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

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(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.
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