FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
APREMILAST IMPURITIES
2. APPLICANT (S)
(a) NAME: Wanbury Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS:
Wanbury Ltd., BSEL Tech park, B-wing, 10th floor, sec -30A, opp. Vashi Railway station, Vashi, Navi- Mumbai-400703, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

APREMILAST IMPURITIES
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to novel impurities of Apremilast, Formula (III) and Formula (IV) . The present invention further relates to a process for preparation of Apremilast of Formula (I) or pharmaceutically acceptable salts, free from impurities of Formula (II), Formula (III), and/or Formula (IV).
BACKGROUND OF THE INVENTION:
Apremilast is chemically known as N-{2-[(IS)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-

dihydro-ltf-isoindol-4-yl}acetamide and is represented by Formula (I).
Apremilast is a FDA approved drug used for treatment of Psoriasis and Psoriasis arthritis. It may also be useful for other immune system related inflammatory diseases. The drug acts as a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4) and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. The US-FDA approved Apremilast for the treatment of moderate to severe plaque psoriasis. It is also being tested for its efficacy in treating other chronic inflammatory diseases such asankylosing spondylitis, Behcet? s disease, and rheumatoid arthritis.
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

U.S. Patent No. 6,020,358 discloses a process for the preparation of racemic 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-acetylaminoisoindoline-l,3-dione of Formula (V) , wherein 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine of Formula (VI) is coupled with 3-acetamidophthalic anhydride of Formula (VII) as shown below in scheme no. I.
The U.S. Patent No. 6,020,358 also teaches separation of individual isomers from racemates by the techniques known in the art such as chromatography by using a chiral absorbant or by forming salts with a chiral acid.
The U.S. Patent Nos. 6,011,050 and 6,962,94 0 discloses same process for the preparation of racemic 2™ [1- (3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione of Formula (V) as shown above in scheme no. I.
U.S. Patent Publication no. 2010/0129363 and 2014/0004182 discloses a process for the preparation of Apremilast of Formula (I) , wherein (S) -2-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)-eth-2-yl amine N-acetyl-L-leucine salt of Formula VIII is coupled with 3-acetamidophthalic anhydride of Formula (VII) to provide Apremilast of Formula (I) as shown below in scheme no. II.
PCT Publication No. 2 012/083153 discloses a process for the preparation of Apremilast of Formula (I), wherein (S) -2-(3-ethoxy-4-methoxyphenyl)-2-(methyl
sulfonyl)ethanamine of Formula (IX) is coupled with 4-nitroisobenzofuran-1,3 dione of Formula (X) to provide Formula (XI), followed by reduction of Formula (XI) gives Formula (XII). The resulting Formula (XII) react with acetic anhydride in presence of acetic acid to give Apremilast of Formula (I) as shown below in scheme no. III.

All the above prior art processes for the preparation of Apremilast of Formula (I) may forms impurities/ byproducts (such as, Formula (11)/ Formula (III) and Formula (IV) which lead to lower the overall yield and purity that fails to comply with the pharmaceutical standards. The above mentioned drawbacks call for an alternative process of obtaining chemically pure and pharmaceutically acceptable Apremilast of Formula (I) , which should be cost effective, eco-friendly, commercially viable, reproducible on industrial scale and meet the needs of regulatory agencies.
Like any synthetic compound, Apremilast of Formula (I) can contain extraneous compounds or impurities. These impurities may be, for example, starting materials, by-

products of the reaction, products of side reactions, or degradation products.
Prior art processes discloses several techniques for the purification of Apremilast of Formula (I) such as, column chromatography, crystallization etc. The present inventors surprisingly found that in prior art does not mentioned certain identified and unidentified impurities that do removed with the purification techniques reported in prior arts by solvent purification and crystallization.
Hence, there is a long-felt need for the industrially applicable and consistently reproducible purification process to provide highly pure Apremilast of Formula (I) having acceptable levels of certain impurities, which complies with the requirements of pharmacopoeias and regulatory agencies.
The present invention is thus directed to an industrially advantageous process for the purification of Apremilast which improves the economics by employing less expensive and less hazardous raw materials and is more productive. These processes are used to remove those impurities which may result from the chemical instability of Apremilast [e.g. Formula (III), Formula (IV) etc.]
According to Q7A ICH (International conference on Harmonization) instruction, Active Pharmaceutical Ingredient (API) is freed from impurities to the maximum

possible extent. National inspection and control offices usually require that the content of an individual impurity in an API should not exceed the limit of 0.1%. All the substances (generally referred as an impurity) contained in an API over the limit of 0.1% should be isolated and characterized.
Accordingly, present inventors identify, isolate and characterized the novel impurities of Formula (III) and Formula (IV).
OBJECT OF THE INVENTION:
The main object of the present invention is to identify and isolate novel impurities of Formula (III) and Formula (IV) .
Another object of present invention is to provide a process for preparation of novel impurities of Formula (III) and Formula (IV).
Another object of present invention is to provide a process for obtaining chemically pure and pharmaceutically acceptable Apremilast of Formula (I) which is substantially free from impurities of Formula (II), Formula (III) and Formula (IV).
Yet another object of the present invention is to provide simple, economic and industrially scalable process for

the preparation of Apremilast of Formula (I) which is substantially free from impurities of Formula (II), Formula (III) and Formula (IV).
SUMMARY OF THE INVENTION:
According to first aspect, the present invention relates to novel impurities of Formula (III) and Formula (IV).
According to another aspect, the present invention relates to a process for the preparation of novel impurities of Formula (III) and Formula (IV) .
According to another aspect, the present invention relates to a process for the preparation of novel impurities of Formula (III) and Formula (IV) comprises:
a) reacting Apremilast of Formula (I) with base at 55-60°C for 2 hours in water;
b) cooling the reaction mass to 25-30°C and wash with methylene dichloride;
c) adding hydrochloric acid to the reaction mass in aqueous layer up to pH 2; and

d) isolating novel impurities of Formula (III) and Formula (IV) by column chromatography.
According to another aspect, the present invention relates to a process for obtaining chemically pure and pharmaceutically acceptable Apremilast of Formula (I) , which is free from impurities of Formula (II) , Formula (III), and Formula (IV).
According to another aspect, the present invention relates to a simple, economic and industrially scalable process for the preparation of Apremilast of Formula (I).
According to another aspect, the present invention relates to a process for obtaining chemically pure and pharmaceutically acceptable Apremilast of Formula (I) , which is free from impurities of Formula (II) , Formula (III), and/or Formula (IV) comprises:
a) reacting (S)-1-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl) ethanamine of Formula (IX) with 3-acetamidophthalic anhydride of Formula (VII) in presence of acetic acid at 30-35°C;

b) heating the reaction mass to 75-80°C and stirr for 8-10 hours;
c) subjecting the organic layer to distillation/ evaporation to obtain a yellow color oily compound;
d) dissolving the yellow color oily compound in a polar protic solvent by heating at 65-70°C;
e) cooling the solution obtained in step d) to 25-30°C to precipitate out crude Apremilast of Formula (I); and
f) purifying crude Apremilast of Formula (I) in polar protic solvent or polar aprotic solvent or mixture(s) thereof to obtain chemically pure and pharmaceutically acceptable Apremilast of Formula (I).
According to . another aspect, the present invention relates to a process for the purification of Apremilast of Formula (I) comprises:
a) dissolving crude Apremilast of Formula (I) in polar protic solvent or polar aprotic solvent or mixture(s) at 65-70°C;
b) treating solution obtained in step a) with charcoal at 65-70°C for 1 hour;
c) filtering solution obtaining in step b) to obtain filtrate;
d) cooling filtrate obtained in step c) to 25-30°C and stir for 2 hours;
e) obtained solid in step (d) is further purified in methanol : acetone in 1:1 v/v ratio and,

f) isolating chemically pure and pharmaceutically acceptable Apremilast of Formula (I).
Use of impurities of Formula (III) and Formula (IV) as a reference marker in determining purity of Apremilast of Formula (I).
DETAIL DESCRIPTION OF THE INVENTION:
The term "crude Apremilast" refers Apremilast having purity less than 99%.
The term Mchemically pure and pharmaceutically acceptable Apremilast" refers Apremilast having purity more than 99% and the obtained Apremilast comprises the ICH (International Conference on Harmonization) quality guideline.
The present inventors surprisingly found that crude Apremilast may contain impurities of Formula (III) and Formula (IV) which are not disclosed by any prior arts.
The said impurities are having the structural similarity to Apremilast of Formula (I) and carry forward in final product, in such case to get rid of theses impurities are very critical in order to pass the final product as per ICH guideline. So the present invention overcomes this drawback by identifying and isolating the said impurities.

The present invention encompasses a process of
determining the purity of Apremilast of Formula (I)
sample comprises use of impurities of Formula (III) and
Formula (IV) as a reference marker.
In one embodiment, the present invention provides novel impurities of Formula (III) and Formula (IV) .
In another embodiment, the present invention provides a process for the preparation of novel impurities of Formula (III) and Formula (IV) comprises:
a) reacting Apremilast of Formula (I) with base at 55-60°C for 2 hours in water;
b) cooling the reaction mass to 25-30°C and wash with methylene dichloride;
c) adding hydrochloric acid to the reaction mass in aqueous layer up to pH 2; and
d) isolating novel impurities of Formula (III) and Formula (IV) by column chromatography.
The base can be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide but preferably sodium hydroxide.

The novel impurities of Formula (III) and Formula (IV) can be isolated by column chromatography ( (Silica gel: 60-120 mesh, 0.25% Hexane/Ethyl acetate).
In another embodiment, the present invention provides a process for obtaining chemically pure and pharmaceutically acceptable Apremilast of Formula (I) , which is free from impurities of Formula (II) , Formula (III), and/or Formula (IV) comprises:
a) reacting(S)-1-(3-ethoxy-4-methoxyphenyl)-
2(methylsulfonyl)ethanamine of Formula (IX) with 3-acetamidophthalic anhydride of Formula (VII) in presence of acetic acid at 30-35°C;
b) heating the reaction mass to 75-80°C and stir for 8-10 hours;
c) subjecting the organic layer to distillation/ evaporation to obtain a yellow color oily compound;
d) dissolving the yellow color oily compound in a polar protic solvent by heating at 65-7 0°C;
e) cooling the solution obtained in step d) to 25-30°C to precipitate out crude Apremilast of Formula (I); and
f) purifying crude Apremilast of Formula (I) in polar protic solvent or polar aprotic solvent or mixture(s) thereof to obtain chemically pure and pharmaceutically acceptable Apremilast of Formula (I)-
In another embodiment, the present invention provides a process for the purification of Apremilast of Formula (I) comprises:

a) dissolving crude Apremilast of Formula (I) in polar protic solvent or polar aprotic solvent or mixture(s) at 65-70°C;
b) treating solution obtained in step a) with charcoal at 65-70°C for 1 hour;
c) filtering solution obtaining in step b) to obtain filtrate;
d) cooling filtrate obtained in step c) to 25-30°C and stir for 2 hours;
e) obtained solid in step (d) is further purified in methanol : acetone in 1:1 v/v ratio and,
f) isolating chemically pure and pharmaceutically acceptable Apremilast of Formula (I).
The polar protic solvent used for preparation of Apremilast formula (I) and in its purification can be selected from the group consisting of methanol, ethanol, iso-popanol, butanol, water or mixture(s) thereof.
The polar aprotic used for preparation of Apremilast formula (I) or in its purification can be selected from the group consisting of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide or mixture(s) thereof.
The chemically pure and pharmaceutically acceptable Apremilast of Formula (I) can be isolated by the steps of filtration, centrifugation, washing, drying or the combination thereof.

EXAMPLES:
The present invention is described with reference of the following examples. However these examples are for illustrative purpose only and not to be construed as limitations on the scope of the invention.
Example 1: Preparation of crude Apremilast of Formula (I).
To the(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine of Formula (IX) (50 gm) and 3-acetamidophthalic anhydride of Formula (VII) (38.27 gm) was added acetic acid (200 ml) at 30-35°C and then reaction mixture was heated to 75-80°C and stirred for 8-10 hours. After completion of reaction, acetic acid distill out completely from the reaction mixture at 75-80°C and reaction mixture strip out with methanol (50 ml) to obtain yellow color oily compound. The resulting yellow color oily compound was dissolved in methanol (400 ml) at 65-7 0°C and stirred for 1 hour. The reaction mixture is then gradually cooled to 25-30°C to obtain solid. Resulting solid was filtered and washed with methanol (50 ml) to obtain crude Apremilast of Formula
(I) •
Yield: 83.5%
Purity: 97.00%

Example 2: Purification of crude Apremilast of Formula (I) •
The crude Apremilast of Formula (I) (70 gm) was dissolved in methanol (2800 ml) at 65-70°C and Charcoal (0.5 gm) was added to the solution and stirred for 1 hour. The resulting solution was filtered through Hyflow bed and washed the bed with methanol (70 ml) to obtain filtrate. The resulting filtrate was gradually cooled to 25-30°C and stirred for 2 hours to obtain solid. The resulting solid was filtered stirring, washed with methanol (70 ml) and dried at 70-75°C. The isolated dried solid was further purified in methanol-acetone (1:1) mixture (500 ml) to obtain chemically pure and pharmaceutically acceptable Apremilast of Formula (I). Yield: 85.50%; Purity: 99.95%.
Example 3: Preparation and isolation of impurities of Formula (III) and Formula (IV)
A solution of Apremilast of Formula (I) (5 gm) in a water (50 ml) was added sodium hydroxide (1.0 eq. ) and then reaction mixture was heated to 55-60°C and stirred for 2 hours. The resulting reaction mixture cooled to 25-30°C and washed with methylene dichloride (15 ml x 3) . The resulting aqueous layer was added aqueous hydrochloric acid up to pH 2 to obtain reaction mixture containing impurities of Formula (III) and Formula (IV) in (60:4 0%) .

These impurities of Formula (III) and Formula (IV) were separated from the reaction mixture by column chromatography (Silica gel: 60-120 mesh, 0.25% Hexane/Ethyl acetate) and was characterized by mass and 1H-NMR techniques.
Impurity of Formula (III)
MS (ESI positive ion) m/z 479.3 (M + 1)
1H NMR (CDC13, 400 MHz): 5 1.41-1.45 (t, 3H) , 1.99 (s, 3H), 2.80-2.82 (s, 3H), 3.40-3.76 (dd, 2H), 3.83 (s, 3H) , 4.06-4.11 (q, 2H), 5.66-5.72 (t, 1H), 6.81-6.83 (d, 1H), 6.92-6.94 (d, IH) , 7.28 (s, 1H) . 7.70-7.72 (d, IH.) , 8.11-8.13 (d, IH), 8.11-8.24 (dd, IH)
Impurity if Formula (IV)
MS (ESI positive ion) m/z 479.0 (M + 1)
IH NMR (CDCI3, 400 MHz): 5 1.31-1.35 (t, 3H) , 2.04 (s, 3H), 2.92 (s, 3H), 3.57-3.65 (dd, 2H), 3.75-3.77 (s, 3H), 4.01-4.06 (q, 2H) , 5.44-5.50 (t, IH), 6.90-6.97 (dd, 2H) 7.08 (d, IH), 7.34-7.36 (d, IH), 7.47-7.51 (dd, IH). 7.80-7.82 (d, IH), 9.03-9.05 (s, IH), 9.72 (s, IH)

WE CLAIM:
1) A process for obtaining chemically pure and pharmaceutically acceptable Apremilast of Formula (I), which is free from impurities of Formula (II), Formula (III), and Formula (IV) comprises:
a)reacting (S)-1-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethanamine of Formula (IX) with 3-acetamidophthalic anhydride of Formula (VII) in presence of acetic acid at 30-35°C;
b)heating the reaction mass to 75-80°C and stir for 8-10 hours;
c)subjecting the organic layer to distillation/evaporation to obtain a yellow color oily compound;
d)dissolving the yellow color oily compound in a polar protic solvent with heating at 65-7 0°C;
e)cooling the solution obtained in step d) to 25-30°C to precipitate out crude Apremilast of Formula (I); and
f)purifying crude Apremilast of Formula (I) in polar protic solvent or polar aprotic solvent or mixture(s)

thereof to obtain chemically pure Apremilast of Formula (I) .
2) A process for the purification of Apremilast of
Formula (I) comprises:
a)dissolving crude Apremilast of Formula (I) in polar protic solvent or polar aprotic solvent or mixture(s) at 65-70°C;
b)treating solution obtained in step a) with charcoal at 65-70°C for 1 hour;
c)filtering solution obtaining in step b) to obtain filtrate;
d)cooling filtrate obtained in step c) to 25-30°C and stir for 2 hours and filtered;
e)obtained solid in step d is further purified in methanol : acetone in 1:1 v/v ratio and,
f)isolating chemically pure and pharmaceutically acceptable Apremilast of Formula (I).
3) A process according to claim 1, wherein polar protic
solvent is selected from the group consisting of
methanol, ethanol, iso-propanol, butanol, water or

mixture(s) thereof, but preferably used solvent is methanol.
4) A process according to claim 2, wherein polar aprotic is selected from the group consisting of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide or mixture(s) thereof.
5) Impurities of Formula (III) and Formula (IV).
6) A process for the preparation of novel impurities of Formula (III) and Formula (IV) comprises:
a) reacting Apremilast of Formula (I) with base at 55-60°C for 2 hours in water;
b) cooling the reaction mass to 25-30°C and wash with methylene dichloride:
c)adding hydrochloric acid to the reaction mass in aqueous layer up to pH 2; and

d) isolating novel impurities of Formula (III) and Formula (IV) by column chromatography.
7) A process according to claim 6, wherein the base can be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide but preferably base used is sodium hydroxide.
8) Use of impurities of Formula (III) and Formula (IV) as a reference marker in determining purity of Apremilast of Formula (I).