DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

AN IMPROVED PROCESS FOR THE PREPARATION
OF APREMILAST AND ITS INTERMEDIATES

PIRAMAL ENTERPRISES LIMITED, a company incorporated under the Companies Act, 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, State of Maharashtra, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A). The compound can be further converted to the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (hereafter referred to as the compound (1)) commonly known as Apremilast, and its pharmaceutically acceptable salt.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Apremilast (the Compound (1)), is a phosphodiesterase 4 (PDE4) inhibitor indicated for the treatment of adult patients with active psoriatic arthritis. The drug is marketed under the tradename “OTEZLA” in the form of oral tablets. Apremilast has the chemical name N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, and is structurally represented as follows;

Compound (1)

Apremilast being an important phosphodiesterase 4 (PDE4) inhibitor; a number of processes for its preparation are known in the art.

US Patent No. 6,020,358 disclosed the preparation of Apremilast through the aminomethylsulfonyl intermediate 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A), which is illustrated in the below Scheme (I). In the process, preparation of the compound (A) consists of reacting dimethyl sulfone with n-butyllithium at -78 oC to obtain LiCH2SO2CH3; this was added to the stirring solution of 3-ethoxy-4-methoxybenzaldehyde, lithium hexamethyldisilazide and boron trifluoride etherate.

US Patent No. 8,242,310 disclosed preparation of 2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl)-eth-2-ylamine from 3-ethoxy-4-methoxybenzonitrile consisting of reacting dimethylsulfone with n-BuLi at temperature 0-5 oC to obtain LiCH2SO2CH3. This is reacted with 3-ethoxy-4-methoxybenzonitrile at 0-5 oC temperature to form organolithium intermediate compound; which on reduction provides compound (A). The process of US’310 is illustrated in the below Scheme (II).

Similarly, the patent application CN 104803897 provides the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsutfonylethylamine (A) consisting of reacting dimethylsulfone with n-butyl lithium at the temperature of 8 °C to obtain LiCH2SO2CH3. This was reacted with 3-ethoxy-4-methoxybenzonitrile to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) amine, the same on reduction using borane dimethyl sulphide provides compound (A).

Several methods for the preparation of Apremilast and its intermediates are known in the art such as US 9,187,417 and US 8,981,117; Chinese published patent applications CN 103864670, CN 104761474, CN 105330586, CN 105348172; PCT international publication WO-A-2016/066116 and Indian patent application 1401/MUM/2014.

It is evident from the discussion of the process for the preparation of the 1-(3-ethoxy-4-methoxyphenyl)-2-methylsutfonylethylamine (A), described in the afore cited patent documents that the reported methods primarily involve critical reaction conditions, reagents and lengthy workup procedures. For instance, the prior art procedure involves use of n-butyl lithium during the preparation of compound (A) which involves reaction temperature as low as -78 oC to 0-5 oC.
In general, the n-butyl lithium is critical to handle at industrial level which also requires low reaction temperature. Also, the reported processes involve lengthy and complex workup procedures, which renders the process costlier and hence the process is not industrially feasible.

In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of Apremilast and its intermediates; which is simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic, critical and/or costly catalysts, solvents and reagents. Moreover, the process does not require additional purification and critical crystallization procedure. Accordingly, the present invention provides a process for the preparation of Apremilast and its intermediates; which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an improved process for the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) comprising
(a) reacting dihydroxy compound (I) with a methylating agent,
(b) reacting the monohydroxy compound (II) of stage (a) with an amine compound (Z)
(R1ONH2) to provide oxime compound (IIIa),
(c) reacting the oxime compound (IIIa) of stage (b) with an ethylating agent to provide
compound (IVa),
(d) reducing the compound (IVa).

In one aspect, the present invention relates to an improved process for the preparation of 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) comprising;
(i) reacting pyrocatechol with the compound (V),
(ii) reacting the compound (Y) of stage (i) with a metal methanesulfinate compound (VI) (CH3SO2M).

In one aspect, the present invention relates to an improved process for the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) comprising the steps of firstly reacting 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) with dimethyl sulfate to obtain 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one (II); which on further treatment with methoxyamine provides 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (III); followed by the ethylation and subsequent reduction provides desired compound (A).

In one aspect, the present invention relates to an improved process for the preparation of 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) comprising the steps of firstly reacting pyrocatechol with the 2-chloroacetyl chloride (Va) to provide 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (Y1); which on further treatment with sodium methanesulfinate (VIa) provides the desired compound (I).

In an embodiment, there is provided a novel intermediate compound (Y1):

wherein, the R2 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl; the ‘L’ is selected from halogen such as F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulfate.

In an embodiment, there is provided a novel intermediate compound (IV1):

wherein, R1 and R2 are independently selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.

In an embodiment, there is provided a novel intermediate compound (I):

In an embodiment, there is provided a novel intermediate compound (II):

In an embodiment, there is provided a novel intermediate compound (IIIa):

wherein, R1 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.
In an embodiment, there is provided a novel intermediate compound (IVa):

wherein, R1 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.
In an embodiment, there is provided a novel intermediate compound (Y):

wherein, ‘L’ indicates a leaving group selected from halogen such as F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulfate.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) represented by the following formula,

comprising
(a) reacting dihydroxy compound (I) represented by the following formula,

with a methylating agent,
(b) reacting the monohydroxy compound (II) of stage (a) represented by the following formula,

with an amine compound (Z) (R1O-NH2) to provide oxime compound (IIIa) represented by the following formula,

wherein, R1 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl;
(c) reacting the oxime compound (IIIa) of stage (b) with an ethylating agent to provide compound (IVa) represented by the following formula,

(d) reducing the compound (IVa).
The compound (A) obtained by the afore described process is optionally converted into Apremilast or its pharmaceutically acceptable salt.

In the context of the present invention, the term "optionally" when used in reference to any element; including a process step, e.g. conversion of a compound; it is intended to mean that the subject element is subsequently converted, or alternatively, is not converted to a further compound. Both alternatives are intended to be within the scope of the present invention.

In a specific embodiment, the process for the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) comprises the steps of;
(1) dissolving compound (I) in a solvent;
(2) adding a base to the stirring solution of stage (1) and heating the reaction mixture to a temperature of about 60 oC;
(3) adding an methylating agent to the stirring solution of stage (2) and obtaining the compound (II);
(4) dissolving the compound (II) of stage (3) in a solvent and adding a metal acetate;
(5) adding the amine compound (z) to the stirring solution of stage (4) and obtaining the compound (IIIa);
(6) dissolving the compound (IIIa) of stage (5) in a solvent and adding a base;
(7) adding an ethylating agent to the stirring solution of stage (6) and obtaining the compound (IVa);
(8) reducing the compound (IVa) of stage (7) and obtaining the compound (A);
(9) optionally, converting the compound (A) to Apremilast.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (III);

The process as described above further comprises optionally, converting the compound (A) into Apremilast or a pharmaceutically acceptable salt thereof.
The solvent used in any of the process steps from the step (1) to step (9) of the above process (as depicted in the Scheme (III)) is selected from an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.

In an embodiment, the solvent is selected from an alcoholic solvent; halogenated solvent; ketone; an ether solvent; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent; water or a mixture thereof.

The base used in step (2) and step (6) of the above process (as depicted in the Scheme (III)) is selected from an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide; metal alkoxide such as potassium tert-butoxide, sodium tert- butoxide; organic base such as amine, triethylamine, pyridine, picoline, quinoline, piperidine, pyrrolidine, N-methylmorpholine, and combinations thereof.

The term ‘temperature of about 60 oC’ referred to in the step (2) of the above process (as depicted in the Scheme (III)) can range from 55 oC to 65 oC.

The methylating agent used in step (3) of the above process (as depicted in the Scheme (III)) is selected from methyl iodide, methyl bromide, dimethyl Sulfate, methyl chloride and methanol/HCl.

The metal acetate used in step (4) of the above process (as depicted in the Scheme (III)) is selected from sodium acetate, potassium acetate.

The ethylating agent used in step (7) of the above process (as depicted in the Scheme (III)) is selected from ethyl iodide, ethyl bromide, diethyl sulfate, ethyl chloride, ethanol/HCl.

The reduction at step (8) of the above process (as depicted in the Scheme (III)) is carried out in the presence of reducing agents selected from sodium borohydride, potassium borohydride, zinc borohydride, sodium cyanoborohydride, sodium sulfurated borohydride, sodium trioxyacetal borohydride, sodium tri-alkoxy borohydride, sodium hydroxyl borohydride, sodium borohydride anilide, tetrahydrofuran borohydride, di-methyl-butyl borohydride, lithium-aluminum hydride, lithium-aluminum tri-oxymethyl hydride, sodium-aluminum-2-methoxy-ethoxy hydride, and aluminum hydride or metal catalyzed hydrogenation in the presence of a metal catalyst selected from the group consisting of palladium (Pd), Raney Nickel, platinum (Pt), platinum oxide, zinc (Zn), iron (Fe) or tin (Sn).
In an embodiment, the reduction is performed in the presence of BF3.etherate and sodium borohydride.

The term ‘obtaining the product’ referred to in any process step from step (1) to step (9) corresponds to the formation of the desired intermediate compound(s) which is optionally isolated using methods that corresponds to the steps involving addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.
In the context of the present invention, the term "optionally" when used in reference to any element; including a process step e.g. isolation of compound; it is intended to mean that the subject compound is subsequently isolated, or alternatively, is not isolated. Both alternatives are intended to be within the scope of the present invention.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (IV);

The process of the present invention as illustrated in the above Scheme (IV) comprises dissolving 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) in acetone followed by the addition of a base such as potassium carbonate, followed by the addition of methylating agent such as dimethyl sulfate and obtaining the 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one (II). This is followed by reacting the compound (II) with methoxyamine in the presence of sodium acetate to provide 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (III). The compound (III) further treated with ethylating agent such as diethyl sulfate in the presence of potassium carbonate to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (IV); subsequently reducing the compound (IV) using suitable reducing agent such as BF3.Etherate, NaBH4 to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A). (Yield: about 60 %)

In an embodiment, the present invention provides a novel compound represented by the formula (I):

In an embodiment, the present invention provides a novel compound represented by the formula (II):

In an embodiment, the present invention provides a novel compound represented by the formula (IIIa):

wherein, the R1 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.
In an embodiment, the present invention provides a novel compound represented by the formula (IVa):

wherein, the R1 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.

In an embodiment, there is provided a novel intermediate compound (Y1):

wherein, the R2 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl; the ‘L’ is selected from halogen such as F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulfate.

In an embodiment, there is provided a novel intermediate compound (IV1):

wherein, the R1 and R2 are independently selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.
Accordingly in another aspect, the present invention relates to an improved process for the preparation of 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) represented by the following formula,

comprising;
(i) reacting pyrocatechol (X) represented by the following formula,

with the compound (V) represented by the following formula,

wherein, both the ‘L’ indicates a leaving group independently selected from halogen such as CI, Br, I, F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulfate
(ii) reacting the compound (Y) of stage (i) represented by the following formula,

with metal methanesulfinate compound (VI) represented by the following formula,

wherein, the ‘M’ is a metal selected from lithium, sodium, potassium and the like.

The compound (I) obtained by the afore described process is optionally converted into the compound (A) and subsequently to Apremilast or its pharmaceutically acceptable salt.

In a specific embodiment, the process for the preparation of 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) comprises the steps of;
(p) preparing a solution of lewis acid in a solvent,
(q) adding the pyrocatechol compound (X) to the stirring solution of stage (p) at a temperature of about 15 oC,
(r) adding the compound (V) to the stirring solution of stage (q) and stirring the reaction mixture at a temperature of about 30 oC,
(s) obtaining and optionally isolating the compound (Y),
(t) adding a metal methanesulfinate compound (VI) to the stirring solution of compound (Y) and and heating the reaction mixture to a temperature of about 70 oC ,
(u) obtaining the desired product (I)

The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (V);

The process as described above further comprises optionally, converting the compound (I) into the compound (A) and subsequently to Apremilast or a pharmaceutically acceptable salt thereof.

The solvent used in any of the process steps from the step (p) to step (u) of the above process (as depicted in the Scheme (V)) is selected from an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.

In an embodiment, the solvent is selected from an alcoholic solvent; halogenated solvent; ketone; an ether solvent; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent; water or a mixture thereof.

The Lewis acid used at step (p) of the above process (as depicted in the Scheme (V)) is selected from aluminium chloride (AlCl3), ferric chloride (FeCl3), antimony trichloride (SbCl3), aluminium bromide, aluminium iodide, stannous chloride, stannous bromide, titanium chloride, boron trifluoride, boron tribromide, boron trifluoride-dimethylsulfide complex, beryllium chloride, beryllium bromide, zinc chloride, zinc bromide, trimethylsilylchloride, trimethylsilylbromide and trimethylsilyliodide.

The term ‘temperature of about 15 oC’ referred to in the step (q) of the above process (as depicted in the Scheme (V)) can range from 10 oC to 20 oC.

The term ‘temperature of about 30 oC’ referred to in the step (r) of the above process (as depicted in the Scheme (V)) can range from 25 oC to 35 oC.

The term ‘temperature of about 70 oC’ referred to in the step (t) of the above process (as depicted in the Scheme (V)) can range from 65 oC to 75 oC.

The term ‘obtaining the product’ referred to in any process step from step (1) to step (9) corresponds to the formation of the desired intermediate compound(s) which is optionally isolated using methods that corresponds to the steps involving addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.

In the context of the present invention, the term "optionally" when used in reference to any element; including a process step e.g. isolation of compound; it is intended to mean that the subject compound is subsequently isolated, or alternatively, is not isolated. Both alternatives are intended to be within the scope of the present invention.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (VI);

The process of the present invention as illustrated in the above Scheme (VI) comprises preparing a solution of lewis acid such as aluminium chloride (AlCl3) in dichloromethane, followed by the addition of the pyrocatechol (X) at a temperature of about 15 oC. Subsequently adding 2-chloroacetyl chloride (Va) and stirred the reaction mixture at a temperature of about 30 oC to give 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (Y1). Further, the compound (Y1) was dissolved in methanol and added sodium methanesulfinate (VIa). The reaction mixture was heated to a temperature of about 70 oC to provide the desired compound (I). (Yield: 85%)

In an embodiment, the present invention provides a novel compound represented by the formula (Y):

wherein, the ‘L’ indicates a leaving group selected from halogen such as F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulfate.

It is evident from the prior art document such as US 8,242,310 wherein the process for the preparation of the 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethylamine (A) involves formation of organolithium intermediate compounds. The formation of organolithium compound as report in the art involves use of n-butyl lithium as base which requires reaction temperature as low as -78 oC to 0-5 oC. It is also evident that, the n-butyl Lithium is critical to handle at industrial level which also requires complex workup procedures.
The process of the instantly disclosed invention does not refer to the use of any critical metal reagents. The instant process is easy to handle at industrial level; that do not require any critical reaction conditions such as low temperature of -78 oC to 0-5 oC and also the reagents used are not found temperature sensitive even at higher temperatures.
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example-1: 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (Y1)
Charged 1000 mL of dichloromethane in a flask followed by the addition of 300 g of aluminium chloride and 100 g of pyrocatechol (X) at a temperature of about 15 oC. To the stirring solution was added 108.7 g of 2-chloroacetyl chloride (Va) and the reaction mixture was stirred at a temperature of about 30 oC for about 20 hours. The reaction mixture was cooled to a temperature of about 15 oC and to the same was added 1000 mL of aqueous hydrochloric acid solution (30%). The solid was filtered and treated with 750 mL of aqueous acetic acid solution at a temperature of about 95 oC for about an half hour. The reaction mixture was cooled to a temperature of about 10 oC and the precipitated solid was filtered. (Yield: 80%)

Example-2: 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I)
Charged 250 mL of methanol in a flask followed by the addition of 50 g of 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (Y1) and 38.41 g of sodium methanesulfinate (VIa) at a temperature of about 30 oC. The reaction mixture was further heated to a temperature of about 70 oC and stirred for about 15 hours. The reaction mixture was cooled to a temperature of about 30 oC and the solvent was distilled off under vacuum. To the obtained solid was added 125 mL of water and 125 mL of Toluene and stirred at a temperature of about 55 oC for about one hour. The reaction mixture was cooled to a temperature of about 10 oC and the precipitated solid was filtered. (Yield: 85%)

Example-3: 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one (II)
Charged 250 mL of acetone in a flask followed by the addition of 50 g of 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) and 30 g of potassium carbonate. The reaction mixture was heated to a temperature of about 60 oC and to the same was added 27.4 g of dimethyl sulfate; continued stirring for about 18 hours. The reaction mixture was cooled to a temperature of about 30 oC and to the same was added 10 mL of concentrated hydrochloric acid to observe the pH 1-2. The reaction mixture was distilled off under vacuum to obtain slurry and to the same was added 100 mL of water. The obtained solid was filtered and was suspended into 125 mL of ethylacetate. The reaction mixture was heated to a temperature of about 80 oC for about one hour. The reaction mixture was cooled to a temperature of about 30 oC and the precipitated solid was filtered. (Yield: 56%)

Example-4:
1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (III)
Charged 200 mL of isopropyl alcohol in a flask followed by the addition of 50 g of 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one (II), 50 g of sodium acetate and 51.28 g of methoxy amine hydrochloride. The reaction mixture was heated to a temperature of about 85 oC and stirred for about 15 hours. The reaction mixture was distilled off under vacuum and to the residue was added 250 mL of water. The obtained desired solid was filtered and washed with 50 mL water. (Yield: 88%)

Example-5:
1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (IV)
Charged 350 mL of methanol in a flask followed by the addition of 50 g of 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (III) and 21.9 g of sodium hydroxide. The reaction mixture was heated to a temperature of about 60 oC and to the same was added 84.41 g of diethyl sulfate; continued stirring for about 18 hours. The reaction mixture was cooled to a temperature of about 45 oC and distilled off under vacuum. To the residue was added 500 mL of water and the reaction mixture was stirred at a temperature of about 15 oC for about 2 hour. The obtained desired solid was filtered. (Yield: 76%)

Example-6: 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A)
Charged 500 mL of tetrahydrofuran in a flask followed by the addition of 6.3 g of sodium borohydride and the reaction mixture was cooled to a temperature of about 5 oC. To the reaction mixture was added 50 g of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one O-methyl oxime (IV) and 47 g of BF3:etherate solution (49%); continued stirring at a temperature of about 30 oC for about 18 hours. The reaction mixture was cooled to a temperature of about 5 oC and to the same was added 150 mL of aqueous hydrochloric acid solution (10%). The reaction mixture was stirred at a temperature of about 30 oC for about 1 hour and the reaction mixture was distilled off under vacuum to 10 volume of input. To the reaction mixture was added 500 mL of 10% solution of methanol in dichloromethane followed by the addition of 150 mL aqueous sodium hydroxide solution (10%). The separated organic layer was distilled off under vacuum and to the residue was added 650 mL of isopropyl alcohol. The reaction mixture was heated at a temperature of about 80 oC for about one hour and cooled to a temperature of about 5 oC. The obtained desired solid was filtered and washed with 25 mL of isopropyl alcohol. (Yield: 58%)

,CLAIMS:We claim
1. A process for the preparation of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) of the following formula,

comprising,
(a) reacting dihydroxy compound (I) of the following formula,

with a methylating agent,
(b) reacting the monohydroxy compound (II) obtained from stage (a) of the following formula,

with an amine compound (Z) (R1O-NH2) to provide oxime compound (IIIa) of the following formula,

wherein, R1 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl;
(c) reacting the oxime compound (IIIa) obtained from stage (b) with an ethylating agent to provide compound (IVa) of the following formula,

(d) reducing the compound (IVa) obtained from stage (c).

2. The process according to stage (a) of the claim 1, wherein the methylating agent is selected from the group consisting of methyl iodide, methyl bromide, dimethyl sulfate, methyl chloride and/or methanol/HCl.

3. The process according to stage (c) of the claim 1, wherein the ethylating agent is selected from the group consisting of ethyl iodide, ethyl bromide, diethyl sulfate, ethyl chloride and/or ethanol/HCl.

4. The process according to stage (d) of the claim 1, wherein the reduction is carried out in the presence of reducing agent selected from the group consisting of sodium borohydride, potassium borohydride, zinc borohydride, sodium cyanoborohydride, sodium sulfurated borohydride, sodium trioxyacetal borohydride, sodium tri-alkoxy borohydride, sodium hydroxyl borohydride, sodium borohydride anilide, tetrahydrofuran borohydride, di-methyl-butyl borohydride, lithium-aluminum hydride, lithium-aluminum tri-oxymethyl hydride, sodium-aluminum-2-methoxy-ethoxy hydride, sodium borohydride in presence of BF3.etherate, and aluminum hydride, or metal catalyzed hydrogenation in the presence of a metal catalyst selected from the group consisting of palladium (Pd), Raney Nickel, platinum (Pt), platinum oxide, zinc (Zn), iron (Fe) or tin (Sn).

5. The process according to claim 1, wherein the obtained compound (A) is further converted into Apremilast or its pharmaceutically acceptable salt.

6. A process for the preparation of 1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethan-1-one (I) of the following formula,

comprising;
(i) reacting pyrocatechol (X) of the following formula,

with the compound (V) of the following formula,

wherein, both the ‘L’ indicates a leaving group independently selected from halogen such as CI, Br, I, F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulphate.
(ii) reacting the compound (Y) obtained from stage (i) of the following formula,

with metal methanesulfinate compound (VI) of the following formula,

wherein, the ‘M’ is a metal selected from lithium, sodium or potassium.

7. The process according to stage (i) of the claim 6, wherein the reaction is carried out in the presence of a Lewis acid; selected from aluminium chloride (AlCl3), ferric chloride (FeCl3), antimony trichloride (SbCl3), aluminium bromide, aluminium iodide, stannous chloride, stannous bromide, titanium chloride, boron trifluoride, boron tribromide, boron trifluoride-dimethylsulfide complex, beryllium chloride, beryllium bromide, zinc chloride, zinc bromide, trimethylsilylchloride, trimethylsilylbromide or trimethylsilyliodide.
8. The process according to the claim 1 or claim 6, wherein the reaction steps are carried out in the presence of a solvent; selected from an alcoholic solvent; halogenated solvent; ketone; an ether solvent; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent; water or a mixture thereof.

9. A compound (Y1) of following formula;

wherein, the R2 is selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl; the ‘L’ is selected from halogen such as F, alkyl or aryl sulfonyloxy such as OMs, OTs, alkoxy, alkyl or aryl sulfate.

10. A compound (IV1) of following formula;

wherein, the R1 and R2 are independently selected from hydrogen, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted cycloalkyl.