DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF APREMILAST

INTRODUCTION
One of the present invention relate to process for preparation of apremilast. Another aspect of the present invention relate to process for preparation of crystalline form B of apremilast. Another aspect of the present application provides process for preparation of amorphous form of apremilast.
BACKGROUND
Apremilast is a PDE4 inhibitor and acts as an anti-inflammatory 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
Processes for the preparation of apremilast and its intermediates have been disclosed in US6020358B2, US7427638B2, US8242310B2, WO2009120167, 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 first aspect, the present application provides a process for preparation of apremilast of formula (I) or its stereoisomers thereof

which comprises:
(a) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) or its freebase with N-(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (III) in presence of mixture of ketonic solvent and polar solvent to provide apremilast of formula (I);

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

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

which comprises:
(a) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) or its freebase with N-(1,3-Dioxo-1,3-dihydro- isobenzofuran- 4-yl)-acetamide of formula (III) in presence of a mixture of ketonic solvent and polar solvent to provide apremilast of formula (I);

(b) optionally isolating and purifying apremilast;
(c) converting the apremilast obtained in step (b) to crystalline form B of apremilast;
(d) optionally isolating and purifying crystalline form B of apremilast.

Third aspect of the present application relates to process for preparing amorphous form of apremilast comprising:
a) dissolving apremilast in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of apremilast; or adding solution of apremilast to water;
d) isolating the solid;
e) optionally, drying the product at suitable temperature.
The fourth aspect of the present application provides pharmaceutical compositions comprising apremilast of formula (I) prepared according to processes of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of amorphous form of apremilast obtained by the example 4.

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

which comprises:
(a) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) or its freebase with N-(1,3-Dioxo-1,3-dihydro- isobenzofuran- 4-yl)-acetamide of formula (III) in presence of mixture of ketonic solvent and polar solvent to provide apremilast of formula (I);

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

Suitable ketone solvent that may be used in step (a) include, but are not limited to acetone, dialkyl ketone such as ethyl methyl ketone, methyl isobutyl ketone or the like; or mixtures thereof.
Suitable polar solvent that may be used in step (a) include, but are not limited to acid such as acetic acid, formic acid and the like; ethers such as tetrahydrofuran, diethylether and the like; nitriles such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, isopropyl acetate and the like; alcohols such as methanol, ethanol and the like; amides such as dimethylformamide, dimethylacetamide and the like; dimethylsulfoxide, water or mixtures thereof.
In an embodiment, the ratio of ketone to polar solvent in above step lies in the ratio of 25:1 v/v, preferably at about 20:1 v/v.
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, dibenzoyl 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.
Step (b) 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 a particular embodiment, the free base of formula (II) is an amino sulfone intermediate, which is prepared by following the processes known in the literature or by neutralizing the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) with a base to afford amino sulfone.
In second aspect, the present application provides a process for preparation of crystalline form B of apremilast of formula (I) or its stereoisomers thereof:

which comprises:
(a) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) or its freebase with N-(1,3-Dioxo-1,3-dihydro- isobenzofuran- 4-yl)-acetamide of formula (III) in presence of mixture of ketonic solvent and polar solvent to provide apremilast of formula (I);

(b) optionally isolating and purifying apremilast;
(c) converting the apremilast to crystalline form B of apremilast;
(d) optionally isolating and purifying crystalline form B of apremilast.

The reagents, solvents and reaction conditions for step (a) may be selected from one or more suitable reagents, solvents and process conditions as described in the steps of the first aspect of the present invention.
The crystalline form obtained in step b) of the instant invention can be any single crystalline form or one or more mixture of crystalline forms of apremilast known in the art.
The isolation of steps b) and d) can be effected, if desired, by any suitable separation method such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure 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.

The apremilast obtained in step (b) of the present invention may be dried by any of the known drying methods and/or may be further purified by the known purification techniques.

In an embodiment, the crystalline form B of apremilast may be added as a seed crystal in step (c) of the present invention. The quantity of seed crystal may be used from about 0.5 wt% to about 50 wt%, preferably the quantity of seed crystal may be about 0.5 wt% over input material.

In one of the embodiment, the reaction mass obtained in step (c) of the present invention may be stirred at different temperature ranges for suitable time period. Particularly, the reaction mass obtained in step (c) of the present invention may be stirred at a temperature of about 70-95°C for about 2-4 hours, followed by at about 40-65°C for about 10-20 hours and further at about 25-35oC for about 10-30 hours. The stirring temperature and time period may be varied based on the conversion of apremilast obtained in step (b) to crystalline form B of apremilast.

In one of the aspect of the present invention, the apremilast obtained in step (b) may be crystalline form A or a mixture of crystalline form A with other known polymorphic forms of apremilast and preferably, the polymorphic conversion may be monitored by X-ray diffraction analysis.

Third aspect of the present application relates to process for preparing amorphous form of apremilast comprising:
a) dissolving apremilast in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of apremilast; or adding solution of apremilast to water;
d) isolating the solid;
e) optionally, drying the product at suitable temperature.

Suitable solvents of step a) for dissolving apremilast include, but are not limited to dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane; alcohols such as methanol, ethanol, propanol, isopropanol; and mixtures thereof.
In an embodiment, water as an anti-solvent may be added to the reaction solution obtained in either step (a) or step (b) of the present invention by drop wise or in a single lot based on the solvent used in step (a) of the present invention. Optionally, the solution obtained in step (a) or step (b) may be added to water.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.

The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.

Drying in the embodiments of the present invention may be suitably carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
The amorphous apremilast obtained in the third aspect of the present invention is substantially free of crystalline peaks. In an embodiment, the amorphous form of apremilast obtained in the present invention may have less than about 5 wt% of crystalline apremilast, particularly the amorphous form of apremilast may contain less than about 1 wt% of crystalline apremilast.

The glass–liquid transition or glass transition temperature is the reversible transition in amorphous materials from a hard and relatively brittle state into a molten or rubber-like state. The glass-transition temperature (Tg) is always lower than the melting temperature (Tm) of the crystalline state of the material, if one exists. The glass transition temperature of amorphous apremilast of present invention lies in the range of 76.03°C -78.83°C.

The amorphous material obtained in the present invention is subjected to humidification studies at different temperature conditions with different relative humidity percentages. In a particular example, the humidification studies were carried out on amorphous apremilast of present invention at about 30°C and relative humidity of 60% and 90% individually. The amorphous apremilast obtained in the present invention is pure, non-hygroscopic and is stable for about 24 hours at these humidity conditions.

Apremilast obtained in any of the above inventions may optionally be subjected to milling, grinding or sieving techniques to get the required particle size by adopting the procedures known in the art.

All PXRD data reported herein are obtained using a PANalytical X-ray diffractometer with copper Ka radiation.

Fourth embodiment of the present invention 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.
The processes 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, C1-6 alcohols, 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, C2-6 ethers, 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 apremilast (I)

Acetic acid (20ml) was added to a mixture of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (10 g, 36.6 moles) in methyl isobutyl ketone (60ml) and stirred at room temperature. N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (7.88 g, 38.4 moles) was added to the reaction mixture and heated to 96°C and maintained for 30 hours. Water (80ml) was added to the reaction mixture at room temperature. The organic layers were separated and washed with water (40ml) and 10% sodium bicarbonate solution (40ml) and dried over sodium sulfate. The organic layer was heated to 95°C and maintained for half an hour. The reaction mixture was heated to 55°C and seed crystal of apremilast was added. The reaction mixture was maintained at 45°C for eight hours followed by at 25°C for five hours under stirring. The solid was filtered, washed with methyl isobutyl ketone (20 ml) and dried under vacuum at 62°C for twelve hours to provide the title compound as product.
Yield: 12.6 g

Example 2: Preparation of apremilast (I)
Dimethylsulfoxide (2.5ml) was added to a mixture of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (5 g, 18.29 moles) in methyl isobutyl ketone (50ml) and stirred at room temperature. N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (3.94 g, 19.21 moles) was added to the reaction mixture and heated to 96°C and maintained for 15 hours. Water (50ml) was added to the reaction mixture at room temperature. The organic layers were separated and washed with water (20ml) and 10% sodium bicarbonate solution (20ml) and dried over sodium sulfate. The reaction mixture was stirred to 25°C and seed crystal of apremilast was added. The reaction mixture was stirred and maintained at 25°C for six hours. The solid was filtered, washed with methyl isobutyl ketone (10 ml) and dried under vacuum at 62°C for four hours to provide the title compound as product.
Yield: 6.3 g

Example 3: Preparation of crystalline form B of apremilast
Apremilast (100 g, 0.217 moles) was added to methyl isobutyl ketone (900ml) and stirred at 30-35 °C. The reaction mixture was heated to 90-95 °C and stirred for 1-2 hours. The reaction mass was cooled to 75 °C and filtered through micron filter and washed with methyl isobutyl ketone (100ml). The combined filtrate was heated to 90-95 °C. The reaction mass was cooled to 40-45°C and seed crystals of form B of apremilast were added. The reaction mass was maintained at 40 -45°C for 6-7 hours and further at 30-35 °C for 14-16 hours. The reaction mass was filtered over buchner funnel at 30-35 °C and washed with methyl isobutyl ketone (50 ml). The solid obtained was dried under vacuum at 75-85 °C for 8-9 hours to provide the title compound.
Yield: 30 g

Example 4: Preparation of amorphous apremilast
Apremilast (5 g) was dissolved in methanol (150 mL) at 45 ºC. The clear solution was added dropwise to water (250 mL) at 0-5ºC. The solid was filtered, washed with water (200 ml) and was dried at 40ºC under vacuum for about 6-8 hours to provide the title compound.

Example 5: Preparation of amorphous apremilast
Apremilast (5 g) was dissolved in dimethyl sulfoxide (25 mL) at 28 ºC. The clear solution was added dropwise to water (80 mL) at 0-5ºC. The solid was filtered, washed with water (20 ml) and was dried at 40ºC under vacuum for about 6-8 hours to provide the title compound.

Example 6: Preparation of amorphous apremilast
Apremilast (5 g) was dissolved in acetonitrile (25 mL) at 50 ºC. The clear solution was added dropwise to water (50 mL) at 0-5 ºC. The solid was filtered and was dried at 25-30 ºC under vacuum for about 5-6 hours to provide the title compound.

Example 7: Preparation of amorphous apremilast
Apremilast (5 g) was dissolved in a mixture of methanol (8ml) and dimethylsulfoxide (10mL) at 28 ºC. The clear solution was added dropwise to water (100 mL) at 0-5 ºC. The solid was filtered and was dried at 25-30 ºC under vacuum for about 12 hours to provide the title compound.

Example 8: Preparation of amorphous apremilast
Apremilast (1 g) was dissolved in acetone (15 mL) at 50 ºC. The clear solution was added dropwise to water (50 mL) at 0-5 ºC. The solid was filtered and was dried at 25-30 ºC under vacuum for about 5-6 hours to provide the title compound.

Example 9: Preparation of amorphous apremilast
Apremilast (1 g) was dissolved in acetone (15 mL) at 50 ºC. Pre-cooled water (50 mL) was added to apremilast mixture at 0-5 ºC. The solid was filtered and was dried at 25-30 ºC under vacuum for about 5-6 hours to provide the title compound.

Example 10: Humidification of amorphous apremilast

Amorphous apremilast (1 g) was kept in a humidification chamber at 30 ºC and 60% relative humidity for twenty hours and found that the amorphous form is retained as such by X-ray diffractogram.

Example11: Humidification of amorphous apremilast

Amorphous apremilast (1 g) was kept in a humidification chamber at 30 ºC and 90% relative humidity for twenty hours and found that the amorphous form is retained as such by X-ray diffractogram.
,CLAIMS:1) A process for preparation of apremilast of formula (I) or its stereoisomers thereof

which comprises:
(a) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) or its freebase with N-(1,3-Dioxo-1,3-dihydro- isobenzofuran- 4-yl)-acetamide of formula (III) in presence of mixture of ketonic solvent and polar solvent to provide apremilast of formula (I);

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

2) The process as claimed in claim 1, wherein ketonic solvent used in step a) is selected from acetone, dialkyl ketone, ethyl methyl ketone, methyl isobutyl ketone and mixtures thereof.

3) The process as claimed in claim 1, wherein polar solvent used in step a) is selected from acid solvents, ethers, nitriles, esters, alcohols, amides, water and mixtures thereof.

4) A process for preparation of crystalline form B of apremilast of formula (I) or its stereoisomers thereof:

which comprises:
(a) contacting the chiral acid salt of 1-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl-ethylamine of formula (II) or its freebase with N-(1,3-Dioxo-1,3-dihydro- isobenzofuran- 4-yl)-acetamide of formula (III) in presence of mixture of ketonic solvent and polar solvent to provide apremilast of formula (I);

(b) optionally isolating and purifying apremilast;
(c) converting the apremilast to crystalline form B of apremilast;
(d) optionally isolating and purifying crystalline form B of apremilast.

5) A process for preparing amorphous form of apremilast comprising:
a) dissolving apremilast in a suitable solvent or mixture thereof;
b) optionally, heating the solution of step (a);
c) adding water as an anti-solvent to the solution of apremilast; or adding solution of apremilast to water;
d) isolating the solid;
e) optionally, drying the product at suitable temperature.

6) The process as claimed in claim 5, wherein solvent used in step a) is selected from dimethylformamide; dimethylacetamide; dimethyl sulphoxide, nitriles, ketones, ethers, esters, halogenated hydrocarbons, alcohols and mixtures thereof.