DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Apremilast and its intermediate. The invention also relates to preparation of crystalline Form A of apremilast.

(I)
BACKGROUND OF THE INVENTION
The following discussion of prior art is intended to present the invention in 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.

“Apremilast” is a phosphodiesterase-4 (PDE4) inhibitor. Apremilast is chemically known as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Its empirical formula is C22H24N2O7S and the molecular weight is 460.5.

Apremilast is approved in the United States for treatment of adult with active psoriatic arthritis. It is available under the trade name of OTEZLA® as an inhibitor of phosphodieasterase 4 (PDE4) and OTEZLA tablets are supplied in 10, 20 and 30 mg strengths for oral administration.

US Patent No. 6,020,358 discloses racemic 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-
methylsulfonylethyl]-4-acetamidoisoindoline-1,3-dione and process for its preparation.

WO2003/080048 and WO2003/080049 discloses the use of the (-) and (+) enantiomers of apremilast respectively in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.

US Patent No. 7,427,638 discloses stereomerically pure (+)-2-[1-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

WO2009/120167 and US Patent No. 7,893,101 disclose various solid forms including Form A and process for preparation thereof.

IN201711013109 discloses an improved process for preparation of crystalline forms of apremilast.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g. differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g. tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity).

In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of apremilast intermediate and desired polymorphic form.

OBJECTS OF THE INVENTION
The main object of present invention is to provide an improved process for preparation of apremilast.

(I)
wherein the process comprises preparation of intermediate of formula (IV) in presence of non-ionic surfactant.

Another object of the present invention is to provide an improved process for preparation of intermediate of formula (IV), wherein reaction of compound of formula (VI) and (V) is carried out in presence of non-ionic surfactant

(IV)
and further, conversion of intermediate of formula (IV) to apremilast.

Yet another object of the present invention is to provide a process for preparation crystalline Form A of apremilast; comprising recrystallization of apremilast from solvent containing propylene glycol and isopropanol.

Yet another object of the present invention is to provide crystalline Form A; comprising preparation of intermediate of Formula (IV) in the presence of organic acid and non-ionic surfactant, converting compound of formula (IV) to apremilast; recrystallizing apremilast from mixture of propylene glycol and isopropanol.

SUMMARY OF THE INVENTION
In one aspect the present invention provides an improved process for preparation of apremilast;

(I)
comprising reaction of 3-nitrophthalic acid of formula (VI) with (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (V)

(V) (VI)

(IV)
in presence of non-ionic surfactant, converting the resultant intermediate of formula (IV) to apremilast.

Another aspect of the present invention is to provide an improved process for preparation of intermediate of formula (IV) comprising reacting compound of formula (VI) with compound of formula (V) in presence of non-ionic surfactant.

Yet another aspect of present invention is to provide a process for preparation of crystalline Form A of apremilast wherein, the process comprise steps of
a) reacting compound of formula (VI) with compound of formula (V) in presence of non-ionic surfactant;
b) converting intermediate of formula (IV) obtained in step (a) to apremilast; and
c) recrystallizing apremilast from propylene glycol and isopropanol.

Yet another aspect of the present invention is to provide a process for preparation of crystalline Form A of apremilast by recrystallizing apremilast from solvent selected from propylene glycol and isopropanol.

DETAILED DESCRIPTION OF THE DRAWINGS
Fig.1: Illustrate XRPD pattern of apremilast Form A.

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of present invention provides a process for preparation of apremilast;

(I)
accordingly the complete process of present invention can be represented by following scheme.

Scheme 1
For the purpose of present invention intermediate of formula (IV) can be prepared by reacting compound of formula (VI) with compound of formula (V) as represented in stage I of above mentioned scheme.

In an embodiment the process of stage I is carried out in presence of non-ionic surfactant. Non-ionic surfactant can be selected from Tween 80, Polysorbate 80, Polysorbate 20, Poloxamer, Glycerole monostearate, Sorbitan, Triton X-100, Stearyl alcohol. Preferably for the purpose of present invention Triton X-100 is used as non-ionic surfactant.

As used “Triton X-100” herein chemically means 4-(1,1,3,3-Tetramethylbutyl)phenyl-polyethylene glycol, t-Octylphenoxypolyethoxyethanol, Polyethylene glycol tert-octylphenyl ether, 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol or non-ionic detergent having CAS registry number: [9002-93-1]

The process of stage I may be carried out in presence of suitable solvent such as aromatic hydrocarbon, alkanols or water. Suitably the reaction is carried out in presence of toluene, ethanol, water or mixture thereof. The reaction can be advantageously carried out in presence of an organic acid selected from acetic acid, citric acid and oxalic acid preferably the acid is acetic acid.

The intermediate of formula (VI) obtained from stage I can be further converted to apremilast by any process known in the art. For the purpose of present invention the intermediate of formula (IV) can be subjected to hydrogenation in presence of catalyst such as Pd/C. The reaction can be carried out in presence of any suitable solvent such as methanol or ethyl acetate. The intermediate of formula (III) obtained after hydrogenation is acetylated using acetic anhydride to give apremilast. This reaction can be carried out in the presence of organic solvent such as isopropyl acetate under reflux. The crude apremilast can be isolated from the reaction mixture by distillation of the solvent or filtration.

In yet another embodiment the crude apremilast thus obtained is subjected to recrystallization to get crystalline Form A of apremilast. The recrystallization is preferably carried out by using mixture of solvent such as propylene glycol and isopropanol. The recrystallization is carried out under heating preferably to the reflux temperature of solvent used in the process. After completion, pure apremilast that is crystalline Form A of apremilast can be isolated by filtration.

EXAMPLES
Example 1: (S)-2-(1-(3-ethoxy-4-methoxy phenyl)-2-(methylsulfonyl) ethyl)-4-nitroisoindoline-1,3-dione (IV)

In One liter three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, 3-Nitrophthalic acid (20gm) and toluene (90ml) was charged, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (24.36gm) diluted with purified water (40ml) was added to the reaction mixture. To the resultant reaction mixture acetic acid (8gm) and TRITON X-100 (0.8gm) diluted with toluene (10ml) was added and heated to reflux temperature. After cooling, ethanol (120ml) was added slowly and reaction mixture was filtered. Resulting wet-cake was washed with ethanol and dried at 40-50°C under vacuum to obtained (S)-2-(1-(3-ethoxy-4-methoxy phenyl)-2-(methylsulfonyl) ethyl)-4-nitroisoindoline-1,3-dione (IV).

Example 2: (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)isoindoline-1,3-dione (III)

In two liter conical flask (S)-2-(1-(3-ethoxy-4-methoxyphenyl)2-(methylsulfonyl)ethyl)-4-nitroisoindoline-1,3-dione (30gm) in ethyl acetate (210ml) was added and stirred. The reaction mixture thus obtained was charged to hydrogenator. To this 10% palladium on carbon slurry in ethyl acetate (30ml) was added. After completion of reaction solvent was distilled off under vacuum. To the residue methanol (60ml) was added and distilled off. To the residue thus obtained 90ml of methanol was added. This mixture was cooled to 5-10°C. Reaction mixture was filtered and dried under vacuum to obtain (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione.

Example 3: N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (II) [Apremilast crude]

In 250ml round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione (20gm) and isopropyl acetate (120ml) was added. To the resultant mixture 11.4 gm acetic anhydride was added and the reaction mixture was heated to 84-89°C for 16-20hrs. After completion of reaction, reaction mixture was cooled to 25-35°C and filtered. Resulting wet-cake was washed with isopropyl acetate (20ml) dried to obtain N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide.

Example 4: N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (I) [Apremilast Form A]

In 250ml round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, propylene glycol (60ml) in isopropyl acohol (90ml) and N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (crude apremilast 10gm) was added. Resulting reaction mixture was heated to 85-90°C and then gradually cooled to 30-40°C. Product thus obtained was washed with isopropanol (20ml), dried under vacuum and collected as crystalline Form A of apremilast. ,CLAIMS:We Claim:

1. A process for preparation of apremilast (I)

comprising steps of:
a) reacting 3-nitropthalic acid (VI) with (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (V) in the presence of non-ionic surfactant;

b) converting (S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-nitroisoindoline-1,3-dione (IV) as obtained in step a) to apremilast (I); and

c) optionally, recrystallizing apremilast from suitable solvent or mixture thereof.

2. The process as claimed in claim 1, wherein non-ionic surfactant is selected from the group comprising Triton X-100, Tween 80, Polysorbate 80, Polysorbate 20, Poloxamer, Glycerole monostearate, Sorbitan and Stearyl alcohol.

3. The process as claimed in claim 1, wherein non-ionic surfactant is selected from the group comprising Triton X-100, Tween 80, Polysorbate 80, and Polysorbate 20.

4. The process as claimed in claim 1, wherein non-ionic surfactant is Triton X-100.

5. A process for preparation of apremilast crystalline Form A comprising the steps of:
a) reacting compound of formula (VI) with compound of formula (V) in
the presence of non-ionic surfactant;
b) converting intermediate of formula (IV) as obtained in step (a) to apremilast;
c) recrystallizing apremilast from propylene glycol and isopropanol; and
d) isolating crystalline Form A of apremilast.

6. A process for preparation of apremilast crystalline Form A comprising the steps of:
a) recrystallizing apremilast from propylene glycol and isopropanol; and
b) isolating crystalline Form A of apremilast.