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) using catalyst. Another aspect of the present invention provides process for preparation of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (II) involving the use of an enzyme. Another aspect of the present application provides the use of amino sulfone prepared according to present invention for the 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 such as (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine involving classical resolution have been disclosed in US6020358B2, US7427638B2, US8242310B2, US20130217918A1 and US9126906B2.

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) using catalyst. The present invention also provides process preparation of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (II) involving the use of an enzyme.

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

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable base and a suitable solvent to provide an acyl derivative of aminosulfone of formula (V);

wherein R= C1-C6 alkyl, aryl
(b) reacting acyl derivative of amino sulfone of formula (V) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II).

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

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable base and a suitable solvent to provide an acyl derivative of aminosulfone of formula (V);

wherein R= C1-C6 alkyl, aryl
(b) reacting acyl derivative of amino sulfone of formula (V) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II);

(e) converting the (S)- amino sulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

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

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable enzyme and a suitable solvent to provide an acyl derivative of aminosulfone of formula (VI);

wherein R= C1-C6 alkyl, aryl
(b) hydrolyzing an acyl derivative of amino sulfone of formula (VI) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II).

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

which comprises of:
(a) reacting racemic aminosulfone of formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable enzyme and a suitable solvent to provide an acyl derivative of aminosulfone of formula (VI);

wherein R= C1-C6 alkyl, aryl
(b) hydrolyzing an acyl derivative of amino sulfone of formula (VI) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II);

(e) converting the (S)- amino sulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

In fifth 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 (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with catalyst in the presence of a suitable solvent to provide racemic aminosulfone of formula (IV);

(b) optionally purifying racemic amino sulfone of formula (IV).

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

which comprises of:
(a) reacting (R)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine of the formula (III) and its pharmaceutically acceptable salts with catalyst in the presence of a suitable solvent to provide racemic aminosulfone of formula (IV);
(b) optionally purifying racemic amino sulfone of formula (IV);
(c) converting the racemic amino sulfone to (S)-apremilast of formula (I);
(d) optionally purifying apremilast of formula (I).

The seventh 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 the preparation of (S)- aminosulfone of formula (II) and its pharmaceutically acceptable salts

which comprises of:
(a) reacting of racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable base and a suitable solvent to provide an acyl derivative aminosulfone of formula (V);

wherein R= C1-C6 alkyl, aryl
(b) reacting acyl derivative amino sulfone of formula (V) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)-amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II).

Suitable acyl donors that may be used in step (a) include, but are not limited to methyl methoxy acetate, ethyl methoxy acetate, methyl phenylacetate, ethyl acetate, butyl acetate, 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; esters, such as, ethyl acetate, butyl acetate or the like; nitriles, such as acetonitrile, propionitrile 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.
Suitable bases that may be used in step (a) 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.
Suitable enzymes that may be used in step (b) include, but are not limited to hydrolase, amidase, lipase, esterase, protease, acylase and the like. Preferably the enzyme can be selected from Pencilin G acylase and the like. The enzyme used may be selected from wild-type, engineered, immobilized or non-immobilized.
The enzymatic reactions of the present invention may be carried out at pH range of 6-10, preferably at 8.
The temperature at which the enzymatic reactions may be carried out in the present invention may be in between about 25°C and about 50°C, preferably at about 30°C and about 40°C.

Suitable buffer that may be used in step (b) include, but are not limited to phosphate buffer such as 2-Amino-2-hydroxymethyl-propane-1,3-diol (TRIS), 3-Morpholinopropane-1-sulfonic acid (MOPS), 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), triethylamine (TEA), 2-(Cyclohexylamino)ethanesulfonic acid (CHES), N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) and 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; sulfoxide such as dimethyl sulfoxide 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.
Steps (c) and (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.
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 racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable base and a suitable solvent to provide an acyl derivative of aminosulfone of formula (V);

wherein R= C1-C6 alkyl, aryl
(b) reacting acyl derivative of amino sulfone of formula (V) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II);

(e) converting the (S)- amino sulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

In the second aspect of the invention, 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 (III) may be prepared by methods known in the art.
Racemic aminosulfone of formula (III) may be converted to apremilast of formula (I) by methods known in the art.
In the third aspect, the present application provides a process for the preparation of (S)- aminosulfone of formula (II) and its pharmaceutically acceptable salts

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable enzyme and a suitable solvent to provide an acyl derivative aminosulfone of formula (VI);

wherein R= C1-C6 alkyl, aryl
(b) hydrolyzing acyl derivative amino sulfone of formula (VI) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II).

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

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable enzyme and a suitable solvent to provide an acyl derivative aminosulfone of formula (VI);

wherein R= C1-C6 alkyl, aryl
(b) hydrolyzing acyl derivative amino sulfone of formula (VI) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II);

(e) converting the (S)- amino sulfone to apremilast of formula (I);
(f) optionally purifying apremilast of formula (I).

The acyl donor, enzymes, solvent, buffer and process conditions of the third and fourth aspects may be selected from one or more suitable acyl donor, enzymes, solvent, buffer and process conditions as described in the steps (a), (b), (c) and (d) of the first and second aspect of the present invention.

In the fifth 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 catalyst in the presence of a suitable solvent to provide racemic aminosulfone of formula (IV);

(b) optionally purifying racemic amino sulfone of formula (IV).

Suitable catalyst that may be used in step (a) include, but are not limited to ruthenium catalyst such as Shvö’s catalyst or its derivatives, SCRAM catalyst, palladium on carbon, palladium on basic support, Pd(PPh3)4-dppf and the like.

Step (a) 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; esters solvents, such as, for example, ethyl acetate, propyl acetate or the like; and mixtures thereof.
Step (b) which involves the isolation and purification of compound of formula (III) 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
50°C and about 150°C, preferably at about 80°C and about 120°C, based on the solvent or mixture of solvent used in the particular step.

In sixth 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 catalyst in the presence of a suitable solvent to provide racemic aminosulfone of formula (IV)
(b) optionally purifying racemic amino sulfone of formula (IV).
(c) converting the racemic amino sulfone to (S)-apremilast of formula (I);
(d) optionally purifying apremilast of formula (I).

The reagents, solvents and reaction conditions for steps (a) and (b)may be selected from one or more suitable reagents, solvents and process conditions as described in the steps (a) and (b) of the fifth aspect of the present invention.
The intermediates of the present invention may be isolated or may be directly used in the next step.
Seventh 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.

EXAMPLES
Example 1: Preparation of N-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-2-methoxyacetamide (V)
To solution of racemic aminosulfone (IV) (2.73g, 10 mmol), trimethylamine (1.5 mL), DMAP (catalytic) in dichloromethane (50 mL) was added methoxyacetate chloride (950 ?L, 10.1 mmol) dropwise at 0 ?C. The temperature was raised up to 25 ?C over 60 minutes and the mixture was stirred for further 2 hours. The reaction mixture was washed with 1M hydrochloric acid followed by 1M sodium hydroxide and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness to give the title compound as white powder.
Yield: 2.95 g, 85%

Example 2: Preparation of N-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-2-phenylacetamide (V)
To solution of racemic aminosulfone (IV) (2.76g, 10 mmol), trimethylamine (1.5 mL), DMAP (catalytic) in dichloromethane (50 mL) was added phenylacetate chloride (1300 ?L, 10.1 mmol) dropwise at 0 ?C. The temperature was raised up to 25 ?C over 60 minutes and the mixture was stirred for further 2 hours. The reaction mixture was washed with 1M hydrochloric acid followed by 1M sodium hydroxide and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness to give the title compound as white powder.
Yield: 3.90 g

Example 3: Preparation of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine (II)
To a suspension of immobilized Penicillin G Acylase (Codexis, 150 mg) in phosphate buffer (10.0 mL, 100 mM, pH 7.5), N-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-2-phenylacetamide (V) (165 mg, 0.42 mmol) in dimethylsulfoxide(0.5 mL) was added. The reactions were incubated at 38 ?C for 3 days. After 3 days, the reaction was acidified to pH 2 using 1 M hydrochloric acid and extracted with dichloromethane (2 * 25 mL). The aqueous layer was basified with 5M potassium hydroxide, extracted with dichloromethane (2 * 25 mL), dried over magnesium sulfate and evaporated to dryness to give the title compound as product.
Yield: 40 mg, 34%

Example 4: Preparation of (S)-N-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)-2-methoxyacetamide (VI)
To a suspension of Fermase 850 (0.99 g) and racemic amino sulfone (1.00 g, 3.65 mmol) in toluene (100 mL), was added methyl phenylacetate (5.0 mL, 35.5 mmol). The reaction was incubated at 38 ?C for 48 h. The solids were filtered off and washed with toluene. The amide was re-dissolved in mixture of dichloromethane:methanol (1:1) and the immobilised enzyme was filtered off. The filtrate was evaporated to give crude product (S)-2b. The precipitate amide was re-crystallised from boiling toluene to give title compound as product.
Yield: 410 mg, 27%

Example 5: Preparation of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-amine (II)
To the suspension of Penicillin G Acylase (Fermase NA150, Fermenta, 220 mg) in phosphate buffer (100 mM, 10 mL, pH 8.), (S)-N-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-2-methoxyacetamide (VI) (100 mg, 0.255 mmol) in dimethylsufoxide (0.5 mL) was added. The reaction was shaken at 38 ?C for 5 days. The reaction mixture was basified to pH 12 with 1M sodium hydroxide (1 mL) and extracted dichloromethane (50 mL). The organic phase was dried over magnesium sulfate and evaporated to dryness to give the title compound as off-white solid.
Yield: 50 mg, 77%

Example 6: Racemization of (R)-amino sulfone using Shvö catalyst
(R)- aminosulfone (III) ( 100 mg, 0.36 mmol) and Shvö catalyst (12 mg, 0.011 mmol, 1:30) in toluene (3 mL) at room temperature were placed in a Schlenk flask under nitrogen atmosphere. The solution was refluxed and the reaction was monitored by chiral HPLC using AD-H column. The reaction mixture was filtered through celite and evaporated to provide the title compound.
,CLAIMS:We Claim:
Claim 1: A process for the preparation of (S)- aminosulfone of formula (II) and its pharmaceutically acceptable salts

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable base and a suitable solvent to provide an acyl derivative of aminosulfone of formula (V);

wherein R= C1-C6 alkyl, aryl
(b) reacting acyl derivative of amino sulfone of formula (V) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II).
Claim 2: A process for the preparation of (S)- aminosulfone of formula (II) and its pharmaceutically acceptable salts

which comprises of:
(a) reacting racemic aminosulfone of the formula (III) and its pharmaceutically acceptable salts with an acyl donor in the presence of a suitable enzyme and a suitable solvent to provide an acyl derivative of aminosulfone of formula (VI);

wherein R= C1-C6 alkyl, aryl
(b) hydrolyzing an acyl derivative of amino sulfone of formula (VI) with an enzyme in presence of buffer and a suitable solvent;

(c) optionally isolating (S)- amino sulfone of formula (II);
(d) optionally purifying (S)- amino sulfone of formula (II).
Claim 3: The acyl donor according to claims 1 and 2 is selected from methyl methoxy acetate, ethyl methoxy acetate, methyl phenylacetate, ethyl acetate, butyl acetate.
Claim 4: The base according to step a) of claim 1 is selected from organic or inorganic base.
Claim 5: The solvent according to claims 1 and 2 is selected from ether solvents, aromatic hydrocarbon solvents, nitrile solvents, alcohol solvents ester solvents or the like or mixtures thereof.
Claim 6: The enzyme according to claims 1 and 2 is selected from hydrolase, amidase, lipase, esterase, protease, acylase and the like.
Claim 7: The buffer according to claims 1 and 2 is selected from phosphate buffer such as 2-Amino-2-hydroxymethyl-propane-1,3-diol (TRIS), 3-Morpholinopropane-1-sulfonic acid (MOPS), 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), triethylamine (TEA), 2-(Cyclohexylamino)ethanesulfonic acid (CHES), N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES).
Claim 8: A process for the preparation of racemic aminosulfone of formula (IV) and its pharmaceutically acceptable salts

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

(b) optionally purifying racemic amino sulfone of formula (IV).
Claim 9: The catalyst according to claim 8 is selected from ruthenium catalyst
such as Shvö’s catalyst or its derivatives, SCRAM catalyst, palladium on carbon, palladium on basic support, Pd(PPh3)4-dppf and the like.
Claim10: Use of amino sulfone prepared according to preceding claims for the preparation of Apremilast of formula (I).