PROCESS FOR THE PREPARATION OF LINEZOLIDFORM III
FIELD OF THE INVENTION
The present invention relates to improved, commercially viable and industrially applicable process for the preparation of crystalline form III of Linezolid.
BACKGROUND OF THE INVENTION
Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA). The main indications of Linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia).
Chemically, Linezolid is (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] acetamide. The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:
Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia and several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).
WO 9507271, US 5688792 and EP 0717738 of Pharmacia & Upjohn first claimed and disclosed Linezolid and its process of preparation. There is no disclosure about polymorphism of Linezolid in these patents.
It is well known in the art that Linezolid exhibits polymorphism. Till now various crystalline forms of Linezolid have been disclosed in the prior art such as Form I, form II, form III and form IV.

J. Med. Chem., 39(3), 673-9 (1996) discloses preparation of Linezolid, purified by column chromatography and recrystallized from ethyl acetate and hexane as white crystals i.e., crystalline form I having, m.p. 181.5-182.5°C, and an IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447 and 1435 cm'1.
US 6559305 and US6 444813 of Pharmacia & Upjohn, cover and disclose Linezolid crystal "Form II" and its process of preparation comprising mixing greater than 98% enantiomerically pure Linezolid in a solvent or a mixture of solvents, particularly ethyl acetate, at a temperature below 80°C and separating Linezolid crystal "Form II". According to the '305 patent, the crystalline form II of Linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 19.41, 19.69, 19.93, 21.61, 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees; and IR spectrum having bands at 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cm"1.
WO 2012114354 of Lee Pharma describes the anhydrous Linezolid crystalline Form II comprising less than 0.5% of water content, characterised by its XRPD and IR spectra and its process comprising mixing Linezolid in n-butyl acetate at a temperature of 90-95°C for 40-45 min.
WO 2011050826 of Synthon B.V relates to a process for making a crystalline Form A of Linezolid comprising dissolving Linezolid in solvent selected from alcohols, cyclic ethers and aliphatic esters, followed by addition of an anti-solvent and seeded with crystals of crystalline Form A of Linezolid.
WO 2005035530 of Symed labs describes the crystalline Form III of Linezolid, which is prepared by directly heating Linezolid at 90-200°C (or) refluxing in a solvent such as toluene or xylene by optionally crystallization from a seeded solution in a solvent. The crystalline form III of Linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9±0.2 degrees; and an IR spectrum having main bands at about 3338, 1741,

1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm"'.
Though many polymorphic forms of Linezolid have been known in the art but Linezolid form III possesses good commercial valued due to its good thermal stability.
WO 2013190559 of Symed describes process for the preparation of Linezolid crystalline Form III, water has been used as solvent at about 80°C to about 95°C for crystallization process to obtain crystalline Linezolid Form III. This document also discloses a process wherein the suspension of the Linezolid in water is seeded with crystals of Linezolid Form III.
WO 2016/113751 of discloses a process for preparation of Linezolid Form III by suspending crystalline Linezolid in a solvent at 25-30°C and heating the solution to 75-80°C, cooling the reaction mass to 25-30°C and recovering the crystalline Linezolid Form III wherein the solvent used may be selected from a cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g. ethyl acetate; an aliphatic alcohol, e.g. methanol, ethanol, 1-propanol, isopropanol or 1-butanol; toluene, xylene, chloroform, methylene dichloride, acetonitrile, acetone and methyl ethyl ketone
WO 2018051360 of Lee pharma, describes a process for the preparation of crystalline form III of Linezolid, mono chlorobenzene & triethyl amine was added to Linezolid in a round bottom flask. The total content in the flask was heated to 120-125°C and stirred at the same temperature (120 to 125°C) until the solution becomes clear. Then the whole reaction mass was cooled to 25-30°C and stirred for 30-60 minutes. The precipitated solid mass was then filtered and washed with mono chlorobenzene. The filtered solid was then suck dried for 10-15 minutes followed by drying of the wet cake under vacuum at 80-85°C.
The drawbacks of the above mentioned patent applications are that reaction conditions are commercially unsuitable due to high temperature conditions (or) seeding is required to get desired polymorph that may not lead to consistency in getting the desired polymorph. The process for preparing crystalline form of Linezolid has operating temperature more than 90°C, which may lead to the decomposition of the product with inferior quality.

In view of the foregoing, the present inventors have provided herewith the process for the preparation of Linezolid form III with commercially suitable reaction conditions with high yield and purity. The process is simple, efficient more economical and eco-friendly for the preparation of Linezolid form III.
SUMMARY OF THE INVENTION
One aspect of the present invention provides process for preparing Form III of Linezolid, comprising;
a) Linezolid was suspended in an organic solvent,
b) heating the obtained suspension in step a), stirring at about 70°C-85°C for 3-5 hrs,
c) cooling the solution obtained in step b) at 25°C-30°C, and
d) isolating the form III of Linezolid.
Another aspect of the present invention relates to the process for the preparation of crystalline form III of Linezolid, characterized by the infrared spectra (IR spectra) and X-ray powder diffraction patterns (XRPD).
BRIEF DESCRIPTION OF DRAWINGS
Figure- 1: Represents X-ray powder diffraction pattern (XRPD) of crystalline Form III of
Linezolid.
Figure- 2: Represents infrared absorption spectrum (IR spectrum) of crystalline Form III of
Linezolid
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a simple and operationally convenient process for preparing pure crystalline form III of Linezolid.
In one embodiment of the present invention, the process for the preparation of Linezolid involves the acetylation of the non-isolated penunltimate stage comprising (55)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-onewith acetic anhydride in organic solvent to give Linezolid residue.

According to the embodiment of the present invention, the organic solvent used for acetylation reaction is selected from polar solvent such as dichloromethane and the like and non-polar solvents such as toluene, chloroform, preferably dichloromethane and / or chloroform.
In another embodiment of the present invention, provides a process for preparing Form III of Linezolid comprising;
a) Linezolid was suspended in an organic solvent,
b) heating the obtained suspension in step a), stirring at about 70°C-85°C for 3-5 hrs,
c) cooling the solution obtained in step b) at 25°C-30°C, and
d) isolating the form III of Linezolid.
According to the embodiment of the present invention, wherein the suspension of Linezolid form I or II in ethylbenzene and the mixture was heated to 70°C-85°C for 3-5 hrs, preferably 80-85°C for 2-4 hrs. The obtained reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature. The resultant solid was filtered, washed with ethylbenzene and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III
According to the embodiment of the present invention, the suitable organic solvents used for the crystallization is selected from aromatic hydrocarbon solvent such as benzene, ethybenzene, orthodichloro benzene, xylene, toluene and polar aprotic solvents are selected from n-butyl acetate and ethyl acetate. Preferably as ethybenzene, orthodichloro benzene and n-butyl acetate.
X-ray powder diffraction diagram
The XRPD patterns of the figures have a vertical axis that is intensity unit and a horizontal axis that is 20 angle in degrees.
According to the present invention, the crystalline Form III of Linezolid is characterized by X-ray powder diffraction pattern having peaks at 6.65, 7.35, 9.01, 10.97, 12.16, 13.47, 14.69,

15.21, 16.28, 16.82, 17.97, 18.48, 18.70, 19.81, 20.76, 21.83, 22.68, 23.57, 25.12, 26.71, 27.56, 28.26, 29.60 and 30.54± 0.2° 20 values.
According to the present invention, the crystalline Form III of Linezolid is further characterized by Infrared spectrum having peaks at 3339, 3071, 2972, 2927, 2898, 2863, 2818,2699, 1742, 1663, 1546, 1517, 1471, 1452, 1381, 1334, 12774, 1228, 1198, 1146, 1081, 1050, 971, 923, 870, 755, 720, 682, 621, 571 and 462cm"1.
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 intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
EXAMPLES
Example 1: Preparation of N-({(5S)-3-[3-fluoro-4-(morphoIin-4-yl)phenyl]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide polymorphic form III (Linezolid form III)
To a suspension of Linezolid form I (100 g) in ethylbenzene (600 ml) and the mixture was heated to 80-85°C and maintained for 12 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature. The resultant solid was filtered, washed with ethylbenzene (25 ml) and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III
Weight: 100g(%).
Example 2: Preparation of N-({(5S)-3-[3-fluoro-4-(morphoIin-4-yl)phenyI]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide polymorphic form III (Linezolid form III)
To a suspension of Linezolid form I (100 g) in ethylbenzene (600 ml) and the mixture was heated to 80-85°Cand maintained for 6 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature, the resultant solid was

filtered, washed with ethylbenzene (25 ml) and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III.
Weight: 100g(%).
Example 3: Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide polymorphic form III (Linezolid form III)
To a suspension of Linezolid form I (100 g) in orthodichloro benzene (600 ml) and the mixture was heated to 80-85°C and maintained for 12 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature. The resultant solid was filtered, washed with ethyl acetate and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III.
Weight: 90g (%).
Example 4; Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide polymorphic form III (Linezolid form III)
To a suspension of Linezolid form II (100 g) in ethylbenzene (600 ml) was heated to 80-85°C and maintained for 12 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature, the resultant solid was filtered, washed with ethylbenzene (25 ml) and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III.
Weight: 95g (%).
Example 5: Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyI]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide polymorphic form III (Linezolid form III)
To a suspension of Linezolid form II (100 g) in orthodichloro benzene (600 ml) and the mixture was heated to 80-85°C and maintained for 12 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature. The resultant solid was filtered, washed with ethyl acetate and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III.

Example 6: Preparation of N-({(5S)-3-[3-fIuoro-4-(morpholin-4-yl)phenyI]-2-oxo-l, 3-oxazoIidin-5-yl} methyl) acetamide polymorphic form III (Linezolid form III)
To a suspension of Linezolid form I (100 g) in N-butylacetate (600 ml) and the mixture was heated to 80-85°C and maintained for 12 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and it was stirred for 1 hr at the same temperature. The resultant solid was filtered, washed with ethyl acetate and dried at 50-60°C for 8-10 hrs to obtained Linezolid polymorphic form III. Weight: 90g (%).

We claim:
1. A process for preparing crystalline Form III of Linezolid comprising
e) Linezolid was suspended in an organic solvent,
t) heating the obtained suspension in step a), stirring at about 70°C-85°C for 3-5 hrs,
g) cooling the solution obtained in step b) at 25°C-30°C, and
h) isolating the form III of Linezolid.
2. The process as claimed in claims 1, wherein the organic solvent is selected from ethyl benzene and n-butyl acetate. Preferably ethyl benzene.
3. The process as claimed in claim 1, crystalline form III of Linezolid having a powder X-ray diffraction pattern substantially in accordance with Figure-1.
4. The process as claimed in claim 1 and 3, crystalline form III of Linezolid having powder X-ray diffraction pattern characterised by the peaks at 6.65, 7.35, 9.01, 10.97, 12.16, 13.47, 14.69, 15.21, 16.28, 16.82, 17.97, 18.48, 18.70, 19.81, 20.76, 21.83, 22.68, 23.57, 25.12, 26.71, 27.56, 28.26, 29.60 and 30.54 ± 0.2° 20 values.
5. The process as claimed in claim 1, crystalline form III of Linezolid having IR spectrum substantially in accordance with Figure-2.
6. The process as claimed in claim 1 and 5, crystalline form III of Linezolid having IR peaks at 3339, 3071, 2972, 2927, 2898, 2863, 2818, 2699, 1742, 1663, 1546, 1517, 1471, 1452, 1381, 1334, 12774, 1228, 1198, 1146, 1081, 1050, 971, 923, 870, 755, 720, 682, 621, 571 and 462 cm-1.