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2U11/11421U A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date Χ 22 September 2011 (22.09.2011) 2U11/11421Uft A2 (51) International Patent Classification: Dharam [IN/IN]; Jubilant Life Sciences Limited, C-26, C07D 263/20 (2006.01) Sector-59, Noida-201301, Uttar Pradesh (IN). (21) International Application Number: (74) Agent: NAIR, Manoj Vasudevan; M/s Lex Orbis (Intel PCT/IB20 11/000527 lectual Property Practice), 709/710, Tolstoy House, 15-17 Tolstoy Marg, 110 001 New Delhi (IN). (22) International Filing Date: 14 March 201 1 (14.03.201 1) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (26) Publication Langi English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 595/DEL/2010 15 March 2010 (15.03.2010) IN KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (71) Applicant (for all designated States except US): JUBI¬ ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, LANT LIFE SCIENCES LIMITED [IN/IN]; Plot 1A, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, Sector 16A, 201 301 Noida, UP (IN). SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (75) Inventors/ Applicants (for US only): GUPTA, Ashish, (84) Designated States (unless otherwise indicated, for every Kumar [IN/IN]; Jubilant Life Sciences Limited, C-26, kind of regional protection available): ARIPO (BW, GH, Sector-59, Noida-201301, Uttar Pradesh (IN). SINGH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Shishupal [IN/IN]; Jubilant Life Sciences Limited, C-26, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Sector-59, Noida-201301, Uttar Pradesh (IN). PANDA, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Atulya, Kumar [IN/IN]; Jubilant Life Sciences Limited, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, C-26, Sector-59, Noida-201 301, Uttar Pradesh (IN). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, BISWAS, Sujay [IN/IN]; Jubilant Life Sciences Limited, GW, ML, MR, NE, SN, TD, TG). C-26, Sector-59, Noida-201301, Uttar Pradesh (IN). VIR, [Continued on next page] (54) Title: PROCESSES FOR THE PREPARATION OF LINEZOLID < © Figure I (57) Abstract: Disclosed herein a process for preparing linezolid, wherein the resultant linezolide is devoid of impurities and in- © volve easy and economical process. The present invention further relates to preparation of linezolid by employing an azide inter - mediate and process for said intermediate. w o 2 0 1 1 / l 1 4 2 1 o A 2 1II 11 II II 11 I I I 11III III II 11 lllll II 11 111 III II 111 II Published: — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) PROCESSES FOR THE PREPARATION OF LINEZOLID Field of the Invention The present invention relates to the improved processes for the preparation of linezolid. In particular, the present invention is directed to a novel process for the preparation of linezolid, which avoids the use of sodium azide in the reaction. The present invention also includes preparation of linezolid going through a novel intermediate of Formula XIa. The present invention also includes the processes of preparation of linezolid, free of bis-linezolid impurity. Also, the present invention further relates to preparation of linezolid by preparing azide intermediate, and converting it into linezolid in one-pot. It also provides linezolid with high yield and high chemical purity without the use of tedious, complicated purification steps, such as chromatography. Background of the Invention Linezolid, (S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C!6H20FN3O 4 and the following structure (I): (I) US Patent No. 5,688,792 claims linezolid and its use for the treatment of microbial infections. Various processes for preparation of linezolid are described in US 5,688,792; US 7,291,614; US2009093631 and Tetrahedron Lett 40(26), 4855, 1999. The synthesis of linezolid (Scheme-I) given in US 5,688,792, is also disclosed in Bricker, et al., J. Med. Chem., 39, 673-679 (1996) and is given as follows: Scheme-I MeS02CI Et N In the above described synthesis the intermediate azide, (R)-N-[[3-(3-fluoro-4- mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]azide (X) is being prepared by (R)- N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate (IX) using sodium azide as one of the critical reagents. Moreover, it is disclosed in US 2006/0252932 that when the said azide intermediate (X) is reduced to its corresponding amine, (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)- 2-oxo-5-oxazolidinyl] methyl] amine (XI) in the solvent ethyl acetate by hydrogenation using hydrogen gas and a palladium/carbon catalyst, production of undesirable level of reaction by-products occur. The reaction is followed by acetylation of the intermediate amine (XI) to linezolid (I), and undesirably high levels of bis-linezolid (XII), as an impurity, are also obtained in linezolid. (XII) Due to the formation of high levels of impurity, the purification becomes critical, resulting in poor yield of linezolid. Purification techniques such as chromatography is utilized to obtain pure linezolid resulting in low yields of linezolid. Thus, it is desirable to have a simple, safe and efficient industrial process for producing pure intermediate amine (XI) used to prepare linezolid (I), which overcomes the drawbacks disclosed in the prior art. Summary of the Invention The present invention seeks to overcome the prior art limitations and provide a cost effective and industrially favorable process for the preparation of linezolid. In one embodiment, the invention encompasses a process for preparation of linezolid comprising: (a) condensation of 3,4-difluoronitrobenzene (III) with morpholine (II) to obtain 3-fluoro-4-morpholinyl nitrobenzene (IV); (b) reduction of IV obtained in step 'a' to 3-fluoro-4-morpholinyl aniline (V); (c) protection of amino group of V obtained in step 'b' to generate a carbamate derivative like ethyl carbamate (Via) or benzyl carbamate (VIb); and the like (d) conversion of carbamate Via or VIb as obtained in step 'c' into oxazolidinone derivative, (R)-N-[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol (VIII); (e) further, conversion of the hydroxy group of VIII as obtained in step 'd' into a leaving group e.g. mesylate, nosylate, tosylate, triflate, besylate or a halo compound. If the leaving group is tosylate the compound generated is (R)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo- 5-oxazolidinyl]methyl /?-toluenesulfonate (IXa); (f) conversion of IXa as obtained in step 'e' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine./?-TSA salt (XIa), a novel intermediate compound, which helps in providing linezolid in high yield, it also helps in avoiding the use of sodium azide and hence the formation of X and (g) acetylation of XIa as obtained in step 'f to provide linezolid (I), free of bis-linezolid (XII). In another embodiment, the present invention provides a process for preparing a linezolid comprising acetylating (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine.^-TSA salt (XIa) in presence of a base and solvent. In another embodiment, the present invention provides a novel intermediate (S)-N- [[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine . -TSA salt of formula XIa. In yet another embodiment, present invention provides a novel polymorph Form J of (S)-N-[[3 (3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine./?-TSA salt (XIa), which is characterized by a powder X-Ray diffraction pattern with peaks at about 4.1, 15.6, 20.6, 22.7, 23.4 ±0.2° 2Θ, as depicted in Figure I. In another embodiment, present invention provides a novel polymorph Form J of (S)- N-[[3-(3-fluoro-4-mo holinylphenyl)- -oxo-5-oxazolidinyl]methyl amine. -TSA salt (XIa), which is characterized by Infrared spectrum having main bands at about 3440, 1746, 1518, 1421, 1224, 1153, 680 and 564 cm 1, as depicted in Figure II. In another embodiment, present invention provides a novel polymorph Form J of (S)- N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]amine.p-TSA salt (XIa), which is characterized by DSC thermogram as depicted in Figure III and TGA as depicted in Figure IV. In yet another embodiment of the present invention the reaction occurs in a similar fashion as in the first embodiment till the formation of (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa). Further, the reaction comprises (a) treatment of IXa with benzylamine leading to the formation of compound (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl] benzylamine (XIII) (b) hydrogenolysis of XIII as obtained in step 'a' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine (XI), i.e. an amine intermediate and (c) acetylation of XI as obtained in step 'b' to provide linezolid (I).
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