CZ2016226A3 - A method of preparing a THF solvate of apremilast and an amorphous apremilast - Google Patents

Abstract

Process for preparing a solvate of apremilast with tetrahydrofuran of formula I, comprising the reaction of (S) -1- (3-ethoxy-4- methoxyphenyl) -2- (methylsulfonyl) -ethylamine of formula (5) -3 with 3-acetamidophthalic anhydride of formula 5 in admixture tetrahydrofuran and acid or diastereomeric reaction (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) - tartaric acid ethylamine or derivatives thereof of formula (S-6) with a base to form (Y) -1- (3-ethoxy-4- methoxyphenyl) -2- (methylsulfonyl) -ethylamine of formula (5) -3 and its reaction with 3-acetamidophthalate hydride of formula 5 in a mixture of tetrahydrofuran and acid.

Description

A process for preparing the THF solvate of apremilast and amorphous apremilast

Technical field

The invention relates to a novel process for the preparation of (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione solvate with tetrahydrofuran of formula 1.

NHAc which can be advantageously subsequently used for the preparation of amorphous apremilast (1).

BACKGROUND OF THE INVENTION

Apremilast (Formula 2) is an orally available phosphodiesterase 4 (PDE4) inhibitor that inhibits spontaneous production of tumor necrosis factor α (TNF-α) and thus exhibits anti-inflammatory activity. It can be used in the treatment of psoriatic arthritis and is also tested in the treatment of other inflammatory diseases.

Et

NHAc

Apremilast was first described as a racemic mixture of pharmaceutically active substances (WO00025777 A1; EP 1752148 B) prepared by refluxing amine 3 with anhydride 5 in acetic acid (Scheme 1).

(rac) -2

Scheme 1

A few years later, a particular enantiomer, (the S1-isomer commonly referred to as apremilast, which possesses its own biological activity), was described in WO03080049.

WO03080049 describes a process for chiral resolution of racemic amine 3 by N-acetyl-Z-leucine. The resulting diastereoisomeric salt 4 is then refluxed in acetic acid overnight with anhydride 5 and apremilast (2) was obtained in 75% yield. (Scheme 2).

N-Ac-L-leucine

44% ee

Scheme 2

Form B was obtained by experiment according to the example. This is described in WO2009120167 by X-ray powder diffraction and thermal methods, which also mentions forms A, C, D, E, F, G and amorphous form, wherein forms A, B and F are described as pure polymorphic forms and forms C, D, E, G as solvates (form C - toluene, form D dichloromethane, form E - acetonitrile, form G - ethyl acetate). Patent application WO2009120167 mentions the formation of another form, Form H, in the specification, but does not provide any further details.

Patent Application PV 2015-277 discloses Form 1-1. This form is a solvate with tetrahydrofuran, and a 1: 0.5 molar apremilast / THF ratio was found from ¹ H NMR measurements.

····· · · · · · · · · · · · · · ·

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -

2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione with tetrahydrofuran (1) comprising reacting either amine (S) -3 with anhydride 5 or a process comprising reacting the diastereoisomeric salt of (S) -amine and tartaric acid or derivatives thereof (5) -6) wherein R and R are independently H, C 1 -C 12 alkyl, aryl or heteroaryl having one or more heteroatoms, all of which may be further substituted with any of the functional groups with a base such as an alkali hydroxide or alkali carbonate, preferably sodium carbonate or potassium carbonate, to give the free amine (S) -3, which is subsequently reacted with anhydride 5 in tetrahydrofuran / C 2 -C 5 carboxylic acid. For the purposes of the present invention, "any functional group" means: (a) halogens, (b) hydroxy, alkoxy or aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups (i.e. ketones), (e) ) carboxylic acid derivatives. Derivatives wherein R ¹ and R ² are independently of each other acyl groups RC (= O), wherein R is C 1 -C 11 alkyl, C 6 -C 14 aryl, heteroaryl with one or more heteroatoms, all of which may be advantageously used they may be further substituted with any functional groups. The group Y in derivatives 6 may then be hydroxyl OH, O- substituted hydroxyl OR ⁴ , where R ⁴ is any C 1 -C 6 alkyl, C 6 -C 14 aryl, heteroaryl with one or more heteroatoms, all of which may be further substituted with any functional groups. The group Y in derivatives 6 furthermore denotes the amides NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ independently of one another are H, C 1 -C 16 alkyl, C 6 -C 14 aryl, heteroaryl having one or more heteroatoms, all of which may further be substituted with any functional groups, preferably C6-C14 aryl-substituted halogens at any position (Scheme 3).

• ·

(S) -3

RCOOH / THF

1.bázy

R ¹ , R ² = H, C 1 -C ₁₆ alkyl, aryl, heteroaryl. IN Y = OH, OR ^4, NR ⁵ R ⁶ 0 (5-6) Scheme 3

The obtained THF solvate (1) is easy to prepare, stable, excels in high crystallinity and can advantageously be used for the preparation of high purity apremilast with HPLC purity above 99.9%. It can also easily be used to prepare amorphous apremilast (2).

Detailed description of the invention

The present invention provides a process for preparing a solvate of (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) 2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione with tetrahydrofuran (1) comprising either the reaction of an amine (0) -3 with anhydride 5 in tetrahydrofuran / C2-C5 carboxylic acid, preferably tetrahydrofuran / acetic acid, or a process comprising first reacting the diastereoisomeric salt of the amine and tartaric acid or derivatives thereof (5-6) with a base, preferably (?, 7?) -4-chlorotartranilate (5-6a) or (R, R) -O,? 9'-di -? - toluoyl tartrate (5-6b) is then used to give the free amine ( S) -3, which is subsequently reacted with anhydride 5 in a tetrahydrofuran / C2-C5 carboxylic acid mixture, preferably a tetrahydrofuran / acetic acid mixture (Scheme 4). The volume ratio of acetic acid / tetrahydrofuran is preferably 1: 1 to 1: 7, preferably 1: 1.85.

• ·

(S-6b)

Scheme 4

If diastereoisomeric salts with tartaric acid (S-6a) or (5-6b) are used, the reaction can also be carried out without isolation of the amine (S) -3. The use of new and mild conditions for the reaction with anhydride 5 allows the preparation of very pure apremilast having high HPLC purity (> 99.99%), the product being isolated as 1-1 in a high yield of 7887%. The thus prepared apremilast THF solvate (1) exhibits high crystallinity, stability and cleansing ability and can serve as a convenient source for the preparation of amorphous apremilast (2). This can be prepared by precipitation into an antisolvent, preferably water or an organic solvent selected from MTBE or heptane, drying at temperatures of 60-100 ° C, or spray drying from a solution with methanol, ethanol, dichloromethane or acetone.

The advantages of the process according to the invention are easy execution, simple processing, high yield, low number of operations and high purity of the already crude product.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives according to the invention, are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Process for the preparation of apremilast - (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione (2)

A 500 mL three neck flask was equipped with a mechanical stirrer, thermometer, and condenser. To the reaction vessel was charged 25 g (56 mmol) of (S) -2- (3-ethoxy-4-methoxyphenyl) -1 (methylsulfonyl) -eth-2-ylamine salt with N-acetyl-L-leucine, 12.1 g ( 58.8 mmol) of 3-acetamidophthalic anhydride and 250 ml of glacial acetic acid. The mixture was refluxed overnight and then cooled to <50 ° C. The solvent (250 mL of acetic acid) was removed in vacuo and the residue of a deep yellow color was dissolved in 800 mL of ethyl acetate. The resulting solution was washed with water (2 x 250 mL), saturated aqueous NaHCO 3 (2 x 250 mL), brine (2 x 250 mL) and dried over sodium sulfate. The solvent (800 mL ethyl acetate) was evaporated in vacuo and the residue was recrystallized from a binary solvent containing 150 mL ethanol and 75 mL acetone. The solid was collected by vacuum filtration and washed with 2 x 100 mL ethanol. The product was dried under vacuum at 60 ° C to constant weight to give 19.1 g of the title compound; yield 74%, HPLC purity 99. 29%, XRPD confirmed Form B.

Example 2

Preparation of the THF solvate of (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione (1)

11.0 g (40.241 mmol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine (S) -3 and

8.65 g of (3-acetamidophthalic anhydride (42.253 mmol) 5) was refluxed for 21 h in a mixture of 8 mL of AcOH and 50 mL of THF, then the reaction mixture was gradually cooled to 26 ° C, seeded, then slowly cooled to 0 ° C and stirred overnight. The resulting product was filtered off, washed with ice-cold MTBE and dried at 40 ° C under vacuum to give 16.56 g of a white crystalline solid in 83% yield, HPLC 99.99%, NMR apremilast / THF 1: 0.5, XRPD -THF solvate.

Example 3

Preparation of (5) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione THF solvate (1)

11.0 g (40.241 mmol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine (S) -3 and

8.65 g (42.253 mmol) of 3-acetamidophthalic anhydride 5 was refluxed for 21 h in a mixture of 8 ml of butyric acid and 50 ml of THF. Then the reaction mixture was gradually cooled to 26 ° C, seeded, then slowly cooled to 0 ° C and stirred overnight. The precipitated product was filtered off, washed with ice-cold MTBE and dried at 40 ° C under vacuum. 15.52 g of a white crystalline solid were obtained; yield 78%, HPLC 99.2%, NMR apremilast / THF 1: 0.5, XRPD THF solvate.

Example 4

Preparation of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethylamine (S) -3

To the reactor was charged 192.0 g (1.389 mol) of K 2 CO 3 and 3180 ml of demi water. After dissolution, 600.0 g (1.126 mol) of (R /?) - 4-chlortartranilátu (5 ^R) -l- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine (5-6a), and subsequently 3000 mL CH2Cl2. The resulting mixture was stirred vigorously at 30-33 ° C for about 30 min. The organic phase was separated and the aqueous phase was extracted sequentially with 1 x 1500 mL CH 2 Cl 2 (30-33 ° C) and then 1 x 900 mL CH 2 Cl 2 (30-33 ° C). The combined dichloromethane phases were concentrated to a volume of about 1400-1600 mL, followed by 2400 mL of THF. Then, about 2300 ml of solvent was distilled off at atmospheric pressure, the mixture was cooled to 60 ° C and 500 ml of MTBE was added. The mixture was then cooled gradually to -10 ° C over 1.5 h, seeded and stirred for an additional 1.5 h at -10 ° C. The precipitated product was filtered off, washed with 2 x 120 ml of cold THF and dried in 4 ml of THF.

..... ··· · ····· Vacuum dryer at 45-50 ° C. 254.5 g (83%) of white crystals of the title compound of formula (5) -3 were obtained.

Example 5

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

600 g (2.195 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethylamine (S) -3 and 468 g (2.281 mol) of 3-acetamidophthalic anhydride (5) were refluxed 4 h in a mixture of 1200 ml acetic acid and 2220 ml THF. Then the reaction mixture was gradually cooled to 40 ° C and 2100 mL of MTBE was added. At 30 ° C the mixture was seeded and then cooled to -5 ° C over 1.5 h and stirred for a further 2 hours at -5 ° C. The precipitated product was filtered off, washed with 3 x 850 ml ice-cold MTBE and dried at 40-45 ° C under vacuum. 964.3 g of white crystals of the title compound were obtained; yield 87%, HPLC> 99.99%, NMR apremilast / THF 1: 0.6 XRPD THF solvate.

Example 6

Preparation of the (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione THF solvate (1)

96.0 g (0.695 mol) of K 2 CO 3 and 1590 ml of demi water were charged to the reactor. After dissolution, 300.0 g (0.563 mol) of (R, R) -4-chlorotartranilate (S) -1- (3-ethoxy-4-methoxyphenyl) -2 (methylsulfonyl) ethylamine (5-6a) was added followed by 1500. The resulting mixture was stirred vigorously at 30-33 ° C for about 30 min. The organic phase was separated and the aqueous phase was extracted with 2 x 750 mL of CH ₂ Cl ₂ (30-33 ° C). The combined dichloromethane phases were concentrated under reduced pressure to a volume of about 450-480 mL, then 660 mL of THF was added and the remainder of CH ₂ Cl _{2 was} removed by distillation under reduced pressure. Thereafter, 110.7 g (0.540 mol) of 3-acetamidophthalic anhydride (5), 240 ml of acetic acid was added to the reaction mixture, and the reaction mixture was refluxed for 45 h. After cooling to 40 ° C, 600 ml of MTBE were added dropwise. The mixture was seeded at 28-30 ° C, cooled to -8 ° C over 2 h and stirred for a further 2 h at -8 ° C. The precipitated white crystalline solid was filtered off, washed with 3 x 150 ml cold MTBE and dried at 40-45 ° C under vacuum. 223.59 g of the title compound of formula 1 were obtained; yield 83%, HPLC> 99.99%, NMR apremilast / THF 1: 0.5, XRPD THF solvate.

Example 7

Preparation of (5) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione THF solvate (1)

9.6 g (0.0695 mol) of K 2 CO 3 and 159 ml of demi water were charged to the reactor. After dissolution, 38.04 g (0.0563 mol) of (R, R) -di-p-toluoyl-tartrate (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethylamine (S-) were added. 6b) followed by 150 ml of CH 2 Cl 2. The resulting mixture was stirred vigorously at 30-33 ° C for about 30 min. The organic phase was separated and the aqueous phase was extracted with 2 x 75 mL of CH 2 Cl 2 (30-33 ° C). The combined dichloromethane phases were concentrated under reduced pressure to a volume of about 45-48 mL, followed by the addition of 66 mL of THF and the residue CH 2 Cl 2 was distilled off under reduced pressure. Then, 11.07 g (0.0540 mol) of 3-acetamidophthalic anhydride (5), 24 ml of acetic acid was added to the reaction mixture, and the reaction mixture was refluxed for 4-5 hours. After cooling to 40 ° C, 60 ml of MTBE were added dropwise. The mixture was seeded at 28-30 ° C, cooled to -8 ° C over 2 h and stirred for a further 2 h at -8 ° C. The precipitated white crystalline solid was filtered off, washed with 3 x 15 ml cold MTBE and dried at 40-45 ° C under vacuum. 21.26 g of the title compound of formula 1 were obtained; yield 79%, HPLC 99.95%, NMR apremilast / THF 1: 0.5, XRPD THF solvate.

Example 8

Preparation of amorphous apremilast, (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] 4-acetylaminoisoindoline-1,3-dione (2) G (S) - {2- [l- (3) • · (((((((g (g g g -ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-

1,3-dione · ‘/ zTHF (1) was dissolved in 120 ml acetone and the resulting solution was filtered. Then, the filtrate was added dropwise to ice water (0 ° C) over 15 minutes and stirred at 05 ° C for 15-20 minutes. The resulting amorphous was filtered off, washed with 50 ml of cold water, dried on a frit and then in an oven at 40 ° C under vacuum. 33.9 g of the title compound were obtained in amorphous form; yield 91%, HPLC 99.99%, XRPD amorphous form.

Example 9

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

50.0 g of (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-

1,3-dione-ATHF (1) was suspended in 200 ml acetone. The mixture was allowed to warm to 35-40 ° C with stirring and after hot dissolution filtered through a 0.20.4 µm filter. The clear filtrate at 25-30 ° C was added dropwise in 30-35 min to pre-cooled heptane (1200 mL) at 0 to -3 ° C. The temperature was maintained between -3 and + 2 ° C during the addition. The precipitate was further stirred for 15-20 min at 0 ° C. The slightly yellowish substance was filtered off and then washed with 1x50 ml cold heptane. The product was dried in a vacuum oven at 35-45 ° C for 12-24 h. 40.2 g of amorphous material was obtained; yield 87%, HPLC impurity <0.03%, optical purity <0.05%, XRPD amorphous form.

Example 10

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

20.0 g (5) - ^I {2- [l- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-

1,3-dione · ‘/ iTHF (1) was suspended in 120 ml acetone. The mixture was allowed to warm to 35-40 ° C with stirring and after hot dissolution filtered through a 0.210 porosity filter.

0.4 pm. The clear filtrate at 20-25 ° C was spray dried (Biichi B290, Tin = 65-80 ° C). 18 g of an amorphous substance were obtained; sum of impurities by HPLC <0.03%, optical purity <0.05%, XRPD amorphous form.

Example 11

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

20.0 g of (S) - {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-

1,3-dione / 2THF (1) was suspended in 120 ml methanol. The mixture was allowed to warm to 35-40 ° C with stirring and after hot dissolution filtered through a 0.20.4 µm filter. The clear filtrate at 20-25 ° C was spray dried (Biichi B290, Tin = 65-80 ° C). 18 g of an amorphous substance were obtained; sum of impurities by HPLC <0.03%, optical purity <0.05%, XRPD amorphous form.

Claims (11)

A process for preparing apremilast solvate with tetrahydrofuran (Formula 1) comprising reacting (? S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine of formula (S) -3 with 3? -acetamidophthalic anhydride of formula 5 in a mixture of tetrahydrofuran and an acid or by reaction of the diastereomeric salt of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethylamine with tartaric acid or derivatives of formula (S-6) About me R ¹ , R ² = H, C ₁ -C ₁₆ alkyl, aryl, heteroaryl, Y = OH, OR ⁴ , NR ⁵ R ⁶ (S-6) with a base to give (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl amine of formula (S 1 -) 3 and its reaction with 3-acetamidophthalic anhydride of formula 5 in a mixture of tetrahydrofuran and acid. A process for the preparation of a solvate according to claim 1, characterized in that the acid is selected from a number of organic acids, preferably C 2 -C 5 organic acids, preferably acetic, propionic or butyric acid. A process for the preparation of a solvate according to claim 1 or 2, characterized in that the mixture of acid and tetrahydrofuran is in a volume ratio of 1: 1 to 1: 7, preferably 1: 1.85. A process for the preparation of a solvate according to any one of the preceding claims, characterized in that the diastereomeric salt of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine with tartaric acid is (7,7,7-?). ) -4-chlorotartranilate of formula S-6a or (R, N) -alpha-toluoyl-tartrate of formula Y-6b. (S-6a) 9 (S-6b) A process for the preparation of a solvate according to any one of the preceding claims, characterized in that the base is selected from the series of KOH, NaOH, K ₂ CO ₃ , Na ₂ CO 3, preferably K ₂ CO ₃ or Na ₂ CO 3. A process for preparing apremilast solvate with tetrahydrofuran according to claim 1, comprising reacting (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine of formula (S) -3 with 3- acetamidophthalic anhydride of formula 5 in a 1: 1.85 v / v mixture of acetic acid and tetrahydrofuran. A process for preparing apremilast solvate with tetrahydrofuran according to claim 1, comprising reacting (R, R) -4-chlorotartranilate (S) -1- (3-ethoxy-4-methoxyphenyl) -2 (methylsulfonyl) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethylamine with a base selected from K ₂ CO 3 or Na ₂ -ethylamine or (R, R) - di- N -toluoyl tartrate CO 3 to give (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethylamine of formula (S) 3, which is further reacted with 3-acetamidophthalic anhydride of formula 5 in a mixture of acetic acid and tetrahydrofuran in volume ratio 1: 2.75. A process for preparing apremilast with tetrahydrofuran solvate according to any one of the preceding claims, further comprising preparing amorphous apremilast by precipitation into an antisolvent or organic solvent, by drying at temperatures of 60-100 ° C, or by spray drying. A process for the preparation of a solvate according to claim 8, wherein the antisolvent is water. A process for preparing a solvate according to claim 8, wherein the organic solvent is MTBE or heptane. A process for the preparation of a solvate according to claim 8, characterized in that a suspension of apremilast solvate with tetrahydrofuran in methanol, ethanol, dichloromethane or acetone is used for spray drying.