Field of the Invention:
The present invention provides an improved process for the preparation of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-23-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide represented by the following structural formula-1.
Background of the Invention:
N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide commonly known as Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast was approved by the USFDA for the treatment of adults with active psoriatic arthritis.
US7427638B2 specifically describes Apremilast, its related compounds and process for their preparation.
The main object of the present invention is to provide an improved process for the preparation of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide.
Brief description of the invention:
The first aspect of the present invention is to provide an improved process for the
preparation of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1.
The second aspect of the present invention is to provide a process for the purification
of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine chiral amino acid
addition salt compound of general formula-5. .

The third aspect of the present invention is to provide an improved process for the preparation of compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-B of compound of formula-1.
Brief description of the Drawings:
Figure-1: Illustrates the PXRD pattern of l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)
ethanamine (Formula-4)
Figure-2: Illustrates the PXRD pattern of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethanamine N-acetyl-L-leucine salt (Formula-5a)
Figure-3: Illustrates the PXRD pattern of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethanamine (Formula-6)
Figure-4: Illustrates the PXRD pattern of N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)
acetamide (Formula-7)
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "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; "chloro 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, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the aforementioned solvents.

The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, 'potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methyl morpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide and the like; "organosilicon bases" such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like or their mixtures.
The first aspect of the present invention provides an improved process for the preparation of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1, comprising of; a) Reacting the 3-ethoxy-4-methoxybenzonitrile compound of formula-2
with dimethylsulfone in presence of Grignard reagent in a suitable solvent to provide (E)-1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine compound of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine compound of
c) resolution of compound of formula-4 by treating it with a suitable chiral amino acid in a suitable solvent or mixture of solvents to provide chiral amino acid-addition salt compound of general formula-5,
d) treating the compound of general formula-5 with a suitable base in a suitable solvent or mixture of solvents to provide (S)-1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine compound of formula-6,

e) treating the compound of formula-6 with a suitable chiral amino acid in a suitable solvent or mixture of solvents to provide chiral amino acid-addition salt compound of general formula-5,
f) reacting, the compound of general formula-5 with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7
in a suitable solvent to provide compound of formula-1, g) purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.
Wherein, in step-a) the term "Grignard reagent" refers to alkyl/vinyl/aryl magnesium halides; preferably methyl magnesium chloride; and the amount of Grignard reagent used is ranges from 1.0-5.0 mole ratio, preferably from 2.0-4.0 mole ratio per one mole of compound of formula-2;
in step-b) the suitable reducing agent is selected from but not limited to alkali metal borohydrides, LiAlH^ Pd, NaBH(OAc)3, BF3-etherate and the like; and the reduction reaction is carried out optionally in presence of an acid such as acetic acid, formic acid, methanesulfonic acid, trifluoroacetic acid, 4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or combination thereof;
in step-c) & step-e) the suitable chiral amino acid is independently selected from but not limited to 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 amino isobutyric acid, 3-amino propionic acid, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, N-acetyl-leucine and the like;

in step-d) the suitable base is selected from but not limited to inorganic bases, organic bases or their mixtures;
in step-a) to step-g) the suitable solvent wherever necessary is independently selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
In the above process, the 3-ethoxy-4-methoxybenzonitrile compound of formula-2 can be procured from any commercial sources or it can be prepared by any of the processes known in the art.
The N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7 utilized in step-f) of the above aspect can be procured from any commercial sources or it can be synthesized by any of the processes known in the art.
In another embodiment, the N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7 can be prepared by the process as described in our pending Indian patent application IN4513/CHE/2015.
US8242310B2 assigned to Celgene, has described the process for the preparation of l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine compound of formula-4, by reacting 3-ethoxy-4-methoxybenzonitrile compound of formula-2 with Lithiated dimethylsulfone followed by reducing the resulting intermediate to provide compound of formula-4.
In the above described process, Lithiated dimethylsulfone is prepared by reacting dimethylsulfone with n-BuLi 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. Organolithium reagents are typically stored at 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-BuLi is highly reactive species and highly pyrophoric in nature. Its usage has many disadvantages particularly on commercial scale in safety point of view. Hence, in view of all the above concerns usage of n-BuLi is not advisable on large scale.
Hence, there is a significant need to develop alternate process for the preparation of compound of formula-4 from compound of formula-2 by using safer reagents. »
The present inventors earnestly tried to develop alternate process. After numerous trails the present inventors found that the usage of Grignard reagent for the above step has many advantages. The advantages include Grignard reagents are cheaper, easy to handle, non-pyrophoric and industrially viable.
The reaction of compound of formula-2 with dimethyl sulfone in presence of Grignard reagent has provided the product with excellent quality and higher yields. Hence, the present invention is highly advantageous.
The second aspect of the present invention provides a process for the purification of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine chiral amino acid addition salt compound of general formula-5, comprising of; a) Treating the compound of general formula-5
with a suitable base in a suitable solvent or mixture of solvents to provide (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine compound of formula-6,

b) treating the compound of formula-6 with a suitable chiral amino acid in a suitable solvent or mixture of solvents to provide pure compound of general formula-5.
Wherein, in step-a) the suitable base is same as defined in step-d) of the first aspect of > the present invention;
In step-b) the suitable chiral amino acid is same as defined in step-c) of the first aspect of the present invention;
In step-a) & step-b) the suitable solvent is same as defined in first aspect of the present invention. )
The above purification process for compound of general formula-5 can be optionally performed more than one time in order te achieve compound of general formula-5 with enhanced chiral purity.
! US7427638B2 (herein referred as US'638 patent) has described the process for the
preparation of compound of formula-1 by reacting compound of general formula-5 with
compound of formula-7 in presence of acetic acid as reaction solvent. j
However, the present inventors when repeated the process exemplified in above
) US'638 patent using acetic acid as solvent, number of impurities have been observed in the
obtained product and the compound of formula-1 is obtained with very less purity. Hence,
repeated purifications are required to get the high pure product which increases the cost of
the product and hence not. suitable on commercial scale.
5 The present inventors have earnestly tried for alternative process by avoiding acetic
acid as solvent for the above coupling step. After numerous trials, the present inventors surprisingly found the advantageous process by avoiding acetic acid and the said process provides the product with excellent yield and quality. The said improved process is described below.

4
The third aspect of the present invention provides an improved process for the preparation of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1 H-isoindol-4-yl]acetamide compound of formula-1, comprising of reacting the compound of general formula-5
I .chiral
X
amino acid
o
Formula-5 withN-(l53-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7 in presence of a suitable solvent, wherein the solvent is not acetic acid.
In the above process, the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
A preferred embodiment of the present invention provides an improved process for the preparation of compound of formula-1, comprising of reacting the (S)-l-(3-ethoxy-4-methoxyphelnyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt compound of formula-5 a with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7 in presence of dimethylformamide to provide compound of formula-1.
US7893101B2 describes seven crystalline polymorphic forms of Apremilast namely form-A, form-B, form-C, forn>D, form-E, form-F and form-G and also described process for their preparation.
The fourth aspect of the present invention provides a process for the preparation of crystalline form-B of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) optionally filtering the solution,
c) removing the solvent from the solution,
d^ addinc methanol and ethvl acetate to the obtained compound,

e) heating the reaction mixture,
f) cooling the reaction mixture,
g) filtering the solid and drying to provide crystalline form-B of compound of formula-1.
Wherein, in step-c) the solvent is removed by distillation; In step-e) the reaction mixture is heated to temperature ranges from 30°C to 80°C; In step-f) the reaction mixture is cooled to temperature ranges from 30°C to -30°C.
An embodiment of the present invention provides a process for the preparation of crystalline form-B of compound of formula-1, comprising of;
a) Adding methanol and ethyl acetate to compound of formula-1,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the solid and drying to provide crystalline form-B of compound of formula-1.
Wherein, in step-b) the reaction mixture is heated to suitable temperature ranges from 30°C to 80°C;
In step-c) the reaction mixture is cooled to temperature ranges from 30°C to -30°C.
The present invention also provides crystalline polymorphs of various intermediate compounds of the present invention, which are useful for the preparation of pure compound of formula-1.
The PXRD analysis of compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.
The compound of formula-1 of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-l: Preparation of l-(3-ethoxy-4-methoxyphenyI)-2-(methylsulfonyl)
ethanamine (FormuIa-4)
3M Methyl magnesium chloride solution in tetrahydrofuran (235.1 ml) was slowly added to a pre-cooled mixture of 3-ethoxy-4-methoxybenzonitrile compound of formula-2 (50 gm), dimethyl sulfone (53.1 gm) and tetrahydrofuran (250 ml) at 0-5°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. Sodium borohydride (21.5 gm) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C, acetic acid (129.1 ml) was slowly added and stirred the reaction mixture for 30 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Basified the reaction mixture using aqueous sodium carbonate solution at 0-5°C. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Distilled off tetrahydrofuran completely from the reaction mixture under reduced pressure. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with methyl tert.butyl ether. Methyl tert.butyl ether (100 ml) and methanol (100 ml) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and then dried the material to provide the title compound. Yield: 62.0 gm; M.R: 115-120°C.

Example-2: Preparation of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-Ieucine salt (Formula-5a)
A . mixture of l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine compound of formula-4 (100 gm), N-acetyl-L-leucine (38 gm), methanol (400 ml) and N,N-dimethylformamide (400 ml) was heated to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material to provide the title compound. Yield: 85.0 gm.
Example-3: Purification of compound of formula-5a
(S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt compound of formula-5a obtained in above example was added to methanol (500 ml) at 25-30°C. H,eated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material to provide pure title compound. Yield: 75.0 gm.
Example-4: Preparation of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine (Formula-6)
(S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt compound of formula-5a obtained in above example and dichloromethane (450 ml) were added to water (350 ml) at 25-30°C andstirred the reaction mixture for 10 min at the same temperature.' Basified the reaction mixture using aqueous sodium carbonate solution (28 gm of sodium carbonate in 280 ml of water) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol to provide the title compound as a solid. Yield: 40.0 gm.

Example-5: Preparation of compound of formula-5a
Methanol (140 ml) and N,N-dimethylformamide (140 ml) were added to (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine compound of formula-6 obtained in above example at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. N-Acetyl-L-leucine (25.3 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction! mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and then spin dried the material. Methanol (375 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and then dried the material to provide the title compound. Yield: 52.0 gm; M.R: 190-200°C.
Example-6: Preparation of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsuIfonyI) ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide (Formula-1)
A mixture of N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7 !(22.9 gm), (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt compound of formula-5a (50 gm) and N,N-dimethylformamide (150 ml) was heated to 85-90°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C arid quenched with aqueous sodium bicarbonate solution. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature..Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium bicarbonate solution followed by with aqueous HC1 solution and then finally washed with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Methanol (150 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and then dried the material to provide the title compound. Yield: 40.0 gm; M.R: 145-155°C.

Example-7: Preparation of crystalline form-B of compound of formula-1
A mixture of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1 (75 gm) and dichloromethane (525 ml) was stirred for 20 min at 25-30°C. Filtered the reaction mixture and distilled off the solvent completely from the filtrate and then co-distilled with methanol. Methanol (225 ml) and ethyl acetate (75 ml) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and then dried the material to provide the title compound. Yield: 64.0 gm; M.R: 150-160°C.
Example-8: Preparation of amorphous form of compound of formula-1
A solution of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1 (0.4 gm) in dichloromethane (2 ml) was added to n-heptane (50 ml) at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. Yield: 320.0 mg.
Example-9: Preparation of amorphous form of compound of formula-1
A sblution of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1 (500 mg) in acetone (6 ml) was added to pre-cooled water (40 ml) at 0-5°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. Yield: 390.0 mg.
Example-10: Preparation of amorphous form of compound of formula-1
A solution of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2?3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1 (500 mg) in methanol (20 ml) was added to pre-cooled water (40 ml) at 0-5°C and stirred the reaction

mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. Yield: 382.0 mg.
Example-11: Preparation of amorphous form of compound of formula-l
A solution of ,N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-1 (500 mg) in dimethylsulfoxide (3 ml) was added to pre-cooled water (40 ml) at 0-5°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. Yield: 350.0 mg.
Example-12: Preparation of crystalline form-B of compound of formula-l
A solution of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide compound of formula-l (500 mg) in acetone (10, ml) was added to pre-heated n-heptane (50 ml) at 55-60°C and stirred the reaction mixture for 5 min at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. Yield: 400.0 mg.
Example-13: Preparation of crystalline form-B of compound of formula-l
A mixture of dimethylformamide and water (6 ml) in 1:1 ratio was added to N-[2-[(1S)-1 -(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-253 -dihydro-1,3 -dioxo-1H-isoindol-4-yl]acetamide compound of formula-l (500 mg) at 25-30°C. Slowly heated the reaction mixture to 55-60°C and stirred for 5 hrs at the same temperature. Filtered the solid and then drifed the material to provide the title compound. Yield: 410.0 mg.
Example-14: Preparation of crystalline form-B of compound of formula-l
Same as the process as exemplified in above example-13 but instead of DMF/water mixture, a mixture of THF and water (10 ml) in 1:1 ratio has been used as solvent system. Yield: 380.0 mg.
17

Example-15: Preparation of l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine (Formula-4)
3M Methyl magnesium chloride solution in tetrahydrofuran (235.15 Lt) was slowly
added to a pre-cooled mixture of 3-ethoxy-4-methoxybenzonitrile compound of formula-2
(50 Kg), dimethyl sulfone (53.12 Kg) and tetrahydrofuran (500.Lt) at 0-5°C under nitrogen
atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hrs at
the same temperature. Sodium borohydride (21.5 Kg) was added to the reaction mixture at
25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-
5°C, acetic acid (129 Lt) was slowly added and stirred for 45 min at the same temperature. |
Raised the temperature of the reaction mixture to 25-30°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Water was slowly added to the reaction mixture at 0-5°C and basified the reaction mixture using aqueous sodium carbonate solution. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Distilled off tetrahydrofuran completely from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with methyl tert.butyl ether under reduced pressure. Methyl tert.butyl ether (100 Lt) and methanol (100 Lt) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 90 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried the material to provide the title compound. Yield: 55.3 Kg; Purity by HPLC: 99.5%. Imine impurity: Not detected; Benzaldehyde impurity: Not detected; Benzonitrile impurity:
Not detected. j
i
i
Example-16: Preparation of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)
i
ethanamine N-acetyl-L-leucine salt (Formula-5a)
N-aqetyl-L-leucine (19 Kg) was added to a mixture of l-(3-ethoxy-4-methoxy
phenyl)-2-(methylsulfonyl)ethanamine compound of formula-4 (50 Kg), methanol (200 Lt) '
and Dimethyl formamide (200 Lt) at 25-30°C. Heated the reaction mixture to 55-60°C and

stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. The obtained solid was added to water (175 Lt) at 25-30°C. Dichloromethane (225 Lt) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Basified the reaction mixture using aqueous sodium carbonate solution at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Dimethylformamide (85 Lt) and methanol (85 Lt) were added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. N-Acetyl-L-leucine (12.7 Kg) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. The obtained solid was added to water (150 Lt) at 25-30°C. Dichloromethane (200 Lt) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Basified the reaction mixture using aqueous sodium carbonate solution at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Dimethylformamide (75 Lt) and methanol (75 Lt) were added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. N-Acetyl-L-leucine (11.1 Kg) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. Methanol (125 Lt) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and dried the material to get the title compound. Yield: 20.6 Kg; Purity by HPLC: 99.98%.
Imine impurity: Not detected; Benzonitrile impurity: Not detected; (R)-isomer impurity: 0.05%.

Example-17: Preparation of 3-aminophthalic acid hydrochloride (FormuIa-9a)
3-Nitrophthalic acid compound of formula-8 (25 Kg) was added to a solution of sodium bicarbonate (24.75 Kg) in water (175 Lt) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Iron powder (0.65 Kg) and charcoal (2.5 Kg) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 95-100°C. 80% Hydrazine hydrate solution (14.75 Lt) was slowly added to the reaction mixture at 90-95°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Cooled the filtrate to 10-15°C, slowly acidified the reaction mixture using aqueous hydrochloric acid solution and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried the material. Aqueous hydrochloric acid solution was added to the obtained compound at 25-30°C and stirred the reaction mixture for 90 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 90 min at the same temperature. Filtered the solid, washed with isopropyl alcohol and then dried the material to get the title compound. Yield: 16.-5 Kg.
Example-18: Preparation of N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide (Formula-7)
A mixture of 3-aminophthalic acid hydrochloride compound of formula-9a (16 Kg) and acetic anhydride (52.18 Kg) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 85-90°C and stirred for 4 hrs at the same temperature. Slowly cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether and then dried the material to get the title compound. Yield: 12.1 Kg.
Example-19: Preparation of compound of formula-1
A mixture of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt compound of formula-5a (20 Kg) and dimethylformamide (60 Lt) was stirred for 10 min at 25-30°C. N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)acetamide compound of formula-7 (9.2 Kg) was added to the reaction mixture at 25-30°C. Heated the

reaction mixture to 85-90°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and aqueous sodium bicarbonate solution was added to it. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium bicarbonate solution followed by with aqueous hydrochloric acid and then with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol under reduced pressure. Methanol (60 Lt) was added to the obtained compound at 25-30°C and stirred for 5 hrs at the same temperature. Filtered the solid, washed with methanol and dried the material to provide the title compound. Yield: 16.3 Kg; Purity by HPLC: 99.89%.
Example-20: Preparation of crystalline form-B of compound of formula-1
A mixture of compound of formula-1 (15 Kg) and dichloromethane (105 Lt) was stirred for 20 min at 25-30°C. Filtered the reaction mixture, distilled off the solvent completely from the filtrate and co-distilled with methanol under reduced pressure. Methanol (45 Lt) and ethyl acetate (15 Lt) were added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Heated the reaction mixture to 60-65 °C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and then dried the material to get the title compound. Yield: 11.4 Kg; Purity by HPLC: 99.93%. Water content by KFR: 0.23 %w/w. Particle size distribution: D(0.1) is 2.50 \xm; D(0.5) is 6.63 |im; D(0.9) is 19.8 |im.