DESC:Field of invention
The present invention provides an improved process for preparation of an apremilast.

Background of invention
Tumor necrosis factor alpha (TNFa) is a cytokine produced by monocytes and macrophages. It is found in synovial cells and macrophages in the tissues. It can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons.
Apremilast is a TNFa inhibitor and marketed in United States under the brand name OTEZLA®. Apremilast is indicated for the treatment of psoriatic arthritis. It is also used to treat moderate to severe plaque psoriasis in certain patients. The chemical structure of apremilast described in compound 1 as below.

Compound 1
Apremilast is a white to pale yellow powder in appearance. The drug substance is the S- enantiomer of N-[2-[1-(3-ethoxy-4-methoxy-phenyl)-2-(methylsulfonyl) ethyl]-2, 3-dihydro-1, 3-dioxo-1H-isoindol-4-yl] acetamide.
The US Patent 7,427,638 describes S- enantiomer of apremilast as a product and process for preparation thereof.
The US Patent 8,242,310 describes a process for preparation of amine compound of formula (I) by reacting benzonitrile compound of formula (IV) with Lithiumdimethylsulfone compound. This process in not useful and not viable at commercial scale due to human hazards and temeprature sensitiveness. Hence, it is need to establish a robust process , which would be cost-effective and viable at large scale.

Summary of invention
The present invention also provides the process for preparation of intermediate of formula (A) and its conversion to apremilast in subsequent steps. The invention provides an improved process for preparation of Apremilast.

Objective of the invention
The object of this invention is to provide an improved process for preparation of racemic amine of compound of formula (A), which is an intermediate of apremilast.
In another object of the present invention is to provide an improved process for preparation of apremilast from racemic amine compound of formula (A).
In another object of the present invention is to provide a novel process for preparation apremilast through green, eco-friendly, feasible and cost-effective method.

Brief Description of Drawings
Fig. 1 depicts Differential Scanning Calorimetry (DSC) of apremilast.
Fig. 2 depicts Thermal Gravimetric Analysis (TGA) of apremilast.
Fig. 3 depicts Infra- Red Spectroscopy (IR) of apremilast.
Fig. 4 depicts X- ray Powder Diffraction (XRPD) of apremilast.

Detailed description
The present invention provides an improved process for preparation of apremilast via intermediate of formula (A) and its process. This intermediate is prepared by using cheap, cost effective and non-hazardous reagents. The present invention provides an improved process for preparation of apremilast (compound of formula C) as below in reaction scheme 1.

One of the aspects of this invention is to provide a process for preparing compound of formula (A) i.e. racemic amine in step-1 in which 3-ethoxy-4-methoxybenzonitrile is reacted with dimethyl sulfone and a base in an organic solvent. The reaction mass is treated with a reducing agent to give racemic amine compound of formula (A). The base used is in organic or organic base known in the art. The base includes, but not limited to sodium hydride, sodium hydroxide, potassium hydroxide, potassium-HMDS, sodium- HMDS, triethylamine, and diisopropyl amine etc. The organic solvent used in this reaction can be selected from methanol, ethanol, n-butanol, diethyl ether, diisopropyl ether, ethyl acetate, and tetrahydrofuran solvent. The reducing agent can be used as lithium aluminium hydride, sodium borohydride, DIBAL, etc. or any reducing agent known in the art. In step-1, the reaction can be carried out about 0 to 65 °C. The compound of formula (A) may be in isolated or non-isolated form. The compound of formula (A) can be recrystallized with the use of solvent or mixture of solvents known in the art.
The racemic amine can be converted to their chiral acid salts i.e. the compound of formula (B). The compound 1 salts include, but not limited to salts formed with alanine, aspartic acid, glutamine, N-acetyl-leucine, phenylethylamine, mandelic acid, tartaric acid and citric acid. The preferred acid for preparation of amine salt is N-acetyl-L- leucine. This reaction can be carried out in any water miscible or immiscible solvent/s known in the art.
Another aspect of this invention is to provide an improved process for preparation of apremilast i.e. compound of formula (C) from amine salt. The chiral amine salt is reacted with 3-acetamidophthalic anhydride in presence of a solvent or mixture of solvents or an acid or base condition. The solvents include, but not limited to water miscible or immiscible solvents. Organic acid or inorganic acid, such as acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid etc.
After completion of reaction, the resultant solid can be treated with an organic solvent or mixture of solvents. The solvent include, but not limited to ketone, alcohol, hydrocarbon, ether, water, ester, nitrile, halohydrocarbon and amide solvents or water miscible or immiscible solvents known in the art.
The precipitated final compound can be treated with solvents include, not limited to, ketone, alcohol, hydrocarbon, ether, water, ester, nitrile, halohydrocarbon and amide solvents or water miscible or immiscible solvents known in the art.
Analytical Methods
1) Powder X-Ray Diffraction (PXRD)
Using a PANalytical X’Pert powder diffraction meter, the x-ray powder diffraction pattern was measured at room temperature using a Cu Ka filled tube (45 kV 40 mA) as the x-ray source. Data collection was done in 2theta continuous scan mode in the range of 3.5° to 40°.
2) Thermogravimetric analysis
Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 25 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.
3) Differential Scanning Calorimetry
Differential Scanning Calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument. 2-3 mg samples were placed in crimped aluminum pans and heated from 30 °C to 250 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute.
4) Nuclear Magnetic Resonance
H1NMR and 13CMR was performed using Bruker NMR instrument at 400 MHz in CDCl3 as solvent.
5) Infra- red Spectoscopy
IR spectroscopy was performed using a Spectrum 400 using a neat liquid sample or dispersion of solid sample material in KBr.
6) Mass Spectrometry
Measurements of mass of sample which is subject to a temperature program were obtained on Waters.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.

Example 1
Step-I: Process for preparation of 2-(-3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-eth-2-ylamine:
In a 2 litre round bottom flask, 300 ml of tetrahydrofuran was charged followed by 32 gms of dimethylsulfone. This reaction mass was cooled for 15 to 20 minutes at 0°C. After cooling, potassium-hexamethyldisilazane was added followed by 20 ml of tetrahydrofuran. The reaction mass was stirred for an hour at 0 to 5 °C. After stirring, 30 gms of 3-ethoxy-4-methoxybenzonitrile was dissolved in 90 ml tetrahydrofuran and was added to the above reaction mass. The reaction mass was stirred for 30 minutes. After stirring, 23 gms of sodium borohydride was added followed by tetrahydrofuran and acetic acid and the total reaction mass was stirred for 2 hours at 0 to 5 °C. After completion of reaction, sodium hydroxide solution was added to it and stirred for 30 minutes. The reaction mass was warmed and further heated for 3 to 4 hours at 60 to 62°C. After completion of reaction, the reaction solution was allowed to cool to room temperature for half an hour. The layers were separated. The aqueous layer was treated with ethyl acetate and the organic layer was treated with hydrochloric acid. The solution was stirred. The layers were separated. The organic layer was treated with 20% sodium hydroxide solution and the solid was precipitated. The solid was filtered, washed and dried at 50°C and further 30.2 gms of material was unloaded.
Step-II: Process for preparation of 2-(-3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-eth-2-ylamine N-acetyl-L-leucine salt:
In a 500 ml round bottom flask, 200 ml of methanol was added followed by 20 gms of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth-2-ylamine. The reaction mass was stirred and 76 gms of N-Acetyl-L-Leucine added and reaction mass was stirred. The reaction mass was heated for 2 hours at 60 to 65°C, After heating, the reaction mass was cooled at room temperature and it was stirred at room temperature for 3 to 4 hours. The slurry was filtered. Washed with 30 ml methanol, material was unloaded and dried under vacuum for 2 hours at 45°C. Yield: 14.36 gm. Further, this material is purified with methanol.
Step-Ill: Process for preparation of Apremilast:
In a 250 ml round bottom flask, 50 ml acetic acid was charged followed by 10 gms of 2-( -3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-eth-2-ylamine N-acetyl-L- leucine salt and it was stirred at room temperature for a few minutes. Then 4.82 gms of 3- acetamidophthalic anhydride was added and reaction mass was heated for 11 to 12 hours at 80 to 90 °C. The solvent was removed under vacuum and ethyl acetate was added followed by sodium bicarbonate solution. The layers were separated. The organic layer was washed and solvent was evaporated under vacuum. In the distilled residue, 90 ml ethanol and 30 ml acetone added and was stirred it for 2 hours at room temperature. The solid was precipitated. The solid was filtered and washed with ethanol. The material was unloaded and dried under vacuum for longer hours at 60 o C. Yield: 6.41 gm. This material will be crystalized using a solvent or mixture of solvents known in the art.
Example 2
Step-I: Process for preparation of 2-(-3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-eth-2-ylamine:
In a flask, 5 litres of tetrahydrofuran was charged followed by 1.06 kg of dimethylsulfone. This reaction mass was cooled for 25 to 30 minutes at 0°C. After cooling, 1M potassium-hexamethyldisilazane was added followed by 10 litres of tetrahydrofuran. The reaction mass was stirred for an hour at 0 to 10 °C. After stirring, 1 kg of 3-ethoxy-4-methoxybenzonitrile was dissolved in 2 litres tetrahydrofuran and was added to the above reaction mass. The reaction mass was stirred for 30 minutes and cooled. After cooling, 0.433 kg of sodium borohydride was added followed by tetrahydrofuran and 5 litres of acetic acid and the total reaction mass was stirred for 3- 4 hours at 0 to 10 °C. After completion of reaction, sodium hydroxide solution was added to it and stirred for 45 minutes. The reaction mass was warmed and further heated for 3 to 4 hours at 60 to 65°C. After completion of reaction, the reaction solution was allowed to cool to room temperature for half an hour. The layers were separated. The combined organic layer was treated with aq. HCl and water was added to the concentrated mass. The aqueous layer was treated with ethyl acetate. Finally sodium hydroxide solution was added to the aqueous layer and solid was precipitated. The solid was filtered, washed with water and dried at 50°C and further 1.0 kg (65%) of material was unloaded.
Step-II: Process for preparation of 2-(-3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-eth-2-ylamine N-acetyl-L-leucine salt:
In a flask, 10 litres of methanol was added followed by 1 kg of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth-2-ylamine. The reaction mass was stirred and 0.38 kg of N-Acetyl-L-Leucine added and reaction mass was stirred. The reaction mass was heated for 2- 3 hours at 60 to 70°C. After heating, the reaction mass was cooled at room temperature and it was stirred at room temperature for 3 to 4 hours. The slurry was filtered and washed with 1.5 litres of methanol. The wet cake was washed with adequate quantities of methanol and water. Material was unloaded and dried under vacuum for 2 hours at 45°C. Yield: 0.60 kg (73.5%).
Step-Ill: Process for preparation of Apremilast:
In a flask, 5 litres of acetic acid was charged followed by 1 kg of 2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-eth-2-ylamine N-acetyl-L- leucine salt and it was stirred at room temperature for a few minutes. Then 0.482 kg of 3- acetamidophthalic anhydride was added and reaction mass was heated for 11 to 12 hours at 75 to 90 °C. Cool the reaction mass. The solvent was removed under vacuum and ethyl acetate was added followed by sodium bicarbonate solution. The layers were separated. The slurry of carbon in ethyl acetate is added to the above reaction mass. Stir and filter the mass. The organic layer was washed with ethyl acetate and solvent was evaporated under vacuum. In the residue, is added 5 litres of acetone and heated to 40-50 0C. The clear solution is filtered through micron paper. The solution is partially distilled and 6 litres of methanol is added to it. The solution is seeded with Apremilast. The solid was precipitated. The slurry is stirred for 3-4 hours at room temperature and was filtered and washed with methanol. The material was unloaded and dried under vacuum for longer hours at 50- 600C. Yield: 0.75 gm (72.8%).
The H1NMR data is (CDCl3) d: 1.471, t, 3H; 2.264, s, 3H; 2.884, s, 3H; 3.851, s, 3H; 3.73- 3.77, dd, 1H; 4.08- 4.13, q, 2H; 4.52- 4.58, dd, 1H; 5.85- 5.89, dd, 1H; 6.83- 8 .75, m, 6H; 9.461, s, 1H. The C13MR data is (CDCl3) d: 14.58, 24.84, 41.51, 48.38, 54.27, 55.81, 64.38, 111.30, 112.26, 114.99, 118.08, 120.17, 124.80, 135.99, 137.47, 148.48, 149.58, 167.36, 169.07, and 169.36. DSC at 159.14°C.
,CLAIMS:1. An improved process for preparation of Apremilast of formula (C), comprising steps:

a) treating 3- ethoxy-4-methoxy-benzonitrile with dimethyl sulfone and a base in an organic solvent to get compound of formula (A), in presence of reducing agent,

b) treating compound of formula (A) with chiral acid in organic solvent to give compound of formula (B), 2-(-3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-eth-2-ylamine N-acetyl-L-leucine salt,

c) treating step b) with 3-acetamidophthalic anhydride in presence of solvent,
d) isolating Apremilast from reaction mixture thereof.

2. The process according to claim 1, wherein the reducing agent is sodium borohydride.

3. A process for preparation of Apremilast of formula (C), comprising:

a) reacting Compound of formula (A) with N- acetyl L- leucine in organic solvent to give Compound of formula (B); 2-(-3-ethoxy-4-methoxyphenyl)-1- (methanesulfonyl)-eth-2-ylamine N-acetyl-L-leucine salt,

b) treating step a) with 3-acetamidophthalic anhydride in presence of solvent and isolating Apremilast.

4. A process for the preparation of compound of formula (A) comprising of steps:
a) reacting 3- ethoxy- 4- methoxy- benzonitrile with dimethyl sulfone in presence of base in an organic solvent,
b) treating step a) with reducing agent in an organic solvent,
c) isolating the compound of formula (A).

5. The process of claim 4, wherein the bases are sodium hydride, sodium hydroxide, potassium hydroxide, potassium-HMDS, sodium HMDS, triethyl amine, and diisopropyl amine etc.

6. The process according to claim 5, wherein base is potassium-HMDS.

7. The process according to claim 4, wherein the organic solvents are methanol, ethanol, n-butanol, diethyl ether, diisopropyl ether, tetrahydrofuran, ethyl acetate.

8. The process according to claim 7, wherein the solvent is methanol.