WO2016192694A1

WO2016192694A1 - A process for preparing the key intermediate of apremilast, using enzymatic resolution of the racemic amines

Info

Publication number: WO2016192694A1
Application number: PCT/CZ2016/000061
Authority: WO
Inventors: Jan DOUBSKY; Robert Klvana; Jindrich Richter; Petr LEHNERT
Original assignee: Zentiva, K.S.
Priority date: 2015-06-05
Filing date: 2016-06-02
Publication date: 2016-12-08
Also published as: CZ2015383A3

Abstract

The invention relates to a preparation method of (S)-l-(3-ethoxy-4-methoxyphenyl)- 2-(methylsulfonyl)-ethyl-amine (S)-l, or its N-acyl derivatives of general formula (S)-2. The amine (S)-l is the key intermediate in the synthesis of (S)-{2-[l-(3-ethoxy-4- methoxyphenyi)-2-methyisulfonylethyl]-4-acetylaminoisoindolin-l ?3-dione, known as Apremilast. In this synthesis, the amine (S)-l, or its respective salts, are subjected to condensation with 3-acetamidophthalic anhydride 4, providing the desired product 3 (Scheme 1).

Description

A process for preparing the key intermediate of apremilast, using enzymatic resolution of the racemic amines

Technical Field

The invention relates to a preparation method of (iS)-l-(3-ethoxy-4-methoxyphenyl)- 2-(methylsulfonyl)-ethyl-amine (S)-l, or its N-acyl derivatives of general formula (S)-2:

(S>-2

Figure 1

The amine (S)-l is the key intermediate in the synthesis of (5)-{2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylemyl]-4-acetylaminoisoindolin-l,3-dione 3, known as Apremilast. In this synthesis, the amine (S)-l, or its corresponding salts, are subjected to condensation with 3-acetamidophthalic anhydride 4, providing the desired product 3 (Scheme 7).

Racemic 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (rac)-l actually consists of an equimolar mixture (1:1) of two opposite enantiomers (S)-l and (R)-l. Reactions catalyzed by enzymes are generally characterized by high stereoselectivity with respect to the substrates. Therefore, in the presence of a suitable enzyme and the acyl donor 5 derivatization of just one of the two enantiomers preferentially occurs. The product of this reaction is either a mixture of the desired chiral amine (S)-l and N-acyl derivative (R)-2 (method /, Scheme 1), or a mixture of the amine (R)-l and N-acyl derivative of the desired amine (S)-2 (method ii, Scheme 1).

Scheme 1 In the first case (method i), the optically pure amine (S)-l can, after separation from the respective derivative (R)-2, be directly used for the synthesis of Apremilast 3. In the second case (method ii), after enzymatic resolution and separation of the products, the desired amine (5)-l is chemically released from the corresponding derivative (S)-2.

The said enzymatic resolution only makes it possible to achieve max. 50% yield because the contents of each of the two opposite enantiomers S)-l and (R)-l in the racemic amine (rac)-\ are just 50%. However, in the presence of a suitable racemization catalyst continuous mutual conversion of the (S) and (R) isomers occurs, which makes it possible to theoretically achieve up to 100% yield of the desired isomer, or its derivative. This method is generally known as the enzymatic dynamic kinetic resolution (hereinafter only: DKR; Figure 2).

Thus, the present invention represents a very efficient, economically advantageous and in addition environment-friendly preparation method of the key intermediate of the synthesis of Apremilast 3, i.e. (5)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl- amine

catalyst

Figure 2 Background Art

Apremilast 3 {Scheme 1) is an orally available inhibitor of phosphodiesterase 4 (PDE4), which inhibits spontaneous production of the tumor necrosis factor a (TNF-α), thus exhibiting an anti-inflammatory activity. It can be used for the treatment of psoriatic arthritis and it is also being tested for the treatment of other inflammatory diseases.

Apremilast 3 was first described as a racemic mixture of active pharmaceutical ingredients (WO 2000/25777 Al; EP 1126839 B). A few years later, in an application (WO 2003/080049) a particular enantiomer, (5)-isomer, commonly only referred to as Apremilast 3 was described, which is the carrier of the biological activity as such. Thus, it is the chiral amine (S)-l that is the key intermediate for the synthesis of Apremilast 3. An application (WO 2003/080049) describes the procedure of chiral resolution of the racemic amine (rac)-l with the use of N-acetyl-L-leucine and subsequent use of the corresponding salt 6 for the synthesis of Apremilast 3 (Scheme 2).

Using this procedure, the desired enantiomer (S)-l was isolated in the yield of 44%, or 89% (based on the theoretical content of 50% of formula (S)-l in the racemic amine (rac)-X). Also, later applications (US 2008/0234359 Al; EP 2431371 Al) make use of the use N- acetyl-L-leucine, or derivatives of chiral amino acids in general, for chiral resolution of the racemic amine (rac)-l and subsequent use of the corresponding salt 6 for synthesis of Apremilast 3 (Scheme 2).

Besides the above mentioned ones, a number of asymmetrical syntheses of the desired enantiomer of formula (5)-l have been described that use chiral catalysts of transition metals, e.g. rhodium (US2013/217919 Al; US2014/81032 Al). However, these procedures are not suitable for industrial production of (5)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)- ethylamine (S)-l, or Apremilast 3, in economic terms.

At present, Dynamic Kinetic Resolution (DKR, Figure 2) belongs to well-established and frequently used methods not only in the laboratory, but also in the industrial scale (P. Hoyos, V. Pace, A. R. Alcantara: Adv. Synth. Catal. 2012, 354, 2585-2611; A. Schmid, J. S. Dordick, B. Hauer, A. Kiener, M. Wubbolts, B. Witholt: Nature 2001, 409, 258-268; A. Kamal, M. A. Azhar, T. Krishnaji, M. S. Malik, S. Azeeza: Coord. Chem. Rev. 2008, 252, 569-592; O. Kirk, and M. W. Christensen: Org. Process Res. Dev. 2002, 6, 446-451). In the industrial scale, this method is also used for a number of amines of the benzyl type, i.e. for compounds that are structurally close to the racemic amine (rac)-l.

Enzymes that are generally usable for enzymatic resolution or for DKR belong to the wider group of so-called hydrolases (international identification EC 3), comprising e.g. lipases, esterases, peptidases etc. Besides free enzymes or cell cultures, enzymes immobilized on solid carriers can be advantageously used as they make it possible to carry out the above mentioned reactions also in organic solvents without the presence of water or other additives. One of the most commonly used immobilized enzymes is Novozym 435®, which is lipase B of the Candida antarctica (CAL-B) yeast, usually bound to polymers of the acrylate type.

Suitable N-acyl donors 5 (Scheme 1; Y-donor in Figure 2) are most frequently esters of carboxylic acids 5a, less frequently free carboxylic acids 5b and their corresponding anhydrides 5c, or more rarely also derivatives of carbonic acid 5d (Figure 3) (C. E. Hoben, L. Kanupp, J.-E. Backvall: Tetrahedron Lett. 2008, 49, 977-979).

In the case of DKR, complexes of some transition metals are most frequently used as the racemization catalysts, especially those of ruthenium, iridium, palladium, rhodium or vanadium (Figure 4), or even pure transition metals, possibly adsorbed on suitable carriers (e.g. Pd/C, Pd/CaC0₃, Pd/BaS0₄, Rh/C, Rh/Al₂0₃ etc.).

i = Me, Et, CF₃, MeOCH₂, and the like

Rz = alkyls and aryls (also substituted in any manner)

R₃ = Me, Et, t-Bu, PhCH_z, allyl, and the like

Figure 3

7a Ar = Ph "^shv0 8 10 7b Ar = 4-MeOC₆H₄ Ar = Ph, PhCH₂, 4-CF₃C₆H₄, 4-F-C₆H₄

. -iOSi tis

Ph₃SiCT V OSiPI¾

11 X = CI, I 12

Figure 4

Disclosure of Invention

The invention provides a process for preparing (_iS)-l-(3-ethoxy-4-methox phenyl)-2- (methylsulfonyl)-ethyl-amine (S)-l, or its N-acyl derivatives of the general formula (S)-2, generally using enzymatic resolution of the corresponding racemic amine (rac)-l (Scheme 3)

Scheme 3 Racemic 1 -(3-ethoxy-4-memoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (rac)-l consists of the equimolar mixture (1 :1) of two opposite enantiomers and In the presence of a suitable acyl donor 5 and a suitable enzyme from the group of so-called hydrolases (international identification EC 3), comprising e.g. Upases, esterases, peptidases etc., derivatization of one of both the enantiomers preferentially occurs. Then, the product of such a reaction is either a mixture of the desired chiral amine and N-acyl derivative (R)- 2 (method i, Scheme 3), or a mixture of the amine (R)-l and N-acyl derivative of the desired amine (5)-2 (method κ, Scheme 3).

Suitable acyl-donors 5 (Figure 3 and Figure 5) usable for enzymatic resolution of the racemic amine {rac)-\ are generally the following compounds: a) esters of carboxylic acids 5a, b) carboxylic acids 5b, c) anhydrides of carboxylic acids 5c or d) esters of carbonic acid (referred to as carbonates) 5 d. In the case of all these compounds, R^R² is R³ independently stand for H (except 5c and 5d), a Ci-Ci alkyl, aryl or heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted by any functional groups. For the purposes of this invention, the term "any functional group" refers to: (a) halogens, (b) hydroxy, alkoxy or aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups (i.e. ketones), (e) derivatives of carboxylic acids. In the case of the esters 5a, the R² group may also stand for any alkenyl group (i.e. so-called enol esters).

Figure 5

The derivatives 5a-5c can advantageously be used, wherein R stands for the 0¾._ηΧ_η group (n = 1 to 3), wherein X is any Ci-Cis alkyl, any halogen (F, CI, Br and I), or alkoxy group OR⁴, wherein R⁴ stands for any Ci-Qs alkyl or C6-C₁₀ aryl. Concerning the esters 5a, the enol esters can also be preferentially used, i.e. compounds wherein R² is a vinyl or isopropenyl. Suitable carbonates 5d are compounds wherein R³ independently stands for a Ci-Cig alkyl, aryl or heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted by any functional groups in the sense of the above mentioned definition. Preferably, especially the carbonates 5d, wherein R³ is a -Ce alkyl, phenyl, benzyl or allyl.

Enzymes usable for the above mentioned enzymatic resolution {Scheme 3) can be any enzymes belonging to the wider group of so-called hydrolases (international identification EC 3), comprising e.g. lipases, esterases, peptidases etc. Besides free enzymes or cell cultures, enzymes immobilized on solid carriers can be advantageously used as they also make it possible to carry out the above mentioned reactions in organic solvents without the presence of water or other additives. Out of immobilized enzymes, the following enzymes can especially be advantageously used: Novozym 435® (E.C. 3.1.1.3; lipase B from Candida antarctica CAL-B yeast, bound to a polymer of the acrylate type), Subtilisin (E.C. 3.4.21.62; protease from Bacillus species, covalently bound on an amino-acrylate polymer), or Penicilin-G amidase (E.C. 3.5.1.11; amidase from Escherichia coli, immobilized on an epoxy-acrylate polymer).

It has been unexpectedly found out that especially the carbonates 5d (R³ = C1-C3) provide, in the presence of the immobilized lipase Novozym 435®, the desired enantiomer of the amine in the form of the respective carbamates (S)-2a (Scheme 4), in high chemical yields and in addition with high chiral purity. A clear advantage of this transformation is the possibility to use the respective carbonates 5d not only as the acyl donors, but also directly as the reaction media. In addition, the carbonates 5d are commonly commercially available, cheap and entirely environment-friendly compounds. In terms of industrial production, its economy and environmental aspects, these are all significant innovative elements.

(rac)-1 5d (S)-2a Scheme 4

Enzymatic resolution also offers another prospective advantage, which is the above described enzymatic dynamic kinetic resolution (Figure 2). In the presence of suitable racemization catalysts, continuous mutual conversion of the enantiomers (<S -1 and (R)-l can be achieved with the use of this method, which makes it possible to theoretically achieve up to 100% yield of the desired isomer, or its derivative while without the presence of racemization catalysts the maximum yield can only be 50%. In terms of industrial production and its economy this fact also represents a substantial advantage.

It has been surprisingly found out that under the conditions of enzymatic resolution of the racemic amine (rac)-X, in the presence of suitable racemization catalysts, mutual conversion of the two enantiomers (S)-l and (R)-l (represented in the racemic amine in the molar ratio of 1:1) can be efficiently achieved, i.e. the chemical yield of the desired enantiomer (5)-l in the form of the respective derivatives (5)-2 can exceed 50% (Scheme 5). Especially complexes of some transition metals, preferably complexes of ruthenium - referred to as the Shvo catalysts 7a and 7b (Figure 4) have proved to be suitable racemization catalysts for this transformation (Figure 4).

Scheme 5

Detailed description of the invention

The invention provides a process for preparing (S)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethyl-amine (S)-l, or its iV-acyl derivatives of the general formula (S)-2, generally using enzymatic resolution of the corresponding racemic amine (mc)-l. In another aspect, the invention provides a process for preparing (5)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethyI-amine (S)-l, or its N-acyl derivatives of general formula (S)-2, generally using the enzymatic dynamic kinetic resolution (Figure 2, Scheme 5), i.e. enzymatic resolution in the presence of any racemization catalysts. Still another aspect of the invention provides conversion of the derivatives of general formula (S)-2 to the chiral amine (S)-l and its use for the preparation of apremilast 3 (Scheme 1). Racemic 1 -(3-emoxy-4-methoxyphenyl)-2-(memylsulfonyl)-emyl-amine (rac)-l consists of the equimolar mixture (1:1) of two opposite enantiomers (S -l and (R)-l. In the presence of a suitable acyl-donor 5 and a suitable enzyme from the group of hydrolases (international identification EC 3), derivatization of preferentially only one of the two enantiomers occurs. Such reaction produces either a mixture of the desired chiral amine (5)-l and the N-acyl derivative (R -2 (method i, Scheme 3), or a mixture of the amine (R)-l and N- acyl derivative of the desired amine (S)-2 (method ii, Scheme 3).

Saa ₁ = MeOCH₂; R₂ = Me 5da R₃ = Me

Sab R, = MeOCH₂; R₂ = /-Pr 5db _j = Et

5ac R_f = CH₃; R₂ = Et 5dc R₃ = CH₂Ph

5ad R, = CH₃; R₂ = /-Pr

5ae R, = CH₃; R₂ = CH=CH₂

5ae R, = CH₃; R₂ = C(CH₃)=CH₂

Saf R₁ = CF₃; R₂ = Et

Figure 6

Suitable acyl-donors 5 {Figure 6) usable for enzymatic resolution of the racemic amine (rac)- 1 are generally the following compounds: a) esters of carboxylic acids 5a, b) carboxylic acids 5b, c) anhydrides of carboxylic acids 5c or d) esters of carbonic acid (referred to as carbonates) 5d. In the case of all these compounds, R ,R , R independently stand for H (except 5c and 5d), a Q-C^ alkyl, aryl or heteroaryl with one or more heteroatoms wherein all these groups may be further substituted by any functional groups. For the purposes of this invention, the term "any functional group " refers to: (a) halogens, (b) hydroxy, alkoxy or aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups (i.e. ketones), (e) derivatives of carboxylic acids. In the case of the esters 5a, the R² group may also stand for any alkenyl group (i.e. enol esters).

Either esters of the general formula 5a, in the particular case esters Saa - Saf, or carbonates of the general formula 5d, in particular the compounds 5da - Sdc, can be preferably used {Figure 6). All the above mentioned acyl donors 5a and 5b are liquid substances, commonly commercially available and, in addition, inexpensive, so they can be advantageously used not only as acyl donors, but also as reaction media (solvents), which are, moreoverm environment-friendly.

The enzymes usable for the above mentioned enzymatic resolution {Scheme 3) can be any enzymes belonging to the wider group of hydrolases (international identification EC 3), comprising e.g. lipases, esterases, peptidases etc. Besides free enzymes or cell cultures, enzymes immobilized on solid carriers can be advantageously used as they also make it possible to carry out the above mentioned reactions in organic solvents without the presence of water or other additives. Out of immobilized enzymes, the following enzymes can especially be advantageously used: Novozym 435® (E.C. 3.1.1.3; lipase B from Candida antarctica CAL-B yeast, bound to a polymer of the acrylate type), Subtilisin (E.C. 3.4.21.62; protease from Bacillus species, covalently bound on an amino-acrylate polymer), or Penicilin-G amidase (E.C. 3.5.1.11; amidase from Escherichia coli, immobilized on an epoxy-acrylate polymer).

It has been surprisingly found out that especially the carbonates 5d (R³ = Cx-C^), preferably the dimethyl carbonate 5da, and also the esters of carboxylic acids 5a, preferably especially the esters of methoxyacetic acid 5aa and 5ab, provide, in the presence of immobilized lipases, preferably the immobilized lipase Novozym 435®, the desired enantiomer (S)-l in the form of the respective derivatives (S)-2aa, or (5)-2ba {Scheme 6) in high chemical yields and in addition with high chemical purity.

Scheme 6

Immobilized lipases are highly resistant to the environment of common solvents as well as to elevated temperatures. Thus, the above mentioned reactions {Scheme 6) can be conducted either without the presence of any solvents (the acyl donors 5 serve as a solvent at the same time), or in a wide range of commonly available solvents. Applicable solvents comprise aliphatic or aromatic hydrocarbons and their halo derivatives, ethers, alcohols, derivatives of carboxylic acids (e.g. amides and nitriles), or sulfur derivatives, such as sulfones and sulfoxides. Advantageously, especially ethers can be used as f-butyl methyl ether (MTBE), cyclopentyl methyl ether (CPME), or cyclic 2-memyltetxahydrofuran ( eTHF).

However, in economical and environmental terms it is even more advantageous to carry out the above mentioned enzymatic resolution (Scheme 6) without the use of solvents. Especially, dimethyl carbonate (DMC) can be preferably used, which serves, in the particular case, not only as an acyl donor 5, but also as a solvent. DMC is well-known and frequently recommended as a cheap and at the same time environment-friendly solvent.

The reaction itself can be carried out in a wide temperature range. The temperature of the reaction mixture mainly influences the reaction rate: with an increased temperature the reaction gets accelerated, i.e. the reaction time gets shorter. It is suitable to carry out the above mentioned reactions at elevated temperatures (depending on the use of a possible solvent and its physical characteristics), preferably in the temperature range of 50 to 125°C.

It has been surprisingly found out that under the conditions of enzymatic resolution of the racemic amine (rac)~l, in the presence of suitable racemization catalysts, mutual conversion of the two enantiomers (S)-l and (R)-l (represented in the racemic amine in the molar ratio of 1 :1) can be efficiently achieved, i.e. the chemical yield of the desired enantiomer (S)-l in the form of the respective derivatives (S)-2 can exceed 50% (Scheme 5). A number of complexes of transition metals as well as pure transition metals, both free, or adsorbed on various carriers, have turned out to be suitable racemization catalysts for this transformation (Figure 4).

Advantageously, the so-called "Shvo catalysts" 7a and 7b can mainly be used in combination with the acyl donors 5aa, 5ab and 5da and with immobilized lipase Novozym 435® as the enzyme (Scheme 7). Under these conditions, the respective derivatives (S)-2 of the desired amine (S)-l can be obtained in chemical yields of up to 90% (i.e. 40% of the undesired enantiomer (R)-l transformed) while the chiral purity achieves up to 97%.

Scheme 7

To be able to use the protected derivatives (S)-2 for the preparation of apremilast 3 {Scheme 1), it is first necessary to convert them, in a suitable way, to the desired free amine (S)-l (method ii, Scheme 1), The RCO acyl groups belong to groups that are commonly used to protect amines. Thanks to this, a number of methods and agents have been described, enabling carrying out such transformations even under very moderate conditions.

In the particular case of the derivatives (5)-2aa and (S)-2ba, either strong acids, or strong bases can be used equally successfully for the conversion to the free amine (S)-l {Scheme 8). Suitable acids are any strong mineral acids, preferably HC1, HBr or H₂S0₄. As the strong bases, for example, hydroxides of alkali metals or alkaline earth metals can be used, preferably LiOH, NaOH, KOH and Ba(OH)₂. Further, also some carbonates, preferably Na₂C0₃ and K₂C0₃.

(S)-2aa (S)-2ba (SH

Scheme 8

In both the above mentioned cases (use of acids or bases), the reactions can be conducted in a wide temperature range, preferably at the temperatures from 50 to 150°C, depending on the used agent and solvent. As the solvents, for both the approaches mainly protic polar solvents can be used, including water, or their mixtures with aprotic polar solvents, preferably, e.g., with ethers such as dimethoxyethane, tetrahydrofuran and dioxane. Suitable protic solvents are: a) water; b) alcohols of the general formula R OH, wherein R⁴ stands for any Ci-Cg alkyl (branched as well as unbranched); c) diols of the general formula HO-R⁵-OH, wherein R^s stands for (CHR⁶)_n, wherein n = 2-4 and R⁶ independently stands for H, a C_rC₃ alkyl or CH₂OH; d) diols of the general formula HO-R⁵-OH, wherein R⁵ stands for [(C]¾)n Z(CH2)n]m, wherein independently: n = 1-4, m = 1-4 and Z stands for O, S or NR⁷, wherein R⁷ is H or any Ci-C₈ alkyl, possibly substituted by another hydroxy group; e) liquid carboxylic acids of the general formula R⁸COOH, wherein R⁸ stands for H or any C_\- Cg alkyl. Out of the above mentioned protic solvents, especially water, methanol, ethanol, propanols, butanols, ethylene glycol, propylene glycols, diethanolamine and triethanolamine can be advantageously used.

In the case of the carbamate (S)-2aa, other specific agents can also be used for its transformation to the free amine (S)-l, such as trialkyl halo silanes of the general formula (R⁹)₃SiX, wherein R⁹ independently represents a Ci-C₆ alkyl and X may be Cl, Br or I. Especially, trimethyl silyl iodide MesSil (TMSI) can be preferably used; the reaction itself can be conducted in various polar solvents, preferably in dichloromethane or in acetonitrile.

The invention is clarified in a more detailed way using the examples below. These examples, which illustrate the improvement of the procedure in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.

Experimental part

General:

The chemical purity of all the said compounds was determined by means of high- performance liquid chromatography (HPLC equipped with a UV/VIS detector). The analyses were conducted in an XSelect® HSS C18 SB column (100x4.6 mm; 2.5 μηι stationary phase) using an acetonitrile/10 mM phosphate buffer mixture (pH = 2.5) as the mobile phase (temperature 45 °C; flow 0.8 ml/min; detection at 230 run).

The chiral purity (general stereometric purity) of all the said compounds was determined by means of high-performance liquid chromatography (HPLC equipped with a UV/VIS detector). The analyses were conducted in a Chiracel® OZ-3 column (150x4.6 mm; 3 μιη stationary phase) using a hexane/ethanol 75:25 mixture as the mobile phase (temperature 35 °C; flow rate 1.2 ml/min; detection at 280 nm).

The term "laboratory temperature" refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C. Unless indicated otherwise, the term "equivalent" (or abbreviated "equiv.") always means "molar ratio" in the text and tables below. The indication ee means "enantiomeric excess" (in percent) of a pure isomer (R or S) in its mixture with the racemate (RS) mixture, and its calculation is based on the equation: ee = (\R - S\)/(R + S)- 100 = \%R -%S\ [%].

Abbreviations and names of the chemical compounds:

(rac)-l 1 -(3 -Emoxy-4-memoxyphenyl)-2-(memylsulfonyl)-ethyl-amine

(iS)-l (5)- 1 -(3-Emoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine

(if )-l (R)- 1 -(3 -Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine

2aa Methyl ( 1 -(3 -ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl)ethyl)carbamate

(5)-2aa Methyl (S)-(l -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)- carbamate

(S)-2ba (5)-N-(l-(3-emoxy-4-memoxyphenyl)-2-(memylsulfonyl)-ethyl)-2- methoxyacetamide

Novozym 435 Lipase B from Candida antarctica yeast (E.C. 3.1.1.3; CAL-B) immobilized on methacrylate polymer (>5000 U/g).

TMSI Trimethyl silyl iodide

DMC Dimethyl carbonate

MeTHF 2-Methyltetrahydrofuran

MTBE /-Butyl methyl ether

CPME Cyclopentyl methyl ether

Examples

Example 1

Methyl (5 -( 1 -(3 -emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (5)-2aa

0.13 g (0.48 mmol) of the racemic amine {rac)-\ is suspended in a mixture of CPME (0.4 ml) and dimethyl carbonate (0.1 ml). Novozym 435 (60 mg) is added to the white suspension and the mixture is maintained at a temperature of 85-90°C, being moderately stirred. After 43 hours, the reaction mixture contains 44% of the starting amine 1 and 53% of the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced pressure. The concentrated product is stirred up in 2M aqueous HC1 and extracted with 2 x 3 ml of dichloromethane. The combined organic extracts are concentrated. The process provides 75 mg of the carbamate 2aa (47%) containing 92% of (S)-2aa.

Example 2

Methyl (S)-(l-(3-emoxy-4-memoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)~l is suspended in a mixture of CPME (0.4 ml) and dimethyl carbonate (0.1 ml). Novoz m 435 (60 mg) and 5% Pd on CaC0₃ (16 mg) are added to the white suspension. The mixture is maintained at 80°C, being moderately stirred. After 24 hours, the reaction mixture contains 45% of the starting amine 1 and 53% of the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced pressure. The concentrated product is stirred up in 2M aqueous HC1 and extracted with 2 x 3 ml of dichloromethane. The combined organic extracts are concentrated. The process provides 75 mg of the carbamate 2aa (47%) containing 82% of (5)-2aa.

Examples 3-7

Methyl (5)-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (S)-2aa The procedure described in Example 1 was precisely repeated in the subsequent experiments. All, and the only, changes (solvent type, temperature, reaction time, or addition of a catalyst) are specified in Table 1. Table 1. ^a Content of the carbamate 2aa in the reaction mixture (according to HPLC);

* Content of (S)-2aa in the isolated carbamate 2aa (according to HPLC).

Example 8

Methyl (5)-( 1 -(3-emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (5)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)-\ is suspended in dimethyl carbonate (0.5 ml). Novozym 435 (60 mg) is added to the white suspension. The mixture is maintained at 70°C, being moderately stirred. After 40 hours, the reaction mixture contains 25% of the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced pressure. The concentrated product is stirred up in 2M aqueous HC1 and extracted with 2 x 3 ml of dichloromethane. The combined organic extracts are concentrated. The process provides 35 mg of the carbamate 2aa (22%) containing 92% of (.S)-2aa.

Example 9

Methyl (<S)-(1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)-l is suspended in dimethyl carbonate (0.5 ml). Novozym 435 (60 mg) is added to the white suspension. The mixture is maintained at 90°C, being moderately stirred. After 18 hours, the reaction mixture contains 44% of the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced pressure. The concentrated product is stirred up in methanol (5 ml). The white crystalline product is aspirated and dried. The process provides 44 mg of the carbamate 2aa (28%) containing 92% of (S)-2aa.

Example 10

Methyl (5)-(l-(3-emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbaniate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)-l is suspended in dimethyl carbonate (0.5 ml). Novozym 435 (100 mg) is added to the white suspension. The mixture is maintained at 90°C, being moderately stirred. After 5 hours, the reaction mixture contains 46% of the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced pressure. The concentrated product is stirred up in methanol (5 ml). The white crystalline product is aspirated and dried. The process provides 40 mg of the carbamate 2aa (25%) containing 97% of (S)-2aa. Example 11

Methyl (5 -(l-(3-emoxy-4-memoxyphenyl)-2-(methylsulfonyl)ethyl)carbarnate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine {rac)-\ is suspended in dimethyl carbonate (0.5 ml). Novozym 435 (100 mg) and 52 mg (0,048 mmol) of the racemization catalyst 7a are added to the white suspension (Figure 4). The mixture is maintained at 90°C, being moderately stirred. After 5 hours, the reaction mixture contains 90% of the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced pressure. The concentrated product is stirred up in methanol. The white crystalline product is aspirated and dried. The process provides 108 mg of the carbamate 2aa (68%) containing 97% of(S)-2aa.

Example 12

(S)-N-( 1 -(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2-methoxyacetamide (S)- 2ba

50 mg of Novozym 435, 20 ml of CPME; 0.87 ml (8.757 mmol) of methyl methoxy acetate 5aa are added to 0.342 g (1.251 mmol) of the racemic amine (rac)-l and the reaction mixture is stirred at 105 °C for 37 h. The resulting mixture containing 48% of the respective amide 2ba is filtered, concentrated at a reduced pressure on an evaporator and the product is isolated with the use of column chromatography on silica gel (an ethyl acetate/hexane mixture as the mobile phase). The process provides 199 mg (46%) of the crystalline compound (S)-2ba with the chiral purity of ee 97% and chemical purity of 99.3% (HPLC). Example 13

{S)-N-( 1 -(3 -emoxy-4-memoxyphenyl)-2-(memylsulfonyl)-ethyl)-2-methoxyacetamide (5)- 2ba

50 mg of Novoz m 435, 20 ml of CPME and 0.121 ml (8.757 mmol) of isopropyl methoxy acetate Sab are added to 0.342 g (1.251 mmol) of the racemic amine {rac)-\ and the reaction mixture is stirred at 105°C for 37 h. The resulting mixture containing 47% of the respective amide 2ba is filtered, concentrated at a reduced pressure on an evaporator and the product is isolated with the use of column chromatography on silica gel (an ethyl acetate/hexane mixture as the mobile phase). The process provides 194 mg (45%) of the crystalline compound (S)-2ba with the chiral purity of ee 95% and chemical purity of 99.2% (HPLC).

Example 14

(S)-N-(l-(3-emoxy-4-memoxyphenyl)-2-(^ (S)- 2ba

50 mg of Novozym 435, 136 mg (0.1251 mmol) of the racemization catalyst 7a {Figure 4), 20 ml of CPME and 0.87 ml (8.757 mmol) of methyl methoxy acetate 5aa are added to 0.342 g (1.251 mmol) of the racemic amine (rac)-l. The reaction mixture is stirred at 105°C for 37 h. The resulting mixture is filtered, concentrated at a reduced pressure on an evaporator and the product is isolated with the use of column chromatography on silica gel (an ethyl acetate/hexane mixture as the mobile phase). The process provides 346 mg (80%) of the crystalline compound (5)-2ba with the chiral purity of ee 91% and chemical purity of 99.4% (HPLC). Example 15

(S)-N-( 1 -(3 -ethoxy-4-methoxyphenyl)-2-(memylsulfonyl)-emyl)-2-methoxyacetamide (5)- 2ba 50 mg of Novoz m 435, 136 mg (0.1251 mmol) of the racemization catalyst 7b

(Figure 4), 20 ml of CPME and 0.87 ml (8,757 mmol) of methyl methoxy acetate 5aa are added to 0.342 g (1.251 mmol) of the racemic amine (mc)-l. The reaction mixture is stirred at 105°C for 37 h. The resulting mixture is filtered, concentrated at a reduced pressure on an evaporator and the product is isolated with the use of column chromatography on silica gel (an ethyl acetate/hexane mixture as the mobile phase). The process provides 389 mg (90%) of the crystalline compound (S)-2ba with the chiral purity of ee 97% and chemical purity of 99.4% (HPLC).

Example 16

(S)- 1 -(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (S)-l

0.5 g of triethanolamine and 0.5 ml of a 50% (by weight) aqueous solution of NaOH are added to 345 mg (1 mmol) of the amide (5)-2ba from Example 15. The mixture is gradually heated up in a flask to 120°C and at this temperature the heating and stirring continues for another 6 hours. After cooling to the laboratory temperature the reaction mixture is diluted with water (5 ml) and extracted with toluene (3 5 ml). The combined toluene phases are washed with water (2 5 ml) and salt brine (1 5 ml). After evaporation at a reduced pressure on an evaporator the amount of 243 mg (89%) of the crystalline amine (S)-l is obtained with the chiral purity of ee 97% and the chemical purity of 99.7% (HPLC).

Example 17

(5)-l -(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine

2 ml of ethylene glycol and 0.5 ml of a 50% (by weight) aqueous solution of KOH are added to 331 mg (1 mmol) of the carbamate (5)-2aa obtained according to the process of Example 11. The mixture is heated in a flask at 100°C for 12 hours. After cooling to the laboratory temperature the reaction mixture is diluted with water (10 ml) and extracted with MTBE (3 x 5 ml). The combined ether phases are washed with water (2 x 5 ml) and salt brine (1 5 ml). After evaporation at a reduced pressure on an evaporator the amount of 249 mg (91%) of the crystalline amine (S)-l is obtained with the chiral purity of ee 92% and the chemical purity of 99.5% (HPLC).

Example 18

(5 -l-(3-Emoxy-4-methoxyphenyl)-2-(memylsulfonyl)-emyl-amine (S)-l

215 μΐ TMSI (1.5 mmol) are added to a solution of 331 mg (1 mmol) of the carbamate (S)-2aa obtained with the use of the process of Example 11 in 10 ml of dry DCM and the mixture is heated up to boil for 12 hours. The reaction mixture is then concentrated at a reduced pressure on an evaporator, diluted with water (10 ml) and after neutralization with a 1M aqueous solution of NaOH it is extracted with MTBE (3 x 5 ml). The combined ether phases are washed with water (2 5 ml) and salt brine (1 x 5 ml). After evaporation at a reduced pressure on an evaporator the amount of 211 mg (77%) of the crystalline amine (S)-l is obtained with the chiral purity of ee 94% and the chemical purity of 99.7% (HPLC).

Example 19

(jS)-l-(3-Emoxy-4-memoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (S)-l

2 ml of a commercial solution of HBr in acetic acid (33% solution - by weight) are added to 331 mg (1 mmol) of the carbamate (S)-2aa obtained with the use of the process of Example 11 and the mixture is stirred at 25 °C for 24 hours. The reaction mixture is concentrated at a reduced pressure on an evaporator, diluted with water (10 ml) and after neutralization with a 1M aqueous solution of NaOH it is extracted with MTBE (3 x 5 ml). The combined ether phases are washed with water (2 x 5 ml) and salt brine (1 5 ml). After evaporation at a reduced pressure on an evaporator the amount of 257 mg (94%) of the crystalline amine (S)-l is obtained with the chiral purity of ee 94% and the chemical purity of 99.2% (HPLC). Example 20

(S)- { 2- [ 1 -(3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-acetylaminoisoindoline- 1,3- dione (3) 137 g (0.5 mmol; 97% ee) of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)- ethylamine (S)-l (see Example 16), 108 mg (0.525 mmol) of 3-acetamidophthalic anhydride 4 and 5 ml of glacial acetic acid were charged into a 25ml flask. The mixture was refluxed overnight and then cooled down to the laboratory temperature. Then, the mixture was concentrated at a reduced pressure and the residue was dissolved in 25 ml of ethyl acetate. The obtained solution was washed with water (2 x 5 ml), saturated aqueous solution of NaHCC^«3 (2 x 5 ml), salt brine (2 x ml) and dried with sodium sulfate. The solvent was evaporated at a reduced pressure and the rest was crystallized from a mixture of ethanol / acetone 2:1 (by volume). The separated crystals were isolated by filtration on frit, washed with ethanol and dried at a reduced pressure (0.5 kPa) at 60°C. The process provided 194 mg otApremilast 1 (yield 84%, 97% ee, HPLC 99.8%)

Example 21

(S)- { 2- [ 1 -(3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-acetylaminoisoindoline- 1,3- dione (3)

1.21 g (4.43 mmol; 97% ee) of (S)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine (S)-l (obtained using the process of Example 16), 954 mg (4.65 mmol) of 3-acetamidophthalic anhydride 4 and 18 ml of glacial acetic acid were charged into a 50ml flask. The mixture was refluxed for 3 h and cooled down to 20°C. After that, 35 ml of water was gradually added, under continuous stirring the mixture was inoculated with crystals of Apremilast 3 (10 mg) and stirred at 20°C for another 15 hours. The separated crystals were aspirated, washed with a mixture of acetic acid - water (volume ratio 2:5) and dried at a reduced pressure. The amount of 1.875 g of yellowish crystals of the product 3 was obtained (yield 92%, 98% ee, HPLC 99.1%).

Claims

1. A process for preparing apremilast, (S)~{2-[l-(3-ethoxy-4-methoxyphenyl)-2- memylsmfonylethyl]-4-acetylaniinoisoindoline-l,3-dione of formula 3

characterized in that it comprises a reaction of the racemic amine of formula (mc)-l

wherein Me is methyl and Et is ethyl, with N-acyl donors of formula 5

wherein R is H, a Ci-Cig alkyl, C6-Q4 aryl or Ci-Cg heteroaryl with one or more heteroatoms, or a C1-C18 alkoxy group, wherein all said groups can be further substituted by any functional groups; the donor is OH, any C_t-Cig alkoxy, C1-C9 aryloxy, CrQs alkylthio group or a Cj- Ci8 acyloxy group;

in the presence of an enzyme from the group of hydrolases, preferably in the presence of a racemization catalyst,

which produces either (i) directly the chiral amine of formula (S)-i,

or (ii) iV-acylated amine of formula (S)-2,

((^-2) which is converted, by treatment with a base or an acid in the presence of a solvent, to the chiral amine (S)-l, wherein the amine (S)-l obtained in step (i) or (ii) is further subjected to a reaction with 3-acetamidophthalic anhydride of formula 4,

thus producing apremilast of formula 3.

2. The process according to claim 1, characterized in that the N-acyl donor is selected from esters of carboxylic acids of formula 5a, carboxylic acids of formula 5b, anhydrides of carboxylic acids of formula 5c or derivatives of carbonic acid of formula 5d, preferably in the form of esters of carboxylic acids of formula 5a and derivatives of carbonic acid of formula 5d, wherein ^l, R², R³ are independently H, except formulae 5c and 5d, a Q-Cis alkyl, aryl or heteroaryl with one or more heteroatoms, wherein all these groups may also by further substituted by any functional groups.

3. The process according to claims 1 and 2, characterized in that the N-acyl donor is an ester of carboxylic acids of formula 5a and is selected from methyl methoxyacetate, isopropyl methoxyacetate, ethyl acetate, isopropyl acetate, vinyl acetate, isopropenyl acetate or ethyl trifiuoroacetate, preferably methyl methoxyacetate.

4. The process according to claims 1 and 2, characterized in that the N-acyl donor is a derivative of carbonic acid of formula 5d, selected from dimethyl carbonate, diethyl carbonate or dibenzyl carbonate, preferably dimethyl carbonate.

5. The process according to claims 1-4, characterized in that the enzyme from the group of hydrolases is selected from lipases, esterases or peptidases, which are free or immobilized on solid carriers, the enzyme preferably being Novozym 435, i.e. lipase B from Candida Antarctica yeast, preferably bound to polymers of the acrylate type, Subtilisin or Penicilin-G amidase.

6. The process according to claims 1-5, characterized in that the reaction of the racemic amine of formula (rac)-l with the N-acyl donor of formula 5 is carried out in the presence of a racemization catalyst, which is a transition metal, selected from Ru, Ir, Pd, Pt or Rh, which is free or adsorbed on a carrier, selected from active carbon, aluminium oxide and calcium carbonate, or said catalyst is complexes of transition metals selected from Ru, Ir, Pd, Rh or V, preferably complexes of transition metals, especially the Shvo catalysts.

7. The process for preparing apremilast according to any one of the preceding claims, characterized in that it comprises a reaction of the racemic amine of formula (rac)-i with dimethyl carbonate under treatment with Novozym 435, preferably in the presence of a racemization catalyst, producing methyl-(S)-(l-(3-ethoxy-4-methox phenyl)-2- (methylsulfonyl)ethyl)carbamate of formula (S)-2aa.

8. (iS -(l-(3-emoxy-4-memoxyphenyl)-2-(memylsulfonyl)emyl)carbam (S)-2aa.

9. The process for preparing apremilast according to any one of the preceding claims, characterized in that it comprises a reaction of the racemic amine of formula (rac)-l with methyl methoxyacetate or isopropyl methoxyacetate under treatment with Novozym 435, preferably in the presence of a racemization catalyst, producing (5 -iV-(l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl)-2-methoxyacetamide of formula (S)-2ba.

10. (S)-N-( 1 -(3 -emoxy-4-methoxyphenyl)-2-(memylsulfonyl)-e1ihyl)-2-methoxyacetamide (S)-2ba.

11. Use of (5)-(l-(3-ethoxy-4-methoxyphenyi)-2-(methylsulfonyl)ethyl)carbamate of formula (S)-2aa or ^5)-N-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2- methoxyacetamide of formula (5)-2ba for the preparation of apremilast.

12. The process for preparing apremilast according to claims 1-7 and 9, characterized in that the N-acyled amine of formula (5)-2 is converted, in the presence of a solvent, to the free amine (5)-l by treatment with an acid selected from hydrochloric, hydrobromic, and sulfuric acid, or a base selected from LiOH, KOH, NaOH, Ba(OH)₂, Na₂C0₃, and K₂C0₃.

13. The process according to claim 12, characterized in that the N-acyled amine of formula (S)-2 is selected from methyl-(5)-(l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl)carbamate or (S)-N-( 1 -(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethyl)-2-methoxyacetamide.

14. The process for preparing apremilast according to claims 1 to 7, 9 and 12, characterized in that the solvent is selected from protic polar solvents such as water, CI -8 alcohols, diols, C1-C8 carboxylic acids or their mixtures with aprotic polar solvents selected from ethers such as dimethoxyethane, THF and dioxane, a preferred solvent being water, methanol, ethanol, ethylene glycol, propylene glycol, diethanolamine, dimethoxyethane, THF, dioxane or their mixtures.

15. The process according to any one of claims 1 to 7, 9 and 12 to 14, characterized in that the reaction of the amine of formula (S)-l with 3-acetamidophthalic anhydride of formula 4 is conducted in the presence of water, an organic solvent, or their mixtures, said organic solvent being preferably selected from the group comprising C2-C5 carboxylic acids, especially acetic acid, nitriles of C2-C5 carboxylic acids, especially acetonitrile, and polar aprotic solvents such as dimethyl foraiamide, dimethyl acetamide, dimethyl sulfoxide, and further hydrocarbons, preferably e.g. toluene, xylenes, α,α,α-trifluorotoluene, chlorobenzene and n-butyl chloride.

16. The process for preparing apremilast according to claim 1, characterized in that it comprises a reaction of the racemic amine (rac)-l with dimethyl carbonate, under treatment with Novozym 435, producing methyl (S)-(l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl)carbamate of formula (iS)-2aa, preferably in the presence of a racemization catalyst, , the resulting carbamate being converted, with the use of hydrobromic acid in the presence of acetic acid, to the chiral amine of formula (S -l, which provides, through the subsequent reaction with 3-acetamidophthalic anhydride of formula 4 in glacial acetic acid, the desired (S)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindolin-l,3-dione of formula 3.