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 racemic 2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (IV) from (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III). Another aspect of the present application provides the use of racemic amine prepared according to present invention in preparation 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
(S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of formula (II) is one of the key intermediates 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.
Synthetic routes to apremilast often rely on classical resolution of racemic amino sulfone (IV) to obtain required (S)-enantiomer (II), which results in significant waste stream of the unwanted (R)-enantiomer of formula (III), herein after referred as (R)-aminosulfone.

In view of the importance of PDE4 inhibitors, cost-effective and novel methods of making such intermediates are always of interest. The present invention provides a cost and yield-improving process to recycle the (R)-amino sulfone (III) to racemic aminosulfone (IV).

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

which comprises of:
(a) reacting of (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with a halogenating reagent in the presence of a suitable solvent to provide an halogenated amine of formula (V);

wherein X= Cl, F, Br, I
(b) treating halogenated amine of formula (V) in presence of a suitable base in a suitable solvent to provide enamine of formula (VI);

wherein X= Cl, F, Br, I

(c) converting the enamine of formula (VI) to racemic aminosulfone of formula (IV) in presence of reducing agent and a suitable solvent;
(d) optionally purifying racemic amino sulfone of formula (IV).

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

which comprises of:
(a) reacting of (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with a halogenating reagent in the presence of a suitable solvent to provide an halogenated amine of formula (V);

wherein X= Cl, F, Br, I
(b) treating halogenated amine of formula (V) in presence of a suitable base in a suitable solvent to provide enamine of formula (VI);

wherein X= Cl, F, Br, I

(c) converting the enamine of formula (VI) to racemic aminosulfone of formula (IV) in presence of reducing agent and a suitable solvent;
(d) optionally purifying racemic amino sulfone of formula (IV);
(e) converting the racemic amino sulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

Third embodiment of the present invention provides novel compound of formula (V)

wherein X= Cl, F, Br, I

The fourth 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 excipients, carriers and diluents.

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

which comprises:
(a) reacting of (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with a halogenating reagent in the presence of a suitable solvent to provide an halogenated amine of formula (V);

wherein X= Cl, F, Br, I
(b) treating halogenated amine of formula (V) in presence of a suitable base in a suitable solvent to provide enamine of formula (VI);

(c) converting the enamine of formula (VI) to racemic aminosulfone of formula (IV) in presence of reducing agent and a suitable solvent;
(d) optionally purifying racemic amino sulfone of formula (IV).

Suitable halogenating reagents that may be used in step (a) include, but are not limited to trichloroisocyanuric acid, N,N’-dichlorobis(2,4,6-trichlorophenyl)urea, N-chlorosuccinimide, N-bromosuccinimide, sodium hypochlorite, sodium hypobromite 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, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; water and mixtures thereof.
Suitable bases that may be used in step (b) include, but are not limited to organic bases such as, 2,4,6-collidine, 2,6-di-tert-butyl-4-methylpyridine, 1-diethylamino-2-propanol, N-ethylamino-2-propanol, N-ethyldiisopropylamine, 4-ethylmorpholine, 1-ethylpiperidine, 2,6-lutidine, N-methylmorpholine, 1-methylpiperidine, tribenzylamine, triethylamine, DBU, pyridine, LDA, NaHMDS, KHMDS, sodium hydride, potassium hydride and the like. Suitable inorganic bases include, but are not limited to alkali hydrides, such as, for example, sodium hydride, potassium hydride or the like; alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide or the like; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like.
Step (b) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (b) 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; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like and mixtures thereof.
Step (c) may be carried out in one or more suitable reducing agents. Suitable reducing agents that may be used in step (c) include, but are not limited to sodium borohydride, lithium borohydride, sodium cyanoborohydride, di-isobutyl aluminum hydride and the like.
Step (c) 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; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents such as chloroform, dichloromethane or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; water and mixtures thereof.

Step (d) 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.
The temperature at which the above steps may be carried out in between about -20°C and about 100°C, preferably at about 0°C and about 25°C, based on the solvent or mixture of solvent used in the particular step.
In second aspect, the present application provides a process for preparation of apremilast of formula (I) or its stereoisomers thereof:

which comprises of:
(a) reacting of (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with a halogenating reagent in the presence of a suitable solvent to provide a halogenated amine of formula (V);

wherein X= Cl, F, Br, I
(b) treating halogenated amine of formula (V) in presence of a suitable base in a suitable solvent to provide enamine of formula (VI);

wherein X= Cl, F, Br, I

(c) converting the enamine of formula (VI) to racemic aminosulfone of formula (IV) in presence of reducing agent and a suitable solvent;
(d) optionally purifying racemic aminosulfone of formula (IV);
(e) converting the racemic aminosulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

The reagents, solvents and reaction conditions for steps (a), (b), (c) and (d) may be selected from one or more suitable reagents, solvents and process conditions as described in the steps (a), (b), (c) and (d) of the first aspect of the present invention.
Racemic aminosulfone of formula (IV) may be converted to apremilast of formula (I) by methods known in the art.
The intermediates of the present invention may be isolated or may be directly used in the next step.
Third embodiment of the present invention provides novel compound of formula (V).

wherein X= Cl, F, Br, I

The present invention further includes the use of novel compound of formula (V) for the preparation of apremilast or its intermediates.
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 excipients, carriers 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 or isopropanol), 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.
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 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine (VI)
(R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of formula (III) (1.40 g, 5.12 mmol, 82.9% ee) was dissolved in dichloromethane (60 mL) at room temperature. Water (15 mL) was added to the reaction mixture and the pH of the solution was 7.6. NaDCC (707 mg, 2.76 mmol) was added to reaction mixture at 25 ?C and the pH of the mixture increased to 8.5. The mixture was vigorously stirred for 45 minutes at 25 ?C. The organic layer was washed with water (30 mL) and the aqueous phase was separated. DBU (825 µL, 5.52 mmol) was added to the organic layer and it was stirred for 1 h at room temperature. The reaction mixture was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate and evaporated to dryness to provide the title compound as a yellow solid.
Yield: 1.38 g (99%).

Example 2: Preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine (VI)
(R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of formula (III) containing 20% N-Ac-Leucine (1.56 g, 5.06 mmol, 82.9% ee) was dissolved in dichloromethane (60 mL) at room temperature. Water (15 mL) was added and the pH of the solution was adjusted to 9.5 with 1M sodium hydroxide. NaDCC (712 mg, 2.76 mmol) was added to the reaction mixture and the pH decreased to 8.9. The mixture was vigorously stirred for 45 minutes at 25 ?C. Water (30 mL) was added to the reaction mixture and layers were separated. DBU (825 µL, 5.52 mmol) was added to the organic layer and stirred for 1 h at room temperature. The reaction mixture was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate and evaporated to dryness to provide the title compound as a yellow solid.
Yield: 1.40 g (>99%).

Example 3: Preparation of 2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine (IV)
Enamine of formula (VI) (503 mg, 1.85 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (10 mL). Citric acid (889 mg, 4.62 mmol) was added to the reaction mixture and stirred at 30 ?C for 15 min and then, cooled to 0 ?C. Sodium borohydride (142 mg, 3.75 mmol) was added to reaction mixture portionwise at 0 ?C, keeping the temperature below 5 ?C. The mixture turned foggy towards the end of the addition and was stirred for 1 h at 0 °C. Water (10 mL) was added to the reaction mixture and the aqueous layer was washed with ethyl acetate (20 mL). The aqueous solution having pH 3-4 was separated, cooled to 0 ?C and basified to pH 11-12 using 5M potassium hydroxide. A white solid precipitated upon stirring for 30 min at 0 ?C. The white solid was filtered off, washed with water (15 mL) and dried under vacuum to give the title compound. Yield: 255 mg (50%).
,CLAIMS:
1) A process for preparation of racemic aminosulfone of formula (IV) and its pharmaceutically acceptable salts

which comprises:
(a) reacting of (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with a halogenating reagent in the presence of a suitable solvent to provide a halogenated amine of formula (V);

wherein X= Cl, F, Br, I
(b) treating halogenated amine of formula (V) in presence of a suitable base in a suitable solvent to provide enamine of formula (VI);

(c) converting the enamine of formula (VI) to racemic aminosulfone of formula (IV) in presence of reducing agent and a suitable solvent;
(d) optionally purifying racemic amino sulfone of formula (IV).
2) The process as claimed in claim 1, wherein halogenating reagent used in step a) is selected from sodium dichloroisocyanurate (NaDCC), trichloroisocyanuric acid, N,N’-dichlorobis(2,4,6-trichlorophenyl)urea, N-chlorosuccinimide, N-bromosuccinimide, sodium hypochlorite and sodium hypobromite.

3) The process as claimed in claim 1, wherein reducing agent used in step c) is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride and di-isobutyl aluminum hydride.

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

which comprises:
(a) reacting (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with a halogenating reagent in the presence of a suitable solvent to provide a halogenated amine of formula (V);

wherein X= Cl, F, Br, I
(b) treating halogenated amine of formula (V) in presence of a suitable base in a suitable solvent to provide enamine of formula (VI);

wherein X= Cl, F, Br, I
(c) converting the enamine of formula (VI) to racemic aminosulfone of formula (IV) in presence of reducing agent and a suitable solvent;
(d) optionally purifying racemic aminosulfone of formula (IV);
(e) converting the racemic aminosulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

5) A novel compound of formula (V).

wherein X= Cl, F, Br, I

6) The use of novel compound of formula (V) as claimed in claim 5 in the preparation of apremilast of formula (I) or its intermediates.