DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR PREPARATION OF APREMILAST AND ITS INTERMEDIATES

INTRODUCTION
One of the present invention relate to process for preparation of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the formula (II) and their use in preparation of apremilast. Another aspect of the present application provides process for resolution of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the formula (II) and their use in preparation of apremilast.

BACKGROUND
Apremilast is a PDE4 inhibitor and acts as an anti-inflammatory agent for the treatment of a variety of conditions, including asthma, chronic obstructive pulmonary disease, psoriasis and other allergic, autoimmune and rheumatologic conditions and is represented by structure of formula (I).

I
1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (II) is one of the key intermediate useful in the preparation of apremilast.

II
Processes for the preparation of apremilast and its intermediates have been disclosed in US6020358B2, US7427638B2, US8242310B2, US20130217918A1 and US20130217919A1.

In view of the importance of PDE4 inhibitors, cost-effective and novel methods of making such drugs and their intermediates are always of interest.

SUMMARY
In the first aspect, the present application provides a process for preparation of aminosulfone of formula (II) or its stereo isomers and their pharmaceutically acceptable salts

which comprises:
(a) reacting benzonitrile of formula (III) with dimethyl sulfone in the presence of a base in a suitable solvent to provide a compound of formula (IVa), followed by its conversion to provide enamine of formula (IV);
Wherein M=Na, K
(b) reducing enamine of formula (IV) in presence of a suitable solvent to provide aminosulfone of formula (II);

(c) optionally purifying amino sulfone of formula (II).

In second aspect, the present application provides a process for preparation of apremilast of formula (I) or its stereoisomers thereof

which comprises:
(a) contacting 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethylamine of formula (II) with a chiral acid in presence of a suitable solvent to form a chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (V);
(c) optionally treating chiral acid salt of aminosulfone of formula (V) with base to form chiral aminosulfone of formula (Va);

(d) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V) or chiral aminosulfone of formula (Va) with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (VI) in presence of a suitable solvent to provide apremilast of formula (I);

(e) optionally purifying apremilast of formula (I).

In third aspect, the present application provides a process for preparation of apremilast of formula (I) or its stereoisomers thereof:

which comprises:
(a) reacting benzonitrile of formula (III) with dimethyl sulfone in the presence of a base in a suitable solvent to provide a compound of formula (IVa), followed by its conversion to provide enamine of formula (IV);
Wherein M=Na, K
(b) reducing enamine of formula (IV) in presence of a suitable solvent to provide aminosulfone of formula (II);
(c) optionally purifying amino sulfone of formula (II);
(d) contacting 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (II) with a chiral acid in presence of a suitable solvent to form a chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V);
(e) optionally isolating and purifying chiral acid salt of aminosulfone of formula (V);
(f) optionally treating chiral acid salt of aminosulfone of formula (V) with base to form chiral aminosulfone of formula (Va);
(g) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V) or chiral aminosulfone of formula (Va) with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (VI) in presence of a suitable solvent to provide apremilast of formula (I);
(h) optionally purifying apremilast of formula (I).

The fourth aspect of the present application provides desoxo impurity of Apremilast, which is designated as Impurity M and having the following structure:

The fifth aspect of the present application provides pharmaceutical compositions comprising apremilast of formula (I) prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

DETAILED DESCRIPTION
In the first aspect, the present application provides a process for preparation of aminosulfone of formula (II) or its stereo isomers and their pharmaceutically acceptable salts

which comprises:
(a) reacting benzonitrile of formula (III) with dimethyl sulfone in the presence of a base in a suitable solvent to provide a compound of formula (IVa), followed by its conversion to provide enamine of formula (IV);

Wherein M=Na, K
(b) reducing enamine of formula (IV) in presence of a suitable solvent to provide aminosulfone of formula (II);

(c) optionally purifying amino sulfone of formula (II).

Step (a) may be carried out in one or more suitable bases. Suitable base that may be used in step (a) include, but are not limited sodium amide, potassium amide, C1-C20 alkoxide of sodium, C1-C20 alkoxide of potassium, C1-C20 alkoxide of magnesium, sodium hydride, potassium hydride and the like.
Step (a) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran,1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; ketone solvents, such as, for example, acetone, dialkyl ketone or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like or amide solvents, such as, for example, dimethylacetamide, dimethylformamide or the like, dimethylsulfoxide or mixtures thereof.
In an embodiment, the salt of enamine of compound of formula (IVa) may be directly subjected to reduction without converting its corresponding enamine of formula (IV) to afford amino sulfone of formula (II). The substantially similar reaction conditions may be adopted to that of free base of enamine compound (IV).
Any reducing agent known in the art for reducing an enamine to an amine can be used for the reduction in step (b). The reducing agent that may be used in step (b) include, but are not limited to sodium triacetoxyborohydride, sodium borohydride, sodium cyano borohydride, Palladium, Raney-nickel and the like.
The reduction in step (b) can occur in the presence of an acid such as, but not limited to, acetic acid, methanesulfonic acid, trifluoroacetic acid, 4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, benzene sulfonic acid and the like.
Step (c) which involves the isolation and purification of compound of formula (II) or its pharmaceutically acceptable salt can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The temperature at which the above steps may be carried out in between about
0 °C and about 100 °C, preferably at about 5 °C and about 60 °C, based on the solvent or mixture of solvent used in particular step.
In second aspect, the present application provides a process for preparation of apremilast of formula (I) or its stereoisomers thereof

which comprises:
(a) contacting 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethylamine of formula (II) with a chiral acid in presence of a suitable solvent to form a chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (V);
(c) optionally treating chiral acid salt of aminosulfone of formula (V) with base to form chiral aminosulfone of formula (Va);

(d) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V) or chiral aminosulfone of formula (Va) with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (VI) in presence of a suitable solvent to provide apremilast of formula (I);

(e) optionally purifying apremilast of formula (I).

Step (a) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; ketone solvents, such as, for example, acetone, dialkyl ketone or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like or amide solvents, such as, for example, dimethylacetamide, dimethylformamide or the like or acids such formic acid, acetic acid, propionic acid, or water, and mixtures thereof.
Suitable chiral acids that may be used in step (a) include, but are not limited to individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, di toluoyl tartaric acid, dibenzoyal tartaric acid, mandelic acid, lactic acid, ibuprofen, malic acid, pyrrolidone-5-carboxylic acid, naproxen, 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid, and the like. The resolution may also be carried out under any of the Pope-Peachey resolution conditions. For Pope Peachey resolution, an organic or inorganic acid in water along with chiral resoluting agent can be used for the chiral resolution process at any of the mole ratios between chiral acid, organic/inorganic acid and water.
Step (b) which involves the isolation and purification of compound of formula (II) or its pharmaceutically acceptable salt can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
Step (c) may be carried out in the presence of one or more suitable bases. Suitable base that may be used in step (c) include, but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like.
Step (d) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (c) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; ketone solvents, such as, for example, acetone, dialkyl ketone or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like or amide solvents, such as, for example, dimethylacetamide, dimethylformamide or acid like formic acid, acetic acid, propionic acid, butanoic aicd, methane sulphonic acid, benzene sulphonic acid, or anhydride like acetic anhydride, propionic anhydride in combination with water or mixtures thereof.
Step (e) which involves the isolation and purification of compound of formula (I) can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.

The temperature at which the above steps may be carried out in between about
0 °C and about 100 °C, preferably at about 25°C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
In third aspect, the present application provides a process for preparation of apremilast of formula (I) or its stereoisomers thereof:

which comprises:
(a) reacting benzonitrile of formula (III) with dimethyl sulfone in the presence of a base in a suitable solvent to provide a compound of formula (IVa), followed by conversion to provide enamine of formula (IV);
Wherein M=Na, K
(b) reducing enamine of formula (IV) in presence of a suitable solvent to provide aminosulfone of formula (II);
(c) optionally purifying amino sulfone of formula (II);
(d) contacting 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (II) with a chiral acid in presence of a suitable solvent to form a chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V);
(e) optionally isolating and purifying chiral acid salt of aminosulfone of formula (V);
(f) optionally treating chiral acid salt of aminosulfone of formula (V) with base to form chiral aminosulfone of formula (Va);
(g) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V) or chiral aminosulfone of formula (Va) with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (VI) in presence of a suitable solvent to provide apremilast of formula (I);
(h) optionally purifying apremilast of formula (I).

The reagents, solvents and reaction conditions for steps (a), (b), (c), (d), (e), (f) (g) and (h) may be selected from one or more suitable reagents, solvents and process conditions as described in the steps of the first and the second aspects of the present invention.

In fourth aspect, the present application provides desoxo impurity of Apremilast, which is designated as Impurity M and having the following structure:

The desoxo impurity of Apremilast (Impurity M) indicates that two apremilast units are linked together by a methylene bridge on the methyl carbon of the chiral amino sulphoxide chain. This impurity formation may occur via the cyclocondensation of 2,2'-(propane-1,3-diyldisulfonyl)bis(1-(3-ethoxy-4-methoxyphenyl)ethan-1-amine) of formula (VIII) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide of formula (VI) in presence of acetic acid in MIBK solvent. The diamine which leads to the formation of Desoxo impurity of Apremilast (Impurity M). The impurity M of Apremilast is characterized by 1H-NMR, IR , Mass spectra and other relevant 2D NMR studies.

The present invention provides Apremilast (I) substantially free of Impurity M. The present invention further provides Apremilast (I) having 0.01 to about 0.15% w/w of Impurity M by area percentage in HPLC. In another embodiment, the invention provides a pharmaceutical composition comprising Apremilast (I) having 0.01 to about 0.15% w/w of Impurity M by area percentage in HPLC.
Specifically, in one of the embodiment Apremilast (I) obtained in any of the inventions described herein is having less than 0.1% w/w of impurity M by area percentage in HPLC.
In fifth aspect, the present application provides a pharmaceutical compositions comprising apremilast of formula (I) prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.
The process of the present invention is easy to handle, environment friendly, provides better yield and purity and it may also be practiced on industrial scale.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6alcohols, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, 4-methyl-pentane-2-one or the like.
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.

EXAMPLES:
Example 1: Preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethen-1-amine (IV):
Dimethyl sulfone (53.1 g, 564 mmoles) was added to mixture of tetrahydrofuran (1000 ml) and dimethylsulfoxide (50 ml) and stirred at room temperature for 5-10 minutes. Sodium amide (22.02 g, 564 mmoles) was added slowly to the reaction mixture at 40°C and stirred for 10-15 minutes. 3-ethoxy-4-methoxy benzonitrile (50 g, 282 mmoles) in tetrahydrofuran (200 ml) was added to the reaction mixture over a period of 30 minutes and was stirred for three hours at room temperature. The reaction mixture was distilled under reduced pressure at 40-45 °C. Water (750ml) was added to the reaction mass and stirred at 35-40°C for 30 minutes. The solid was filtered, washed with water (150 ml) and dried under reduced pressure at 45-50 °C to give the title compound.
Yield: 63.7 g (83%)

Example 2: Preparation of 2-(3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-ethyl-2-amine (II)
1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine (IV) (5 g, 18.43 mmoles) was added to methanol (25 ml) and cooled to 5 °C. Methanolic hydrochloric acid (10%, 5 ml) was added to reaction mixture. Sodium cyano borohydride (1.7 g, 63.85 mmoles) was added to the reaction mixture and maintained at 5 °C for three hours. Methanol was distilled at 35 °C. Water (5 ml) was added to the reaction mixture at room temperature and pH adjusted to 12-13 with 10 % sodium hydroxide solution (8 ml) at 5 °C. The reaction mixture was stirred at 5 °C for three hours. The solid was filtered, washed with water (5 ml) and dried under reduced pressure at 50-55 °C to give the title compound.
Yield: 2.7g (53.68%)

Example 3: Preparation of 2-(3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-ethyl-2-amine (II)
1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine (IV) (5 g, 18.43 mmoles) was added to methanol (125 ml) at room temperature. Citric acid (7 g, 36.4 mmoles) was added to reaction mixture. Sodium cyano borohydride (1.7 g, 63.85 mmoles) was added to the reaction mixture at 5°C and maintained for one hour. Methanol was distilled at 35 °C. Water (50 ml) was added to the reaction mixture at room temperature and pH adjusted to 12-13 with 20 % sodium hydroxide solution (15 ml) at 5 °C. The reaction mixture was stirred at 5 °C for three hours. The solid was filtered, washed with water (15 ml) and dried under reduced pressure at 50-55 °C to give the title compound.
Yield: 4.4 g (88%)

Example 4: Preparation of 2-(3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-ethyl-2-amine (II)
Dimethyl sulfone (0.639 g, 0.067 mmoles) was added to dimethylsulfoxide (10 ml) and stirred at room temperature for 5-10 minutes. Potassium tertiary butoxide (1.89 g, 0.169 mmoles) was added slowly to the reaction mixture at 30°C and stirred for three hours. 3-ethoxy-4-methoxy benzonitrile (1.0 g, 0.056 mmoles) in tetrahydrofuran (2 ml) was added to the reaction mixture over a period of 30 minutes and was stirred for three hours at room temperature. Sodium borohydride (0.213 g, 0.056 mmoles) was added to the reaction mixture at 30 °C and maintained for one hour. Ammonium chloride (10 ml) was added to the reaction mixture and extracted with ethyl acetate (20 ml). The ethyl acetate layer was washed with water (10 ml). The ethyl acetate layer was distilled at 30 °C to provide crude compound. The crude compound was washed with methyl tertiary butyl ether to provide the title compound as pale yellow colored solid.
Yield: 750 mg (50%)

Example 5: Resolution of 2-(3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-ethyl-2-amine (II) using (-)-dibenzoyl-L-tartaric acid
2-(3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-ethyl-2-amine (II) (95 g, 348 mmoles) and (2R,3R)-2,3-bis(benzoyloxy)succinic acid (91 g, 243 mmoles) were added to water (1805 ml) and acetic acid (332.5 ml) and stirred at room temperature. The temperature of reaction was slowly raised to 97 °C and maintained for three hours. The reaction mass was cooled to room temperature and solid was separated. The solid was filtered and was washed with water (100ml). The solid was dried at 70 °C for ten hours to give (-)-dibenzoyl-L-tartaric acid salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine.
Yield: 78.3 g (35.6%)
Chiral purity: 98.10%

Example 6: Resolution of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethan-1-amine (II) using (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid
2-(3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-ethyl-2-amine (II) (20 g, 73.2 mmoles) and (2R,3R)-2,3-bis(benzoyloxy)succinic acid monohydrate (28.3 g, 73.2 mmoles) were added to dimethylformamide (20 ml) and methanol (200 ml) and stirred at room temperature. The temperature of reaction was slowly raised to 65 °C and maintained for two hours. The reaction mass was cooled to room temperature. The solid separated was filtered under vacuum at 30°C and was washed with methanol (10 ml). The solid was taken in methanol (200 ml) and dimetylformamide (40) and heated to 65 °C. The reaction mixture was maintained at 65 °C for two hours and allowed to cool to room temperature. The solid was filtered under vacuum at 30°C, washed with methanol (10 ml) and dried at 70 °C for two hours. The solid was taken in methanol (168 ml) and dimethylformamide (72 ml) and heated to 65 °C. The reaction mixture was maintained at 65 °C for two hours and allowed to cool to room temperature. The solid was filtered under vacuum at 30°C, washed with methanol (10 ml) and dried at 70 °C for two hours to give of (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine.
Yield: 48.3 g (12.4%)
Chiral purity: 91.02%

Example 7: Preparation of Apremilast (I)

N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.705 g, 8.31 mmoles) and (-)-dibenzoyl-L-tartaric acid salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (5 g, 7.92 mmoles) were added to acetic acid (50 ml) and stirred at room temperature. The temperature of reaction was slowly raised to 95 °C and maintained for fifteen hours. The reaction mixture was distilled under reduced pressure at 60-65 °C for thirty minutes. Ethyl acetate (50 ml) and saturated bi carbonate solution (30 ml) was added to the reaction mass and stirred at 35-40°C for two hours. The solid was filtered under vacuum at 30°C and was washed with water (5 ml). Ethanol (30 ml) and acetone (15 ml) was added to the solid and heated to 55°C and maintained for 2 hours. The solid was filtered under vacuum at 30°C and dried at 65 °C for five hours to give apremilast as a product.

Example 8: Preparation of Apremilast (I)
N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (5 g, 7.92 mmoles) and (-)-dibenzoyl-L-tartaric acid salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (1.70 g, 8.31 mmoles) were added to dimethylformamide (25 ml) and stirred at room temperature. The temperature of reaction was slowly raised to 95 °C and maintained for eight hours. Water (50 ml) and ethyl acetate (20 ml) was added to the reaction mass at room temperature and stirred for fifteen minutes. The solid was filtered and slurried in hexane (20 ml). The solid was filtered and dried at 65 °C for thirty minutes to give apremilast as a product.
Yield: 2.8 g (77%)

Example 9: Process for the preparation of desoxo impurity of Apremilast (Impurity M)
Racemic amino sulfone of formula (II) (150 g) obtained after distillation the solvent from mother liquor from one of the plant batches, N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (113 g) , methyl isobutyl ketone (300 mL) and acetic acid (700 mL) were charged into a round bottom flask and stirred at room temperature. The mixture was heated to 98-100°C and maintained for 3 hours. The solvent from the reaction mass was evaporated under vacuum at below 60°C. Dichloromethane (300 mL) water (200 mL) were charged to the reaction mass at room temperature and stirred for 10 minutes. The organic layers were separated and washed with water (2X200mL). The combined organic layer was distilled under vacuum. Methyl isobutyl ketone (750 mL) was added to the residue and maintained for 15 hours at room temperature. The solid was filtered and washed with methyl isobutyl ketone (100 mL) and dried under vacuum at 85°C for 10-12 hours. Dried compound was adsorbed on silica gel and subjected to flash column chromatography and impurity was separated by collecting the required fraction.

1H NMR (400 MHz, CDCl3) d (ppm): 1.45 (s, 6H), 9.4 (2NH), 8.75 (d, 2H), 7.65(t, 2H) 7.48 (d, 2H), 5.85 (m, 2H), 4.6 & 3.65 (m, 4H), 4.1 (4H), 7.15 (d, 4H), 6.8 (d, 2H), 3.8 (6H), 3.15 (t, 4H), 2.4 (m, 2H), 2.25 (s, 6H);

Mass Spectral data: m/Z = 931 (M-1) and m/Z = 955 (Na adduct).
,CLAIMS:WE CLAIM:

1) A process for preparation of aminosulfone of formula (II) or its stereo isomers and their pharmaceutically acceptable salts

which comprises:
(a) reacting benzonitrile of formula (III) with dimethyl sulfone in the presence of a base in a suitable solvent to provide a compound of formula (IVa), followed by its conversion to provide enamine of formula (IV);

Wherein M=Na, K
(b) reducing enamine of formula (IV) in presence of a suitable solvent to provide aminosulfone of formula (II);

(c) optionally purifying amino sulfone of formula (II).

2) The process as claimed in claim 1, wherein base used in step a) is selected from sodium amide, potassium amide, C1-C20 alkoxide of sodium, C1-C20 alkoxide of potassium, C1-C20 alkoxide of magnesium, sodium hydride and potassium hydride.

3) The process as claimed in claim 1, wherein step b) is carried out in the presence of an acid selected from acetic acid, methanesulfonic acid, trifluoroacetic acid, 4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and benzene sulfonic acid.

4) A process for preparation of apremilast of formula (I) or its stereoisomers thereof

which comprises:
(a) contacting 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (II) with a chiral acid in presence of a suitable solvent to form a chiral acid salt of 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (V);
(c) optionally treating chiral acid salt of aminosulfone of formula (V) with base to form chiral aminosulfone of formula (Va);

(d) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (V) or chiral aminosulfone of formula (Va) with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (VI) in presence of a suitable solvent to provide apremilast of formula (I);

(e) optionally purifying apremilast of formula (I).

5) The process as claimed in claim 4, wherein solvent used in step d) is selected from ethers, ketone solvents, aromatic hydrocarbon solvents, nitrile solvents, alcohol solvents, ester solvents, amide solvents, acid solvents, water and mixtures thereof.

6) A process for preparation of apremilast of formula (I) or its stereoisomers thereof:

which comprises:
(a) reacting benzonitrile of formula (III) with dimethyl sulfone in the presence of a base in a suitable solvent to provide a compound of formula (IVa), followed by its conversion to provide enamine of formula (IV);

Wherein M=Na, K
(b) reducing enamine of formula (IV) in presence of a suitable solvent to provide aminosulfone of formula (II);
(c) optionally purifying amino sulfone of formula (II);
(d) contacting 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (II) with a chiral acid in presence of a suitable solvent to form a chiral acid salt of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (V);
(e) optionally isolating and purifying chiral acid salt of aminosulfone of formula (V);
(f) optionally treating chiral acid salt of aminosulfone of formula (V) with base to form chiral aminosulfone of formula (Va);
(g) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (V) or chiral aminosulfone of formula (Va) with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (VI) in presence of a suitable solvent to provide apremilast of formula (I);
(h) optionally purifying apremilast of formula (I).

7) A compound of desoxo impurity of Apremilast (Impurity M).

8) Apremilast of formula (I) substantially free of desoxo impurity (Impurity M).