FORM 2


THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"PROCESS FOR THE PREPARATION OF AC1TRETIN"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate BIdg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

PRIORITY
[0001] This application claims the benefit to Indian Provisional Application No.
9I4/MUM/2005, filed on August 5, 2005, and entitled "PROCESS FOR THE PREPARATION OF ACITRETIN", the contents of each of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
|0002] The present invention generally relates to a process for the preparation of
substantially pure acitretin.
2. Description of the Related Art
(0003) Acitretin, also known as (all-trans)-9-(4-methoxy-2,3,6-trimethylphenyl)-
3,7-dimethyl-2,4,6,8-nonatetraenoic acid, can be represented by the structure of Formula I.

Acitretin, an aromatic analogue of retinoic acid, is a member of the retinoid family, a group of compounds related to retinol (vitamin A). The tetraene side chain in acitretin exists in all-trans (or E) configuration. Acitretin is indicated for the treatment of severe psoriasis in adults and is marketed under the trade name Soriatane®. See, e.g., The Merck Index, Thirteenth Edition, 200!, p. 110, monograph 114; and Physician's Desk Reference, "Soriatane," 60th Edition, pp. 1028-1035 (2005).
[0004] U.S. Patent No. 4,105,681 ("the '681 patent") discloses processes for the
preparation of acitretin. Each of the processes in the '681 patent employ a Wittig reaction or its modification such as a Wittig-Horner procedure and provides a mixture of stereoisomers. Attempts at preparing acilretin of the desired purity by following the processes taught in Examples 1-3 of the ‘681 patent were unsuccessful. See, e.g., U.S. Patent Application Publication No. 2004/0192949. A similar Wittig process has been illustrated in Example 6 of DE 2636879 which provided only 47% of the all trans-isomer along with 51% of the 11-cis isomer, as an impurity.
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[0005] U.S. Patent Application Publication No. 2004/0192949 further discloses the
purification of acitretin by contacting crude acitretin with one or more solvent, optionally
in the presence of a free radical scavenger, and isolating substantially pure acitretin from a
mixture thereof. However, a drawback associated with this process is it is commercially
not suitable because of the instability of acitretin in most of the solvents.
|0006] In light of the above drawbacks in the prior art processes, there is a need for
the development of a simple and efficient process for the preparation of the desired all trans-isomer of 9-(4-methoxy-2,3,6-trimethyl phenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid (acitretin) in relatively high purity. It would also be desirable to provide a process for preparing substantially pure acitretin from a complex mixture of cis-trans isomers.
SUMMARY OF THE INVENTION
[0007] In accordance with one embodiment of the present invention, a process for
the preparation of substantially pure acitretin of Formula I is provided:

the process comprising (a) contacting a salt of crude acitretin with one or more solvents;
and (b) isolating substantially pure acitretin.
[0008] 1" accordance with a second embodiment of the present invention, a lithium
salt of acitretin is provided.
[0009] The process of the present invention overcomes the problems associated
with the prior art and provides a practical process for the preparation of substantially pure
acitretin from a complex mixture of cis-trans isomers involving solvent treatment. The
process of the present invention also advantageously avoids the tedious and cumbersome
purification process of column chromatography and has benefits with respect to economics
and convenience to operate on a commercial scale.
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DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0010] The present invention is directed to a process for the preparation of
substantially pure acitretin of Formula I.

The process of the present invention includes at least (a) contacting a salt of crude acitretin with one or more solvents; and (b) isolating substantially pure acitretin from the product of step (a).
[0011] In step (a) of the process of the present invention, a salt of crude acitretin is
contacted with one or more solvents to provide a substantially pure salt of acitretin. Useful salts of acitretin include, but are not limited to, sodium, lithium, magnesium, potassium, strontium, magnesium, barium, calcium and the like. The term "crude acitretin" as used herein shall be understood to mean acitretin containing a mixture of various cis-trans isomers as impurities. Crude acitretin is well known and may be obtained by any of the synthetic routes described in the prior art.
[0012] Suitable solvents for use in step (a) include, but are not limited to, ketones,
alcohols, cyclic ethers, aliphatic ethers, nitriles, esters, water, alkanes, and the like and mixtures thereof. Useful ketones include, but are not limited to, acetone, methyl isobutyl ketone, and the like and mixtures thereof. Useful alcohols include, but are not limited to, methanol, ethanol, isopropanol, and the like and mixtures thereof. Useful cyclic ethers include, but are not limited to, tetrahydrofuran, dioxane, and the like and mixtures thereof. Useful nitriles include, but are not limited to, acetonitrile and the like and mixtures thereof. Useful esters include, but are not limited to, ethyl acetate, and the like and mixtures thereof. Useful alkanes include, but are not limited to, n-hexane, heptane and the like and mixtures thereof.
[0013] The step of contacting the salt of crude acitretin with one or more solvents
to provide a substantially pure salt of acitretin can be accomplished by, for example, stirring, slurrying, dissolving or a combination thereof the salt of crude acitretin and the one or more solvent. In this step, the substantially pure salt of crude acitretin can
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precipitate out of the solution and then optionally recovered by, for example, filtration.
The term "substantially pure salt of acitretin" as used herein shall be understood to mean a
salt of acitretin having an assay of greater than or equal to about 98% as determined by
high performance liquid chromatography (HPLC).
[0014] In step (b) of the process of the present invention, the product substantially
pure acitretin can be isolated from the substantially pure salt of acitretin by, for example,
acidifying, cooling, filtering, or a combination thereof. The term "substantially pure
acitretin" as used herein shall be understood to mean acitretin having an assay of greater
than or equal to about 98% as determined by HPLC and preferably greater than or equal to
about 99%.
[0015] As one skilled in the art will readily appreciate, the steps of contacting and
isolating in the process of the present invention may be repeated to achieve the desired
results.
[0016] The following examples are provided to enable one skilled in the art to
practice the invention and are merely illustrative of the invention. The examples should
not be read as limiting the scope of the invention as defined in the features and advantages.
Experimental
[0017] The purity was measured by high performance liquid chromatography
under the following conditions:
Column: Lichrosphere PAH, 250 X 4.0 mm, 5u or equivalent
Moving phase: 0.3% v/v solution of glacial acetic acid R in a mixture of 8 volumes of
water R and 92 volumes of ethanol R, wherein R means reagent grade
Detector: UV, 360 nm
Flow rate: 0.6 ml/minute
Retention time: 6.2 minutes
EXAMPLE 1
[0018] Step I: Process for Salt Preparation and Purification.
[0019] Crude acitretin (10 g) was dissolved in tetrahydrofuran (220 ml). Next, an
aqueous sodium hydroxide solution (8 ml, 50%) was added to the solution and stirred at
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25-30°C for 6 hours. The suspension was then filtered to obtain a wet cake of a sodium
salt of acitretin. Next, the wet cake of the sodium salt of acitretin was added in acetone
(50 ml) and stirred at 25-30°C for I hour. The suspension was then filtered, washed with
acetone ( 20 ml) and dried under vacuum at 25-30°C for 4 hours to obtain a substantially
pure sodium salt of acitretin (7.7 g, purity 99.5 % as determined by HPLC ).
[0020] Step II: Process for Isolation of Acitretin
[0021] The substantially pure sodium salt of acitretin obtained in step I was added
in water (80 ml) and acidified with 30% HCI and stirred for 30 minutes at 25 to 30°C to obtain a suspension. The suspension was then filtered, washed with water and dried at 25-30°C to obtain substantially pure acitretin (7 g, assay 99.45% as determined by HPLC).
EXAMPLE 2
[0022] Step I: Process for Salt Preparation and Purification
[0023] Crude acitretin (10 g) was dissolved in tetrahydrofuran (200 ml). An
aqueous lithium hydroxide solution (8 ml, 50%) was added to the solution and stirred at
25-30°C for 6 hours. Next, tetrahydrofuran was distilled out completely at 25-30X under
vacuum and acetone (50 ml) was added and stirred at 25-30°C for 1 hour to obtain a
suspension. The suspension was then filtered, washed with acetone (20 ml) and dried
under vacuum at 25-30X for 4 hours to obtain a substantially pure lithium salt of acitretin
(7.3 g, purity 98.5 % as determined by HPLC).
[0024] Step II: Process for Isolation of Acitretin
[0025] The substantially pure lithium salt of acitretin obtained in step II was added
in water (80 ml) and acidified with 30% HCI and stirred for 30 minutes at 25-30°C to obtain a suspension. The suspension was then filtered, washed with water and dried at 25-30X to obtain substantially pure acitretin (6.7 g, assay 98.5% as determined by HPLC).
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[0026] While the above description contains many specifics, these specifics should
not be construed as limitations of the invention, but merely as exemplifications of preferred embodiments thereof. Those skilled in the art will envision many other embodiments within the scope and spirit of the invention as defined by the features and advantages appended hereto.
Dated this Fourth (04,h) day of August, 2006

(Signed)
VISHAL AMRUTLAL SODHA
SENIOR MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED

WE CLAIM:
1. A process for the preparation of substantially pure acitretin of Formula I:

the process comprising (a) contacting a salt of crude acitretin with one or more solvents; and (b) isolating substantially pure acitretin from the product of step (a).
2. The process of Claim 1, wherein the salt of crude acitretin is sodium, potassium, magnesium, strontium, lithium, calcium or barium.
3. The process of Claims 1 and 2, wherein the solvent is selected from the group consisting of a ketone, alcohol, ether, ester, water, nitrile, alkane and mixtures thereof.
4. The process of Claim 3, wherein the ketone solvent is selected from the group consisting of acetone, methyl isobutyl ketone and mixtures thereof.
5. The process of Claim 3, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof.
6. The process of Claim 3, wherein the ether solvent is a cyclic ether selected from the group consisting of tetrahydrofuran, dioxane and mixtures thereof.
7. The process of Claim 3, wherein the nitrile solvent is acetonitrile.
8. The process of Claim 3, wherein the ester solvent is ethyl acetate.
9. The process of Claim 3, wherein the alkane solvent is selected from the group consisting of n-hexane, heptane and mixtures thereof.

10. The process of Claims 1 and 2, wherein the solvent is selected from the group consisting of an acetone, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, water, n-hexane and mixtures thereof.
11. The process of Claims 1-10, wherein the step of contacting comprises stirring the salt of crude acitretin and the one or more solvent.

12. The process of Claims 1-10, wherein the step of contacting comprises slurrying the salt of crude acitretin and the one or more solvent.
13. The process of Claims 1-10, wherein the step of contacting comprises dissolving the salt of crude acitretin and the one or more solvent.

14. The process of Claims 1-13, wherein the step of isolating the substantially pure acitretin comprises acidifying the substantially pure salt of acitretin.
15. The process of Claim 14, wherein the substantially pure salt of acitretin is acidified with a mineral acid in an organic solvent.

16. The process of Claim 15, wherein the mineral acid is hydrochloric acid.
17. The process of Claim 15, wherein the mineral acid is aqueous hydrochloric acid.
18. The process of Claims 15-17, wherein the organic solvent is water.
19. The process of Claims 1-18, wherein the substantially pure acitretin isolated in step (b) has a purity of greater than or equal to about 98%.
20. The process of Claims 1-18, wherein the substantially pure acitretin isolated in step (b) has a purity of greater than or equal to about 99%.
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21. A lithium salt of acitretin.
22. Substantially pure lithium salt of acitretin.
23. Substantially pure lithium salt of acitretin having a purity of greater than or equal to about 98%.
24. Substantially pure lithium salt of acitretin having a purity of greater than or
equal to about 99%.
Dated this Fourth (04,h) day of August, 2006

(Signed). VISHAL AMRUTLAL SODHA SENIOR MANAGER-IPM GLENMARK PHARMACEUTICALS LIMITED
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ABSTRACT
[0027] A process for the preparation of substantially pure acitretin of Formula I is
provided:

the process comprising (a) contacting a salt of acitretin with one or more solvents; and (b) isolating substantially pure acitretin from the product of step (a).