U.S. patent application number 11/362312 was filed with the patent office on 2006-11-16 for crystalline forms of linezolid intermediate.
Invention is credited to Viviana Braude, Serguei Fine, Tamas Koltai, Tamar Nidam.
Application Number | 20060258655 11/362312 |
Document ID | / |
Family ID | 36498839 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060258655 |
Kind Code |
A1 |
Koltai; Tamas ; et
al. |
November 16, 2006 |
Crystalline forms of linezolid intermediate
Abstract
The present invention relates to novel crystalline forms of the
linezolid intermediate
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine referred to herein as Form A, Form B, and Form C.
Inventors: |
Koltai; Tamas; (Netanya,
IL) ; Nidam; Tamar; (Yehud, IL) ; Braude;
Viviana; (Kadima, IL) ; Fine; Serguei;
(Qiriat-Arbaa, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36498839 |
Appl. No.: |
11/362312 |
Filed: |
February 24, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60656778 |
Feb 24, 2005 |
|
|
|
60656646 |
Feb 24, 2005 |
|
|
|
60690822 |
Jun 14, 2005 |
|
|
|
Current U.S.
Class: |
514/235.2 ;
544/137 |
Current CPC
Class: |
A61K 31/5377 20130101;
C07D 413/10 20130101; C07D 263/20 20130101; C07D 413/14 20130101;
A61P 31/14 20180101 |
Class at
Publication: |
514/235.2 ;
544/137 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 413/02 20060101 C07D413/02 |
Claims
1. A crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) characterized by a powder X-ray diffraction (PXRD)
pattern with peaks at 13.2.+-.0.2, 14.8.+-.0.2, 15.1.+-.0.2, and
25.0.+-.0.2 degrees 2 theta.
2. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 1 further characterized by PXRD peaks at
3.0.+-.0.2, 16.1.+-.0.2, 17.9.+-.0.2, 19.3.+-.0.2, and 23.0.+-.0.2
degrees 2 theta.
3. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 1 which contains less than 5% by weight of
other crystalline forms of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II).
4. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 1, characterized by a powder X-ray diffraction
(PXRD) pattern substantially as indicated in FIG. 1.
5. A crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II), characterized by a powder X-ray diffraction (PXRD)
pattern with peaks at 15.6.+-.0.2, 19.2.+-.0.2, 22.5.+-.0.2, and
24.3.+-.0.2 degrees 2 theta.
6. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 5 further characterized by PXRD peaks at
7.2.+-.0.2, 14.6.+-.0.2, 16.5.+-.0.2, 20.1.+-.0.2, and 23.0.+-.0.2
degrees 2 theta.
7. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 5 which contains less than 5% by weight of
other crystalline forms of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II).
8. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 5, characterized by a powder X-ray diffraction
(PXRD) pattern substantially as indicated in FIG. 2.
9. A crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II), characterized by a powder X-ray diffraction (PXRD)
pattern with peaks at 5.8.+-.0.2, 11.5.+-.0.2, 19.6.+-.0.2, and
26.3.+-.0.2 degrees 2 theta.
10. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 9 further characterized by PXRD peaks at
13.2.+-.0.2, 20.4.+-.0.2, 21.6.+-.0.2, 22.3.+-.0.2, 23.0.+-.0.2,
and 23.8.+-.0.2 degrees 2 theta.
11. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 9 which contains less than 5% by weight of
other crystalline forms of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II).
12. The crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of claim 9, characterized by a powder X-ray diffraction
(PXRD) pattern substantially as indicated in FIG. 3.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional
application Ser. Nos. 60/656,778, filed Feb. 24, 2005, 60/656,646,
filed Feb. 24, 2005, and 60/690,822, filed Jun. 14, 2005, which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the solid state chemistry
of the linezolid intermediate
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine.
BACKGROUND OF THE INVENTION
[0003] Linezolid
[(S)--N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]a-
cetamide] is an antimicrobial agent. Linezolid is an oxazolidinone,
having the empirical formula C.sub.16H.sub.20FN.sub.3O.sub.4 and
the following structure (I): ##STR1##
[0004] Linezolid is described in The Merck Index (13th edition,
Monograph number: 05526, CAS Registry Number: 165800-03-3) as white
crystals, with a melting point of 181.5-182.5.degree.. Linezolid,
as well as a process for its preparation, is disclosed in U.S. Pat.
No. 5,688,792 (Example 5), European Patent No. 717738, Israeli
Patent No. 110,802, Canadian Patent No. 2,168,560, and
International Patent Publication WO 95/07271.
[0005] Crystalline Form III linezolid is disclosed in U.S. Pat. No.
6,559,305.
[0006] Linezolid is marketed in the United States by Pfizer, Inc.
as an injection, tablets, and oral suspension under the name
ZYVOX.RTM.. Its main indications are nosocomial pneumonia, skin and
skin-structure infections, and vancomycin-resistant Enterococcus
faecium infections.
[0007] U.S. Pat. No. 5,688,792 claims linezolid and its use for the
treatment of microbial infections. This patent also discloses, but
does not claim, the following method of preparation: ##STR2##
[0008] This method of preparation was also disclosed in Bricker, et
al., J. Med. Chem., 39 673-679 (1996), where it was stated that the
above route avoids the use of phosgene to make the carbamate
precursor of the oxazolidinone ring. The authors also disclose that
the use of NaN.sub.3 can be avoided by using potassium phthalimide,
followed by deblocking of the phthalimide with aqueous methyl
amine.
[0009] In the above-described synthesis, the intermediate amine,
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) ##STR3## is reacted without isolation with acetic
anhydride as an oily product, or in solution, to produce the
acetamide, linezolid (I). This is followed by procedures for
isolating the linezolid such as those described in U.S. Pat. No.
5,688,792, at col. 15, 11. 22-28 (chromatography and separation of
the desired fraction, followed by evaporation and trituration of
the product to obtain pure linezolid).
[0010] In the above-described syntheses, the intermediate azide
R--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
azide (III) ##STR4## is reduced to its corresponding amine,
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) in the solvent ethyl acetate by hydrogenation using
hydrogen gas and a palladium/carbon catalyst. These reaction
conditions lead to the production of an undesirable level of
reaction by-products, and, following the acetylation of the
intermediate amine (II) to linezolid (I), to undesirably high
levels of bis-linezolid (IV). ##STR5##
[0011] The present invention relates to the solid state physical
properties of an intermediate of linezolid,
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II). These properties can be influenced by controlling the
conditions under which
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) is obtained in solid form. One important solid state
property is its rate of dissolution in aqueous fluid or its
behavior on compaction and its storage stability.
[0012] These practical physical characteristics are influenced by
the conformation and orientation of molecules in the unit cell,
which defines a particular polymorphic form of a substance. The
polymorphic form may give rise to thermal behavior different from
that of the amorphous material or another polymorphic form. Thermal
behavior is measured in the laboratory by such techniques as
capillary melting point, thermogravimetric analysis (TGA) and
differential scanning calorimetry (DSC) and can be used to
distinguish some polymorphic forms from others. A particular
polymorphic form may also give rise to distinct spectroscopic
properties that may be detectable by powder X-ray crystallography,
solid state .sup.13C NMR spectrometry and infrared
spectrometry.
SUMMARY OF THE INVENTION
[0013] The present invention is based on the finding that the
linezolid intermediate
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) can be obtained in at least three different crystalline
forms: Form A, Form B, and Form C.
[0014] In one embodiment, the present invention provides a
crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) referred to herein as Form A, characterized by a powder
X-ray diffraction (PXRD) pattern with peaks at 13.2.+-.0.2,
14.8.+-.0.2, 15.1.+-.0.2, and 25.0.+-.0.2 degrees 2 theta or
substantially as indicated in FIG. 1.
[0015] In one embodiment, the present invention provides a
crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) referred to herein as Form B, characterized by a powder
X-ray diffraction (PXRD) pattern with peaks at 15.6.+-.0.2,
19.2.+-.0.2, 22.5.+-.0.2, and 24.3.+-.0.2 degrees 2 theta or
substantially as indicated in FIG. 2.
[0016] In one embodiment, the present invention provides a
crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) referred to herein as Form C, characterized by a powder
X-ray diffraction (PXRD) pattern with peaks at 5.8.+-.0.2,
11.5.+-.0.2, 19.6.+-.0.2, and 26.3.+-.0.2 degrees 2 theta or
substantially as indicated in FIG. 3.
[0017] These new crystalline forms were found to be chemically pure
(by HPLC) and found to be a single crystalline form (by PXRD). Each
form contains less than about 5% of other crystalline forms of
intermediate amine (II) and contains less than about 5% of the
intermediate azide (III).
FIGURES
[0018] FIG. 1 shows the powder X-ray diffractogram of linezolid
intermediate amine (II) Form A.
[0019] FIG. 2 shows the powder X-ray diffractogram of linezolid
intermediate amine (II) Form B.
[0020] FIG. 3 shows the powder X-ray diffractogram of linezolid
intermediate amine (II) Form C.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention is based on the finding that the
linezolid intermediate
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) can be obtained in at least three different crystalline
forms: Form A, Form B, and Form C. Thus, the present invention
provides novel solid crystalline forms of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II), referred to herein as Form A, Form B, and Form C.
[0022] The crystalline Forms A, B, and C may be distinguished by
their respective powder X-ray diffraction (PXRD) patterns. The
crystalline forms have characteristic PXRD peak positions in the
range of 2-40 degrees two theta. Crystalline Forms A, B, and C can
be identified by these characteristic peak positions and the
identity and quantify of their crystalline impurities can also be
determined.
[0023] In one embodiment, the present invention provides a
crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) referred to herein as Form A, characterized by a powder
X-ray diffraction (PXRD) pattern with peaks at 13.2.+-.0.2,
14.8.+-.0.2, 15.1.+-.0.2, and 25.0.+-.0.2 degrees 2 theta. Form A
maybe further characterized by PXRD peaks at 3.05 +0.2,
16.1.+-.0.2, 17.9.+-.0.2, 19.3.+-.0.2, and 23.0.+-.0.2 degrees 2
theta, substantially as depicted in FIG. 1.
[0024] In one embodiment, the present invention provides a
crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) referred to herein as Form B, characterized by a powder
X-ray diffraction (PXRD) pattern with peaks at 15.6.+-.0.2,
19.2.+-.0.2, 22.5.+-.0.2, and 24.3.+-.0.2 degrees 2 theta. Form B
may be further characterized by PXRD peaks at 7.2.+-.0.2,
14.6.+-.0.2, 16.5.+-.0.2, 20.1.+-.0.2, and 23.0.+-.0.2 degrees 2
theta, substantially as depicted in FIG. 2.
[0025] In one embodiment, the present invention provides a
crystalline
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) referred to herein as Form C, characterized by a powder
X-ray diffraction (PXRD) pattern with peaks at 5.8.+-.0.2,
11.5.+-.0.2, 19.6.+-.0.2, and 26.3.+-.0.2 degrees 2 theta. Form C
may be further characterized by PXRD peaks at 13.2.+-.0.2,
20.4.+-.0.2, 21.6.+-.0.2, 22.3.+-.0.2, 23.0.+-.0.2, and 23.8.+-.0.2
degrees 2 theta, substantially as depicted in FIG. 3.
[0026] The characteristic PXRD peaks of the novel crystalline forms
of the intermediate amine (II) are shown in Table 1, with the most
characteristic peaks indicated in bold. TABLE-US-00001 TABLE 1
Characteristic PXRD peaks in degrees 2 theta Form A Form B Form C
3.0 7.2 5.8 13.2 14.6 11.5 14.8 15.6 13.2 15.1 16.5 19.6 16.1 19.2
20.4 17.9 20.1 21.6 19.3 22.5 22.3 23.0 23.0 23.0 25.0 24.3 23.8
26.3
[0027] The crystalline Forms A, B, and C of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) of the present invention may be substantially pure with
respect to other crystalline forms, i.e., the novel forms contain
less than about 10%, preferably less than about 5%, and even more
preferably less than about 1% (by weight) of other crystalline
forms of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II). In certain embodiments, the novel crystalline forms
contain less than about 10%, preferably less than about 5%, and
even more preferably less than about 1% (by weight) of amorphous
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II).
[0028] The present invention is not intended to encompass true
solutions of
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) wherein the crystal structure of the novel crystalline
Forms A, B, and C and the properties that distinguish the novel
crystalline forms of the present invention are lost. Thus, the
preferred form of the present invention is that of solid forms of
crystalline Forms A, B, and C. However, the use of the novel forms
to prepare solutions (e.g., so as to provide a material for
conversion into linezolid (I)) is considered to be within the
contemplation of the invention.
[0029] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the preparation of the composition and methods
of use of the invention. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may
be practiced without departing from the scope of the invention.
HPLC Method
[0030] Column Hypersil Gold 150.times.4.6, 5.mu.
[0031] Detection limit: 0.1%
[0032] Eluents: K.sub.2HPO.sub.4 0.01M: MeOH A: 80:20 B: 50:50
TABLE-US-00002 TABLE 2 Time A B Flow 0 100 0 1.5 15 57 43 2 25 35
65 2
Powder X-Ray Diffraction
[0033] Powder X-ray diffraction data were obtained by methods known
in the art using a SCINTAG.RTM. powder X-ray diffractometer model
X'TRA.RTM. equipped with a solid state detector. Copper radiation
of 1.5418 .ANG. was used. A round aluminum sample holder with round
zero background quartz plate was used, with cavity of 25(diameter)*
0.5(depth) mm. The obtained characteristic peaks were in the range
of 2-40 degrees two theta.
EXAMPLES
Example 1
Preparation of Intermediate Amine (II) Crystalline Form B
[0034] In a 1L reactor, 6 g
R--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
azide (III) was charged with 150 ml ethyl acetate, followed by 0.6
g 10% Pd/C. The system was flushed 3 times with nitrogen and 3
times with hydrogen. The pressure of hydrogen was set to 1.5 atm.
The reaction mixture was stirred at RT and the reaction followed by
TLC or HPLC until completion. The reaction mixture was filtered
through celite and the solution was evaporated to obtain 4.6 g
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) as a white solid. The crystals were analyzed by PXRD and
showed a novel form of) the intermediate amine (II) (Form B, 91.7%
total purity by HPLC).
Example 2
Preparation of Intermediate Amine (II) Crystalline Form C
[0035] In a 10L reactor, 150 g
R--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
azide (III) was charged, followed by 15 g Pd/C in 5L toluene.
Finally 500 ml ammonium hydroxide was added. The system was flushed
3 times with nitrogen and 3 times with hydrogen. The pressure of
hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT
and the reaction followed by TLC or HPLC until completion. The
reaction mixture was filtered through celite.
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) precipitated on standing and/or cooling as a white
solid, was filtered, and dried at 50.degree. C. overnight. The
crystals obtained were analyzed by PXRD and showed a novel form of
the intermediate amine (II) (Form C, 98.6% total purity by
HPLC).
Example 3
Preparation of Intermediate Amine (II) Crystalline Form A
[0036] In a three necked flask, 6.4 g
R--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
azide (III) was charged, followed by 2.5 g ammonium formate, 23 ml
ethanol, and 2.6 g zinc powder. The reaction mixture was stirred at
RT and the reaction followed by TLC or HPLC until completion. 60 ml
acetone were then added. The reaction mixture was filtered and by
evaporation
S--N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine (II) was obtained as a solid. The crystals obtained were
analyzed by PXRD and showed a novel form of the intermediate amine
(II) (Form A, 96.5% total purity by HPLC).
* * * * *