U.S. patent application number 10/730949 was filed with the patent office on 2004-07-01 for method for synthesizing leflunomide.
Invention is credited to Avrutov, Ilya, Gershon, Neomi, Liberman, Anita.
Application Number | 20040127532 10/730949 |
Document ID | / |
Family ID | 22669359 |
Filed Date | 2004-07-01 |
United States Patent
Application |
20040127532 |
Kind Code |
A1 |
Avrutov, Ilya ; et
al. |
July 1, 2004 |
Method for synthesizing leflunomide
Abstract
A process for synthesizing leflunomide from
5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline is
provided. Further provided is the leflunomide prepared by the
inventive process, which is substantially free of
difficult-to-separate impurities often found in leflunomide
prepared by known methods, including
N-(4-trifluoromethylphenyl)-2-cyano-- 3-hydroxycrotonamide,
5-methyl-N-(4-methylphenyl)-isoxazole-4-carboxamide and
N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide. The
invention further provides pharmaceutical compositions and dosage
forms containing highly pure leflunomide and methods of treating
disease using the leflunomide.
Inventors: |
Avrutov, Ilya; (Bat Hefer,
IL) ; Gershon, Neomi; (Kfar Saba, IL) ;
Liberman, Anita; (Ramat Aviv, IL) |
Correspondence
Address: |
KENYON & KENYON
Suite 700
1500 K Street
Washington
DC
20005
US
|
Family ID: |
22669359 |
Appl. No.: |
10/730949 |
Filed: |
December 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10730949 |
Dec 10, 2003 |
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09779928 |
Feb 8, 2001 |
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6723855 |
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60182635 |
Feb 15, 2000 |
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Current U.S.
Class: |
514/378 ;
548/248 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 11/02 20180101; A61P 29/00 20180101; A61P 17/06 20180101; C07D
261/18 20130101; A61P 19/02 20180101; A61P 37/06 20180101; A61P
3/10 20180101; A61P 27/02 20180101; A61P 35/00 20180101; A61K 31/42
20130101 |
Class at
Publication: |
514/378 ;
548/248 |
International
Class: |
C07D 261/18; A61K
031/42 |
Claims
We claim:
1. A process for preparing leflunomide comprising the steps of a)
chlorinating 5-methylisoxazole-4-carboxylic acid by contacting it
with a chlorinating agent thereby forming crude
5-methylisoxazole-4-carboxylic acid chloride, b) optionally
evaporating excess chlorinating agent or volatile byproducts of the
chlorination under reduced pressure, whereby evaporation leaves a
residue of unevaporated material containing
5-methylisoxazole-4-carboxylic acid chloride, c) contacting the
so-formed crude 5-methylisoxazole-4-carboxylic acid chloride or
residue with 4-trifluoromethylaniline in the presence of an alkali
metal or alkaline-earth metal bicarbonate in an acylation solvent
system comprising at least one solvent component selected from the
group consisting of water, ethyl acetate, toluene and dimethyl
acetamide, and d) isolating the leflunomide.
2. The process of claim 1 wherein the chlorinating step is
conducted in the absence of N,N-dimethylformamide.
3. The process of claim 1 wherein the chlorinating step is
conducted in the absence of a catalyst.
4. The process of claim 1 wherein the chlorinating step is
conducted neat at a temperature of from about 40.degree. to about
55.degree. C.
5. The process of claim 1 wherein 5-methylisoxazole-4-carboxylic
acid is contacted with the chlorinating agent in an inert
chlorination solvent at a temperature of from about 50.degree. C.
to about 80.degree. C.
6. The process of claim 5 wherein the inert chlorination solvent is
toluene.
7. The process of claim 1 wherein the chlorinating agent is
selected from the group consisting of thionyl chloride, oxalyl
chloride, benzoyl chloride, PCl.sub.5 and PCl.sub.3.
8. The process of claim 7 wherein the chlorinating agent is thionyl
chloride.
9. The process of claim 1 wherein the at least one solvent
component of the acylation solvent system is water.
10. The process of claim 1 wherein the acylation solvent system is
a mixture of toluene and water.
11. The process of claim 1 wherein the acylation solvent system is
a mixture of toluene and N,N-dimethyl acetamide.
12. The process of claim 1 wherein the crude
5-methylisoxazole-4-carboxyli- c acid chloride or residue is
contacted with 4-trifluoromethylaniline at a temperature of from
about 20.degree. C. to about 65.degree. C.
13. The process of claim 12 wherein the crude
5-methylisoxazole-4-carboxyl- ic acid chloride or residue is
contacted with 4-trifluoromethylaniline at a temperature of from
about 40.degree. C. to about 60.degree. C.
14. The process of claim 1 wherein the crude
5-methylisoxazole-4-carboxyli- c acid chloride or residue is
contacted with from about 1 to about 1.2 molar equivalents of
4-trifluoromethylaniline with respect to
5-methylisoxazole-4-carboxylic acid.
15. The process of claim 1 wherein the alkali metal or
alkaline-earth metal bicarbonate is present in from about 1.05 to
about 1.2 molar equivalents with respect to the
5-methylisoxazole-4-carboxylic acid chloride.
16. The process of claim 1 wherein contacting the crude
5-methylisoxazole-4-carboxylic acid chloride or residue with
4-trifluoromethylaniline is conducted at a concentration of from
about 4 to about 14 volumes of the acylation solvent system per one
weight part of 5-methylisoxazole-4-carboxylic acid chloride.
17. The process of claim 16 wherein contacting the crude
5-methylisoxazole-4-carboxylic acid chloride or residue with
4-trifluoromethylaniline is conducted at a concentration of from
about 4 to about 14 volumes of the acylation solvent system per one
weight part of 5-methylisoxazole-4-carboxylic acid chloride.
18. The process of claim 1 wherein the leflunomide is isolated by
precipitation from the acylation solvent system.
19. The process of claim 18 wherein the leflunomide is precipitated
at a temperature of from about 0.degree. C. to about 25.degree.
C.
20. The process of claim 18 wherein the leflunomide obtained by
precipitation is substantially free of
N-(4-trifluoromethylphenyl)-2-cyan- o-3-hydroxycrotonamide.
21. The process of claim 20 wherein the leflunomide obtained by
precipitation contains about 150 ppm or less of
N-(4-trifluoromethylpheny- l)-2-cyano-3-hydroxycrotonamide.
22. The process of claim 21 wherein the leflunomide obtained by
precipitation contains about 100 ppm or less of
N-(4-trifluoromethylpheny- l)-2-cyano-3-hydroxycrotonamide.
23. The process of claim 22 wherein the leflunomide obtained by
precipitation contains about 50 ppm or less of
N-(4-trifluoromethylphenyl- )-2-cyano-3-hydroxycrotonamide.
24. The process of claim 23 wherein the leflunomide obtained by
precipitation contains about 10 ppm or less of
N-(4-trifluoromethylphenyl- )-2-cyano-3-hydroxycrotonamide.
25. The process of claim 18 wherein the leflunomide obtained by
precipitation is substantially free of
5-methyl-N-(4-methylphenyl)-isoxaz- ole-4-carboxamide.
26. The process of claim 18 wherein the leflunomide obtained by
precipitation is substantially free of
N-(4-trifluoromethylphenyl)-3-meth- yl-isoxazole-4-carboxamide.
27. Leflunomide prepared by a process comprising the steps of: a)
providing 5-methylisoxazole-4-carboxylic acid chloride and b)
contacting the 5-methylisoxazole-4-carboxylic acid chloride with
4-trifluoromethylaniline in the presence of an alkali metal or
alkaline-earth metal bicarbonate in an acylation solvent system
comprising at least one solvent component selected from the group
consisting of water, ethyl acetate, toluene and dimethyl acetamide,
and c) isolating the leflunomide.
28. The leflunomide of claim 27 wherein
5-methylisoxazole-4-carboxylic acid chloride is provided as crude
5-methylisoxazole-4-carboxylic acid or a residue by: a)
chlorinating 5-methylisoxazole-4-carboxylic acid by contacting it
with a chlorinating agent to form crude
5-methylisoxazole-4-carboxylic acid chloride and b) optionally
evaporating excess chlorinating agent or volatile byproducts of the
chlorination under reduced pressure, whereby the evaporation leaves
a residue of unevaporated material containing
5-methylisoxazole-4-carboxyli- c acid chloride.
29. The leflunomide of claim 27 which is substantially free of
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
30. The leflunomide of claim 29 containing about 150 ppm or less of
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
31. The leflunomide of claim 30 containing about 100 ppm or less of
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
32. The leflunomide of claim 31 containing about 50 ppm or less of
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
33. The leflunomide of claim 32 containing about 10 ppm or less of
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
34. The leflunomide of claim 27 which is substantially free of
5-methyl-N-(4-methylphenyl)-isoxazole-4-carboxamide.
35. The leflunomide of claim 27 which is substantially free of
N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide.
36. The leflunomide of claim 27 substantially free of
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide,
5-methyl-N-(4-methylphenyl)-isoxazole-4-carboxamide and
N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide.
37. A pharmaceutical composition comprising the leflunomide of any
of claims 27 through 36.
38. A pharmaceutical dosage form comprising the pharmaceutical
composition of claim 37.
39. A method of treating rheumatoid arthritis comprising
administering to a patient in need of such treatment a
therapeutically effective amount of the leflunomide of any of
claims 27 through 36.
40. A method of regulating cell proliferation comprising
administering to a patient a an amount of the leflunomide of any of
claims 27 through 36 sufficient to inhibit cell proliferation.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the anti-proliferative
compound leflunomide and to a process for synthesizing
leflunomide.
BACKGROUND OF THE INVENTION
[0002] Pyrimidine biosynthesis is an essential function of cells.
It is the biosynthetic pathway to the DNA base constituents of
uracil, cytosine and thymine and produces precursors of molecules
used in the synthesis of ATP, several cofactors and other important
cell components. Uracil, cytosine and thymine are essential to DNA
replication during cell proliferation. [Prescott, L. M.; Harley, J.
P.; Klein D. A. Microbiology 203 (4th ed., McGraw Hill, 1999)].
Many diseases are caused by or are aggravated by the failure of
natural mechanisms to regulate cell proliferation, such as cancer
and some inflammatory diseases like rheumatoid arthritis. Most
cancer therapies attempt to suppress the proliferation of rapidly
dividing cells. Disruption of the pyrimidine biosynthesis pathway
is one way to suppress proliferation of rapidly dividing cells
because the disruption interferes with the cell's ability to
replicate DNA.
[0003] Pyrimidine biosynthesis is a series of enzymatically
catalyzed processes that convert carbamoyl phosphate and aspartic
acid into cytidine triphosphate. About midway along the pathway
lies the conversion of dihydroorotic acid to orotic acid by the
dehydroorotate dehydrogenase enzyme. Leflunomide
N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carb- oxamide (I),
disrupts pyrimidine biosynthesis by inhibiting this enzyme. 1
[0004] Leflunomide has been shown to be effective for treatment of
the inflammatory disease rheumatoid arthritis although the
mechanism by which it causes this particular therapeutic effect is
not completely understood.
[0005] The first report of the anti-rheumatic property of
leflunomide appeared in U.S. Pat. No. 4,284,786, which disclosed
that leflunomide reduced symptoms of adjuvant arthritis in a rat
model. This patent also reported that leflunomide may be prepared
by reacting a 4-trifluoromethylaniline ("TFMA") with a
5-methylisoxazole-4-carboxylic acid ("MIA") derivative. In U.S.
Pat. No. 4,284,786, Example (a1), 5-methylisoxazole-4-carboxylic
acid chloride ("MIA-Cl") is reacted with two molar equivalents of
TFMA in acetonitrile. This preparation is uneconomical on a large
scale because acetonitrile is an expensive solvent.
[0006] TFMA is used as a scavenger of the HCl byproduct in the
reaction of Example (a1). TFMA is too expensive to be used in this
manner in a commercial process. We found that using triethyl amine
("Et.sub.3N," pK.sub.b=3.25) as an acid scavenger as described in
Example (a3) of the '786 patent causes significant decomposition of
leflunomide to
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide ("HCA") of
formula (II). 2
[0007] Although HCA is the active metabolite of leflunomide that
forms in a patient's body, its presence in a pharmaceutical
composition is problematic for accurate dosing and also affects
other aspects of pharmaceutical processing. An alternative process
for making leflunomide that is described in the '786 patent uses
the Schotten-Baumann procedure to produce leflunomide with a
minimum of contamination by HCA (Example a2 of the '786 patent).
However, careful simultaneous addition of MIA-Cl and KOH is
required for pH control. Any failure in the simultaneous delivery
can lead to a rapid decomposition of leflunomide to HCA. A batch
preparation which would not require the equipment, maintenance or
sophisticated mechanical expertise for careful flow control would
be preferable for a large scale commercial process for
manufacturing leflunomide.
[0008] In addition to the problem of HCA formation, the production
of substantially pure leflunomide is problematic because of the
formation of byproducts derived from impurities in the starting
materials. Two such impurities have chemical reactivities similar
to MIA and TFMA and are carried through the process of the '786
patent to form byproducts that must be removed before the
leflunomide can be used as an active ingredient in pharmaceutical.
3-Methyl-isoxazole-4-carboxylic acid is a common impurity in
commercially available MIA. 3-Methyl-isoxazole-4-carbo- xylic acid
originating in MIA is transformed by chlorination and reaction with
TFMA to
N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide (III).
Another troublesome impurity in leflunomide derives from 4-methyl
aniline, which is commonly present in minor amounts in TFMA
obtained from commercial sources. 4-Methyl aniline forms
5-methyl-N-(4-methylphenyl)-is- oxazole-4-carboxamide (IV) upon
reaction with MIA-Cl. 3
[0009] It thus would be highly desirable to have available a
process for preparing leflunomide substantially free of impurites
(II), (III) and (IV) that could be conducted without careful
reagent flow control and without costly solvents and bases.
[0010] The manufacture of the intermediate MIA-Cl in sufficient
purity is also problematic for reasons other than the presence of
impurities in the starting materials and the sensitivity of
leflunomide to base-induced decomposition. According to a method
disclosed in U.S. Pat. No. 4,892,963, Example 2(vi), MIA-Cl may be
prepared by reacting MIA with thionyl chloride in the presence of
N,N-dimethylformamide ("DMF") as a catalyst. It has been found that
minor amounts of DMF left in the product after evaporation of
excess thionyl chloride causes the MIA-Cl to discolor quickly.
Discolored MIA-Cl produces leflunomide that is also discolored and
too low in purity to be used as an active pharmaceutical
ingredient. Additional purification steps are required to render
the leflunomide pharmaceutically acceptable. Therefore, it is
highly desirable that the MIA-Cl that is used to prepare
leflunomide be as free as possible of DMF. High vacuum distillation
is required to substantially remove high boiling DMF
(bp=153.degree. C. at 760 torr) from the MIA-Cl. The high vacuum
(from 0.1 to 20 torr) required for that separation requires an
additional investment in equipment. Further, it has been reported
that even trace amounts of DMF remaining in the residue after high
vacuum distillation can lead to discoloration of the obtained
MIA-Cl and color problems with leflunomide.
[0011] MIA-Cl has been prepared without DMF as catalyst.
[Doleschall, G.; Seres, P. J. Chem. Soc. Perkin Trans. I, 1988,
1875-1879]; [Fossa, P.; Menozzi, G.; Schenone, P. Il Farmaco, 1991,
46, 789-802]. However, high reaction temperatures and distillation
of the resulting MIA-Cl were required. High reaction temperatures
also can lead to discoloration of the MIA-Cl. Moreover, MIA-Cl can
explode during distillation if the temperature is allowed to get to
high. [Doleschall, et al., at p. 1877]. It therefore would also be
highly desirable in a process for preparing leflunomide in high
purity from MIA, via an MIA-Cl intermediate, that the MIA-Cl be
formed under conditions that do not require that it be distilled
before it is used to make leflunomide.
SUMMARY OF THE INVENTION
[0012] The present invention provides a practicable, economic
process for preparing leflunomide in high yield, high purity and on
a large scale from 5-methylisoxazole-4-carboxylic acid and
4-trifluoromethylaniline. The inventive process comprises the steps
of chlorinating 5-methylisoxazole-4-carboxylic acid to form
5-methylisoxazole-4-carboxyli- c acid chloride, contacting the
resulting 5-methylisoxazole-4-carboxylic acid chloride, without
intermediate distillation, with 4-trifluoromethylaniline in the
presence of an alkali metal or alkaline-earth metal bicarbonate and
a solvent and crystalizing the leflunomide from the solvent.
Suitable reaction solvents include water, ethyl acetate, toluene
and dimethyl acetamide.
[0013] The present invention provides leflunomide substantially
free of HCA and other impurities. The present invention further
provides compositions and dosage forms for treating rheumatoid
arthritis and other proliferative diseases that contain leflunomide
made according to the present invention as well as methods of
treating rheumatoid arthritis and other proliferative diseases with
leflunomide.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides a practicable, economic
process for synthesizing leflunomide in high yield, high purity and
on a large scale. We have discovered an improved process for
preparing leflunomide from the commercially available materials
5-methylisoxazole-4-carboxylic acid ("MIA") and
4-trifluoromethylaniline (Aldrich Cat. No. 22,493-6, 1998-1999). As
described in Doleschall, G.; Seres, P. J. Chem. Soc. Perkin Trans.
I, 1988, 1875-1879, MIA may be prepared by reacting ethyl
acetoacetate, acetic anhydride, triethyl orthoformate to form ethyl
ethoxymethyleneacetoacetate and reacting the product of that
reaction with hydroxylamine hydrochloride and sodium acetate
trihydrate.
[0015] The process of the present invention is represented
schematically as follows and includes experimental aspects which
are set forth in the accompanying detailed written description.
4
[0016] The process is a two step synthesis of leflunomide from
5-methylisoxazole-4-carboxylic acid and 4-trifluoromethyl aniline
which does not require a distillation between the first and second
step in order to purify the intermediate
5-methylisoxazole-4-carboxylic acid chloride ("MIA-Cl"). The
leflunomide product of the second step can be precipitated from the
reaction mixture in high purity. Although it may be desirable to
further purify the leflunomide, leflunomide can be obtained in a
pharmaceutically acceptable state of purity without further
purification by using the method of this invention.
[0017] In the first step, the chlorinating step, MIA is contacted
with a chlorinating agent to convert it to the corresponding acyl
chloride, MIA-Cl. Those skilled in the art will appreciate that if
the reaction of MIA with a chlorinating agent does not go to
completion, it is necessary to distill MIA-Cl in order to separate
it from unreacted MIA. Otherwise, the process will suffer a "double
hit." Some of the MIA will not be converted to the necessary
intermediate compound, MIA-Cl, resulting in a lower yield, and the
unconverted MIA will compete for TFMA by forming a salt that
renders the TFMA less reactive toward the MIA-Cl, which further
lowers the yield. Therefore, the chlorinating reaction needs to go
to substantial completion with or without a catalyst. It has been
found that MIA can be converted to MIA-Cl in reasonable reaction
times and at a lower temperature than by known methods without
using DMF as a catalyst. The MIA-Cl produced according to the
process of the present invention is suitable for use in the second
step of the inventive process for synthesizing leflunomide, without
distillation or other purification apart from evaporation of
volatile substances.
[0018] The preferred chlorinating agent is thionyl chloride,
SOCl.sub.2, though other chlorinating agents may be used, such as
oxalyl chloride, benzoyl chloride, PCl.sub.5 or PCl.sub.3. In the
Examples that follow, thionyl chloride was used. The chlorinating
agent is preferably used in 5 molar excess or greater.
[0019] MIA and the chlorinating agent may be contacted at room
temperature in a vessel equipped with means for mechanically
agitating (e.g. stirring), heating and evacuating the vessel. The
order of addition of MIA and the chlorinating agent is not
critical. Either before or after contacting, the temperature of the
vessel is preferably raised to between about 40.degree. C. and
about 55.degree. C., more preferably between about 45.degree. C.
and about 50.degree. C. and the reaction mixture is preferably
agitated at this temperature for an amount of time sufficient for
completion of the reaction, typically 4 to 6 hours. The time
required for complete reaction will depend upon temperature, the
ratio of MIA to the chlorinating agent and solvent, if any. The
MIA-Cl obtained after the reaction between MIA and the chlorinating
agent is substantially complete is referred to hereinafter as
"crude MIA-Cl."
[0020] Any excess chlorinating agent and volatile byproducts should
be removed after the MIA has been substantially converted to
MIA-Cl. Removal of the excess chlorinating agent and volatile
byproducts is preferably conducted by evaporation under vacuum.
Evaporation is preferably done at a pot temperature of 80.degree.
C. or less under a vacuum of about 50 torr or greater because these
conditions do not evaporate MIA-Cl at a significant rate or require
expensive high vacuum equipment.
[0021] The chlorinating step may be conducted either neat or in an
inert chlorination solvent. An inert chlorination solvent is any
solvent that does not react with thionyl chloride or MIA-Cl.
Preferred inert chlorination solvents have a boiling point higher
than 76.degree. C., the boiling point of thionyl chloride, and can
therefore function as a chaser during evaporation of excess thionyl
chloride. Alternative preferred inert chlorination solvents may
have a boiling point above or below 76.degree. C. and form
azeotropes with thionyl chloride. A particularly preferred inert
chlorination solvent is toluene. When the chlorinating step is
conducted in a solvent, the ratio of MIA to inert chlorination
solvent is preferably from about 1:3 to about 1:10.
[0022] Evaporation of excess thionyl chloride and other byproducts
tends to occur faster at a given temperature and pressure when the
chlorination is performed in an inert chlorination solvent than
when it is performed neat. For instance, at 80.degree. C. and 55
torr, complete evaporation takes about 3 to 6 hours from a reaction
mixture in toluene, much less than the 9-18 hours that may be
required when no solvent is used. However, using a solvent tends to
slow the chlorination reaction. A reaction performed in solvent can
be accellerated by using a higher temperature (e.g. 78-80.degree.
C.). Although higher temperatures tend to cause discoloration when
the chlorination is conducted neat, there is little or no
discoloration when the reaction is conducted in toluene at the
reflux temperature of thionyl chloride. Accordingly, the preferred
temperature range for chlorinating MIA is from about 50.degree. C.
to about 80.degree. C. when an inert chlorination solvent is used.
The resulting MIA-Cl is suitable for use in the second, acylation,
step of the invention without distillation. The contents remaining
in the vessel after removal of any excess chlorinating agent or
volatile byproducts is referred to hereinafter as "the
residue."
[0023] In the second step, the acylation step, of the inventive
process, the crude MIA-Cl or residue is contacted with TFMA. The
acylation step produces HCl in addition to leflunomide. The. HCl
will tend to form a hydrochloride salt with unreacted TFMA,
deactivating it toward nucleophilic addition to the acyl chloride
functionality of MIA-Cl. An acid scavenger is therefore provided in
order to prevent this deactivation.
[0024] The use of acid scavengers in acylation reactions that
eliminate HCl is known to the art. Compounds such as leflunomide
that are base sensitive may be decomposed by injudicious selection
of an acid scavenger. In addition to discussing the use of NaOH and
Et.sub.3N as acid scavengers, U.S. Pat. No. 4,284,786 suggests the
use of carbonates, alcoholates and amine bases like pyridine,
picoline and quinoline, though the list is hardly exhaustive of the
possibilities that may be tried. No examples of such processes are
disclosed. We found that none of the bases mentioned were suited to
making leflunomide that is free of significant contamination with
HCA.
[0025] It has now been found that sodium bicarbonate (NaHCO.sub.3)
and other alkali metal and alkaline-earth metal (i.e. Groups I and
II) bicarbonates are far superior acid scavengers to those
suggested by the '786 patent. Particularly preferred acid
scavengers are NaHCO.sub.3 and potassium bicarbonate (KHCO.sub.3),
the most preferred being NaHCO.sub.3.
[0026] The acylation step of the present invention is conducted in
a solvent system rather than neat. The acylation solvent system may
be a one-component system or a system of two or more components.
The solvent components include water, esters (preferably ethyl
acetate), aromatic hydrocarbons such as toluene and substituted and
unsubstituted carboxamides such as N,N-dimethylacetamide.
Accordingly, the acylation solvent system may include any of these
components individually or in mixtures with each other and any
other solvents whose presence does not significantly retard the
reaction of MIA-Cl and TFMA. The preferred solvent components of
the present invention are water, toluene and
N,N-dimethylacetamide.
[0027] Water may be used alone advantageously because bicarbonates
are generally soluble in water. However, dissolution of the
bicarbonate is not an essential feature of this invention. For
instance, sodium bicarbonate may scavenge HCl as a suspended solid
or sediment in reactions conducted in ethyl acetate and
toluene.
[0028] In the acylation step of the inventive process, the crude
MIA-Cl or residue is contacted with TFMA in the presence of the
above-described bicarbonates in the acylation solvent system.
Preferably, the crude MIA-Cl or residue is added to a solution or
suspension of TFMA and the bicarbonate in the acylation solvent
system. The addition should be conducted at a temperature of from
about 20.degree. C. to about 65.degree. C., more preferably about
40.degree. C. to about 60.degree. C. External heat may be applied
to attain the desired temperature and, in addition, the
exothermicity of the reaction may assist in achieving and/or
maintaining the reaction temperature. The temperature of the
reaction mixture should not be allowed to rise above about
65.degree. C. When necessary, the temperature may be modulated by
adjusting the rate of addition of MIA-Cl or by external
cooling.
[0029] TFMA is preferably used in slight excess over MIA-Cl,
preferably from 1 to 1.2 molar equivalents, more preferably about
1.05 molar equivalents.
[0030] The bicarbonate acid scavenger is also preferably used in
only modest molar excess over MIA-Cl, preferably from about 1 to
about 3 molar equivalents, more preferably about 1.0-1.5 molar
equivalents, yet more preferably about 1.05 to about 1.2 molar
equivalents and most preferably about 1.1 molar equivalents. Alkali
metal and alkaline-earth metal bicarbonates typically have been
used in large excess over the substrates of the reaction when they
have been used as acid scavengers. It has been found that a large
excess of bicarbonate is not required for acid scavenging in the
reaction of MIA-Cl with TFMA.
[0031] The acylation step of the inventive process is preferably
conducted in a relatively highly concentrated solution. One of the
advantages of high concentration is the improved yield of
leflunomide that is obtained when leflunomide is precipitated from
the reaction mixture, as described below. Accordingly, the
acylation is preferably conducted using from about 4 to about 14 ml
of solvent per gram of MIA-Cl, more preferably from about 5 to
about 7 ml of solvent per gram of MIA-Cl.
[0032] Progress of the acylation may be monitored by any of the
methods known to the chemical arts such as thin layer
chromatography, gas chromatography or HPLC chromatography.
[0033] Leflunomide can be isolated in high purity by precipitation
from the acylation reaction mixture. To precipitate leflunomide,
the reaction mixture should be allowed to cool, preferably to a
temperature of between about 0.degree. C. and about 25.degree. C.,
most preferably about 25.degree. C. or ambient temperature of the
laboratory or facility. The reaction mixture also may be cooled to
any temperature that does not solidify it. The precipitated
leflunomide may then be separated by filtration, decantation and
the like, preferably by filtration, and optionally washed and/or
dried. Leflunomide obtained by crystallization from the reaction
mixture is substantially free of HCA (II),
N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide (III)
and 5-methyl N-(4-methylphenyl)-isoxazole-4-carboxamide (IV). Using
the present inventive process, leflunomide can be obtained that
contains HCA (II) in less than about 150 ppm, more preferably less
than about 100 ppm and most preferably less than about 50 ppm.
[0034] Leflunomide also may be isolated by other methods known in
the art. For example, it can be isolated by evaporation of volatile
substances and chromatography of the residue or crystallization of
leflunomide from the residue using an appropriate recrystallization
solvent. Likewise, leflunomide also may be separated from other
substances by extraction techniques.
[0035] The resulting leflunomide may be used directly or after
further purification in pharmaceutical compositions and dosage
forms as described, for instance, in commonly-assigned co-pending
application Ser. No. [Attorney docket No. 1662/50702] which is
herein incorporated by reference in its entirety.
[0036] The leflunomide obtained by practice of the present
invention is suitable for the treatment of autoimmune disease like
rheumatoid arthritis, systemic lupus erythematosis and multiple
sclerosis; psoriasis, atopic dermatitis, asthma, urticaria,
rhinitis, uveitis, type II diabetes, liver fibrosis, cystic
fibrosis, colitis, and cancers and acute immunological diseases
such as sepsis, allergies, graft-versus-host disease and
host-versus-graft disease. The leflunomide obtained by the
presently claimed process may be presented to a patient in need of
therapy in the form of a dosage. Dosage forms are made from
pharmaceutical compositions. Pharmaceutical compositions may
contain a pharmaceutically acceptable vehicle, i.e. one or more
pharmaceutical excipients in addition to the leflunomide.
[0037] The pharmaceutical compositions of the present invention may
have few or many excipients depending upon the release rate desired
and the dosage form used. For example, pharmaceutical compositions
of the present invention may contain diluents such as
cellulose-derived materials like powdered cellulose,
microcrystalline cellulose, microfine cellulose, methyl cellulose,
ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and
other substituted and unsubstituted celluloses; starch;
pregelatinized starch; inorganic diluents like calcium carbonate
and dibasic calcium diphosphate and other diluents known to the
pharmaceutical industry. Yet other suitable diluents include waxes,
sugars and sugar alcohols like mannitol and sorbitol, lactose,
lactose monohydrate and spray dried lactose, acrylate polymers and
copolymers, as well as pectin, dextrin and gelatin. Such diluents
may affect the rate of dissolution and absorption.
[0038] Other excipients include tablet binders, such as povidone,
acacia gum, pregelatinized starch, sodium alginate, glucose and
other binders used in wet and dry granulation and direct
compression tableting processes. Excipients that may also be
present in a solid composition further include disintegrants like
sodium starch glycolate, crospovidone, low-substituted
hydroxypropyl cellulose and others. Additional excipients include
tableting lubricants like magnesium and calcium stearate, sodium
stearyl fumarate and polyethylene glycol; flavorings; sweeteners;
preservatives; pharmaceutically acceptable dyes; and glidants such
as silicon dioxide and talc.
[0039] Whether used in pure form or in a composition, leflunomide
obtained by the claimed process may be in the form of a powder,
granules, aggregates or any other solid form. The leflunomide may
also be used to prepare solid pharmaceutical compositions by
blending, mixing, wet granulation, dry granulation or other
methods.
[0040] The dosages may be adapted for administration to the patient
by oral, buccal, parenteral, ophthalmic, rectal and transdermal
routes. Oral dosages include tablets, pills, capsules, troches,
sachets, suspensions, powders, lozenges, elixirs and the like. The
leflunomide also may be administered as suppositories, ophthalmic
ointments and suspensions, and parenteral suspensions. The most
preferred route of administration of the leflunomide is oral.
[0041] Capsule dosages will contain the solid composition within a
capsule which may be made of gelatin or other encapsulating
material. Tablets and powders may be coated. Tablets and powders
may be coated with an enteric coating. The enteric-coated powder
forms may have coatings comprising phthalic acid cellulose acetate,
hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol
phthalate, carboxymethylethylcellulose, a copolymer of styrene and
maleic acid, a copolymer of methacrylic acid and methyl
methacrylate, and like materials, and if desired, they may be
employed with suitable plasticizers and/or extending agents. A
coated tablet may have a coating on the surface of the tablet or
may be a tablet comprising a powder or granules with an
enteric-coating.
[0042] Preferred oral dosages of the present invention contain from
about 20 mg to about 100 mg of leflunomide obtained by the process
of the present invention.
[0043] Having thus described the present invention with reference
to certain preferred embodiments, the following examples are
provided to further illustrate the inventive process for
synthesizing leflunomide. One skilled in the art will recognize
variations and substitutions in the methods as described and
exemplified which do not depart from the spirit and scope of the
invention.
EXAMPLES
Example 1
Preparations of 5-methylisoxazole-4-carboxylic acid chloride
[0044] a) A mixture of 5-methylisoxazole-4-carboxylic acid (5 g,
39.4 mm) and SOCl.sub.2 (15 ml, 205.8 mm) was stirred at
47.5.+-.2.5.degree. C. for 4 h. Excess SOCl.sub.2 was then
evaporated under low vacuum (50 torr) at 50.degree. C. The pale
yellow liquid residue (5.7 g) was more than 99%
5-methylisoxazole-4-carboxylic acid chloride by HPLC.
[0045] b) A mixture of 5-methylisoxazole-4-carboxylic acid (5 g,
39.4 mm), SOCl.sub.2 (15 ml, 205.8 mm) and toluene (15 ml) was
heated to 79.+-.1.degree. C. and stirred for about 4-5 h. Excess
SOCl.sub.2 and toluene were evaporated under vacuum (50 torr) at
70.degree. C. to give the title compound (.gtoreq.99% purity) as a
pale yellow liquid residue identical to that of Example 1(a).
Example 2
Preparations of Leflunomide
[0046] a) 4-Trifluoromethylaniline (5.75 g, 35.7 mm) was suspended
in a solution of NaHCO.sub.3 (3.16 g, 37.6 mm) in water (30 ml).
The suspension was warmed to 50.degree. C. and then rapid stirring
was begun. 5-Methylisoxazole-4-carboxylic acid chloride prepared by
the procedure of Example 1 (5 g, 34.4 mm) was added dropwise to the
rapidly stirred suspension over 20 min. After cessation of the
addition, the mixture was stirred for another 2 h. The mixture was
then allowed to cool to ambient temperature and leflunomide was
isolated as a white powder by filtration. Drying at 60.degree. C.
gave leflunomide (8.2 g, 88%) in 96% purity by HPLC analysis.
[0047] b) 4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved
in a mixture of NaHCO.sub.3 (3.16 g, 37.6 mm), toluene (70 ml) and
water (15 ml). The mixture was heated to 60.degree. C. and then
5-methylisoxazole-4-carboxylic acid chloride was added dropwise
over about 20 min. After cessation of the addition, stirring was
continued for another two hours. The mixture was allowed to cool
and precipitated leflunomide was isolated as a white powder by
filtration. The powder was dried at 60.degree. C. until no change
in mass was observed over a 24 hour period, at which point the
white powder (8.2 g, 88%) was determined to be 99.5% leflunomide by
HPLC analysis.
[0048] c) 4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved
in a mixture of NaHCO.sub.3 (3.16 g, 37.6 mm),
N,N-dimethylacetamide (0.7 ml, 7.5 mm) and toluene (70 ml). The
mixture was warmed to 40.degree. C. and
5-methylisoxazole-4-carboxylic acid chloride (5 g, 34.4 mm) was
added dropwise over 20 min. The mixture was stirred at this
temperature for another 3 h. and then it was heated to reflux
temperature. The hot mixture was washed with water (3.times.10 ml).
The organic phase was allowed to cool to ambient temperature, which
induced leflunomide to precipitate as a white powder. The powder
was isolated by filtration and then dried at 60.degree. C. to give
leflunomide (8.0 g, 86%) in 99.5% purity.
* * * * *