DESC:
FORM 2

THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule13)

1.TITLE OF THE INVENTION:

“PROCESS FOR PREPARATION OF LINEZOLID”
2. APPLICANT

(a) NAME: VIRDEV INTERMEDIATES PVT. LTD.

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Block 46-47, Plot No 2, Moje Palsana - 394315,
Taluka Palsana, District Surat, Gujarat, India.

3.PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed.

Technical Field:
The present invention relates to an in-situ process for preparation of Linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities.
Background and prior art:
Linezolid is an antimicrobial agent and first disclosed in US5688792 among a list of oxazine and thiazine oxazolidinone derivatives. Linezolid is the first antibacterial agent belonging to oxazolidinone class, invented by US Pharmacia & Upjohn Corporation. It is significantly useful in treatment of infections of soft tissues, skin as well as pneumonia. Linezolid, chemically known as N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and represented by the following structure:

Processes for preparation of linezolid were described in US 5837870; WO 99/24393; WO 95/07271, US 2011/0275805A1, WO2009/063505A2, US 7291614 B2, WO2007/116284A1, WO2010/084514A2, J. Med. Chem. 39(3), 673-679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
Chinese Chemical Letters 17 (3): 302–4 (2006) disclose preparation of linezolid starting from (S)-glyceraldehyde acetonide.
A process for synthesis of Linezolid is reported by Dr. Reddy’s in Tetrahedron Letters 40 (26): 4855–6 (1999) using 1,2,5,6-dianhydro-3,4-isopropylidine-D-mannitol as starting material.
The prior art processes for preparing 5-aminomethyl substituted oxazolidinones, however, are associated with many drawbacks due to the involvement of use of butyl lithium at low temperatures; use of phosgene gas etc. It is well known that handling of phosgene gas as well as butyl lithium is difficult on industrial scale. Some of the prior art processes involve azide intermediates which are difficult to operate on larger manufacturing scale.
Further, all these processes involve isolation of intermediates at various stages using solvents, which result in reduction of yield of the intermediate compounds and hence the end product causing a cost escalation.
Further, IN229267 discloses linezolid polymorphic form III and process for preparation thereof. IN’267 is granted for process for preparation of polymorphic form III of Linezolid, however, the claim for polymorphic form III is refused under section 3(d) of IPA, 1970.
Similarly, Linezolid polymorphic Form II and process for preparation thereof is disclosed in Indian patent application No. 623/MUMNP/2004, however, only process claims were granted and the claims for polymorphic form II was refused under section 3(d).
The other process patents granted in India IN213062 and IN213063 suffers from multiple process steps even though the starting material is chlorohydrin compound of formula V or formula VI, which are advanced intermediates.

Therefore, there is need in the art to provide an in-situ process for preparation of Linezolid polymorphic form II free of impurities in cost-effective and industrially viable manner, which becomes the objective of the invention and for which protection is sought.
Accordingly, the present inventors have come up with a novel process starting from much basic and easily available starting material and at the same time involving much fewer operational steps. In fact, the key reaction is an inventive process which involves an in-situ process for synthesis of linezolid starting from Phenyl amine compound of formula II to (S)-N-[3-[3-fluro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxozolidinyl]methyl]phthalimide of formula III. The instant process is cost-effective and industrially scalable.

Summary of the invention
In line with the above objectives, the present invention provides an in-situ process for preparation of Linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities.
Accordingly, in one aspect, in-situ process for preparation of linezolid polymorphic Form II comprises:
a) Condensing 3,4-Diflouronitrobenzene with Morpholine in ethyl acetate at room temperature followed by addition of a base, raising the temperature to 78-80°C followed by distillation of Ethyl Acetate to obtain compound of formula I;

b) hydrogenating compound of formula I using 5% Pd/C in methanol to obtain compound of formula II;

c) refluxing compound of formula II with R (-) Epichlorohydrin in Isopropyl alcohol to a temperature 80-88°C until completion of the reaction, followed by treating with Potassium Phthalamide to obtain reaction mass; which is in-situ further reacted with carbonyl imidazole to obtain intermediate III;

d) reacting intermediate III with Hydrazine Hydrate in Methanol at ambient temperature until completion of the reaction, extracting the mass in MDC, filtering and partially concentrating, followed by acetylating with Acetic Anhydride, distilling the solvent and washing, triturating with IPA to obtain crude Linezolid of formula IV;

e) refluxing slowly the solution of crude linezolid of formula (IV) in methanol, filtering and concentrating the filtrate by distillation to obtain a mass followed by seeding said mass with linezolid polymorphic Form II at low temperature and isolating the pure crystals of linezolid polymorphic Form II.

Description of drawings
Fig 1 depicts XRD data of the linezolid polymorphic Form II prepared according to example 8 which matches with the XRD described in 623/MUMNP/2004.
Fig 2 depicts DSC of linezolid polymorphic Form II prepared according to example 8.
Fig 3 depicts HPLC chromatogram of Linezolid finished product according to example 12.
Fig 4 depicts HPLC chromatogram of Linezolid polymorphic Form II according to example 8.

Detailed description of the invention:
The present invention describes an in-situ process for preparation of linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities that is easier to carry on industrial scale.
Accordingly, in a preferred embodiment, the in-situ process for preparation of linezolid polymorphic form II which comprises the following steps.
The condensation of 3, 4-Diflouronitrobenzene with Morpholine was carried in ethyl acetate solvent at room temperature. This was followed by addition of a base selected from ethylamine, triethylamine, pyridine, and the like; preferably triethylamine and the temperature was raised to 78-80°C and maintained at this temperature until completion of reaction. After competition of the reaction, ethylacetate was distilled, water was added, the mass cooled and filtered to obtain solid, which was dried to obtain compound of formula I.

The hydrogenation of compound of formula I using 5% Pd/C was conducted in methanol. The catalytic hydrogenation process was carried out with hydrogen pressure (0.3 kg/cm2 – 2.0 kg/cm2) and temperature (28°-35°C) for a period of 2-4 hrs while monitoring reaction progress by TLC. After completion of reaction, the reaction mass was cooled, filtered to remove the catalyst, methanol was distilled out, water was added, cooled and filtered to get compound of formula II.

Further, the reaction of compound of formula II to compound III was carried in-situ, wherein compound II was reacted with R (-) Epichlorohydrin in Isopropyl alcohol at 80-88°C and progress of reaction was monitored by TLC. After completion of reaction, IPA was distilled out and the reaction mass was treated with Potassium Phthalamide in DMF. After the completion of reaction, the reaction mass was quenched with ice water, extracted with MDC and back extracted with water. The MDC layer was partially distilled off to remove the traces of water azeotropically, and the reaction mass was reacted with carbonyl diimidazole to obtain compound III.

In another process variant, the carbonylation was undertaken in THF solvent. After completion of reaction, THF was recovered by distillation, the mass was treated with water and ethyl acetate, cooled and filtered the solids to isolate compound III.
The compound III was treated with hydrazine hydrate in methanol at 68-70 deg.C until completion of the reaction, After completion of reaction methanol was distilled off, the reaction mass was diluted with MDC and acetylated with acetic anhydride. After completion of reaction MDC was distilled off and IPA was added to obtain crude Linezolid of formula IV.
Finally, the crude Linezolid of formula IV was purified in methanol to get pure crystalline Linezolid in Polymorph Form-II. Accordingly, the solution of crude linezolid of formula (IV) in methanol was refluxed until dissolution followed by addition of active carbon. The mixture was further refluxed for about an hour at same temperature; the mass was filtered and concentrated by distillation. This was followed by seeding the mass under cooling with linezolid polymorphic form II to isolate the pure crystals of linezolid polymorphic Form II.
In an embodiment, the present invention provides a process for synthesis of linezolid as provided in example below and further purification in methanol to obtain polymorphic Form II .
The polymorph Form II was characterized by XRD and DSC data that match with the XRD values disclosed in Indian patent application No. 623/MUMNP/2004.
The Linezolid polymorphic Form II obtained in the present process is substantially free of the specified pharmacopoeal impurities and unspecified impurities such as N-[3-chloro-2 (R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline (D) and N-[3-Phthalimido-2(R)-hydroxy propoyl-3-fluoro-4-morpholinylaniline (E) as depicted in HPLC chromatogram.(fig 3 and fig 4 respectively).
The limits may vary with change in analytical instrument / lab / operating analyst / sensitivity of detection etc. and the total impurities do not exceed 0.5%. As per Indian Pharmacopoeia 2014 monograph on linezolid the acceptance limit for any single impurity is Not More Than 0.5 % and for total impurities is Not More Than 1.0%
Nevertheless, as per USP pending monograph, 2013, the individual impurities are identified by Relative Retention Time and are structurally defined in the table reproduced below. It describes the limits of impurities in terms of relative retention time and acceptance criteria.
Name Relative retention time Acceptance criteria, NMT (%)
Linezolid related compound
C (linezolid amine)a 0.19 0.08
Linezolid 1.0 -
Linezolid related compound
B (thiolinezolid)b 1.66 0.08
Linezolid related compound
A (linezolid
azide)c 1.70 0.08
Any individual unspecified impurity - 0.08
Total impurities - 0.5
a (S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one
b (S)-N-{[3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl] methyl}thioacetamide
c (R)-5-(Azidomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one
The specified and unspecified impurities in form of compounds A, B, C and additional impurities D and E are as follows:
Impurity A: (R)-5-(Azidomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one
ImpurityB: (S)-N-{[3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl}thio-acetamide.
Impurity C: (S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one.
Impurity D: N-[3-chloro-2 ( R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline
Impurity E: N-[3-Phthalimide-2( R)-hydroxy propoyl-3fluoro-4-morpholinylaniline.
Thus, Linezolid polymorphic Form II obtained from the process of instant invention not only comply with the limit/absence of the specified and unspecified impurities A, B, C of USP’s pending monograph but also is free of additional impurities such as D and E.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the invention. The examples included herein are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

Examples:
Example-1
Preparation of Compound-I (3-Fluoro-4-morpholinylnitrobenzene)
Ethyl acetate (230 ml) and 3,4-Difluoronitrobenzene (200 gms) were added in a reactor and morpholine (134 gms) was added gradually at 25°-30°C temperature. Triethylamine (40 gms) was added slowly maintaining temperature at 30°-35°C and the mass was heated to 78°-80°C. It was maintained at that temperature till the reaction was completed by monitoring with TLC. Ethyl acetate was removed in vacuo, resultant slurry mass was diluted with water, cooled to 25-30°C, maintained for an hour and filtered to obtain Compound-I. Product was washed with water (130 ml) and dried at 55°-60°C for 4-6 hrs to obtain Compound-I (276 gms).
Example-2
Preparation of Compound-I (3-fluoro-4-morpholinylnitrobenzene)
The process was carried out as in Example-I with reactants quantities as 3,4-Difluoronitrobenzene (220 gms), morpholine (142 gms) and triethylamine (43 gms). Yield of compound-I was observed to be 298 gms.
Example- 3
Preparation of compound-II (3-Fluoro-4-morpholinylaniline)
In a catalytic pressure hydrogenation vessel were added methanol (800 ml), and Compound-I (115 gms) as obtained above. The reaction mass was stirred to dissolve Compound-I while maintaining temperature at 22°-28°C. Palladium – Carbon Catalyst (5%, 2.15 gm) was then introduced. The reaction mass was flushed with nitrogen gas and then with hydrogen gas. Catalytic hydrogenation process was carried out with hydrogen pressure (0.3 kg/cm2 – 2.0 kg/cm2) and temperature (28°-35°C) for a period of 2-4 hrs, while monitoring reaction progress by TLC. After completion of reaction, the mass was cooled to 20°-25°C, filtered to remove the catalyst and concentrated to remove methanol partially (580 ml – 630 ml) at 45°-52°C. Reaction mass turned into thick slurry. It was added with water (390 ml), stirred for half an hour, cooled to 20°-25°C, filtered, washed with cold water (120-150 ml), and finally dried at 60°-65°C in a tray drier to obtain compound-II (92 gms).
Example-4
Preparation of Compound-III (3-Fluoro-4-morpholinylamine)
The process was carried out as in Example-3, with adopting modifications as under: Compound-I (80 gms), methanol (900 ml), palladium-carbon catalyst (5%, 1.35 gm), hydrogen gas pressure (0.6 kg/cm2 – 2.8 kg/cm2). The reaction was observed to be completed in 3.5 hrs and yield of compound-II was found to be 61.0 gms.
Example-5
Preparation of compound-II (3-Fluoro-4-morpholinylaniline)
Catalytic hydrogenation process was performed in a similar way as described in Example-3, and quantities of reactants as described in Example-4, but hydrogen pressure was restricted to 0.1 kg/cm2-0.2 kg/cm2. The reaction was monitored by TLC for completion over a period of eight hours. Yield of compound-II was found to be 64 gms.
Example-6
Preparation of compound-III (S)-N-[[3-[3-fluro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]phthalimide.
Compound-II (200 gms) was added in a reactor flask containing 4.2 lit of isopropanol and was dissolved under stirring for about 15-20 minutes at 28°-30°C. R(-)-epichlorohydrin (112 gms) was then gradually added to the reaction mass over a period of 1 hour.
The reaction mass was heated to reflux and was maintained for about 20-24 hrs at 80°-88°C. The progress of reaction was monitored by TLC at periodic intervals after 16 hrs. Isopropanol was distilled out from the reaction mass after completion of the reaction and then N,N-dimethyl forrmamide (DMF) was gradually added (540 ml). The reaction mass was cooled to 35°-38°C and stirred for 15-20 minutes. Potassium phthalamide (222 gms) was next added over a period of 1.5 hours under moderate stirring. The reaction mass was maintained further at 35°-40°C for 15-20 minutes and then slowly heated to 94°-98°C with careful control on temperature. Heating was stopped and the temperature of reaction mass rose to 122°-130°C. The reaction progress was quickly monitored by TLC and reaction was completed in 15-30 minutes period. Reaction mass was cooled to 45°-50° and then slowly poured in to a vessel containing ice (1.4 kg), water (3.8 lit) and methylene dichloride solvent (1.6 lit), with vigorous stirring. After 15-20 minutes of stirring, the organic layer was separated. The aqueous layer was extracted further with MDC (500 ml × 3 times). Combined MDC layer was repeatedly extracted with water (350 ml × 4 times), dried over anhydrous sodium sulphate, filtered and partially concentrated to remove water azeotropically. Fresh MDC was added equal to the quantity of solvent removed by distillation (approximately 600-700 ml). Moisture content of the reaction mass was observed to be 0.1%. the reaction mass was next cooled to 30°C and carbonyl diimidazole (146 gm) was added to it over a period of half an hour. The reaction mass temperature was then raised to 35°-37°C and maintained for 20-26 hrs under monitoring by TLC. Reaction was completed in 22 hrs. Water (290 ml) was added in the reaction mass and organic layer was separated. The organic layer was re-extracted with water (250 ml × 3 times), all aqueous layer pooled up and extracted with MDC (220 ml × 1), MDC extracts pooled up and dried over anhydrous sodium sulphate and filtered MDC extracts was then treated with active carbon (6 gms), filtered and concentrated to remove solvent in vacuo. The residual mass was added with methanol (70 ml) and solvent was stripped under vacuum. The mass was again added with methanol (380 ml), heated to 60°-65°C under stirring, maintained for about half an hour, cooled to 25°-28°C, and maintained for 1 hr. The product mass was filtered and solid obtained was washed with methanol (50 ml). The product mass dried in a tray dryer at 60°-65°C for 4-5 hrs to obtain compound-III (234 gms, moisture content 0.15%, HPLC purity 96.37%, Assay 97.52%, melting point 196°-200°C, SOR (-) 48.93°).
Example-7
Preparation of Compound-(IV), Linezolid
Methanol (1.28 lit) and compound-III (225 gm) were charged in a reaction flask and stirred for 15 minutes at 30°-35°C. Hydrazine hydrate (138 gms) was introduced in the reactor and mass was gradually heated to 68°-70°C over a period of 10-15 minutes. It was maintained at 68°-70°C under mild reflux for a period of 2 hrs. Completion of reaction was confirmed by TLC and methanol was partially removed by distilling out about 750 ml – 800 ml. Reaction mass is cooled to 30°-35°C, 2.95 lit of water was slowly introduced followed by extraction with MDC (1.25 Lit × 1, 0.45 lit × 2). MDC extract was washed with water (0.45 lit × 2), dried over anhydrous sodium sulphate, filtered and concentrated partially to remove 0.8 lit MDC. The reaction mass was cooled to 10°-12°C, and acetic anhydride (122 gms) was added in about an hour while maintaining the temperature at 10°-12°C. Reaction mass temperature was then raised to 28°-30°C and maintained for 2 hrs. Reaction completion was ascertained by TLC and solvent was distilled off completely. Two lots of IPA were added in succession (60 ml × 2) and the mass was stripped off to remove the solvent completely. Third lot of IPA (235 ml) was added followed by cooling the mass to 25°-30°C and then to 2°-5°C. It was maintained under slow stirring for 2 hrs, filtered to isolate the product and washed with IPA (2°-5°C, 50 ml × 2). Linezolid isolated thus was dried first at 40°-45°C for 3 hrs followed by at 60°-70° for 3-4 hrs (Yield 145 gms, HPLC purity above 99.0%, Assay 99.02%, SOR (-)9.99°, IR match value with a working standard of Linezolid polymorph form-II 86.44%).
Example-8
Purification of Linezolid
Linezolid (140 gms) obtained as above was added in a reaction flask containing methanol (1.4 lit) and heated under stirring to achieve slow reflux (68°-72°C). After dissolution, active carbon (7 gms) was added, reflux maintained for 1 hrs, and the mass was filtered hot followed by washing of suspended matter with methanol (100 ml). The clear filtrate was concentrated by distillation to remove approximately 50% of methanol. Resultant mass was slowly cooled to 35°C while adding linezolid polymorph form-II (4.2 gms), and finally to 24°-27°C. The mass was maintained at this temperature for 2 hrs under slow stirring, the product was isolated by filtration, washed with methanol (cooled to 10°-15°, 40 ml × 4 times), and dried at 40°-45°C for 2 hrs followed by at 45°-55°C for 3-4 hrs (yield 113 gms, HPLC purity above (99.586%) Assay 99.52%, SOR (-)10.18°C, IR match value with a working standard of Linezolid polymorph-II 99.16%).
Example-9
Purification of Linezolid
The Process of purification was carried out as per the one described in example-8, and quantities of materials used as: Linezolid (91 gm), methanol (955 ml), active carbon (5.46 gms). Linezolid polymorph form-II seed material (2.73 gms) and methanol for washing (25 ml × 4 times). (Yield of purified linezolid 75.5 gms, HPLC purity above 99.5%).
Example-10
Preparation of Compound (IV), Linezolid
Methanol (1.35 lit) and compound-III (225 gm) were charged in a reaction flask and stirred for 15 minutes at 30°-35°C. Hydrazine hydrate (146 gms) was introduced in the reactor and mass was gradually heated to 68°-70°C over a period of 10-15 minutes. It was maintained at 68°-70°C under mild reflux for a period of 2 hrs. completion of reaction was confirmed by TLC and methanol was partially removed by distilling out about 750 ml – 800 ml. Reaction mass is cooled to 30°-35°C, 2.83 lit of water was slowly introduced followed by extraction with MDC (1.25 Lit × 1, 0.45 lit × 2). MDC extract was washed with water (2.83 lit), dried over anhydrous sodium sulphate, filtered and concentrated partially to remove 0.8 lit MDC. The reaction mass was cooled 10°-12°C, and acetic anhydride (132 gms) was added in about an hour while maintaining the temperature at 10°-12°C. Reaction mass temperature was then raised to 28°-30°C and maintained for 2 hrs. Reaction completion was ascertained by TLC and solvent was distilled off completely. Two lots of IPA were added in succession (60 ml × 2) and the mass was stripped off to remove the solvent completely. Third lot of IPA (235 ml) was added followed by cooling the mass to 25°-30°C and then to 2°-5°C. It was maintained under slow stirring for 2 hrs, filtered to isolate the product and washed with IPA (2°-5°C, 50 ml × 2). Linezolid isolated thus was dried first at 40°-45°C for 3 hrs followed by at 60°-70° for 3-4 hrs (Yield 139.5 gms, HPLC purity above 99.0%, Assay above 99.0% %, SOR(-)9.90°, ).
Example-11
Preparation of Compound-III (S)-N-[[3-[3-fluro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide.
Compound-II (200 gms) was added in a reactor flask containing 4.2 lit of isopropanol and was dissolved under stirring for about 15-20 minutes at 28°-30°C. R(-)-epichlorohydrin (112 gms) was then gradually added to the reaction mass over a period of 1 hour.
The reaction mass was heated to reflux and was maintained for about 20-24 hrs at 80°-88°C. The progress of reaction was monitored by TLC at periodic intervals after 16 hrs. Isopropanol was distilled out from the reaction mass after completion of the reaction and then N,N-dimethyl formamide (DMF) was gradually added (540 ml). The reaction mass was cooled to 35°-38°C and stirred for 15-20 minutes. Potassium phthalamide (222 gms) was next added over a period of 1.5 hours under moderate stirring. The reaction mass was maintained further at 35°-40°C for 15-20 minutes and then slowly heated to 94°-98°C with careful control on temperature. Heating was stopped and the temperature of reaction mass rose to 122°-130°C. The reaction progress was quickly monitored by TLC and reaction was completed in 15-30 minutes period. Reaction mass was cooled to 45°-50° and then slowly poured in to a vessel containing ice (1.4 kg), water (3.8 lit) and methylene dichloride solvent (1.6 lit), with vigorous stirring. After 15-20 minutes of stirring, the organic layer was separated. The aqueous layer was extracted further with MDC (500 ml × 3 times).
Combined MDC layer was repeatedly extracted with water (350 ml × 4 times), dried over anhydrous sodium sulphate, filtered and concentrated to remove the solvent. THF (5.32 lit) was added and mass was stirred for half an hour at 28°-30°C. Carbonyl diimidazole (132 gms) was added over a period of 15-20 minutes, reaction mass was heated to 38°-40°C and maintained for 24 hours with TLC monitoring. Reaction was completed, THF was recovered by distillation, and residue was added with ethyl acetate (530 ml) and water (265 ml) at 40°-45°C. Resultant mass was stirred, cooled to 2°-5°C, maintained for 3 hrs, filtered and washed with a mixture of cold ethyl acetate (95 ml) and water (40 ml). The product mass was dried at 50°-60°C for 5-6 hrs to obtain compound-III (210 gms, HPLC purity 98.3%, Assay 98.05%, SOR (-) 53.79°).
Example-12
Preparation of Compound-(IV), Linezolid
Compound-(III) obtained in example-11 (72 gms) and methanol (430 ml) were charged in a reactor, treated with hydrazine hydrate (47 gms) and slowly heated to 68°-70°. Reaction was completed in 2.5 hrs, methanol was partially distilled of (260 ml), reaction mass cooled to 30°-35°C and added with water (910 ml) and MDC (430 ml) to extract organic mass. Aqueous layer was multiple extracted with MDC (430 ml × 1, 215 ml × 3), all MDC extracts pooled up, washed with water (430 ml), dried over anhydrous sodium sulphate, filtered and partially concentrated to remove MDC (150 ml). Resultant solution was cooled to 10°-12°C, added with acetic anhydride (44 gms) over one hour and then stirred at 28°-30°C for 2.5 hrs to complete acetylation. MDC was distilled out and residue was added with two subsequent lots of IPA (40 ml × 2) followed by stripping to remove solvent at 50°-55°C. Compound-(IV) was isolated by adding, IPA (75 ml), Cooling to 0°-5°C, maintaining for 2 hrs, filtration, washing with cold IPA (15 ml × 2), and drying at 60°-65°C for 4-5 hrs (yield 49 gms, HPLC purity 99.83%, Assay 99.44%, SOR (-) 9.34°). Linezolid isolated thus shows superior purity and assay as compared to the one isolated in experiment-7.
Example-13
Purification of Linezolid
Linezolid (45 gms) (Compound-IV) isolated in the example-12 was purified by dissolving in methanol (450 ml), refluxing for 1 hrs with addition of active carbon (2.25 gm), hot filtration of solution, removing partial quantity of methanol (230 ml) by distillation, and gradual cooling to 25°-28°C while adding linezolid polymorph-II (1.35 gm). The purified product was filtered, washed with cold methanol (20 ml × 3 times) and dried at 40°-45°C for 2 hrs and at 45°-55°C for 3-4 hrs (yield 35.5 gms, HPLC purity 100%, Assay 99.93%, SOR(-)9.69°, IR match value with working standard of linezolid polymorph-II 98.23%).

,CLAIMS:We claim,
1. An in-situ process for preparation of Linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities, wherein said process comprises;
a. Condensing 3, 4-Diflouronitrobenzene with Morpholine in ethyl acetate at room temperature followed by addition of a base, raising the temperature to 78-80°C followed by distillation of Ethyl Acetate to obtain compound of formula I;

b. hydrogenating compound of formula I using 5% Pd/C in methanol to obtain compound of formula II;

c. refluxing compound of formula II with R (-) Epichlorohydrin in isopropyl alcohol to a temperature 80-88°C until completion of the reaction, followed by treating with Potassium phthalamide to obtain reaction mass; which is in-situ further reacted with carbonyl diimidazole to obtain intermediate III;

d. reacting intermediate III with Hydrazine Hydrate in methanol at ambient temperature until completion of the reaction, extracting the mass in MDC, filtering and partially concentrating, followed by acetylating with Acetic Anhydride, distilling the solvent and washing with IPA to obtain crude Linezolid of formula IV;

e. refluxing slowly the solution of crude linezolid of formula (IV) in methanol, filtering and concentrating the filtrate by distillation to obtain a mass followed by seeding said mass with linezolid polymorphic form II at low temperature and isolating the pure crystals of linezolid polymorphic Form II.

2. The in-situ process according to claim 1, wherein Linezolid polymorphic form II is free from the additional impurities, N-[3-chloro-2 -(R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline and N-[3-Phthalimido-2(R)-propoyl-3-fluoro-4-morpholinylaniline as evidenced in fig 3 and fig 4 respectively.

3. Linezolid polymorphic Form II prepared by the in situ process according to claim 1;

wherein the said Form II is free from the additional impurities N-[3-chloro-2 (R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline and N-[3-Phthalimido-2(R)-hydroxypropoyl-3fluoro-4-morpholinylaniline as evidenced in fig 3 and fig 4 respectively.

Dated this 12th day of May, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates