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 (S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the formula (II) and its use in preparation of apremilast. Another aspect of the present application provides crystalline form of (S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the formula (II).

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
(S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the 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) and its pharmaceutically acceptable salts

which comprises:
(a) contacting racemic 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethylamine of formula (III) 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 (IV);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (IV);
(c) treating chiral acid salt of aminosulfone of formula (IV) with base in suitable solvent to form chiral aminosulfone of formula (II);

(d) optionally isolating and purifying aminosulfone 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 racemic 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethylamine of formula (III) 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 (IV);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (IV);
(c) treating chiral acid salt of aminosulfone of formula (IV) with base in suitable solvent to form chiral aminosulfone of formula (II);

(d) contacting chiral aminosulfone of formula (II) with N-(1,3-dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (V) 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 crystalline form of aminosulfone of formula (II) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.97, 17.81, 19.85 and 26.07 ? 0.2 degrees 2?. In embodiments, the present application provides form of aminosulfone of formula (II) characterized by its PXRD pattern having additional peaks located at about 11.88, 15.88, 21.96 and 26.72 ? 0.2 degrees 2?. Still in other embodiments, the present application provides crystalline form of aminosulfone of formula (II) characterized by its PXRD pattern having additional peaks located at about 12.10, 20.72 and 22.18 ? 0.2 degrees 2?.

In fourth aspect, the present application provides crystalline form of aminosulfone of formula (II) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.97, 11.88, 12.10, 15.88, 17.81, 19.85, 20.72, 21.96, 22.18, 26.07 and 26.72 ? 0.2 degrees 2?.

In fifth aspect, the present application provides crystalline form of aminosulfone of formula (II) that can be characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 1.

The sixth 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.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of aminosulfone of formula (II), obtained in the present invention.

DETAILED DESCRIPTION

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

which comprises:
(a) contacting racemic 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (III) 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 (IV);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (IV);
(c) treating chiral acid salt of aminosulfone of formula (IV) with base in suitable solvent to form chiral aminosulfone of formula (II);

(d) optionally isolating and purifying chiral aminosulfone of formula (II).

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, and the like; ketone solvents, such as, for example, acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, and the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, and the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol and 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, and the like or amide solvents, such as, for example, dimethylacetamide, dimethylformamide, N-methylpyrollidine and the like or acids such formic acid, acetic acid, propionic acid; water or 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, methoxyacetic acid, tartaric acid, diacetyltartaric acid, di-toluoyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, derivatives of mandelic acid such as acetyl mandelic acid, propyl mandelic acid, lactic acid, ibuprofen, malic acid, pyrrolidone-5-carboxylic acid, naproxen, and the like. Specifically suitable chiral acids that may be used in step (a) include, but are not limited to tartaric acid, dibenzoyl tartaric acid and di toluoyl tartaric acid. More specifically the suitable chiral acid may be dibenzoyl tartaric acid. The resolution may also be carried out under any of the Pope-Peachey resolution conditions or any conventional method of resolution. 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 (IV) 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.

Any suitable solvent that is capable to dissolve the salt may be used for the purification to increase the chiral purity to a desired level.

Step (c) may be carried out in the presence of one or more suitable bases and one or more suitable solvents. Suitable base that may be used in step (c) include, but are not limited to organic bases like pyridine, piperidine, pyrimidine, triethylamine, diethylamine, diisopropyl ethylamine, 1,1,3,3-tetramethylguanidine, DBU, DABCO etc, inorganic bases like metal carbonates such as sodium carbonate, potassium carbonate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like.

Step (c) 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 but are not limited to aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; water, and mixtures thereof.

Step (d) 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.

Optionally, the resulted chiral amino sulfone of formula (II) may be subjected to purification in one or more suitable solvents.

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 70°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 racemic 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (III) 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 (IV);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (IV);
(c) treating chiral acid salt of aminosulfone of formula (IV) with base in a suitable solvent to form chiral aminosulfone of formula (II);

(d) contacting chiral aminosulfone of formula (II) with N-(1,3-dioxo-1,3-dihydro-isobenzofuran- 4-yl)-acetamide of formula (V) in presence of a suitable solvent to provide apremilast of formula (I);

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

The reagents, solvents and reaction conditions for steps (a), (b) and (c) 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.

In one of the embodiments, step (d) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (d) 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 such as ethyl methyl ketone and 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 acids like formic acid, acetic acid, propionic acid, butanoic acid, methane sulphonic acid, benzene sulphonic acid, or anhydride like acetic anhydride, propionic anhydride; water or mixtures thereof.

The temperature at which the above steps may be carried out in between about 0°C and about 150°C, preferably at about 25°C and about 110°C, based on the solvent or mixture of solvent used in particular step.

Alternatively, the step (d) of second aspect of invention may be performed by any suitable process disclosed in the prior references.

In third aspect, the present application provides crystalline form of aminosulfone of formula (II) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.97, 17.81, 19.85 and 26.07 ? 0.2 degrees 2?. In embodiments, the present application provides form of aminosulfone of formula (II) characterized by its PXRD pattern having additional peaks located at about 11.88, 15.88, 21.96 and 26.72 ? 0.2 degrees 2?. Still in other embodiments, the present application provides crystalline form of aminosulfone of formula (II) characterized by its PXRD pattern having additional peaks located at about 12.10, 20.72 and 22.18 ? 0.2 degrees 2?.

In fourth aspect, the present application provides crystalline form of aminosulfone of formula (II) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.97, 11.88, 12.10, 15.88, 17.81, 19.85, 20.72, 21.96, 22.18, 26.07 and 26.72 ? 0.2 degrees 2?.

In fifth aspect, the present application provides crystalline form of aminosulfone of formula (II) that can be characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 1.

In one of the embodiments, the amino sulfone of formula (II) obtained in the first aspect of the invention is substantially similar to the X-ray pattern disclosed as Figure 1.

The PXRD data reported herein is obtained by using a PANalytical X-ray Diffractometer, with copper Ka radiation.

Amino sulfone of formula (II) and/or apremilast of formula (I) obtained in the present invention is having more than 95 % chemical and chiral purity. The process of the present invention is easy to scale-up at commercial level and is also eco-friendly.

In sixth aspect, 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 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, C1-6 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 (S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethylamine of the formula (II)
(-)-Dibenzoyl-L-tartaric acid salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (15 g, 0.079 moles) was added to water (150 ml) and stirred at room temperature. 10% aqueous sodium hydroxide solution (25 ml) was added to the reaction mixture and stirred at room temperature. Toluene (150 ml) was added to the reaction mixture and stirred for three hours at room temperature. The layers were separated and dichloromethane (75 ml) was added to the aqueous layer and stirred for 30 minutes at room temperature. The organic layer was separated and distilled under vacuum at below 50°C to provide the title compound as product.
Yield: 6.5 g

Example 2: Preparation of (S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethylamine of the formula (II)
Sodium hydroxide (7 g, 0.175 moles) was added to water (110 ml) at room temperature and cooled to 0-5°C. (-)-Dibenzoyl-L-tartaric acid salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (50 g, 0.079 moles) was added to reaction mixture and stirred at 0-5°C for two hours. The reaction mixture was filtered and wet solid was washed with water (50 ml). The solid was dried in oven at 60-75°C to provide the title compound.
Yield: 18.5 g

Example 3: Preparation of Apremilast (I)

(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (6.5 g, 0.023 moles) were added to toluene (120 ml) and stirred at room temperature. Acetic acid (30 ml) and N-acetylphthalic anhydride (5.12 g, 0.024 moles) was added to the reaction mixture at room temperature. The temperature of reaction mixture was raised to 100-105oC and maintained for 8-10 hours. Distilled the solvent at below 60°C under vacuum and cooled the reaction mixture to room temperature. Methyl ethyl ketone (150 ml) was added to the reaction mixture at room temperature. The temperature of reaction mixture was raised to 50-60oC and 10% sodium bicarbonate solution (150 ml) was added followed by water (50 ml). The layers were separated and the organic layer was distilled upto one-fourth of its initial volume under vacuum and cooled to 0-5°C. The reaction mixture was maintained at 0-5°C for 1-2 hours. The solid was filtered, washed with methyl ethyl ketone (15 ml) and dried in oven to provide apremilast as product.
Yield: 8.5 g

Example 4: Preparation of Apremilast (I)

(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (5 g, 0.018 moles) were added to methyl ethyl ketone (50 ml) and stirred at room temperature. The reaction mixture was refluxed to remove the water under azeotropic conditions. Acetic acid (10 ml) and N-acetylphthalic anhydride (3.94 g, 0.019 moles) was added to reaction mixture at room temperature. The temperature of reaction mixture was raised to 80–85°C and maintained for 8-10 hours. The reaction mixture was cooled to 60°C and 10% sodium bicarbonate solution (150 ml) was added to reaction mixture at 50-60 °C. The layers were separated and the organic layer was distilled under vacuum to a minimum volume and cooled the mass to 0-5 °C. The reaction mixture was maintained at 0-5°C for two hours. The solid was filtered, washed with methyl ethyl ketone (5 ml) and dried in oven to provide apremilast as product.
Yield: 6 g

Example 5: Preparation of Apremilast (I)
(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (4 g, 0.014 moles) were added to methyl ethyl ketone (40 ml) and stirred at room temperature. Acetic acid (8 ml) and N-acetylphthalic anhydride (3.15, 0.015 moles) was added to reaction mixture at room temperature. The temperature of reaction mixture was raised to 100 –105°C and maintained for 6-10 hours. Water (40 ml) was added to the reaction mixture at 25-30°C and the reaction mixture was stirred at 50-60°C for fifteen minutes. The layers were separated and 10% sodium bicarbonate solution (32 ml) was added to the organic layer at 50-60°C. The layers were separated and 10% sodium chloride solution (32 ml) was added to organic layer. The organic layer was separated, distilled under vacuum to minimum volume and cooled the mass to 0-5°C. The reaction mixture was maintained at 0-5 °C for two hours. The solid was filtered, washed with methyl ethyl ketone (8 ml) and dried in oven to provide apremilast as product.
Yield: 4.8 g
,CLAIMS:1) A process for preparation of aminosulfone of formula (II) and its pharmaceutically acceptable salts

which comprises:
a) contacting racemic 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (III) 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 (IV);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (IV);
(c) treating chiral acid salt of aminosulfone of formula (IV) with base in suitable solvent to form chiral aminosulfone of formula (II);

(d) optionally isolating and purifying chiral aminosulfone of formula (II).

2) The process as claimed in claim 1, wherein chiral acid used in step a) is selected from individual enantiomers of 10-camphorsulfonic acid, camphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, di-toluoyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, derivatives of mandelic acid such as acetyl mandelic acid, propyl mandelic acid, lactic acid, ibuprofen, malic acid, pyrrolidone-5-carboxylic acid and naproxen.

3) The process as claimed in claim 1, wherein base used in step c) is selected from pyridine, piperidine, pyrimidine, triethylamine, diethylamine, diisopropyl ethylamine, 1,1,3,3- tetramethylguanidine, DBU, DABCO, sodium carbonate, potassium carbonate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide.

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

which comprises:
(a) contacting racemic 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of formula (III) 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 (IV);

(b) optionally isolating and purifying chiral acid salt of aminosulfone of formula (IV);
(c) treating chiral acid salt of aminosulfone of formula (IV) with base in a suitable solvent to form chiral aminosulfone of formula (II);
(d) contacting chiral aminosulfone of formula (II) with N-(1,3-dioxo-1,3-dihydro-isobenzofuran-4-yl)-acetamide of formula (V) 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 crystalline form of chiral aminosulfone of formula (II) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.97, 17.81, 19.85 and 26.07 ± 0.2 degrees 2?.
7) The crystalline form of chiral aminosulfone of formula (II) according to claim 6, further comprising 2-theta peaks, located at about 11.88, 15.88, 21.96 and 26.72 ± 0.2.

8) The crystalline form of chiral aminosulfone of formula (II) according to claim 6 and 7, further comprising 2-theta peaks, located at about 12.10, 20.72 and 22.18 ± 0.2.

9) A X-ray diffractogram of crystalline form of chiral aminosulfone of formula (II) substantially as shown in figure 1.