conventional methods Such as cooling, seeding, partial removal of the solvent from ON the solution, by adding an anti-solvent to the Solution, evapo ration, vacuum distillation, or a combination thereof. 0171 The solvent used for isolating and/or recrystallizing F N C the (R)-2-hydroxypropyl-carbamate compound of formula VII oran (R)-2,3-epoxypropyl-carbamate compound of for 5 H mula IX is selected from the group as described herein above. ---, 0172. In another embodiment, the reaction in step-(b) is optionally carried out in the presence of a base. Specifically, or an enantiomeric form or a mixture of enantiomeric forms the base is an organic or inorganic base selected from the thereof. group as described hereinabove. 0181. In another embodiment, a most specific (R)-2,3- 0173. In one embodiment, the reaction in step-(b) is car epoxypropyl-carbamate compound of formula IX prepared ried out in the presence of a solvent. Exemplary solvents used by the process described herein is N-2(R)-2,3-epoxypropyl in step-(b) include, but are not limited to, water, an alcohol, a N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and ester of formula IXa (formula IX, wherein R is ethyl): mixtures thereof. 0.174 Specifically, the solvent used in step-(b) is selected from the group acetonitrile, propionitrile, N,N-dimethylfor mamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, and mixtures thereof. Most IXa specific solvents are acetonitrile, N,N-dimethylformamide, and mixtures thereof. 0.175. In one embodiment, the potassium phthalimide in step-(b) is used in a ratio of about 1 to 2 equivalents, specifi cally about 1.1 to 1.5 equivalents, with respect to the (R)-2- hydroxypropyl-carbamate compound of formula VII or the (R)-2,3-epoxypropyl-carbamate compound of formula IX in F 1Y 7 order to ensure a proper course of the reaction. He1 No lsO %3 0176). In one embodiment, the reaction in step-(b) is car ried out at a temperature of about 0°C. to the reflux tempera ture of the solvent used, specifically at a temperature of about or an enantiomeric form or a mixture of enantiomeric forms 20°C. to the reflux temperature of the solvent used, and most thereof. US 2016/01 02064 A1 Apr. 14, 2016 23

0182. According to another aspect, there is provided a from the group consisting of Cl, Br, I, methanesulfonyloxy, process for the preparation of (R)-phthalimido-2-hydrox toluenesulfonyloxy and trifluoromethanesulfonyloxy group; ypropyl-carbamate compound of formula IV: more specifically the leaving group Y is C1 or toluenesulfo nyloxy; and a most specific leaving group is Cl. 0185. The process for the preparation of (R)-phthalimido IV 2-hydroxypropyl-carbamate compound of formula IV dis closed herein is carried out by using the methods, reagents and parameters as described hereinabove. 0186. According to another aspect, there is provided a process for the preparation of (R)-2-hydroxypropyl-carbam ate compound of formula VII or the (R)-2,3-epoxypropyl carbamate compound of formula IX: r VII or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, Nu cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted aralkyl, comprising reacting the F 1N1 Sy (R)-2-hydroxypropyl-carbamate compound of formula VII or the (R)-2,3-epoxypropyl-carbamate compound of formula RO lsO 6H IX: IX r VII Nu 1Y 7 O F N1\1\y (or 1sO

RO 1.O 6H or an enantiomeric form or a mixture of enantiomeric forms IX thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or Substituted or unsubstituted aralkyl, and Y is a leaving group r Such as a halogenora Sulfonyloxy group; comprising reacting Nu a (R)-2-hydroxypropyl-aniline compound of formula XV or N-2(R)-2,3-epoxypropyl-3-fluoro-4-(4-morpholinyl) F 1Y 7 aniline of formula X: O O 1s XV or an enantiomeric form or a mixture of enantiomeric forms r thereof, wherein R is as defined in Formula IV, and Y is a N leaving group such as a halogen or a Sulfonyloxy group; with potassium phthalimide, optionally in the presence of a base, to produce the (R)-phthalimido-2-hydroxypropyl-carbamate F 1N1y compound of formula IV or an enantiomeric form or a mix 6H ture of enantiomeric forms thereof. X 0183 Inone embodiment, the radical R in the compounds of formulae IV, VII & IX is methyl, ethyl, propyl, isopropyl. isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-ni trobenzyl, dibromophenyl or p-methoxybenzyl; and most specifically R is methyl, ethyl, benzyl or tert-butyl. 0184. In one embodiment, the leaving group Yin the com pound of formula VII is a halogen, or an alkyl or aryl Sulfo nyloxy group. Specifically, the leaving group Y is selected US 2016/01 02064 A1 Apr. 14, 2016 24 or an enantiomeric form or a mixture of enantiomeric forms 0.192 a) reacting a (R)-2-hydroxypropyl-aniline com thereof, or a salt thereof, wherein Y is a leaving group such as pound of formula XV or N-2(R)-2,3-epoxypropyl-3- a halogen or a Sulfonyloxy group; fluoro-4-(4-morpholinyl)aniline of formula X: 0187 with a suitable activating agent, optionally in the presence of a base, wherein the activating agent is a car XV bonate compound of formula XIVa, or a chloroformate compound of formula XIVb: rNu XIVa. O O F 11y ---. (or) 6H XIVb X 1.O O

wherein the radical R is as defined above; to produce the e (R)-2-hydroxypropyl-carbamate compound of formula VII F N1)-7a.Y or the (R)-2,3-epoxypropyl-carbamate compound of formula O IX or an enantiomeric form or a mixture of enantiomeric forms thereof. 0193 or an enantiomeric form or a mixture of enantio meric forms thereof, or a salt thereof, wherein Y is a 0188 In one embodiment, the radical R in the compounds leaving group Such as a halogen or a Sulfonyloxy group; of formulae VII, IX, XIVa & XIVb is methyl, ethyl, propyl. 0194 with potassium phthalimide, optionally in the isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, presence of a base, to produce N-3-phthalimido-2-(R)- benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl, hydroxypropyl-3-fluoro-4-(4-morpholinyl)aniline of and most specifically R is methyl, ethyl, benzyl or tert-butyl. formula XIII: 0189 In one embodiment, the leaving group Yin the com pound of formula VII & XV is a halogen, or an alkyl or aryl Sulfonyloxy group. Specifically, the leaving group Y is XIII selected from the group consisting of Cl, Br, I, methanesulfo nyloxy, toluenesulfonyloxy and trifluoromethanesulfonyloxy group; more specifically the leaving group Y is Clortoluene Sulfonyloxy; and a most specific leaving group is C1. 0190. The process for the preparation of (R)-2-hydrox ypropyl-carbamate compound of formula VII or the (R)-2,3- epoxypropyl-carbamate compound of formula IX disclosed herein is carried out by using the methods, reagents and parameters as described hereinabove. 0191). According to another aspect, there is provided a process for the preparation of (R)-phthalimido-2-hydrox 0.195 or an enantiomeric form or a mixture of enantio meric forms thereof, or a salt thereof, and ypropyl-carbamate compound of formula IV: 0196) b) reacting the N-3-phthalimido-2-(R)-hydrox ypropyl-3-fluoro-4-(4-morpholinyl)aniline of formula XIII or an enantiomeric form or a mixture of enantiomeric IV forms thereof, or a salt thereof; with a suitable activating agent, optionally in the presence of a base, wherein the activating agent is a carbonate compound of formula XIVa, or a chloroformate compound of formula XIVb:

XIVa. O O ---. (or) XIVb O or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or 1. substituted or unsubstituted aralkyl; which comprises: US 2016/01 02064 A1 Apr. 14, 2016 25

0.197 wherein the radical R is as defined in Formula 0208. In one embodiment, the reaction in step-(b) is car IV: to produce the (R)-phthalimido-2-hydroxypropyl ried out in the presence of a base. Specifically, the base is an carbamate compound of formula IV or an enantiomeric organic or inorganic base, and most specifically an organic form or a mixture of enantiomeric forms thereof. base, selected from the group as described herein above. 0198 In one embodiment, the radical R in the compounds 0209 Specific bases are trimethylamine, tributylamine, of formulae IV. XIVa & XIVb is methyl, ethyl, propyl, iso triethylamine, diisopropylethylamine and N-methylmorpho propyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, ben line; and most specifically diisopropylethylamine. 0210. In one embodiment, the reaction in step-(b) is car Zyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl, and ried out in the presence of a solvent. Exemplary solvents used most specifically R is methyl, ethyl, benzyl or tert-butyl. herein include, but are not limited to, water, an alcohol, a 0199. In one embodiment, the leaving group Yin the com hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a pound of formula XV is a halogen, or an alkyl or aryl Sulfo polar aprotic solvent, a halogenated hydrocarbon solvent, and nyloxy group. Specifically, the leaving group Y is selected mixtures thereof. A most specific solvent is dichloromethane. from the group consisting of Cl, Br, I, methanesulfonyloxy, 0211. In one embodiment, the activating agent of formula toluenesulfonyloxy and trifluoromethanesulfonyloxy group; XIVa or XIVb is used in a ratio of about 1 to 3 equivalents, more specifically the leaving group Y is C1 or toluenesulfo specifically about 1.1 to 1.5 equivalents, with respect to the nyloxy; and a most specific leaving group is Cl. N-3-phthalimido-2-(R)-hydroxypropyl-3-fluoro-4-(4- 0200. In another embodiment, the reaction in step-(a) is morpholinyl)aniline of formula XIII in order to ensure a optionally carried out in the presence of a base. Specifically, proper course of the reaction. 0212. In one embodiment, the reaction in step-(b) is car the base is an organic or inorganic base selected from the ried out at a temperature of about 0°C. to the reflux tempera group as described hereinabove. ture of the solvent used, specifically at a temperature of about 0201 In one embodiment, the reaction in step-(a) is car 10°C. to the reflux temperature of the solvent used, and most ried out in the presence of a solvent. Exemplary solvents used specifically at a temperature of about 20°C. to about 40°C. in step-(a) include, but are not limited to, water, an alcohol, a The reaction time may vary between about 30 minutes to hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a about 8 hours, specifically about 1 hour to about 5 hours, and polar aprotic solvent, a halogenated hydrocarbon solvent, and more specifically about 1 hour to about 2 hours. mixtures thereof. 0213. The reaction mass containing the (R)-phthalimido 0202 Specifically, the solvent used in step-(a) is selected 2-hydroxypropyl-carbamate compound of formula IV from the group acetonitrile, propionitrile, N,N-dimethylfor obtained may be subjected to usual work up, followed by mamide, N,N-dimethylacetamide, dimethylsulfoxide, isolation and/or recrystallization from a suitable solvent by the methods as described herein above. dichloromethane, dichloroethane, and mixtures thereof. Most 0214. According to another aspect, there is provided a specific solvents are acetonitrile, N,N-dimethylformamide, process for the preparation of N-3-phthalimido-2-(R)-hy and mixtures thereof. droxypropyl-3-fluoro-4-(4-morpholinyl)aniline of formula 0203. In one embodiment, the potassium phthalimide in XIII: step-(a) is used in a ratio of about 1 to 2 equivalents, specifi cally about 1.1 to 1.5 equivalents, with respect to (R)-2- hydroxypropyl-aniline compound of formula XV or N-2(R)- XIII 2,3-epoxypropyl-3-fluoro-4-(4-morpholinyl)aniline of formula X in order to ensure a proper course of the reaction. 0204. In one embodiment, the reaction in step-(a) is car ried out at a temperature of about 0°C. to the reflux tempera ture of the solvent used, specifically at a temperature of about 20°C. to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used. The reaction time may vary between about 1 hour to about 10 hours, and specifically about 3 hours to about 6 hours. 0205 The reaction mass containing the N-3-phthal imido-2-(R)-hydroxypropyl-3-fluoro-4-(4-morpholinyl) aniline of formula XIII obtained in step-(a) may be subjected or an enantiomeric form or a mixture of enantiomeric forms to usual work up Such as a washing, an extraction, a pH thereof, or a salt thereof adjustment, an evaporation, a layer separation, a decoloriza 0215 comprising reacting N-2(R)-2,3-epoxypropyl-3- tion, or a combination thereof. The reaction mass may be used fluoro-4-(4-morpholinyl)aniline of formula X: directly in the next step to produce the (R)-phthalimido-2- hydroxypropyl-carbamate compound of formula IV, or the compound of formula XIII may be isolated and/or recrystal lized and then used in the next step. 0206. In one embodiment, the N-3-phthalimido-2-(R)- hydroxypropyl-3-fluoro-4-(4-morpholinyl)aniline of for mula XIII is isolated and/or re-crystallized from a suitable solvent by the methods described herein above. 0207. The solvent used for isolating and/or recrystallizing the N-3-phthalimido-2-(R)-hydroxypropyl-3-fluoro-4-(4- morpholinyl)aniline of formula XIII is selected from the group as described herein above. US 2016/01 02064 A1 Apr. 14, 2016 26 or an enantiomeric form or a mixture of enantiomeric forms sium hydroxide, potassium hydroxide, Sodium carbonate, thereof, or a salt thereof, with potassium phthalimide, option potassium carbonate, Sodium bicarbonate, potassium bicar ally in the presence of a base, to produce N-3-phthalimido bonate, sodium tert-butoxide, sodium isopropoxide, potas 2-(R)-hydroxypropyl-3-fluoro-4-(4-morpholinyl)aniline of sium tert-butoxide, or a combination thereof, and most spe formula XIII or an enantiomeric form or a mixture of enan cifically potassium carbonate, Sodium hydroxide and tiomeric forms thereof, or a salt thereof. potassium hydroxide. 0216. The process for the preparation of N-3-phthal 0223) In one embodiment, the reaction between the (R)- imido-2-(R)-hydroxypropyl-3-fluoro-4-(4-morpholinyl) 2-hydroxypropyl-aniline compound of formula XV and the aniline of formula XIII disclosed herein is carried out by base is carried out in the presence of a solvent. using the methods, reagents and parameters as described 0224 Exemplary solvents used herein include, but are not hereinabove. limited to, water, an alcohol, a hydrocarbon solvent, an ester, 0217. According to another aspect, there is provided a a ketone, an ether, a nitrile, a polar aprotic solvent, a haloge process for the preparation of N-2(R)-2,3-epoxypropyl-3- nated hydrocarbon solvent, and mixtures thereof. fluoro-4-(4-morpholinyl)aniline of formula X: 0225 Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, n-bu tanol, ethyl acetate, methyl acetate, isopropyl acetate, tert butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, Xylene, tetrahy drofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, dig lyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichlo romethane, dichloroethane, and mixtures thereof. Most spe cific solvents are water, dichloromethane, and mixture thereof. 0226. In one embodiment, the reaction between the (R)- or an enantiomeric form or a mixture of enantiomeric forms 2-hydroxypropyl-aniline compound of formula XV and the thereof, or a salt thereof; base is carried out at a temperature of about 0°C. to the reflux 0218 comprising reacting (R)-2-hydroxypropyl-aniline temperature of the solvent used, specifically at a temperature compound of formula XV: of about 10°C. to the reflux temperature of the solvent used, and most specifically at a temperature of about 20°C. to about 40°C. The reaction time may vary between about 1 to about 16 hours, specifically about 6 hour to about 15 hours, and more specifically about 12 hours to about 14 hours. 0227. The reaction mass containing the of N-2(R)-2,3- epoxypropyl-3-fluoro-4-(4-morpholinyl)aniline of formula X obtained may be subjected to usual work up, followed by isolation and/or recrystallization from a suitable solvent using the methods as described herein above. 0228. The solids obtained in any of the above process steps described hereinabove may be collected by filtration, filtra tion under vacuum, decantation, centrifugation, filtration or an enantiomeric form or a mixture of enantiomeric forms employing a filtration media of a silica gel or celite, or a thereof, or a salt thereof, wherein Y is a leaving group such as combination thereof. a halogen or a sulfonyloxy group; with a base to produce the 0229 Aptly the processes of the invention are adapted to N-2(R)-2,3-epoxypropyl-3-fluoro-4-(4-morpholinyl) the preparation of oxazolidinone derivatives, preferably Lin aniline of formula X or an enantiomeric form or a mixture of eZolid, in high enantiomeric and chemical purity. enantiomeric forms thereof, or a salt thereof. 0230. The novel intermediate compounds of formulae III, 0219. In one embodiment, the leaving group Yin the com IV, V, VI, VII, VIII, IX, X, XI and XII employed for the pound of formula XV is a halogen, or an alkyl or aryl Sulfo preparation of linezolid disclosed herein allows the product to nyloxy group. Specifically, the leaving group Y is selected be easily isolated and purified, thereby producing a product from the group consisting of Cl, Br, I, methanesulfonyloxy, with 60-80% overall yield. toluenesulfonyloxy and trifluoromethanesulfonyloxy group; 0231. The highly pure linezolid obtained by the above more specifically the leaving group Y is C1 or toluenesulfo processes may be further dried in, for example, a Vacuum nyloxy; and a most specific leaving group is Cl. Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle 0220. In one embodiment, the base is an organic or inor Dryer or a pilot plant Rota vapor, to further lower residual ganic base, and most specifically an inorganic base. Solvents. Drying can be carried out under reduced pressure 0221 Exemplary bases include, but are not limited to, until the residual solvent content reduces to the desired hydroxides, alkoxides, bicarbonates and carbonates of alkali amount Such as an amount that is within the limits given by or alkaline earth metals; ammonia, collidine, trimethylamine, the International Conference on Harmonization of Technical tributylamine, triethylamine, diisopropylethylamine, N-me Requirements for Registration of Pharmaceuticals for Human thylmorpholine, and 1-alkylimidazole. Use (“ICH) guidelines. 0222 Specific bases are aqueous ammonia, potassium 0232. In one embodiment, the drying is carried out at phosphate, sodium hydroxide, calcium hydroxide, magne atmospheric pressure or reduced pressures, such as below US 2016/01 02064 A1 Apr. 14, 2016 27 about 200 mm Hg, or below about 50 mm Hg, attemperatures pyl-N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid such as about 35°C. to about 90° C., and specifically at about tert-butyl ester of formula IIIb (formula III, wherein R is 75°C. to about 85°C. The drying can be carried out for any tert-butyl): desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product IIIb. specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like. 0233. In another embodiment, the highly pure linezolid obtained by the processes disclosed herein has a total purity, includes both chemical and enantiomeric purity, of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. 0234. According to another aspect, there is provided a or an enantiomeric form or a mixture of enantiomeric forms novel (R)-phthalimido-2-acetyloxypropyl-carbamate com thereof. pound of formula III: 0237. In another embodiment, a most specific (R)-phthal imido-2-acetyloxypropyl-carbamate compound of formula III disclosed herein is N-3-phthalimido-2-(R)-acetyloxypro III pylN-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid benzyl ester of formula IIIc (formula III, wherein R is ben Zyl):

IIIc

RO 1sO ÖAc O or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, Ac cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or p1No O O substituted or unsubstituted aralkyl; and Ac' represents an acetyl group. 0235. In one embodiment, a most specific (R)-phthal or an enantiomeric form or a mixture of enantiomeric forms imido-2-acetyloxypropyl-carbamate compound of formula thereof. III disclosed herein is N-3-phthalimido-2-(R)-acetyloxypro 0238 According to another aspect, there is provided a pyl-N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid novel (R)-phthalimido-2-hydroxypropyl-carbamate com ethyl ester of formula IIIc (formula III, wherein R is ethyl): pound of formula IV:

IIIa IV

F N N ...s. 5 O

or an enantiomeric form or a mixture of enantiomeric forms or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C straight or branched chain alkyl, thereof. cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or 0236. In another embodiment, a most specific (R)-phthal substituted or unsubstituted aralkyl. imido-2-acetyloxypropyl-carbamate compound of formula 0239. In one embodiment, a most specific (R)-phthal III disclosed herein is N-3-phthalimido-2-(R)-acetyloxypro imido-2-hydroxypropyl-carbamate compound of formula IV US 2016/01 02064 A1 Apr. 14, 2016 28 disclosed herein is N-3-phthalimido-2-(R)-hydroxypropyl 0242. According to another aspect, there is provided a N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl novel (R)-amino-2-acetyloxypropyl-carbamate compound of ester of formula IVa (formula IV, wherein R is ethyl): formula V:

IV a

OAc RO

or an enantiomeric form or a mixture of enantiomeric forms or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C straight or branched chain alkyl, thereof. cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or 0240. In another embodiment, a most specific (R)-phthal substituted or unsubstituted aralkyl; and Ac' represents an imido-2-hydroxypropyl-carbamate compound of formula IV acetyl group. disclosed herein is N-3-phthalimido-2-(R)-hydroxypropyl 0243 According to another aspect, there is provided a N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid tert novel (R)-amino-2-hydroxypropyl-carbamate compound of butyl ester of formula IVb (formula IV, wherein R is tert butyl): formula VI:

VI IVb

ON F 1-1Ns. HC 3 -N i H RO HC O O O HC or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, or an enantiomeric form or a mixture of enantiomeric forms cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or thereof. substituted or unsubstituted aralkyl, 0241. In another embodiment, a most specific (R)-phthal 0244. According to another aspect, there is provided a imido-2-hydroxypropyl-carbamate compound of formula IV novel (R)-2-hydroxypropyl-carbamate compound of formula disclosed herein is N-3-phthalimido-2-(R)-hydroxypropyl VII: N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid benzyl ester of formula IVc (formula IV, wherein R is benzyl): VII

IVc O 1. OH F N 1a1n RO O ls i H p1No O O or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or or an enantiomeric form or a mixture of enantiomeric forms Substituted or unsubstituted aralkyl; and Y is a leaving group thereof. Such as a halogen or a Sulfonyloxy group. US 2016/01 02064 A1 Apr. 14, 2016 29

0245 According to another aspect, there is provided a 0248. According to another aspect, there is provided a novel (R)-2-acetyloxypropyl-carbamate compound of for novel (R)-acetamido-2-hydroxypropyl-carbamate com mula VIII: pound of formula XI:

VIII N O O

F r H 11-y RO ls,O

Ac ...s. or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or or an enantiomeric form or a mixture of enantiomeric forms substituted or unsubstituted aralkyl. thereof, wherein R is C straight or branched chain alkyl, 0249 According to another aspect, there is provided a cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or novel (R)-acetamido-2-acetyloxypropyl-carbamate com Substituted or unsubstituted aralkyl;Y is a leaving group Such as a halogen or a Sulfonyloxy group, and Ac’ represents an pound of formula XII: acetyl group. 0246 According to another aspect, there is provided a XII novel (R)-2,3-epoxypropyl-carbamate compound of formula IX: N O O

H IX F rris, RO -NO OAc

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or e Y.Y substituted or unsubstituted aralkyl; and Ac' represents an O acetyl group. RO OYO (0250. In a preferred embodiment, the radical R in the compounds of formulae III, IV, V, VI, VII, VIII, IX, XI and or an enantiomeric form or a mixture of enantiomeric forms XII is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, thereof, wherein R is C. Straight or branched chain alkyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibro cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or mophenyl or p-methoxybenzyl; and most specifically R is substituted or unsubstituted aralkyl. methyl, ethyl, benzyl or tert-butyl. 0251. In another embodiment, the leaving group Y in the 0247 According to another aspect, there is provided a compound of formulae VII & VIII is a halogen, or an alkyl or novel N-2(R)-2,3-epoxypropyl-3-fluoro-4-(4-morpholi aryl Sulfonyloxy group. Specifically, the leaving group Y is nyl)aniline of formula X: selected from the group consisting of Cl, Br, I, methanesulfo nyloxy, toluenesulfonyloxy and trifluoromethanesulfonyloxy group; more specifically the leaving group Y is C1 or toluene Sulfonyloxy; and a most specific leaving group is C1. 0252) According to another aspect, the present invention also encompasses the use of the novel compounds of formu lae III, IV, V,VI,VII, VIII, IX, X, XI and XII disclosed herein for preparing Linezolid. Instrumental Details: HPLC Method for Measuring Chemical Purity: or an enantiomeric form or a mixture of enantiomeric forms 0253) The chemical purity was measured by HPLC using thereof, or a salt thereof. Shimadzu LC-2010 CHT system with LC solutions software US 2016/01 02064 A1 Apr. 14, 2016 30 or its equivalent under the following conditions: reaction, the reaction mass was cooled to room temperature Column-Kromasil 100 C18, 250 mmx4.6 mm, 5 um or (25-30°C.), followed by the addition of water (200 ml) and Equivalent; Detector wavelength=254 nm; Flow Rate=0.5 then stirring the mass for 1 hour at the same temperature. The ml/minute; Injection volume=20 uL: Oven temperature=40° separated solid was filtered, washed with methanol (50 ml) C.; Run time=30 minutes; Diluent=Acetonitrile; and then dried at 70-75° C. to produce 26.7 g of pure Lin Elution=Isocratic; Mobile Phase=Water (400 ml):acetonitrile eZolid as a white crystalline solid (Yield: 86%; Purity by (600 ml):triethylamine (1.8 ml):acetic acid (1.3 ml). HPLC: 99.9%). 0254 The following examples are given for the purpose of illustrating the present invention and should not be consid Example 3 ered as limitation on the scope or spirit of the invention. Preparation of (S)-N-3-Fluoro-4-(4-morpholinyl) EXAMPLES phenyl-2-oxo-5-oxazolidinyl-methylamine Example 1 Step-1: N-3-Phthalimido-2-(R)-hydroxypropyl-N- 3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid Preparation of N-(5S)-3-3-fluoro-4-(4-morpholi ethyl ester nyl)phenyl-2-oxo-5-oxazolidinylmethylacetamide 0259 N-Ethyldiisopropyl amine (16 g., 0.124 mol) was (Linezolid) added to a suspension of N-3-phthalimido-2-(R)-hydrox Step-1: N-3-Phthalimido-2-(R)-acetyloxypropyl-N- ypropyl-3-fluoro-4-(4-morpholinyl)aniline (39.9 g, 0.1 mol) 3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid in methylene chloride (360 ml) at 25-30° C. Ethyl chlorofor mate (12 g, 0.11 mol) was slowly added to the resulting ethyl ester solution at 25-30° C. during the time period of about 30 0255 Acetic anhydride (51 g, 0.5 moles) was added to minutes, followed by stirring the mass at the same tempera N-3-phthalimido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4- ture for 1 to 2 hours. The reaction mass was washed subse morpholinyl)phenyl-carbamic acid ethyl ester and the con quently with 4N hydrochloric acid solution (100 ml), water tents were heated to 50–55°C., followed by maintaining the (100 ml) and saturated brine solution (100 ml) and then con reaction mixture at the same temperature for 4 to 6 hours. centrated the resulting mass to produce 45g of N-3-phthal After completion of the reaction, the resulting mass was dis imido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4-morpholi tilled, to remove the excess acetic anhydride, to produce 47.2 nyl)phenyl-carbamic acid ethyl ester as a residue (Yield: g of N-3-phthalimido-2-(R)-acetyloxypropyl-N-3-fluoro 95.5%; Purity by HPLC: 98.5%). 4-(4-morpholinyl)phenyl-carbamic acid ethyl ester, which is 0260 Mass (m/z): 472 (M+1). directly used in the next reaction step (Yield: 92%; Purity by HPLC: 98.2%). Step-2: (S)-N-3-Fluoro-4-(4-morpholinyl)phenyl 0256 Mass (m/z): 514 (M+1). 2-oxo-5-oxazolidinyl-methylamine Step-2: Preparation of Linezolid 0261 Potassium carbonate (13.8 g., 0.1 mol) and hydra zine hydrate (80%) (18.75 g, 0.3 mol) were added to a solu 0257 Potassium carbonate (12.7g, 0.092 mol) and hydra tion of N-3-phthalimido-2-(R)-hydroxypropyl-N-3- zine hydrate (13.8 g., 0.276 mol) were added to a solution of fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl ester N-3-phthalimido-2-(R)-acetyloxypropyl-N-3-fluoro-4- (47.1 g, 0.1 mol) in methanol (280 ml) and the mixture was (4-morpholinyl)phenyl-carbamic acid ethyl ester (47.2 g, heated to reflux, followed by maintaining the resulting mass 0.092 mol) in methanol (200 ml) and the mixture was heated at reflux for 2 to 4 hours. After completion of the reaction, the to reflux, followed by maintaining the resulting mass at reflux solvent was distilled off completely and the resulting crude temperature for 4 to 6 hours. After completion of the reaction, product was taken in ethylene chloride (200 ml) and the the solvent was distilled off completely, water (250 ml) was resulting organic layer was washed water (100 mlx3) and added to the resulting mass and then extracted with methyl then the solvent was distilled off to produce 24.5g of (S)-N- chloride (150 mlx3). The resulting organic layer was washed 3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl with water (100 mlx3) and then concentrated to obtain crude methylamine (Purity by HPLC: 99.1%). product. Ethyl acetate (100 ml) was added to the resulting crude product and then stirred for 1 hour at 25-30°C. The Example 4 separated solid was filtered and then dried at 70-75° C. to produce 25 g of pure Linezolid as a white crystalline solid Preparation of N-3-Phthalimido-2-(R)-hydroxypro (Yield: 81%; Purity by HPLC: 99.8%). pyl-N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl ester Example 2 Step-1: N-3-Chloro-2-(R)-hydroxypropyl-N-3- Preparation of Linezolid fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl ester 0258 Potassium carbonate (12.7 g., 0.092 mol) and 40% monomethylamine (28.5 g., 0.37 mol) were added to a solu 0262 N-Ethyldiisopropyl amine (16.1 g, 0.125 mol) was tion of N-3-phthalimido-2-(R)-acetyloxypropyl-N-3- added to a solution of N-3-chloro-2-(R)-hydroxypropyl-3- fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl ester fluoro-4-(4-morpholinyl)aniline (28.85g, 0.1 mol) in meth (47.2g, 0.092 mol) in methanol (200 ml) and the mixture was ylene chloride (285 ml) at 25-30° C. Ethyl chloroformate (11 heated to reflux, followed by maintaining the resulting mass g, 0.1 mol) was added to the resulting solution at 25-30°C., at reflux temperature for 4 to 6 hours. After completion of the followed by stirring the solution at the same temperature for US 2016/01 02064 A1 Apr. 14, 2016

4 hours. The reaction mass was washed Subsequently with morpholinyl)phenyl-carbamic acid ethyl ester (27.9 g, 0.086 10% hydrochloric acid solution (100 ml), water (100 ml) and mol) in dimethylformamide (80 ml) and the resulting suspen saturated brine solution (100 ml) and then concentrated the sion was heated to 90-95°C., followed by maintaining the resulting mass under reduced pressure to produce 35 g of resulting mass for 3 hours at the same temperature. The reac N-3-chloro-2-(R)-hydroxypropyl-N-3-fluoro-4-(4-mor tion mass was cooled to room temperature (25-30°C.), fol pholinyl)phenyl-carbamic acid ethyl ester as an oily residue lowed by the addition of water (400 ml) and then stirring the (Yield: 97.2%). mass for 1 hour. The separated solid was filtered and then 0263 Mass (m/z): 361 (M+1). washed with water (50 ml) to produce 28.2 g of N-3-phthal imido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4-morpholi Step-2: N-3-Phthalimido-2-(R)-hydroxypropyl-N- nyl)phenyl-carbamic acid ethyl ester as a cream-yellow col 3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ored solid (Purity by HPLC: 95.5%). ethyl ester 0269 All ranges disclosed herein are inclusive and com 0264. Potassium phthalimide (21.5 g., 0.116 mol) was binable. While the invention has been described with refer added to a solution of N-3-chloro-2-(R)-hydroxypropyl-N- ence to a preferred embodiment, it will be understood by 3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl those skilled in the art that various changes may be made and ester (35 g, 0.097 mol) in dimethylformamide (87.5 ml) and equivalents may be substituted for elements thereof without the resulting suspension was heated to 100-110° C. and then departing from the scope of the invention. In addition, many maintained for 3 hours at the same temperature. The reaction modifications may be made to adapt a particular situation or mass was cooled to room temperature (25-30°C.), followed material to the teachings of the invention without departing by the addition of water (400 ml) and then stirring the mass from essential scope thereof. Therefore, it is intended that the for 1 hour. The separated solid was filtered to produce 30 g of invention not be limited to the particular embodiment dis N-3-phthalimido-2-(R)-hydroxypropyl-N-3-fluoro-4-(4- closed as the best mode contemplated for carrying out this morpholinyl)phenyl-carbamic acid ethyl ester as an yellow invention, but that the invention will include all embodiments colored solid (Purity by HPLC: 95.8%). falling within the scope of the appended claims. 1-69. (canceled) Example 5 70. A process for the preparation of Linezolid of formula I: Preparation of N-3-Phthalimido-2-(R)-hydroxypro pyl-N-3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid ethyl ester Step-1: N-2(R)-2,3-epoxypropyl-3-fluoro-4-(4- N morpholinyl)aniline O O 0265 50% Sodium hydroxide solution (9 g) and water (30 ml) were added to a solution of N-3-chloro-2-(R)-hydrox F -, ypropyl-3-fluoro-4-(4-morpholinyl)aniline (28.85 g, 0.1 H mol) in methylene chloride (200 ml), followed by stirring the N- N CH3 solution for 13 to 14 hours at room temperature (25-30°C.). After completion of the reaction, water (100 ml) was added to the reaction mass, followed by separation of the layers. The Solvent was distilled off from the resulting organic layer to get 24.6 g of N-2(R)-2,3-epoxypropyl-3-fluoro-4-(4-morpholi or an enantiomeric form or a mixture of enantiomeric nyl)aniline as a residue (Yield: 97.6%). forms thereof, which comprises: Step-2: N-2(R)-2,3-epoxypropyl-N-3-fluoro-4-(4- a) acetylating (R)-phthalimido-2-hydroxypropyl-carbam morpholinyl)phenyl-carbamic acid ethyl ester ate compound of formula IV: 0266 N-Ethyldiisopropyl amine (15.6 g., 0.12 mol) was added to a solution of N-2(R)-2,3-epoxypropyl-3-fluoro-4- (4-morpholinyl)aniline (24.6 g., 0.097 mol) in methylene IV chloride (250 ml) at 25-30° C. Ethylchloroformate (11 g, 0.1 mol) was added to the resulting solution at 25-30°C., fol lowed by stirring the solution at the same temperature for 2 hours. The reaction mass was washed Subsequently with water (100 ml) and saturated brine solution (100 mlx2) and then evaporated the solvent to produce 27.9 g of N-2(R)-2, 3-epoxypropyl-N-3-fluoro-4-(4-morpholinyl)phenyl-car bamic acid ethyl ester (Yield: 88.8%). RO 1. O OH O 0267 Mass (m/z): 325 (M+1).

Step-3: N-3-Phthalimido-2-(R)-hydroxypropyl-N- or an enantiomeric form or a mixture of enantiomeric 3-fluoro-4-(4-morpholinyl)phenyl-carbamic acid forms thereof, wherein R is C. Straight or ethyl ester branched chain alkyl, cycloalkyl, haloalkyl, Substi 0268 Potassium phthalimide (18.5g, 0.1 mol) was added tuted or unsubstituted aryl, or substituted or unsubsti to a solution of N-2(R)-2,3-epoxypropyl-N-3-fluoro-4-(4- tuted aralkyl: US 2016/01 02064 A1 Apr. 14, 2016 32

with an acetylating agent, optionally in the presence of a 74. The process of claim 73, wherein the radical R in the base, to produce an (R)-phthalimido-2-acetyloxypro compounds of formula III is methyl, ethyl, propyl, isopropyl. pyl-carbamate compound of formula III: isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-ni trobenzyl, dibromophenyl or p-methoxybenzyl; and wherein the reagent is hydrazine hydrate or aqueous methyl amine. III 75. A process for the preparation of (R)-phthalimido-2- acetyloxypropyl-carbamate compound of formula III:

F N N 5 III RO 1.O Ac O

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is as defined in formula IV. and Ac' represents an acetyl group; and b) reacting the (R)-phthalimido-2-acetyloxypropyl-car bamate compound of formula III with a suitable reagent, optionally in the presence of a base, to produce the Linezolid of formula I. 71. The process of claim 70, wherein the radical R in the or an enantiomeric form or a mixture of enantiomeric compounds of formulae III and IV is methyl, ethyl, propyl. forms thereof, wherein R is C. Straight or branched isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl: stituted aryl, or substituted or unsubstituted aralkyl; and wherein the acetylating agent used in step-(a) is acetyl chlo Ac' represents an acetyl group; ride, acetyl bromide, acetyl iodide, acetic anhydride, sodium acetate, or a combination thereof, and wherein the reagent comprising acetylating (R)-phthalimido-2-hydroxypro used in step-(b) is a primary amine formation agent. pyl-carbamate compound of formula IV: 72. The process of claim 71, wherein the radical R is methyl, ethyl, benzyl or tert-butyl; wherein the acetylating agent used in step-(a) is acetic anhydride; and wherein the primary amine formation agent used in step-(b) is hydrazine hydrate or aqueous methylamine. IV 73. A process for the preparation of Linezolid of formula I, or an enantiomeric form or a mixture of enantiomeric forms thereof, comprising reacting the (R)-phthalimido-2-acety loxypropyl-carbamate compound of formula III:

III

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is as defined above; with an acetylating agent optionally in the presence of a base to produce an (R)-phthalimido-2-acetyloxypropyl-car F N N bamate compound of formula III or an enantiomeric form or a mixture of enantiomeric forms thereof. 5Ac 76. The process of claim 75, wherein the radical R in the ...s. O compounds of formulae III & IV is methyl, ethyl, propyl. isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, or an enantiomeric form or a mixture of enantiomeric benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl: forms thereof, wherein R is C. Straight or branched and wherein the acetylating agent is acetyl chloride, acetyl chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub bromide, acetyl iodide, acetic anhydride, sodium acetate, or a stituted aryl, or substituted or unsubstituted aralkyl; and combination thereof. Ac' represents an acetyl group; 77. A process for the preparation of Linezolid of formula I, with a reagent, optionally in the presence of a base, to or an enantiomeric form or a mixture of enantiomeric forms produce the Linezolid of formula I. thereof, which comprises: US 2016/01 02064 A1 Apr. 14, 2016 33

a) reacting (R)-phthalimido-2-hydroxypropyl-carbamate oran enantiomeric form or a mixture ofenantiomeric faints compound of formula IV: thereof, or a salt thereof comprising reacting (R)-phthalimido-2-hydroxypropyl

IV carbamate compound of formula IV: IV

F N N 5 H ...s. O

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or or an enantiomeric form or a mixture of enantiomeric branched chain alkyl, cycloalkyl, haloalkyl, Substi forms thereof, wherein R is C straight or branched tuted or unsubstituted aryl, or substituted or unsubsti chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub tuted aralkyl, with a reagent, optionally in the pres stituted aryl, or substituted or unsubstituted aralkyl; with ence of a base, to produce (S)-N-3-fluoro-4-(4- a reagent, optionally in the presence of a base, to produce morpholinyl)phenyl)-2-oxo-5-oxazolidinyl-methyl the aminomethyl compound of formula II, or an enan amine of formula II: tiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof. 80. The process of claim 79, wherein the radical R in the II compounds of formula IV is methyl, ethyl, propyl, isopropyl. isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-ni trobenzyl, dibromophenyl or p-methoxybenzyl; and wherein the reagent is hydrazine hydrate or aqueous methyl amine. 81. A process for the preparation of (R)-phthalimido-2- hydroxypropyl-carbamate compound of formula IV: IV

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof and b) acetylating the amine compound of formula II with an acetylating agent to produce the Linezolid of formula I. 78. The process of claim 77, wherein the radical R in the compounds of formula IV is methyl, ethyl, propyl, isopropyl. isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-ni trobenzyl, dibromophenyl or p-methoxybenzyl; wherein the reagent used in step-(a) is hydrazine hydrate or aqueous or an enantiomeric form or a mixture of enantiomeric methyl amine; and wherein the acetylating agent used in forms thereof, wherein R is C. Straight or branched step-(b) is acetylchloride, acetyl bromide, acetyl iodide, ace chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub tic anhydride, sodium acetate, or a combination thereof. stituted aryl, or substituted or unsubstituted aralkyl: 79. A process for the preparation of (S)-N-3-fluoro-4-(4- comprising reacting N-3-phthalimido-2-(R)-hydrox morpholinyl)phenyl-2-oxo-5-oxazolidinyl-methylamine of ypropyl-3-fluoro-4-(4-morpholinyl)aniline of formula formula II: XIII: XIII

II US 2016/01 02064 A1 Apr. 14, 2016 34

or an enantiomeric form or a mixture of enantiomeric -continued forms thereof, or a salt thereof, with an activating agent, X optionally in the presence of a base, wherein the activat ing agent is a carbonate compound of formula XIVa, or r a chloroformate compound of formula XiVb: N XIVa. O O F N1yH 2. 7 ---. (or) O XIVb O or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, whereinY is a leaving group selected from a halogen ora Sulfonyloxy group; 1. with an activating agent, optionally in the presence of a base, wherein the activating agent is a carbonate com pound of formula XIVa, or a chloroformate com wherein the radical R is as defined in Formula IV; to produce the (R)-phthalimido-2-hydroxypropyl-carbam pound of formula XIVb: ate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof. XIVa. O O 82. The process of claim 81, wherein the radical R in the compounds of formulae IV. XIVa & XIVb is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, ---. (or) XIVb tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxy O benzyl; wherein the reaction between the compounds of for mula XIII and the activating agent is carried out in the pres ence of a base, wherein the base is an organic or inorganic -- base; and wherein the reaction is carried out in the presence of a solvent. wherein the radical R is as defined in Formula IV; to 83. A process for the preparation of (R)-phthalimido-2- produce an (R)-2-hydroxypropyl-carbamate com pound of formula VII oran (R)-2,3-epoxypropyl-car hydroxypropyl-carbamate compound of formula IV: bamate compound of formula IX: IV

VII Nr

F N 11-y (or)

RO -NO 6H or an enantiomeric form or a mixture of enantiomeric IX forms thereof, wherein R is C straight or branched chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub stituted aryl, or substituted or unsubstituted aralkyl: which comprises: a) reacting a (R)-2-hydroxypropyl-aniline compound of ea. formula XV or N-2(R)-2,3-epoxypropyl-3-fluoro-4- Y.O (4-morpholinyl)aniline of formula X: F RO OYO XV or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R and Y areas defined above: and b) reacting the (R)-2-hydroxypropyl-carbamate compound of formula VII or the (R)-2,3-epoxypropyl-carbamate compound of formula IX obtained in step-(a) with potas sium phthalimide, optionally in the presence of a base, to produce the (R)-phthalimido-2-hydroxypropyl-carbam US 2016/01 02064 A1 Apr. 14, 2016

ate compound of formula IV or an enantiomeric form or consisting of Cl, Br, I, methanesulfonyloxy, toluenesulfony a mixture of enantiomeric forms thereof. loxy and trifluoromethanesulfonyloxy group. 84. The process of claim 83, wherein the radical R in the 87. A process for the preparation of (R)-phthalimido-2- compounds of formulae IV, VII, IX, XIVa & XIVb is methyl, hydroxypropyl-carbamate compound of formula IV: ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, IV phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl; and wherein the leaving group Y in the compounds of formulas VII and XV is a halogen, or an alkyl or aryl Sulfonyloxy group. 85. A process for the preparation of (R)-phthalimido-2- hydroxypropyl-carbamate compound of formula IV: IV

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C straight or branched chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub stituted aryl, or substituted or unsubstituted aralkyl: which comprises: a) reacting a (R)-2-hydroxypropyl-aniline compound of formula XV or N-2(R)-2,3-epoxypropyl-3-fluoro-4- or an enantiomeric form or a mixture of enantiomeric (4-morpholinyl)aniline of formula X: forms thereof, wherein R is C. Straight or branched XV chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub stituted aryl, or substituted or unsubstituted aralkyl: comprising reacting the (R)-2-hydroxypropyl-carbam r ate compound of formula VII or the (R)-2,3-epoxypro N pyl-carbamate compound of formula IX: VII F 1-ny (or) 6H Nr X

F N Y (or) O

RO -NO 6H e F N1) aY 7 IX O

r or an enantiomeric form or a mixture of enantiomeric Nu forms thereof, or a salt thereof, whereinY is a leaving group selected from a halogen ora Sulfonyloxy group; with potassium phthalimide, optionally in the pres F 1Y 7 ence of a base, to produce N-3-phthalimido-2-(R)- 1. ?) hydroxypropyl-3-fluoro-4-(4-morpholinyl)aniline RO O of formula XIII:

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is as defined in formula IV. XIII and Y is a leaving group selected from a halogen or a Sulfonyloxy group; with potassium phthalimide, option ally in the presence of a base, to produce the (R)-phthal imido-2-hydroxypropyl-carbamate compound of for mula IV or an enantiomeric form or a mixture of enantiomeric forms thereof. 86. The process of claim 85, wherein the radical R in the compounds of formulae IV, VII & IX is methyl, ethyl, propyl. isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl: and wherein the leaving group Y is selected from the group US 2016/01 02064 A1 Apr. 14, 2016 36

or an enantiomeric form or a mixture of enantiomeric 91. A (R)-phthalimido-2-hydroxypropyl-carbamate com forms thereof, or a salt thereof, and pound of formula IV: b) reacting the N-3-phthalimido-2-(R)-hydroxypropyl 3-fluoro-4-(4-morpholinyl)aniline of formula XIII or an IV enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with an activating agent, optionally in the presence of a base, wherein the activat ing agent is a carbonate compound of formula XIVa, or a chloroformate compound of formula XIVb:

XIVa. O O ...s.

---. (or) or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub XIVb stituted aryl, or substituted or unsubstituted aralkyl. O 92. The compound of claim 91, wherein the radical R is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chlo romethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophe ... nyl or p-methoxybenzyl. 93. A (R)-amino-2-acetyloxypropyl-carbamate compound of formula V: wherein the radical R is as defined in Formula IV; to produce the (R)-phthalimido-2-hydroxypropyl-car bamate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof. 88. The process of claim 87, wherein the radical R in the compounds of formulas IV. XIVa & XIVb is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxy benzyl; and wherein the leaving group Y in the compound of s^n, formula XV is selected from the group consisting of Cl, Br, I, OAc methanesulfonyloxy, toluenesulfonyloxy and trifluo 1sO romethanesulfonyloxy group. 89. A (R)-phthalimido-2-acetyloxypropyl-carbamate or an enantiomeric form or a mixture of enantiomeric compound of formula III: forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub stituted aryl, or substituted or unsubstituted aralkyl; and III Ac' represents an acetyl group. 94. The compound of claim 93, wherein the radical R is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chlo romethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophe nyl or p-methoxybenzyl. 95. A (R)-amino-2-hydroxypropyl-carbamate compound F of formula VI:

or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chair alkyl, cycloalkyl, haloalkyl, Substituted or unsub stituted aryl, or substituted or unsubstituted aralkyl; and s^n, Ac' represents an acetyl group. OH 90. The compound of claim 89, wherein the radical R is 1sO methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chlo romethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophe or an enantiomeric form or a mixture of enantiomeric nyl or p-methoxybenzyl. forms thereof, wherein R is C. Straight or branched US 2016/01 02064 A1 Apr. 14, 2016 37

chain alkyl, cycloalkyl, haloalkyl, Substituted or unsub branched chain alkyl, cycloalkyl, haloalkyl, Substi stituted aryl, of substituted or unsubstituted aralkyl. tuted or unsubstituted aryl, or substituted or unsubsti 96. The compound of claim 95, wherein the radical R is tuted aralkyl: methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chlo N-2(R)-2,3-Epoxypropyl-3-fluoro-4-(4-morpholinyl) romethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophe aniline of formula X: nyl or p-methoxybenzyl. 97. A compound selected from: i) (R)-2-Hydroxypropyl-carbamate compound of formula VII: VII

F N e N1-7Y.a. O

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof V) (R)-Acetamido-2-hydroxypropyl-carbamate compound of formula XI: XI or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, Substi r tuted or unsubstituted aryl, or substituted or unsubsti Nu O tuted aralkyl, and Y is a leaving group selected from a halogen or a Sulfonyloxy group; ii) (R)-2-Acetyloxypropyl-carbamate compound of for F r’sH mula VIII: RO lsO OH VIII or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, Substi tuted or unsubstituted aryl, or substituted or unsubsti F 11-y tuted aralkyl, and Vi) (R)-acetamido-2-acetyloxypropyl-carbamate com Ac pound of formula XII: ... XII or an enantiomeric form or a mixture of enantiomeric r forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, Substi Nu O tuted or unsubstituted aryl, or substituted or unsubsti tuted aralkyl: Y is a leaving group selected from a halogen or a Sulfonyloxy group, and Ac' represents F s^H 1s. an acetyl group; ls OAc iii) (R)-2,3-Epoxypropyl-carbamate compound of formula RO O IX: IX or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is C. Straight or branched chain alkyl, cycloalkyl, haloalkyl, Substi tuted or unsubstituted aryl, or substituted or unsubsti tuted aralkyl, and Ac' represents an acetyl group. 98. The compound of claim 97, wherein the radical R is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chlo romethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophe nyl or p-methoxybenzyl; and wherein the leaving group Y is F RO OYO selected from the group consisting of Cl, Br, I, methanesulfo nyloxy, toluenesulfonyloxy and trifluoromethanesulfonyloxy or an enantiomeric form or a mixture of enantiomeric group. forms thereof, wherein R is C. Straight or