FIELD OF THE INVENTION

The present invention relates to a process for the preparation of l-(3-ethoxy-4-methoxy- phenyl)-2-methylsulfonyl-ethanamine, an intermediate used for the preparation of apremilast.

BACKGROUND OF THE INVENTION

Apremilast chemically known as N-[2-[(15)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-iH-isoindol-4-y l]acetamide is represented by the compound of Formula I:

Formula I

Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP), marketed in the United states under the brand name OTEZLA ^® as oral tablets and indicated for the treatment of adult patients with active psoriatic arthritis and for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Apremilast is first disclosed in United States Patent No. 7,427,638 (the '638 patent).

Many processes for the preparation of N-[2-[(15)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-iH-isoindol-4-y l]acetamide or apremilast are reported. Generally, racemic 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l,3-dione can be prepared using the methods described in United States Patent No. 6,020,358. The corresponding 5 enantiomer can be isolated from the racemic compound by techniques known in the art. The '638 patent discloses a process for the preparation of apremilast wherein it is synthesized from 3-acetamidophthalic anhydride and a chiral amino acid salt of (5)-l-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonylethylamine.

The U. S. Pat. No. 9,187,417 discloses the processes for enantioselective preparation of (5)-l- (3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine, an intermediate which is used for preparation of apremilast by using stoichiometric quantity of chiral auxiliary namely (R)-tert- butylsulfinamide or (S)-a-methylbenzylamine.

The U. S. Pat. No. 9,126,906 discloses the process for the enantiomerically enriched preparation of (5)-l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine by reducing corresponding enamine via hydrogenation in the presence of a metal catalyst and a chiral ligand or a chiral metal catalyst/ligand complex.

Although these methods are enabling and useful for preparing apremilast, there is a need for developing a process which is commercially efficient.

The present invention provides a simple, scalable and economical process for the preparation of apremilast.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of apremilast, comprising:

(a) reacting a compound of Formula V,

Formula V wherein R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -Obenzyl, and L is a leaving group, with dimethylsulfone anion to obtain a compound of Formula IV

Formula IV wherein R is as defined above,

(b) deprotecting the compound of Formula IV to obtain a compound of Formula III

Formula III

, and

(c) converting the compound of Formula III to apremilast.

The present invention also provides a novel intermediate of compound of Formula Va

Formula Va its enantiomers or acid addition salts thereof.

The processes of the present invention are economical and suitable for commercial production of apremilast.

DEFINITIONS

The term "(Ci-C4)aikyl" as used herein refers to an straight or branched chain, saturated monovalent hydrocarbon residue containing 1-4 carbon atoms. Examples of (Ci-C4)alkyl includes but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert- butyl. The term "-0(Ci-C4)alkyl" as used herein refers to a group in which (Ci-C4)alkyl group as defined above, is attached to another group via an oxygen atom. Examples of -0(Ci-C4)alkyl includes but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, teri-butoxy and the like.

The term "(Ci-C4)haloalkyl" as used herein refers to C ₁ -C4 alkyl group as defined above, wherein one or more hydrogen atoms of alkyl group is substituted by one or more halogens. Examples of (Ci-C4)haloalkyl includes but are not limited to trifluromethyl, trichloromethyl.

The term "halogen" as used herein refers to chloro, bromo, iodo or fluoro.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of apremilast, comprising:

(a) reacting a compound of Formula V

Formula V wherein R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -O-benzyl, and L is a leaving group, with dimethylsulfone anion to obtain a compound of Formula IV

Formula IV wherein R is as defined above,

(b) deprotecting the compound of Formula IV to obtain a compound of Formula III

Formula III

, and

(c) converting the compound of Formula III to apremilast.

In one embodiment, R in the compound of Formula IV and V is selected from (Ci-C4)alkyl, (Ci-C ₄ )haloalkyl, -0(Ci-C ₄ )alkyl, and -O-benzyl; preferably R is -0(Ci-C ₄ )alkyl; more preferably R is teri-butoxy.

In another embodiment, L in the compound of Formula V is a leaving group selected from a group consisting of -S(0)2-(Ci-C ₄ alkyl), -S(0)2-(Ci-C ₄ haloalkyl), benzenesulfonyl, p- toluenesulfonyl, -0(Ci-C ₄ )alkyl or halogen. In a preferred embodiment L is p-toluenesulfonyl group.

Accordingly, step a involve reaction of compound of Formula V with dimethylsulfone anion. Dimethylsulfone anion can be prepared by reacting dimethylsulfone with a strong base. Strong base suitable for the purpose can be selected from sodium

(NaHMDS), lithium Ws<trimethylsilyl)amide (LiHMDS), «-butyl lithium («-BuLi), sodium hydride or hydroxide like potassium hydroxide. In one embodiment, the base is NaHMDS or NaH. In another embodiment, the base is NaHMDS. Dimethylsulfone anion is reacted with compound of Formula V. The reaction can be carried out in presence of a solvent. A suitable solvent for the reaction may be selected from a group comprising of ether solvents such as tetrahydrofuran (THF), Me-THF, diethylether, 1,4- dioxane; or halogenated solvents such as dichloromethane, dichloroe thane; or polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone or a mixture thereof. The most preferred solvent is tetrahydrofuran. Alternatively, compound of Formula V and dimethylsulfone may be mixed together in a solvent and then a base may be added thus generating the dimethylsulfone anion in-situ followed by reaction with the compound of Formula V. The reaction may be carried out at a temperature ranging from about -78 °C to about 10 °C, more preferably at a temperature of about -40 °C to about 5 °C; most preferably at a temperature of about -10 °C to 0 °C. The reaction may be carried out for a time sufficient enough to complete the reaction, for example about 30 minutes to 12 hours. The compound of Formula IV may be isolated by the well known techniques in the art such as extraction by the solvent and then evaporation of the solvent under reduced pressure. The obtained compound of Formula IV may be further purified before subjecting it to reaction of step b.

Step b involves deprotecting the compound of Formula IV to obtain compound of Formula III. The deprotection of compound of Formula IV may be carried out by a process known for the deprotection of amino protecting group, such as by using acids, bases or by hydrogenolysis. For instance Boc-deprotection of compound of Formula IV (when R is tert- butoxy) may be carried out by using reagents such as hydrochloric acid, trifluoroacetic acid, and the like.

Step c involves converting the compound of Formula III to apremilast. The compound of Formula III can be converted to apremilast by a process comprising:

(i) reacting the compound of Formula III with a chiral acid HX, to form an acid addition salt of following formula

Acid addition salt

wherein H is hydrogen and X is acid counterpart, and

(ii) reacting the acid addition salt with 3-acetamidophthalic acid or 3-acetamidophthalic anhydride to obtain apremilast.

The compound of Formula III is reacted with a chiral acid HX wherein H is hydrogen and X is acid counterpart. The chiral acid can be selected from amino acids or their derivatives. A preferred chiral acid is N-acetyl-L-leucine. The reaction can be conveniently carried out in presence of a solvent selected from C1-C4 alcohols, acetone and other equivalent ketones, halogenated solvents like dichloromethane and chloroform. In an embodiment the preferred solvent is methanol. The reaction may be carried out at a temperature of 25 °C to reflux temperature of the solvent. The acid addition salt may be separated from the reaction mass by the processes known to a person skilled in the art.

The acid addition salt obtained in above step is reacted with 3-acetamidophthalic acid or 3- acetamidophthalic anhydride in presence of a suitable solvent. The solvent may be selected from acetone and other equivalent ketones, halogenated solvents like dichloromethane and chloroform, ethers like tetrahydrofuran and 1,4-dioxane or acids like acetic acid or formic acid. In a preferred embodiment the solvent is acetic acid. When the solvent is other than acid, an acid like acetic acid or dilute hydrochloric acid may be added to the reaction mixture. The reaction may be carried out at temperature of about 25 °C to reflux temperature of the solvent used for a time sufficient for completion of the reaction. Apremilast may be isolated from the reaction mass as per the common processes known in the art. For instance, by distilling out the solvent to obtain crude and purifying the crude by means of crystallization.

The compound of Formula V used in the above process, may be prepared by reacting 3- ethoxy-4-methoxybenzaldehyde (compound of Formula VIII), a compound of Formula VII and a compound of Formula VI in a suitable solvent (Scheme I)

Scheme I

Formula VIII Formula V

wherein, R in the compound of Formula VII and V and L in the compound of Formula V are as defined above; L in the compound of Formula VI is selected from a group consisting of (C1-C4 alkyl)sulfinate, (C1-C4 haloalkyl)sulfinate, benzenesulfinate, p-toluenesulfinate, - 0(Ci-C4)alkyl or halogen; and the metal is selected from zinc (Zn), iron (Fe), sodium (Na), lithium (Li), potassium (K), calcium (Ca), magnesium (Mg), strontium (Sr) or titanium (Ti); and wherein n is an integer selected from 0 to 4, depending on the valency of metal ion selected. The non-limiting examples of Metal ⁺ -(L) _n ^" (Formula VI) includes sodium benzenesulfinate, sodium p-toluenesulfinate, sodium methanesulfinate, sodium trifluoromethanesulfinate, zinc chloride, lithium bromide, ferric chloride, sodium methoxide, potassium teri-butoxide, titanium ethoxide and the like.

A suitable solvent for the reaction may be selected from alcoholic solvents such as methanol, ethanol; or aromatic hydrocarbon solvents such as toluene; or ether solvents such as tetrahydrofuran (THF), diethylether; or chlorinated hydrocarbons solvents such as dichlorome thane; or polar aprotic solvents such as acetonitrile, DMF; or ester solvents such as ethyl acetate; or water or a mixture thereof. Optionally an acid such as formic acid or acetic acid may be added in the reaction mixture. The reaction may be carried out at a temperature of about room temperature to about reflux temperature of the solvent for a time sufficient to complete the reaction. The product may be isolated by the technique known in the art such as filtration or extraction by using organic solvent.

In a preferred embodiment, the present invention provides a process for the preparation of apremilast, wherein R in the compound of Formula V and IV is teri-butoxy and L in the compound of Formula V is p-toluenesulfonyl group; the process comprises:

(a) reacting a compound of Formula

Formula Va

with dimethylsulfone anion to obtain la IVa

Formula IVa

(b) deprotecting the compound of Formula IVa to obtain a compound of Formula III

Formula III

, and

(c) converting the compound of Formula III to apremilast.

In another embodiment, the steps a, b and c can be performed as per the process disclosed earlier in the specification.

In another aspect, the present invention provides a compound of Formula Va

Formula Va its enantiomers or salts thereof.

The compound of Formula Va can be prepared by one pot process comprising mixing 3- ethoxy-4-methoxybenzaldehyde, teri-butyl carbamate and alkali metal p-toluenesulfinate such as sodium p-toluenesulfinate in a suitable solvent. A suitable solvent for the reaction may be selected from alcoholic solvents such as methanol, ethanol; or aromatic hydrocarbon solvents such as toluene; or ether solvents such as tetrahydrofuran (THF), diethylether; or chlorinated hydrocarbons solvents such as dichlorome thane; or polar aprotic solvents such as acetonitrile, DMF; or ester solvents such as ethyl acetate; or water or a mixture thereof. The preferred solvent is water. Preferably the reaction is carried out in presence of an acid such as formic acid. The reaction may be carried out at a temperature of about room temperature to about 60 °C, more preferably at room temperature, for a time sufficient to complete the reaction.

The complete process for the preparation of apremilast of the present invention can be depicted as in Scheme below:

Formula V

L is a leaving group

R is (C -C,)alkyl, -0(C -C,)alkyl, or -O-benzyl

Formula I Acid addition salt

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

EXAMPLES:

Example 1: Preparation of tert-butyl N-[(3-ethoxy-4-methoxy-phi toly

A solution of 3-ethoxy-4-methoxybenzaldehyde, ieri-butyl carbamate and sodium p- toluenesulfinate in water was stirred at 25-30 °C. Formic acid was added into the reaction mixture and stirred for 48 hours at 25-30 °C. After completion of reaction, the reaction mixture was filtered to obtain the solid product, washed with methanol: water (1:9) mixture and dried in vacuum oven. Yield: 90 %. ¾ NMR (400 MHz, DMSO-d6) δ 8.63-8.66 (d, 1H), 7.73-7.75 (d, 2H), 7.46-7.48 (d, 2H), 7.29 (s, 1H), 7.12-7.15 (dd, 1H), 6.97-7.12 (d, 1H), 5.89-5.91(d, 2H), 4.02-4.07 (q, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 1.36-1.40 (t, 3H), 1.25 (s, 9H). Example 2: Preparation of tert-butyl N-[l-(3-ethoxy-4-methoxy-phenyl)-2- methylsulfonyl-ethyljc

A mixture of dimethylsulfone in dry tetrahydrofuran was cooled to -5 °C to 0 °C and was added a solution of NaHMDS in THF (35 % solution). The resulting suspension was stirred at -5 °C to 0 °C for 1 hour. A solution of teri-butyl N-[(3-ethoxy-4-methoxy-phenyl)-(p- tolylsulfonyl)methyl]carbamate in dry dichloromethane was added into the reaction mass at - 5 °C to 0 °C and stirred fori hour. After completion of reaction, the reaction mixture was quenched with water and diluted with dichloromethane. The organic layer was separated and concentrated under reduced pressure to afford the crude product, which was triturated with isopropanol and hexane mixture to yield off-white solid of title compound. Yield: 90 %. ¾ NMR (400MHZ, CDCb) δ 6.83-6.88 (m, 3H), 5.59-5.60 (broad d, 1H), 5.13-5.14 (broad d, 1H), 4.02-4.26 (q, 2H), 3.84-3.89 (s, 3H), 3.63-3.66 (m, 1H), 3.37-3.41 (m, 1H), 2.61-2.66 (s, 3H), 1.41-1.46 (m, 12H).

Example 3: Preparation of l-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl- ethanamine

To a solution of teri-butyl N-[l-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl- ethyl]carbamate in acetonitrile was added isopropyl alcohol hydrochloride solution (IPA- HC1, 14 %) at 25-30 °C. The resultant reaction mixture was stirred for 12 hours at the same temperature. After completion of the reaction, the reaction mass was concentrated under reduced pressure and partitioned between 10 % aq. NaOH solution and dichloromethane. The organic layer was separated and concentrated under reduced pressure to afford the title compound as white solid. Yield: 95 %. Example 4: Preparation of (S)-2-(3-ethoxy-4-methoxy-phenyl)-2-(methylsulfonyl)-eth- 2-ylamine-N-ace

To 1 liter round bottom flask , l-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine, N-acetyl-L-leucine and methanol were charged and the suspension was stirred at 60 °C to 65 °C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours. The solid was filtered and dried under reduced pressure to obtain the title compound with chiral purity of 85 % desired isomer. Yield: 40 %.

It was further purified by methanol to give pure title compound having chiral purity 99.5%.

Example 5: Apremilast

To a 500 mL RBF the product of example 4, 3-acetamidophthalic anhydride and acetic acid were charged and stirred at 110 °C to 115 °C for 1 hour and the solution was cooled to 60-65 °C. Acetic acid was distilled off completely and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water followed by washing with aq. sodium bicarbonate solution. The dichloromethane layer was separated and distilled off completely. The product was isolated by recrystallization in acetone:ethanol mixture to give apremilast as a light yellow solid with chiral purity of 99.9 % and HPLC purity of 99.8 %. Yield: 75 %.

Example 6: Apremilast

To a 500 mL RBF the product of example 4, 3-acetamidophthalic acid and acetic acid were charged and stirred at 110 °C to 115 °C for 1 hour and the solution was cooled to 60-65 °C. Acetic acid was distilled off completely and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water followed by washing with aq. sodium bicarbonate solution. The dichloromethane layer was separated and distilled off completely. The product was isolated by recrystallization in acetone :ethanol mixture to give apremilast as a light yellow solid with HPLC purity of 99.9 %. Yield: 75 %.