Anhydrous Linezolid crystalline form-II

Background of the invention:

US patent 5688792 discloses the antibacterial agent Linezolid
as well as a process for its preparation. There are many other references for the preparation and isolation of Linezolid. J. Med. Chem 39(3), 673-679 (1996) reports that Linezolid was recrystallized from ethylacetate & hexane as white crystals, with melting point of 181.5-182.5 °C. It also sets for the IR spectrum as 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447 & 1435.

Tetrahedron Lett. 40 (26) 4855 (1999) & US5837870, WO99/24393 discloses Linezolid and process to prepare Linezolid. Both the publications doesn’t set forth the melting point or IR spectrum.

US 6,559,305 B1 discloses the preparation of Linezolid crystal
form-II by mixing greater than 98% enantiomeric pure (S)-3-(3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl methyl acetamide in ethylacetate solvent at temperature below of about 80 °C and separating the Linezolid crystalline form-II.

US20090062534 A1 discloses the novel Linezolid crystalline hemihydrated form with water content ranging from 2.5-3.5 % w/w and to addition salts of Linezolid.

Summary of the invention:
In accordance to meet the above objectives, present invention provides novel process to prepare anhydrous Linezolid crystalline form-II, which comprises;
(i) Dissolving or mixing (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetamide having enantiomeric impurity <0.5% in a solvent at a preferable temperature of about 90-95 °C.
(ii) Precipitating anhydrous Linezolid crystal form-II having enantiomeric impurity <0.5% and purity by HPLC as per ICH limits from the solvent.

The solvent used in the above processes is selected from the group consisting of esters such as n-butyl acetate, alcohols such as sec. butanol and
tert. butanol to yield directly Linezolid crystalline form-II anhydrous.

Brief description of the drawings:

Fig 1: Shows the X-ray diffraction spectrum of anhydrous Linezolid crystalline form-II
(Example-1)
Fig 2: Shows the IR spectrum of anhydrous Linezolid crystalline form-II (Example 1)
Fig 3: Shows the TGA spectrum of anhydrous Linezolid crystalline form-II (Example 1)
Fig 4: Shows the X-ray diffraction spectrum of anhydrous Linezolid crystalline form-II
(Example 2)
Fig 5: Shows the IR spectrum of anhydrous Linezolid crystalline form-II (Example 2)
Fig 6: Shows the TGA spectrum of anhydrous Linezolid crystalline form-II (Example 2)
Fig 7: Shows the X-ray diffraction spectrum of anhydrous Linezolid crystalline form-II
(Example 3)
Fig 8: Shows the IR spectrum of anhydrous Linezolid crystalline form-II (Example 3)
Fig 9: Shows the TGA spectrum of anhydrous Linezolid crystalline form-II (Example 3)

Detailed description of the invention:

While the invention will now be described in detail in connection with certain preferred and optional embodiments. So that various aspects there of may be more fully understood and appreciated. It is not intended to limit the invention to these particular embodiments. Detailed description of the embodiment, which is outlined in a broad sense and featured in the invention, so that those skilled in the art may better understand the detailed process.

According to the present invention, novel anhydrous Linezolid crystalline form-II can be prepared by dissolving or mixing of Linezolid in suitable solvent followed by heating and precipitating from solvent upon cooling.

The solvent used in the above process is selected from the group consisting of esters and alcohols such as n-butyl acetate, sec. butanol and
tert. butanol.
Thus, the processes of the present invention are reliable, convenient and easily reproducible on industrial scale and give substantially identical anhydrous crystalline form-II of Linezolid, which is exemplified through the following examples.

EXAMPLES:

Preparation of anhydrous Linezolid crystalline form-II

Example-1:
Linezolid having an enantiomeric impurity less than 0.5 % (10 gr) is suspended with n-butyl acetate (200 ml). Heated the suspension to 85-90 °C and the mixture is stirred for 40-45 min. Slowly cool the mixture to 25-30 °C and stirred for
30 min and then the mixture is cooled to 0-5 °C and stirred for 60 min. The precipitated solids are filtered to give anhydrous Linezolid crystal form-II. The resulting anhydrous crystalline form-II, complies the water content <0.5% and it is characterized by XRPD spectrum, IR spectrum and TGA spectrum respectively.

Example-2:
Linezolid having enantiomeric impurity less than 0.5 % (10 gr) is suspended with sec. butanol (100 ml). Heated the suspension to 85-90 °C and the clear solution is stirred for 40-45 min. Slowly cool the solution to 25-30 °C and stirred for 30 min and then the mixture is cooled to 0-5 °C and stirred for 60 min. The precipitated solids are filtered to give anhydrous Linezolid crystalline form-II. The resulting crystalline form-II complies the water content <0.5% and it is characterized by XRPD spectrum, IR spectrum and TGA spectrum respectively.

Example-3:
Linezolid having an enantiomeric impurity less than 0.5 % (10 gr) is suspended with tertiary butanol (200 ml). Heated the suspension to 85-90 °C and the mixture is stirred for 40-45 min. Slowly cool the mixture to 25-30 °C and stirred for
60 min. The precipitated solids are filtered to give anhydrous Linezolid crystalline form-II. The resulting crystalline form-II complies the water content <0.5% and it is characterized by XRPD spectrum, IR spectrum and TGA spectrum respectively.

WE CLAIMED:

1. An oxazolidinone antibacterial agent of anhydrous Linezolid Crystalline form-II

2. According to claim 1, Linezolid anhydrous crystalline form-II having XRPD spectrum
of 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 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 ± 0.2° in 2?.

3. According to claim 1, Linezolid anhydrous crystalline form-II having IR spectrum
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.

4. According to claim 1, where anhydrous Linezolid crystalline form-II has the water content <0.5 %.

5. According to claim 1, synthesizing (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-
oxazolidinyl methyl acetamide having enantiomeric purity < 0.5 %.

6. According to claim 1, synthesizing (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-
oxazolidinyl methyl acetamide having compliance of the product with respect to related impurities as per ICH limits.

7. According to claim 1, process to prepare anhydrous crystalline form-II comprises;
a) Mixing the (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetamide in a solvent at a temperature about 90-95 °C.

b) A process according to claim 2, where the solvent is selected from the group consisting of C1-C4 alcohols and esters.

c) A process according to claim 3, where the solvent preferably is tert-butanol.

d) A process according to claim 3, where the solvent more preferably sec-butanol.

e) A process according to claim 3, where the solvent most preferably is n-butyl acetate.
f) A process according to claim 2, where the (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetamide is mixed for at least 40-45 minutes in mentioned solvent.