DESC:FIELD OF THE INVENTION
The present invention relates to processes for preparing aminosulfone compounds, particularly a ß-aminosulfone compound useful as key intermediate for the preparation of sulfone group containing isoindoline-based compounds, particularly Apremilast.
BACKGROUND OF THE INVENTION
The synthesis of sulfone compounds and in particular ß-aminosulfone compounds is of interest because these compounds themselves can have favourable properties and may furthermore be useful in the preparation of compounds with a potential for biological activities. ß-Aminosulfones play an important role in physiological processes and are for instance used as intermediates in the synthesis of a-amino acids, amino alcohols, uridines, adenosines, alkaloids, ß-lactams, etc. ß-Aminophenethyl sulfone derivatives have shown potential to treat inflammatory diseases, in particular globally relevant inflammatory diseases such as arthritis and related arthritic conditions such as psoriatic arthritis, psoriasis, and Crohn's disease. Specifically, this class of compounds shows promising potential as selective phosphodiesterase 4 (PDE IV or PDE4) type inhibitors.
The synthesis of sulfone compounds and in particular ß-aminosulfone compounds may thus provide useful intermediates for the synthesis of anti-inflammatory agents, preferably active for treatment of psoriatic arthritis, and in particular for the synthesis of Apremilast.
Apremilast chemically known as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl) ethyl]-2, 3-dihydro-1, 3-dioxo-1H-isoindol-4-yl] acetamide is represented by the compound of formula A:

All the synthetic processes of Apremilast utilize the key aminosulfone intermediate, 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine represented by a compound of formula (3)

Several methods are known in the art for the preparation of aminosulfone intermediate (3).
US Patent No. 6,020,358 describes a process for preparing 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine wherein the process comprises reacting 3-ethoxy-4-methoxybenzaldehyde with lithium hexamethyldisilylazide and boron trifluoride etherate, followed by addition of dimethyl sulfone and n-butyllithium to yield the ß-aminosulfone compound. However, this process makes use of lithium hexamethyldisilazide which is hazardous and reports a lower yield (Yield = 39%).
US Patent No. 8,242,310 describes a process for the preparation of l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine, by reacting 3-ethoxy-4-methoxybenzonitrile with lithiated dimethylsulfone followed by reducing the resulting intermediate. In this process, lithiated dimethylsulfone is prepared by reacting dimethylsulfone with n-butyllithium in presence of a solvent.
Organolithium compounds are highly reactive species and require specialized handling techniques. They are often corrosive, flammable and sometimes pyrophoric in nature. Alkyl lithium reagents can also undergo thermal decomposition to form the corresponding alkyl species and lithium hydride. They are typically stored below 10°C and reactions are conducted using air free techniques. Organolithium reagents react with ethers, which are often used as solvents.
In particular, n-butyllithium is highly reactive species and highly pyrophoric in nature. Its usage has many disadvantages particularly on commercial scale in safety point of view.
US Patent Nos. 9,126,906 & 9,187,417 disclose processes for enantioselective preparation of chiral ß-aminosulfone intermediates i.e., (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethanamine using expensive as well as toxic materials such as metal catalysts, ligands or chiral auxiliaries. Use of reagents like (R, S)-t-Bu-Josiphos or Rh (cod) 2 OTf is very expensive.
Chinese patent No. 103864670 discloses a process wherein 1-[(R)-amino(phenyl) methyl]-2-naphthol is condensed with 3-ethoxy-4-methoxybenzaldehyde in the presence of triethyl amine in methanol to yield the naphtho[1,2-e][1,3]oxazine derivative, which upon addition of dimethylsulfone lithium salt in tetrahydrofuran gives N-[(2S)-(1-(3-ethyoxyl-4-methoxyphenyl)-2-methylsulfonylethyl)]-(1R)-(a-amino-benzyl)-2-isonaphthol which further under goes hydrogenation over Pd/C in methanol to yield 1-(S)-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine.
PCT publication No. WO/2017/033206 describes a process for preparing 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine, comprising reacting 3-ethoxy-4-methoxy benzonitrile with dimethylsulfone in presence of Grignard reagent in a suitable solvent followed by reduction of the obtained compound with a suitable reducing agent, wherein the Grignard reagent is substituted or unsubstituted alkyl/vinyl/aryl magnesium halide, preferably methyl magnesium chloride.
For at least the above reasons, there is a need to have improved processes for preparing aminosulfone compounds which are useful as intermediates for preparing Apremilast, with increased safety, efficiency and reasonable cost that can be used on an industrial scale.
The present inventors have surprisingly found that a mixture of Grignard reagent with lithium chloride, popularly known as turbo-grignard reagent, when used in the condensation of 3-ethoxy-4-methoxybenzonitrile with dimethyl sulfone showed improvement in yield and purity of the resultant aminosulfone compound.
OBJECT OF THE INVENTION
The main objective of the invention is to provide an improved, cost-effective process for the preparation of the key ß-aminosulfone intermediate for the synthesis of Apremilast, avoiding the use of expensive raw materials/reagents.
It is also an object of the present invention to provide short, simple, environment friendly and industrially viable processes for beneficially providing a ß-aminosulfone compound useful for the preparation of a sulfone group containing isoindoline-based compound Apremilast with high optical purity.
SUMMARY OF THE INVENTION
The present invention is directed towards processes for preparing ß-aminosulfone compounds, particularly 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine, represented by compound of formula (3), useful as a key intermediate for the synthesis of Apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis and psoriatic arthritis.
In one aspect, the present invention provides an improved process for the preparation of ß-aminosulfone compound of formula (3), comprising reacting a compound of formula (1) with dimethyl sulfone in the presence of Turbo-grignard reagent (RMgCl-LiCl) and a suitable solvent to form an intermediate (2), which is further reduced using a suitable reducing agent to yield the aminosulfone compound (3), wherein R is preferably isopropyl, isobutyl and sec-butyl

In a second aspect, the present invention provides an improved process for preparing a compound of formula (3), comprising reacting a compound of formula (1) with a compound (a) in a suitable solvent to form an intermediate (2), which is further reduced using a suitable reducing agent to yield the aminosulfone compound (3)

In a third aspect, the aminosulfone compound (3) obtained from improved, cost-effective processes of the present invention is used for preparing Apremilast in high yield and optical purity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides improved, cost-effective, industrially viable processes for preparing 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine, a key intermediate of Apremilast in high yields and purity, by way of using Turbo-grignard reagent.
RMgCl-LiCl is known as Turbo-grignard reagent, as it allows facile preparation of Grignard reagents at low temperatures. Use of turbo-grignard reagent is known in the art for halogen-magnesium exchange reactions in laboratory as well as on commercial scale. These exchanges were found to occur at significantly lower temperatures and therefore tolerate a broader range of functional groups, showing remarkable progress and developments in preparative organic chemistry.
Surprisingly, the present inventors found that when a mixture of Grignard reagent and lithium chloride was used in the preparation of ß-aminosulfone compounds, it lead to dramatic acceleration of reaction rate while allowing the reaction to take place under mild conditions, with excellent conversion to desired product.
The use of lithium chloride favors the formation of the magnesiated intermediate RMgCl2- -Li+, which displays a higher nucleophilicity compared to RMgCl, thereby showing a reactivity superior to standard Grignard reagents.
None of the prior art processes teaches nor suggests the use of turbo-grignard reagent for the preparation of key intermediate of formula (3).
In one embodiment, the present invention provides an improved process for preparing 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine, represented by compound of formula (3), wherein the process comprises the following steps:
(a) Reacting 3-ethoxy-4-methoxybenzonitrile (1) with dimethyl sulfone in the presence of a turbo-grignard reagent and a suitable solvent to form an intermediate (2);

(b) Subjecting the compound (2) to reduction using a suitable reducing agent to yield the aminosulfone compound (3)

Wherein in step (a), turbo-grignard reagent refers to grignard reagent in combination with lithium chloride, wherein the grignard reagent refers to substituted or unsubstituted, alkyl, aryl, vinyl magnesium chloride. In preferred embodiments, grignard reagent is substituted or unsubstituted, C1-4 alkyl magnesium chloride.
In one preferred embodiment, isopropyl magnesium chloride-lithium chloride is used as turbo-grignard reagent. In a second preferred embodiment, isobutyl magnesium chloride-lithium chloride is used. In a third preferred embodiment, sec-butyl magnesium chloride-lithium chloride is used.
In some preferred embodiments, methyl magnesium chloride-lithium chloride is used as turbo-grignard reagent.
Wherein in step (b), a suitable reducing agent includes without limitation, sodium borohydride (NaBH4), sodium triacetoxyborohydride (Na(OAc)3BH), lithium aluminium hydride (LiAlH4), diisobutylaluminium hydride (DIBAL), lithium tri-tert-butoxyaluminium hydride (LTBA), nickel aluminium alloy and the like. In preferred embodiments, the reducing agent is sodium borohydride.
The reduction in step (b) may be optionally carried out in the presence of an acid, including without limitation, acetic acid, methanesulfonic acid, trifluoroacetic acid, 4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and mixtures thereof.
Examples of suitable solvents for the purpose of present invention include without limitation, hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert- butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chlorinated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; polar solvents; formic acid, acetic acid or mixtures thereof. In preferred embodiments, ether solvent is used, more preferably tetrahydrofuran (THF).
The reaction(s) of present invention is/are carried out at a temperature between about 0°C to about 25°C. In preferred embodiments, the reaction is carried out at a temperature between about 0°C to about 5°C.
In another embodiment, the present invention provides an improved process for preparing N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl) ethyl]-2, 3-dihydro-1, 3-dioxo-1H-isoindol-4-yl] acetamide (Apremilast) represented by a compound of formula A, comprising:
(a) Reacting 3-ethoxy-4-methoxybenzonitrile (1) with dimethyl sulfone in the presence of a turbo-grignard reagent and a suitable solvent to form an intermediate (2);

(b) Subjecting the compound (2) to reduction using a suitable reducing agent to yield the aminosulfone compound (3);

(c) Resolution of compound (3) using a suitable resolving agent in presence of one or more solvents to form a chiral salt, represented by a compound of formula (4);

(d) Reacting the compound (4) with N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide represented by a compound of formula (5) to form compound A

In the present context, the steps (a) to (d) are performed using solvents described as hereinbefore; reduction wherever applicable is performed using reducing agents described as hereinbefore; resolution is performed using techniques known to a person skilled in the art. In preferred embodiments of the invention, resolution of compound (3) is performed using chiral amino acids including without limitation, L isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, 4-aminobutyric acid, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, N-acetyl-L-leucine and the like.
In an embodiment, the chiral salt represented by a compound of formula (4), may be isolated or proceeded to next step without isolation. Optionally, the chiral salt may be converted to the corresponding chiral aminosulfone compound (4i) by treatment with a suitable base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like, in one or more solvents described as hereinbefore.

In another embodiment, the present invention provides an alternate, industrially viable process for preparing the key intermediate (3) of Apremilast, wherein the process comprises the following steps:
(a) Reacting a compound of formula (1) with compound (a) in a suitable solvent to form an intermediate (2);

Wherein in compound (a), X is a halogen, preferably chlorine;
(b) Reducing the compound (2) to obtain the aminosulfone compound (3) using a suitable reducing agent

In the present context, the reaction(s) in steps (a) and (b) is/are carried out using solvents, reducing agents described as hereinbefore.
Further, the present invention provides a novel approach for preparing the compound (a), wherein the process comprises treating compound (b) with azobisisobutyronitrile and N-chlorosuccinimide in chloroform to form compound (c), which is treated with magnesium turnings in suitable solvent to form compound (a),

In yet another embodiment, the present invention provides an improved process for preparation of Apremilast represented by a compound of formula A, comprising:
(a) Reacting a compound of formula (1) with compound (a) in a suitable solvent to form an intermediate (2);

Wherein in compound (a), X is a halogen, preferably chlorine;
(b) Reducing the compound (2) to obtain the aminosulfone compound (3) using a suitable reducing agent;

(c) Resolution of compound (3) using a suitable resolving agent in presence of one or more solvents to form a chiral salt, represented by a compound of formula (4);

(d) Reacting the compound (4) with N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide represented by a compound of formula (5) to form compound A

In the above embodiments, the steps (a) to (d) are performed using solvents described as hereinbefore; reduction wherever applicable is performed using reducing agents described as hereinbefore; resolution is performed using techniques known to a person skilled in the art. In preferred embodiments of the invention, resolution of compound (3) is performed using chiral amino acids including without limitation, L isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, 4-aminobutyric acid, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, N-acetyl-L-leucine and the like.
In an embodiment, the chiral salt represented by a compound of formula (4), may be isolated or proceeded to next step without isolation. Optionally, the chiral salt may be converted to the corresponding chiral aminosulfone compound (4i) by treatment with a suitable bases and one or more solvents described as hereinbefore.
In one embodiment, each compound obtained in each of the abovementioned reactions may be proceeded to further steps without isolation; and if the compound is isolated, may be proceeded to next reaction with or without drying.
In another embodiment, each compound obtained in each of the above-mentioned reactions may be isolated and purified from the reaction mixture by, for example, cooling the reaction mixture, applying an isolation operation of filtration, concentration, extraction and the like to separate a crude reaction product, and applying a general purification operation such as column chromatography, recrystallization and the like.
The crude compound(s) obtained from the improved processes of the present invention may be purified by dissolution in one or more solvents, followed by removing the solvent(s) to give the pure compound(s).
In an embodiment, the improved processes of present invention may be used for preparing stereoisomers, pharmaceutically acceptable salts, hydrates, polymorphs of aminosulfone compounds and intermediates thereof.
Further the process for preparing ß-aminosulfone compounds and intermediates thereof according to the present invention are illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
EXAMPLES:
Example 1: Preparation of (Z)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethenamine (2)
(a) Using sec-butyl magnesium chloride-LiCl:
2M sec-butyl magnesium chloride (0.103 moles) was slowly added to a pre-cooled mixture of lithium chloride (0.032moles), dimethyl sulfone (0.056 moles) and THF (50 ml) at 0-5°C under nitrogen atmosphere, maintained at room temperature (RT) and stirred for 90 mins. A solution of 3-ethoxy-4-methoxybenzonitrile (0.028 moles) in THF (50 ml) was added to the above reaction mixture at a temperature of 0-5°C and stirred for 2 hrs. After the completion of reaction, the mixture was charged with Aq. NH4Cl, followed by addition of ethyl acetate and stirred for 10-15 mins at RT. The aqueous and organic layers were separated and extracted with ethyl acetate. The combined organic layers dried over sodium sulfate. The solvent was distilled completely under vacuum to give the crude compound. The crude compound was washed with methyl tert-butyl ether (MTBE), stirred for 10 mins. The filtered solid was washed with MTBE and dried to give the pure title compound (4.0 gm; 52.2 % yield)
(b) Using isopropyl magnesium chloride-LiCl:
2M isopropyl magnesium chloride (0.103 moles) was slowly added to a pre-cooled mixture of lithium chloride (0.032moles), dimethyl sulfone (0.056 moles) and THF (50 ml) at 0-5°C under nitrogen atmosphere, maintained at RT and stirred for 90 mins. A solution of 3-ethoxy-4-methoxybenzonitrile (0.028 moles) in THF (50 ml) was added to the above reaction mixture at a temperature of 0-5°C and stirred for 2 hrs. After the completion of reaction, the mixture was charged with Aq. NH4Cl, followed by addition of ethyl acetate and stirred for 10-15 mins at RT. The aqueous and organic layers were separated and extracted with ethyl acetate. The combined organic layers dried over sodium sulfate. The solvent was distilled completely under vacuum to give the crude compound. The crude compound was washed with methyl tert-butyl ether, stirred for 10 mins. The filtered solid was washed with MTBE and dried to give the pure title compound. (4.2 gm; 56% yield)
(c) Using iso-butyl magnesium chloride-LiCl:
2M isobutyl magnesium chloride (0.103 moles) was slowly added to a pre-cooled mixture of lithium chloride (0.032 moles), dimethyl sulfone (0.056 moles) and tetrahydrofuran (50 ml) at 0-5°C under nitrogen atmosphere, maintained at RT and stirred for 90 mins. A solution of 3-ethoxy-4-methoxybenzonitrile (0.028 moles) in THF (50 ml) was added to the above reaction mixture at a temperature of 0-5°C and stirred for 2 hrs. After the completion of reaction, the mixture was charged with Aq. NH4Cl, followed by addition of ethyl acetate and stirred for 10-15 mins at RT. The aqueous and organic layers were separated and extracted with ethyl acetate. The combined organic layers dried over sodium sulfate. The solvent was distilled completely under vacuum to give the crude compound. The crude compound was washed with methyl tert-butyl ether, stirred for 10 mins. The filtered solid was washed with MTBE and dried to give the pure title compound. (3.8 gm; 50% yield)
Example 2a: Preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine (3): Compound (2) obtained from any of methods described under Example 1 (18.43 mmoles) was added to methanol (25 ml) and cooled to 0-5°C. Methanolic hydrochloric acid (10%, 5 ml) was added to reaction mixture. Sodium borohydride (63.85 mmoles) was added to the reaction mixture and maintained at 0-5°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 0-5°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. (3.25 gm; 65% yield)
Example 2b: Preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine (3): Compound (2) obtained from any of methods described under Example 1 (3.5 gm, 0.013 moles) was added to THF (35 ml) and cooled to 0-5°C. Sodium borohydride (1.43 gm, 0.038 moles) was added, followed by slow addition of Trifluoroacetic acid (10%, 5 ml) to the reaction mixture at 0-5°C for two hours. The RM was maintained for 18 hours at RT. After completion of reaction, water (35 ml) was added to the RM at temperature below 10°C and pH adjusted to 12-13 with sodium hydroxide solution (4 ml). The reaction mixture was stirred for 30 mins at same temperature. The solid was filtered, washed with water (30 ml) followed by addition of methanol (3.5 ml) and water (11 ml), heated to about 60°C ± 5°C and stirred for 30 mins. The RM was cooled to 0.5°C. The solid was filtered, washed with methanol (1.5 ml) and water (4.6 ml), followed by drying to obtain the title compound. (2.33 gm, 66% yield)
Example 3: Preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt (4):
To Compound (3) (2 gm, 0.007 moles) obtained from method described under Example 2a or 2b, was added N-acetyl-L-leucine (0.8 gm, 0.0046 moles) and methanol (50 ml) at RT. The RM was heated to about 60°C ± 5°C and maintained for 3 hours. After the reaction was complete, the RM was cooled to RT and maintained at same temperature for 2-3 hours. The compound obtained was filtered and washed with methanol (6 ml). The resulting solid was charged with water (10 ml), dichloromethane (20 ml) and pH was adjusted to 12-13 with sodium hydroxide solution (2.5 ml). The RM was stirred and layers were separated. The organic layers were combined and washed with water, aq. NaCl. The solvent was distilled under vacuum to give the title compound. (0.6 gm, 30% yield)
Example 4: Preparation of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (A):
Compound (4) (0.5 gm, 0.0018 moles) obtained from Example 3 was charged with compound (5) (0.41 gm, 0.0019 moles), acetic acid (5 ml) and heated to about 100°C ± 5°C. The RM was maintained for 1 hour at 120 ± 5°C. After completion of reaction, RM was cooled to RT and charged with water and ethyl acetate, stirred for 10 mins. The aqueous and organic layers were separated and aqueous layer was extracted with ethyl acetate. Total organic layers were combined and washed with sat. NaHCO3 solution, followed by washing with water. The organic layer was treated with activated carbon, stirred for 15 mins. Filtered the mass through hyflow and washed with ethyl acetate. Distilled off the solvent completely to give pure compound A (0.8 gm, 95% yield)
The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention. Various modifications, alterations and variations, which are apparent to a person skilled in the art, are intended to fall within the scope of the invention.
,CLAIMS:We Claim,
1. An improved process for preparing 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine compound of formula (3), or stereoisomers, pharmaceutically acceptable salts thereof, comprising:
(a) Reacting a compound of formula (1) with dimethyl sulfone in presence of a turbo-grignard reagent and suitable solvent to form a compound of formula (2);
(b) Reducing the compound of formula (2) using a suitable reducing agent to form the compound (3).
2. The process as claimed in claim 1, wherein the turbo-grignard reagent in step (a) refers to RMgCl-LiCl, wherein R represents substituted or unsubstituted, alkyl, aryl, vinyl; suitable solvent includes without limitation, hydrocarbon solvents, ether solvents, ester solvents, polar aprotic solvents, chlorinated solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof; suitable reducing agent includes without limitation, sodium borohydride, sodium triacetoxyborohydride, lithium aluminium hydride, diisobutylaluminium hydride, lithium tri-tert-butoxy aluminium hydride, nickel aluminium alloy and the like.
3. The process as claimed in preceding claims, wherein the turbo-grignard reagent is C1-4 alkyl magnesium chloride in combination with lithium chloride.
4. The process as claimed in preceding claims, wherein the turbo-grignard reagent is methyl magnesium chloride-lithium chloride, isopropyl magnesium chloride-lithium chloride, isobutyl magnesium chloride-lithium chloride, sec-butyl magnesium chloride-lithium chloride.
5. An improved process for preparing N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (Apremilast) represented by a compound of formula A, or stereoisomers, pharmaceutically acceptable salts thereof, comprising:
(a) Reacting 3-ethoxy-4-methoxybenzonitrile compound of formula (1) with dimethyl sulfone in the presence of a turbo-grignard reagent (RMgCl-LiCl) and a suitable solvent to form a compound of formula (2);

Wherein R represents substituted or unsubstituted, alkyl, aryl, or vinyl,
(b) Subjecting the compound of formula (2) to reduction using a suitable reducing agent to form the compound (3);

(c) Resolution of compound (3) using a suitable resolving agent in presence of one or more solvents to form a chiral salt, represented by a compound of formula (4);

(d) Optionally reacting the compound of formula (4) with a base in suitable solvent to form a compound of formula (4i);

(e) Reacting the compound of formula (4) or (4i) with N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl) acetamide represented by a compound of formula (5) to form compound A

6. An improved process for preparing N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (Apremilast) represented by a compound of formula A, or stereoisomers, pharmaceutically acceptable salts thereof, comprising:
(a) Reacting a compound of formula (1) with compound (a) in a suitable solvent to form a compound of formula (2);

Wherein in compound (a), X is a halogen, preferably chlorine;
(b) Reducing the compound of formula (2) using a suitable reducing agent to form a compound of formula (3);

(c) Resolution of compound (3) using a suitable resolving agent in presence of one or more solvents to form a chiral salt, represented by a compound of formula (4);

(d) Reacting the compound (4) with N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide represented by a compound of formula (5) to form compound A

7. The process as claimed in claims 5 and 6, wherein turbo-grignard reagent is methyl magnesium chloride-lithium chloride, isopropyl magnesium chloride-lithium chloride, isobutyl magnesium chloride-lithium chloride, sec-butyl magnesium chloride-lithium chloride;
Suitable reducing agent includes without limitation, sodium borohydride, sodium triacetoxyborohydride, lithium aluminium hydride, diisobutylaluminium hydride, lithium tri-tert-butoxy aluminium hydride, nickel aluminium alloy and the like;
Suitable resolving agent is a chiral amino acid including without limitation, L isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, 4-aminobutyric acid, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, N-acetyl-L-leucine and the like;
Suitable base includes without limitation, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like; and
Suitable solvent(s) include without limitation, hydrocarbon solvents, ether solvents, ester solvents, polar aprotic solvents, chlorinated solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
8. An improved process for preparing the compound (a), comprising treating compound (b) with azobisisobutyronitrile and N-chlorosuccinimide in a suitable solvent to form compound (c), followed by treating the compound (c) with magnesium turnings in suitable solvent to form compound (a),

9. The process as claimed in claim 8, wherein a suitable solvent is chlorinated solvent selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like.