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 INTERMEDIATE

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 N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-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. The amine compound 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine further reacted with 3-acetamidophthalic anhydride in acetic acid to obtain Apremilast (1).

US Patent No. 8,981,117 disclosed preparation of deuterated Apremilast comprising treating d3-aminosulfone leucine salt with a base to obtain d3-aminosulfone free from leucine salt, and further reacted with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide at 70 oC for 24 hours. The process according to US’117 is well illustrated in the below Scheme (II):

Similarly the patent application CN 104447443 provides the preparation of Apremilast (1) comprising the reaction of aminosulfone with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide in the presence of glacial acetic acid and perchloric acid.

Published PCT application WO 2016/199031 described a process for Apremilast (1) comprising, contacting the chiral acid salt of l-(3-Ethoxy-4-methoxy- phenyl)-2-methanesulfonyl- ethylamine or chiral aminosulfone with N-(l,3-Dioxo-l,3- dihydro-isobenzofuran-4-yl)-acetamide in presence of mixture of ketonic solvent and an acid. Similarly, published PCT application WO 2017/039537 and patent application CN105218428 disclosed the reaction of aminosulfone with N-(l,3-Dioxo-l,3- dihydro-isobenzofuran-4-yl)-acetamide in presence of mixture of toluene and an acid.

Several methods for the preparation of Apremilast and its intermediates are known in the art such as CN 105348172A, CN 105330586; published PCT applications WO 2017/033206, WO 2017/ 085568A1, WO 2017/094031 and WO2017105263.

It is evident from the discussion of the process for the preparation of the apremilast (1), described in the afore cited patent documents that the reported methods preliminary involves critical reaction conditions, solvents with high boiling point and lengthy workup procedures. For instance, the prior art procedure involves use of only acetic acid as solvent during the preparation of compound (1) which involves high reaction temperature and longer reaction time; which evidently also leads to the formation of unwanted compounds as impurity. In general, the reported processes involve lengthy and complex workup procedures, which renders the process costlier and hence the processes are 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 apremilast (1) comprising, reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid.

In one aspect, the present invention relates to an improved process for the preparation of pure apremilast (1) wherein the content of des-acetyl apremilast (1a) is less than 1% w/w; comprising reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid; followed by the treatment with an acetylating agent.

In one aspect, the present invention relates to an improved process for the preparation of apremilast (1) comprising reacting des-acetyl apremilast (1a) with an acetylating agent in the presence of a catalyst.

In one aspect, the present invention relates to an improved process for the preparation of pure apremilast (1) having total amount of des-acetyl apremilast impurity content less than 1% w/w, comprising reacting the crude compound (1) containing des-acetyl apremilast (1a), with an acetylating agent in the presence of a catalyst.
In one aspect, the present invention relates to a compound N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (1) (Apremilast), having total amount of genotoxic substances less than 25 ppm, wherein the said genotoxic substances are selected from the group consisting of acetyl chloride, chloro-acetyl chloride, methane sulfonyl chloride, dimethyl sulfate, diethyl sulfate, 3-amino phthalic acid, 4-amino phthalic acid, N-acetyl-3-amino-1,2-benzendicarboxylic acid, N-acetyl-4-amino-1,2-benzendicarboxylic acid and or a mixture thereof.

In one aspect, the present invention relates to a compound N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (1) (Apremilast), having particle size diameter range with D10 between 1 to 5 µm; or D50 between 6 to 20 µm or D90 between 25 to 100 µm.

In one aspect, there is provided compound as apremilast methyl isobutyl ketone (Apremilast : MIBK) solvate.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of apremilast (1) represented by the following formula,

comprising, reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt represented by the following formula,

with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) represented by the following formula,

in presence of ether or amide solvent and optionally, in presence of an acid.
In the context of the present invention, the term "optionally" when used in reference to any element; including a process step, e.g. optionally, in presence; it is intended to mean that the subject element is used, or alternatively, is not used in the reaction. Both alternatives are intended to be within the scope of the present invention.

In an embodiment, the ether solvent is selected from the group consisting of cyclic ethers such as 1,4-dioxane, 1,3-dioxolane, tetrahydropyran (THP), methyl THP, dimethyl THP, ethylene oxide, propylene oxide, butylene oxide, 2-methyltetrahydrofuran, tetrahydrofuran-2-methoxy ether, tetrahydrofuran-2,5-dimethoxy ether, tetrahydrofuran-2-methoxy ethyl ether, tetrahydrofuran-2-ethoxy ether, tetrahydrofuran-2,5-diethoxy ether and tetrahydrofuran-2-methoxy propyl ether; liner ethers such as dimethoxy ethane (DME), diethyl ether, cyclopentyl methyl ether and the like, or a mixture thereof.

In an embodiment, the ether solvent is 1,4-dioxane.

In an embodiment, the amide solvent is selected from the group consisting of cyclic amide such as N-methyl-2-pyrrolidone (NMP), N-alkyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-acetylpyrolidine, N-ethyl-2-pyrrolidone and the like, or a mixture thereof.

In an embodiment, the amide solvent is N-methyl-2-pyrrolidone (NMP).

In an embodiment, the ‘chiral acid’ is any selected from the group consisting of chiral amino acid such as leucine, N-acetyl leucine, alanine, arginine, glycine, isoleucine, phenylalanine, proline, serine, valine and the like; similarly, camphoric acid, tartaric acid, mandelic acid, derivatives of mandelic acid, derivatives of tartaric acid, malic acid and the like.

In an embodiment, the ‘chiral acid’ is N-acetyl leucine.

In a specific embodiment, the process for the preparation of apremilast (1) comprises the steps of;
(i) adding amine compound (A) or its chiral acid salt to an ether or amide solvent;
(ii) adding the isobenzofuran compound (B) and optionally, an acid to the stirring solution of step (i);
(iii) heating the reaction mixture of step (ii) to a temperature of about 80 oC;
(iv) isolating the apremilast (1);

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

wherein, the ‘chiral acid’ is any selected from chiral amino acid such as leucine, N-acetyl leucine, alanine, arginine, glycine, isoleucine, phenylalanine, proline, serine, valine and the like; similarly, camphoric acid, tartaric acid, mandelic acid, derivatives of mandelic acid, derivatives of tartaric acid, malic acid and the like.

The ether solvent used in the step (i) of the above process (as depicted in the Scheme (III)) is selected from cyclic ethers such as 1,4-dioxane, 1,3-dioxolane, tetrahydropyran (THP), methyl THP, dimethyl THP, ethylene oxide, propylene oxide, butylene oxide, 2-methyltetrahydrofuran, tetrahydrofuran-2-methoxy ether, tetrahydrofuran-2,5-dimethoxy ether, tetrahydrofuran-2-methoxy ethyl ether, tetrahydrofuran-2-ethoxy ether, tetrahydrofuran-2,5-diethoxy ether and tetrahydrofuran-2-methoxy propyl ether; liner ethers such as dimethoxy ethane (DME), diethyl ether, cyclopentyl methyl ether and the like, or a mixture thereof.

The amide solvent used in the step (i) of the above process (as depicted in the Scheme (III)) is selected from a cyclic amide such as N-methyl-2-pyrrolidone (NMP), N-alkyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-acetylpyrolidine, N-ethyl-2-pyrrolidone and the like, or a mixture thereof.

The acid used in the step (ii) of the above process (as depicted in the Scheme (III)) is a protic acid selected from acetic acid, formic acid, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.

The term ‘temperature of about 80 oC’ referred to in the step (iii) of the above process (as depicted in the Scheme (III)) can range from 70 oC to 90 oC.

The term ‘isolating’ referred to in step (iv) corresponds to any of the steps involving evaporation, addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.

The reaction of the specific embodiment represented as below scheme (IV):

The process of the present invention as illustrated in the above Scheme (III) and Scheme (IV) comprises dissolving N-acetyl leucine salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (AL) in 1,4-dioxane, followed by the addition of 3-acetamido phthalic anhydride (B) and Acetic acid. The reaction mixture was heated at a temperature about 90 oC for about 9 hours. The desired product apremilast (1) was obtained after workup procedure (yield: about 65%).

In a further embodiment, the present invention relates to an improved process for the preparation of pure apremilast (1) wherein the content of des-acetyl apremilast (1a) is less than 1% w/w; comprising reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid; followed by the treatment with an acetylating agent.

In an embodiment, the crude compound (1) is treated with an acetylating agent in the presence of a catalyst, to provide pure compound (1) having total amount of des-acetyl apremilast impurity content less than 1% w/w.

Accordingly, the present invention relates to an improved process for the preparation of pure apremilast (1) represented by the following formula,

wherein the content of des-acetyl apremilast (1a) is less than 1% w/w;
comprising,
(a) reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt represented by the following formula,

with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) represented by the following formula,

in presence of ether or amide solvent and optionally, in presence of an acid.
(b) treating the crude apremilast of stage (a) with an acetylating agent in the presence of a catalyst.

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

In an embodiment, the ether solvent is selected from the group consisting of cyclic ethers such as 1,4-dioxane, 1,3-dioxolane, tetrahydropyran (THP), methyl THP, dimethyl THP, ethylene oxide, propylene oxide, butylene oxide, 2-methyltetrahydrofuran, tetrahydrofuran-2-methoxy ether, tetrahydrofuran-2,5-dimethoxy ether, tetrahydrofuran-2-methoxy ethyl ether, tetrahydrofuran-2-ethoxy ether, tetrahydrofuran-2,5-diethoxy ether and tetrahydrofuran-2-methoxy propyl ether; liner ethers such as dimethoxy ethane (DME), diethyl ether, cyclopentyl methyl ether and the like, or a mixture thereof.

In an embodiment, the ether solvent is 1,4-dioxane.

In an embodiment, the amide solvent is selected from the group consisting of cyclic amide such as N-methyl-2-pyrrolidone (NMP), N-alkyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-acetylpyrolidine, N-ethyl-2-pyrrolidone and the like, or a mixture thereof.

In an embodiment, the amide solvent is N-methyl-2-pyrrolidone (NMP).

In an embodiment, the ‘chiral acid’ is any selected from the group consisting of chiral amino acid such as leucine, N-acetyl leucine, alanine, arginine, glycine, isoleucine, phenylalanine, proline, serine, valine and the like; similarly, camphoric acid, tartaric acid, mandelic acid, derivatives of mandelic acid, derivatives of tartaric acid, malic acid and the like.

In an embodiment, the ‘chiral acid’ is N-acetyl leucine.

In an embodiment, the ‘acetylating agent’ is any selected from the group consisting of acyl halide such as acetyl chloride; acetic anhydride, acetic acid and the like or mixtures thereof.

In an embodiment, the ‘catalyst’ is any selected from the group consisting of iodine (I2) or similar reaction initiator catalysts.

In a specific embodiment, the process for the preparation of pure apremilast (1) wherein the content of des-acetyl apremilast (1a) is less than 1% w/w comprises the steps of:
(p) adding amine compound (A) or its chiral acid salt to an ether or amide solvent;
(q) adding the isobenzofuran compound (B) and optionally, an acid to the stirring solution of
step (p);
(r) heating the reaction mixture of step (q) to a temperature of about 90 oC;
(s) optionally, isolating the crude apremilast (1);
(t) adding an acetylating agent and a catalyst to the reaction mixture containing the crude
apremilast (1) of step (s);
(u) isolating the pure apremilast (1).

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

wherein, the ‘chiral acid’ is selected from chiral amino acid such as leucine, N-acetyl leucine, alanine, arginine, glycine, isoleucine, phenylalanine, proline, serine, valine and the like; similarly, camphoric acid, tartaric acid, mandelic acid, derivatives of mandelic acid, derivatives of tartaric acid, malic acid and the like.

The ether solvent used in the step (p) of the above process (as depicted in the Scheme (V)) is selected from cyclic ethers such as 1,4-dioxane, 1,3-dioxolane, tetrahydropyran (THP), methyl THP, dimethyl THP, ethylene oxide, propylene oxide, butylene oxide, 2-methyltetrahydrofuran, tetrahydrofuran-2-methoxy ether, tetrahydrofuran-2,5-dimethoxy ether, tetrahydrofuran-2-methoxy ethyl ether, tetrahydrofuran-2-ethoxy ether, tetrahydrofuran-2,5-diethoxy ether and tetrahydrofuran-2-methoxy propyl ether; liner ethers such as dimethoxy ethane (DME), diethyl ether, cyclopentyl methyl ether and the like, or a mixture thereof.

The amide solvent used in the step (p) of the above process (as depicted in the Scheme (V)) is selected from a cyclic amide such as N-methyl-2-pyrrolidone (NMP), N-alkyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-acetylpyrolidine, N-ethyl-2-pyrrolidone and the like, or a mixture thereof.

The acid used in the step (q) of the above process (as depicted in the Scheme (V)) is selected from acetic acid, formic acid, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.

The term ‘temperature of about 90 oC’ referred to in the step (r) of the above process (as depicted in the Scheme (V)) can range from 80 oC to 100 oC.

The acetylating agent used in the step (t) of the above process (as depicted in the Scheme (V)) is selected from acyl halide such as acetyl chloride; acetic anhydride, acetic acid and the like or mixtures thereof.

The catalyst used in the step (t) of the above process (as depicted in the Scheme (V)) is selected from iodine (I2).

The term ‘isolating’ referred to in step (s) or step (u) corresponds to any of the steps involving evaporation, addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.

The reaction of the specific embodiment represented as below scheme (VI):

The process of the present invention as illustrated in the above Scheme (V) and Scheme (VI) comprises dissolving N-acetyl leucine salt of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (AL) in 1,4-dioxane, followed by the addition of 3-acetamido phthalic anhydride (B) and Acetic acid. The reaction mixture was heated at a temperature about 90 oC for about 9 hours. The solvent was evaporated and the crude was dissolved in dichloromethane. To the reaction mixture containing crude apremilast (1) was added acetyl chloride in the presence of catalytic amount of iodine (I2). The desired product pure apremilast (1) wherein the content of des-acetyl apremilast (1a) is less than 1% w/w was obtained after workup procedure (yield: about 70%).

In a further embodiment, the present invention relates to an improved process for the preparation of pure apremilast (1) comprising reacting des-acetyl apremilast (1a) with an acetylating agent in the presence of a catalyst.

Accordingly, the present invention relates to an improved process for the preparation of apremilast (1) represented by the following formula,

comprising, reacting the des-acetyl apremilast (1a) compound represented by the following formula,

with an acetylating agent in the presence of a catalyst.

In an embodiment, the ‘acetylating agent’ is any selected from the group consisting of acyl halide such as acetyl chloride; acetic anhydride, acetic acid and the like or mixtures thereof.

In an embodiment, the ‘catalyst’ is any selected from the group consisting of iodine (I2) or similar reaction initiator catalysts.

In a specific embodiment, the process for the preparation of apremilast (1) comprises the steps of:
(x) adding des-acetyl apremilast (1a) to a solvent;
(y) adding an acetylating agent and a catalyst to the reaction mixture of step (x);
(z) isolating the apremilast (1).

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

The solvent used in the step (x) of the above process (as depicted in the Scheme (VII)) 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); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.

The acetylating agent used in the step (y) of the above process (as depicted in the Scheme (VII)) is selected from acyl halide such as acetyl chloride; acetic anhydride, acetic acid and the like or mixtures thereof.

The catalyst used in the step (y) of the above process (as depicted in the Scheme (VII)) is selected from iodine (I2).

The term ‘isolating’ referred to in step (z) corresponds to any of the steps involving evaporation, addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.

The reaction of the specific embodiment represented as below scheme (VIII):

The process of the present invention as illustrated in the above Scheme (VII) and Scheme (VIII) comprises dissolving des-acetyl apremilast (1a) in dichloromethane followed by the addition of iodine (I2) and Acetyl chloride. The reaction mixture washed with an aqueous base solution and organic layer evaporated to obtain desired apremilast (1) (yield: about 81%)

In an embodiment, there is provided compound as apremilast methyl isobutyl ketone (Apremilast : MIBK) solvate.

It is evident from the prior art document such as US 6,020,358 and other cited reference, that the use of the acetic acid during reaction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) leads to the production of apremilast (1) along with the formation of unwanted des-acetyl apremilast (1a) in higher quantities. Also, the use of acetic acid alone as solvent in reported process leads to complicate the workup procedures and requires multiple purification steps.

The process of the instantly disclosed invention refers to the formation of pure apremilast (1) wherein the content of des-acetyl apremilast (1a) is less than 1% (weight/weight).

In an embodiment, the process of the instantly disclosed invention refers to the formation of pure apremilast (1) wherein the content of des-acetyl apremilast (1a) is less than 0.15% w/w.

There are several guidelines issued by the International Conference on Harmonization (ICH) and EMA that provides the limits for impurities in drug substances and drug products. It is proven that the genotoxic impurities shows adverse health effects, hence it is necessary to determine and control limits based on the daily dose of the drug substance. In order to meet the toxicology requirements, and to address the underlined problem, the scientists have developed this process to control the genotoxic impurities.

In an embodiment, there is provided a compound N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (1) (Apremilast), having total amount of genotoxic substances less than 25 ppm, wherein the said genotoxic substances are selected from the group consisting of acetyl chloride, chloro-acetyl chloride, methane sulfonyl chloride, dimethyl sulfate, diethyl sulfate, 3-amino phthalic acid, 4-amino phthalic acid, N-acetyl-3-amino-1,2-benzendicarboxylic acid, N-acetyl-4-amino-1,2-benzendicarboxylic acid and or a mixture thereof.

Accordingly, the present invention relates to an improved process for the preparation of pure apremilast (1) having total amount of genotoxic substances less than 25 ppm, wherein the said genotoxic substances are selected from the group consisting of acetyl chloride, chloro-acetyl chloride, methane sulfonyl chloride, dimethyl sulfate, diethyl sulfate, 3-amino phthalic acid, 4-amino phthalic acid, N-acetyl-3-amino-1,2-benzendicarboxylic acid, N-acetyl-4-amino-1,2-benzendicarboxylic acid and or a mixture thereof; comprising reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid; followed by the treatment with an acetylating agent.

The inventors studied the quality of the product apremilast (1) with the consideration to the genotoxic impurity. The Table-A consolidates the observations for the genotoxic impurity content in the product apremilast (1) obtained by the instantly presented process.

Genotoxic impurity analysed Detection
acetyl chloride = 8 ppm
chloro-acetyl chloride = 2 ppm
methane sulfonyl chloride = 8 ppm
dimethyl sulfate = 8 ppm
diethyl sulfate = 8 ppm
3-amino phthalic acid = 8 ppm
4-amino phthalic acid = 8 ppm
N-acetyl-3-amino-1,2-benzendicarboxylic acid = 8 ppm
N-acetyl-4-amino-1,2-benzendicarboxylic acid = 8 ppm

Table: A

In an embodiment, there is provided a compound N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (1) (Apremilast), having particle size diameter range with D10 between 1 to 5 µm; or D50 between 6 to 20 µm or D90 between 25 to 100 µm.

Accordingly, the present invention relates to an improved process for the preparation of apremilast (1) having particle size diameter range with D10 between 1 to 5 µm; or D50 between 6 to 20 µm or D90 between 25 to 100 µm; comprising reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid; followed by the treatment with an acetylating agent.

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: Preparation of Apremilast (1):
Charged 50 mL of 1,4-Dioxane in a flask followed by the addition of 5 g of N-acetyl L-Leucine salt of 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (Compound (AL)), 5 mL of glacial acetic acid and 2.3 g of 3-acetamidophthalic anhydride (B). The reaction mixture was heated to a temperature of 85-90 °C and stirred for about 8-10 h. The reaction mixture was cooled and solvent was distilled out under vacuum. To the residue was added 50 mL of dichloromethane followed by the addition of 0.014 g of Iodine (I2) and 0.88 g of Acetyl chloride. The reaction mixture further stirred for 2-4 hr at a temperature of about 25-30 °C. The reaction mixture was washed with aqueous solution of sodium bicarbonate (7-8% solution) and sodium thiosulfate solution (10%). The organic layer was separated and evaporated under vacuum and the residue was dissolved in 40 mL of methyl isobutyl ketone. The reaction mixture was heated at temperature 80-90 °C, followed with subsequent cooling to 25-30 °C temperature and stirred for about 14-16 h. The reaction mixture was further cooled to 0-5 °C temperature and the precipitated solid was isolated. Yield: 3.6 g (70%).

Example-2: Preparation of Apremilast (1) from des-acetyl apremilast (1a):
Charged 50 mL of dichloromethane (MDC) in a flask followed by the addition of 5 g of des-acetyl apremilast (compound (1a)), 0.015g of iodine (I2) and 0.93 g of acetyl chloride. The reaction mixture was stirred at temperature of about 25-30 °C for 8-10 h. The reaction mixture was washed with aqueous solution of sodium bicarbonate (7-8% solution) and sodium thiosulfate solution (10%). The organic layer was separated and evaporated under vacuum and the residue was dissolved in 40 mL of methyl isobutyl ketone. The reaction mixture was heated at temperature 80-90 °C, followed with subsequent cooling to 25-30 °C temperature and stirred for about 14-16 h. The reaction mixture was further cooled to 0-5 °C temperature and the precipitated solid was isolated. Yield: 4.5 g (81%).

Example-3: Preparation of Apremilast (1):
Charged 400 mL of 1,4-Dioxane in a flask followed by the addition of 80 g of N-acetyl L-Leucine salt of 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (Compound (AL)), 20 mL of Glacial acetic acid and 36.77 g of 3-acetamidophthalic anhydride (B). The reaction mixture was heated to a temperature of about 80 °C and stirred for about 8-10 h. The reaction mixture was cooled 25-30 oC and partitioned in 320 mL of Methyl isobutyl ketone and 400 mL of water. The combined organic layer was washed with aqueous solution of sodium bicarbonate (7-8% solution). The separated organic layer was stirred at temperature of about 25-30 °C for 14-16 h. The reaction mixture was further cooled to 0-5 °C temperature and the precipitated solid was isolated. Yield: 54.2 g (65%).

Example-4: Preparation of apremilast methyl isobutyl ketone (MIBK) solvate:
Apremilast (10 g) was dissolved in methyl isobutyl ketone (90 mL) at about 95 °C. The obtained clear solution was filtered and stirred for about 14-16 h at temperature of about 25-30 °C. The reaction mixture was further cooled to 0-5 °C temperature and stirred for 4-5 h. The resulting solid was filtered and dried under vacuum to get a methyl isobutyl ketone solvate of apremilast.

,CLAIMS:We claim

1. A compound N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (1) (Apremilast), having total amount of genotoxic substances less than 25 ppm, wherein the said genotoxic substances are selected from the group consisting of acetyl chloride, chloro-acetyl chloride, methane sulfonyl chloride, dimethyl sulfate, diethyl sulfate, 3-amino phthalic acid, 4-amino phthalic acid, N-acetyl-3-amino-1,2-benzendicarboxylic acid, N-acetyl-4-amino-1,2-benzendicarboxylic acid and or a mixture thereof.

2. The compound according to claim 1, having particle size diameter range with D10 between 1 to 5 µm; or D50 between 6 to 20 µm or D90 between 25 to 100 µm.

3. The compound according to claim 1, having total amount of des-acetyl apremilast impurity content less than 1% w/w.

4. The compound according to claim 1, of the following formula,

which is obtained by a process comprising the step of,
reacting the compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine (A) or its chiral acid salt of the following formula,

with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) of the following formula,

in presence of ether or amide solvent and optionally, in presence of an acid.

5. The compound according to the claim 4, wherein the ether solvent is an cyclic ether solvent selected from the group consisting of 1,4-dioxane, 1,3-dioxolane, tetrahydropyran (THP), methyl THP, dimethyl THP, ethylene oxide, propylene oxide, butylene oxide, 2-methyltetrahydrofuran, tetrahydrofuran-2-methoxy ether, tetrahydrofuran-2,5-dimethoxy ether, tetrahydrofuran-2-methoxy ethyl ether, tetrahydrofuran-2-ethoxy ether, tetrahydrofuran-2,5-diethoxy ether and tetrahydrofuran-2-methoxy propyl ether; liner ethers such as dimethoxy ethane (DME), diethyl ether, cyclopentyl methyl ether and/or a mixture thereof.

6. The compound according to the claim 4, wherein the amide solvent is a cyclic amide solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), N-alkyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-acetylpyrolidine, N-ethyl-2-pyrrolidone and/or mixture thereof.
7. The compound according to the claim 4, wherein the acid is a protic acid selected from acetic acid, formic acid, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid and/or mixture thereof.

8. The compound according to the claim 4, wherein the compound (1) is treated with an acetylating agent in the presence of a catalyst, to provide pure compound (1) having total amount of des-acetyl apremilast impurity content less than 1% w/w.

9. The compound according to the claim 8, wherein the acetylating agent is an acyl halide selected from acetyl chloride; or acetic anhydride; or acetic acid and/or mixture thereof.

10. The compound according to the claim 8, wherein the catalyst is any selected from the group consisting of iodine (I2).

Dated this 11th day of October 2018

_________________________
Sridevi Krishnan
General Manager – Corporate Patents
Piramal Enterprises Limited

To,
The Controller of Patents
The Patent Office
At Mumbai