FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - "AN IMPROVED PROCESS FOR THE PREPARATION OF
LEFLUNOMTOE"
2. Applicant(s)
(a) NAME : ALEMBICJ LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION:
The following specificatioh particularly describes the invention and the manner in which it is to be
performed:
I


Field of the invention:
The present invention relates to an improved process for preparing Leflunomide of
formula (I).

Background of the invention:
The chemical name of Leflunomide is 5-methyl-N-[4-(trifluoromethyl)phenyl]-4-
isoxazolecarboxamide, formula Ci2H9F3N202 and molecular weight is 270.21. The
current pharmaceutical product containing this drug is being sold by Aventis using the
tradename Arava®, in the form of tablets. The structural formula of Leflunomide is
represented by formula (I)
»
Leflunomide is useful in the treatment of active rheumatoid arthritis in adults,
Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA) to
reduce signs and symptoms and to retard structural damage as evidenced by X-ray
erosions and joint space narrowing. It inhibits pyrimidine synthesis by inhibition of
dihydroorotate dehydrogenase (DHODH)
U.S. Pat. No. 4,284,786 describes a process for the preparation of Leflunomide. In
Example (al), 5-methylisoxazole-4-carboxylic acid chloride ("MIA-C1") of formula (II)
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is reacted with two molar equivalents of trifluoromethyl aniline (TFMA) of formula (III)

in acetonitrile. This preparation is uneconomical on a large scale because acetonitrile is
an expensive solvent.
The following term is used in this patent have the meanings as defined below.
"MIA" refers to 5-methylisoxazole-4-carboxylic acid.
"MIA-C1" refers to 5-methylisoxazole-4-carboxylic acid chloride of formula (II)
"TFMA" refers to trifluoromethyl aniline of formula (III)
"HCA" refers to compound of formula (A).
An alternative process for making leflunomide that is described in the '786 patent uses
the Schotten-Baumann procedure to produce leflunomide (Example a2 of the 786
patent). However, careful simultaneous addition of MIA-C1 and KOH is required for pH
control. Any failure in the simultaneous delivery can lead to a rapid decomposition of
leflunomide to HCA of formula (A) which is a major impurity of Leflunomide. 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.
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
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ingredient in pharmaceutical. 3-Methyl-isoxazole-4-carboxylic acid is a common
impurity in commercially available MIA. 3-Methyl-isoxazole-4-carboxylic acid
originating in MIA is transformed by chlorination and reaction with TFMA to N-(4-
trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide (B). 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)-isoxazole-4-carboxamide (C) upon reaction with MIA-C1.

It thus would be highly desirable to have available a process for preparing leflunomide
substantially free of impurites (A), (B) and (C) that could be conducted without careful
reagent flow control and without costly solvents and bases.
In summary, prior art relating to the process for the preparation of Leflunomide suffers
with several drawbacks such as
i) It uses acetonitrile which is an expensive solvent. Acetonitrile is water
miscible and it is required to be removed from the reaction mass before
starting work up procedure. This makes process unnecessarily laborious.
Moreover the product formed is prone to degradation because of the high
temperature used in the solvent removal process,
ii) It requires careful simultaneous addition of MIA-C1 and KOH for pH control
and failure to this can lead to a rapid decomposition of leflunomide to HCA.
iii) It is difficult to achieve purity level due to formation of byproducts.
Hence, there is a need to develop a process which not only overcomes disadvantages of
the prior art but also provide a process which is economical, operationally easy and
industrially applicable.
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The present inventors have observed that when reaction is performed in acetonitrile and
excess TFMA, the impurities are formed in greater quantity.
The present inventors have unexpectedly found that when reaction is conducted in water
immiscible chlorinated solvent, the impurities which are generated by degradation of
Leflunomide can be effectively controlled.
Object of the invention:
It is therefore an object of the present invention is to provide an improved process for the
preparation of Leflunomide.
Another object of the present invention is to provide a process which is cost effective.
Another object of the present invention is to provide a process which is simple and easy
to handle at an industrial scale.
Another object of the present invention is to provide a pharmaceutical composition
comprisiing Leflunomide prepared according to process of present invention as an active
ingredient.

Yet another object of the present invention is to provide a method of treating active
rheumatoid arthritis comprising administering an effective amount of Leflunomide as
prepared according to process of present invention.
Summary of the invention:
Accordingly, present invention provides an improved process of preparation of
Leflunomide of formula (I)
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comprising step of reacting 5-methylisoxazole-4-carboxylic acid chloride ("MIA-C1") of
formula (II)

in a water immiscible chlorinated organic solvent and in the presence of a base.
Detailed description of the invention:
According to the present invention, it provides an improved process for preparation of
Leflunomide of formula (I)

comprising step of reacting 5-methylisoxazole-4-carboxylic acid chloride ("MIA-C1") of
formula (II)

with TFMA of formula (III)
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in a water immiscible chlorinated organic solvent and in the presence of a base.
The example of "water immiscible chlorinated organic solvent" includes but not limited
to dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like or the
mixture thereof.
The example of "base" includes but not limited to alkali metal hydroxide or carbonate,
alkaline earth metal hydroxide or carbonate, an alkali metal alcoholate or alkaline earth
metal alcoholate, or an organic base, such as triethylamine, pyridine, picoline or
quinoline and the like or mixture thereof.
5-methylisoxazole-4-carboxylic acid chloride ("MIA-C1") is prepared according to prior
reference "Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-
Organic Chemistry (1988), (7), 1875-9".
5-methylisoxazole-4-carboxylic acid chloride ("MIA-C1") is reacted with trifiuoromethyl
aniline (TFMA) in the presence of water immiscible chlorinated organic solvent,
preferably dichloromethane, at a temperature ranging from about 0°C to about 5°C. After
completion of the reaction, the mass is quenched in water and diluted with toluene. The
dichloromethane is evaporated preferably under vacuum. The mass is chilled and solid is
isolated. The product is isolated by methods known in the art such as filtration,
decantation or centrifugation. The material is dried in oven at a temperature ranging from
about 80°C to about 85°C optionally under reduced pressure.
The term "precipitation" refers hereinabove means dissolving solid material in a solvent
in which it dissolves and precipitation by adding a solvent in which compound is partially
soluble or less soluble.
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In another embodiment, the present invention provides a pharmaceutical composition by
the methods known in the art, comprising Leflunomide as prepared by the above
mentioned process.
In further embodiment, the present invention provides a method of treating active
rheumatoid arthritis comprising administering an effective amount of Leflunomide as
prepared by the above mentioned process and pharmaceutically acceptable carrier,
diluent, excipient, additive, filter, lubricant, binder, stabilizer, solvent or solvate, to a
patient in need thereof.
The process of the present invention has following advantages:
(i) It eliminates the chance of degradation of Leflunomide which caused due to
i '
evaporation of acetonitrile.
(ii) It eliminates the necessity of removing acetonitrile which is water miscible
before work up procedure,
(iii) The process is simple and easy to handle and does not require special handling
care or critical pH control condition,
(iv) The process is cost effective, simple and easy to handle at an industrial scale.
The following examples illustrate the invention further. It should be understood,
however, that the invention is not confined to the specific limitations set forth in the
individual examples but rather to the scope of the appended claims.
Example-1
Preparation of Leflunomide
5-methylisoxazole-4-carboxylic acid (MIA) (lOOg) is added to thionyl chloride (115ml)
and heated to reflux till complete dissolution of acid. Excess thionyl chloride is distilled
out. The mass is stripped with chloroform (50mlx2) to remove traces of thionyl chloride.
The mass is cooled at ambient temperature and dissolved in dichloromethane (500ml).
The reaction mass is further cooled at 0°C to 5°C. A solution of TFMA (120.5g) and
TEA (115ml) in dichloromethane (500ml) was added slowly to the reaction mass within
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1 hour. An exothermic reaction caused the temperature to increase 20°-35°C. The
reaction mass is stirred for 30min at the same temperature. The progress of the reaction is
monitored on TLC by confirming the absence of TFMA. The reaction mass is quenched
in water (450ml) and diluted with toluene (200ml). The dichloromethane is evaporated
preferably under vacuum. The mass is chilled and filtered and optionally slurry washed
with toluene (100mlx2). The material is dried in oven at 80°C for 6 hours under vacuum.
Yield: 106gm (50%)
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What is claimed is:
1. A process for the preparation of Lefiunomide of formula (I) comprising step of;

reacting 5-methylisoxazole-4-carboxylic acid chloride ("MIA-C1") of formula (II)

in a water immiscible chlorinated organic solvent, in the presence of a base. .

2. The process as claimed in claim 1, wherein the water immiscible chlorinated
organic solvent is selected from the group comprising dichloromethane,
dichloroethane, chloroform and carbon tetrachloride or mixture thereof.
3. The process as claimed in claim 1. wherein the base is selected from the group
comprising alkali metal hydroxide or carbonate, alkaline earth metal hydroxide or
carbonate, an alkali metal alcoholate or alkaline earth metal alcoholate, or an
organic base, such as triethylamine, pyridine, picoline or quinoline and the like or
mixture thereof.
4. A pharmaceutical composition comprising Leflunomide as prepared according to
any preceding claim as active ingredient and pharmaceutically acceptable carrier.

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5. A pharmaceutical composition comprising at least one pharmaceutically acceptable
excipient and Leflunomide, wherein the Leflunomide is made by the method of any
preceding claims,
6. A method for treating active rheumatoid arthritis comprising administering an
effective amount of Leflunomide as prepared according to any preceding claim and
pharmaceutically acceptable carrier, diluent, excipient, additive, filter, lubricant,
binder, stabilizer, solvent or solvate to a patient in need thereof.
Dated this 25th day of January 2006.

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