Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-05-23
2003-05-06
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06559305
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the invention is a novel crystal form of a known compound, linezolid which is pharmaceutically useful as an antibacterial agent.
2. Description of the Related Art
U.S. Pat. No. 5,688,792 discloses the antibacterial agent linezolid as well as a process for its preparation. EXAMPLE 5 reports the linezolid produced had a mp of 181.5-182.5°.
There are many other disclosures of processes to prepare linezolid.
J. Med. Chem
., 39(3), 673-9 (1996) reports the linezolid was, “recrystallized from ethyl acetate and hexanes . . . white crystals, m.p. 181.5-182.5C.” It also sets forth the IR spectrum as “3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435”.
Tetrahedron Lett
., 40(26), 4855 (1999) discloses linezolid and a process to prepare linezolid. However, this document does not set forth the melting point or IR spectrum of the linezolid prepared.
U.S. Pat. No. 5,837,870 (International Publication WO97/37980 of PCT/US97/03458) discloses a process to prepare linezolid. Linezolid is described in EXAMPLE 18, which does not set forth the melting point or IR spectrum of the linezolid prepared.
International Publication WO99/24393 of PCT/US98/20934 discloses a process to prepare linezolid. Linezolid is described in EXAMPLES 8, 9 and 12 which do no set forth the melting point or IR spectrum of the linezolid prepared.
The form of linezolid being used in the clinical trials to support the filing of the NDA is Form II.
SUMMARY OF INVENTION
Disclosed is a (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal “Form II” with a powder X-ray diffraction spectrum of:
d-Spacing (Á)
Two-Theta Angle (°)
Relative Intensity (%)
12.44
7.10
2
9.26
9.54
9
6.37
13.88
6
6.22
14.23
24
5.48
16.18
3
5.28
16.79
100
5.01
17.69
2
4.57
19.41
4
4.50
19.69
2
4.45
19.93
6
4.11
21.61
15
3.97
22.39
23
3.89
22.84
4
3.78
23.52
7
3.68
24.16
1
3.52
25.28
13
3.34
26.66
1
3.30
27.01
3
3.21
27.77
1
Also disclosed is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal “Form II” with an infrared (IR) spectrum as a mineral oil mull: 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
.
Further disclosed is a process to prepare (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal “Form II ” which comprises:
(1) producing (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide in greater than 98% enantiomeric purity,
(2) mixing the greater than 98% enantiomerically pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide in a solvent or mixture of solvents at a temperature below a temperature of about 80° and
(3) separating the (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide crystal “Form II” from the solvent(s).
DETAILED DESCRIPTION OF THE INVENTION
Linezolid, (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, is a known pharmaceutically useful antibacterial agent, see U.S. Pat. No. 5,688,792 (EXAMPLE 5). Linezolid can be used orally or given by IV as a sterile solution.
When linezolid was originally produced, the crystal form was Form I. Form II differs from Form I in its IR spectrum, X-ray powder diffraction spectrum and melting point.
Once linezolid is synthesized, crystal Form II is prepared by starting with linezolid of high enantiomeric purity. It is preferred that the linezolid be more than 98% enantiomerically pure, it is more preferred that the linezolid be more than 99% pure and it is even more preferred that the linezolid be 99.5% pure. The linezolid of greater than 98% enantiomeric purity to be used to form crystal form II can either be in solution or be a solid. The linezolid starting material, solid or solution, is mixed with a solvent selected from the group consisting of:
water,
acetonitrile,
chloroform, methylene chloride, toluene,
R
1
—OH where R
1
is C
1
-C
6
alkyl,
R
1
—CO—R
2
where R
2
is C
1
-C
6
alkyl or phenyl substituted with 1 thru 3 R
1
where R
1
is as defined above, and where R
1
is as defined above,
R
1
—CO—O—R
2
where R
1
is C
1
-C
6
alkyl and R
1
is as defined above,
R
1
—O—R
2
where R
1 is C
1
-C
6
alkyl and R
1
is as defined above. It is preferred that the solvent be selected from the group consisting of water, ethyl acetate, methanol, ethanol, propanol, i-propanol, butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, methylene chloride, toluene, xylene, diethyl ether, or methyl-t-butyl ether. It is more preferred that the solvent be ethyl acetate, acetone, acetonitrile, propanol, or isopropanol. It is most preferred that the solvent be ethyl acetate.
The mixture of linezolid in the solvent is agitated at a temperature below 80° until crystals of Form II are formed and crystals of other solid forms, such as Form I, disappear. It is preferred to dissolve the linezolid in ethyl acetate at a temperature near the boiling point of the solvent. This mixture is cooled to a temperature of about 70°. The mixture may be seeded with crystals of Form II to facilitate crystallization. It is preferred that the solid product is cooled and agitated at a temperature between about 45° and about 60° until the solids consist only of Form II crystals. It is most preferred to maintain the slurry at a temperature of about 55°. It is preferred to mix the linezolid and solvent for at least 10 min, it is even more preferred to mix the linezolid and solvent for at least 20 min and it is most preferred to mix the linezolid and solvent for at least 30 min. The time and temperature will vary depending on the solvent selected. With ethyl acetate it is preferred to mix for not less that 60 minutes.
The crystalline slurry may be further cooled to improve yield, and the solid Form II product may be isolated. The mixture may be further cooled and agitated. Other measures which can be used to facilitate crystallization include, but are not limited to, cooling, concentration of the solution by evaporation or distillation, or through addition of other solvents.
The crystals are isolated by procedures known to those skilled in the art.
Crystal Form II is the most stable form below about 85°. It is preferred to use starting material with less than 0.2% of the R enantiomer of linezolid to minimize or eliminate the formation of a pseudoracemic solid solution of the two enantiomers which tends to crystallize as the Form I solid, even at temperatures below 85°.
It is well known to those skilled in the art that linezolid is useful as an antibacterial agent, see for example U.S. Pat. No. 5,688,792.
DEFINITIONS AND CONVENTIONS
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
DEFINlTIONS
Linezolid refers to (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide the compound of formula:
All temperatures are in degrees Centigrade.
IR refers to infrared spectroscopy.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
The term C
1
-C
6
alkyl means alkyl of 1 thru 6 carbon atoms and isomers thereof where such exist.
REFERENCES:
patent: 5688792 (1997-11-01), Barbachyn et al.
patent
Engelmann John H.
Pharmacia & Upjohn Company
Ramsuer Robert W.
LandOfFree
Linezolid—crystal form II does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Linezolid—crystal form II, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Linezolid—crystal form II will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3039415