Method for purifying vilanterol triphenylacetate

Abstract

A method for purifying vilanterol triphenylacetate is provided, and a method for purifying vilanterol triphenylacetate of formula (I) is provided, comprising crystallizing vilanterol triphenylacetate from a ketone solvent selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone and a mixture thereof.

Description

[0001] This application claims the benefit of European patent application EP20382677.1 filed on July 27, 2020. Technical Field

[0002] The present invention relates to a method for purifying vilanterol triphenylacetate. Background Art

[0003] Vilanterol triphenylacetate is the common name for the compound (R)-4-(2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-hydroxyethyl)-2-(hydroxymethyl)phenol 2,2,2-triphenylacetate, which has the following chemical structure:

[0004]

[0005] Vilanterol triphenylacetate is a selective, long-acting beta2-adrenergic agonist. It is administered as a dry powder by inhalation in combination with umeclidinium bromide and / or fluticasone furoate for the treatment of chronic obstructive pulmonary disease (COPD) and asthma.

[0006] Vilanterol triphenylacetate was first disclosed in document WO 2003 / 024439, which discloses a process for crystallizing vilanterol triphenylacetate in ethanol. However, the product obtained has an undesirably high level of impurities.

[0007] Document WO 2014 / 041565 discloses the crystallization of vilanterol triphenylacetate in acetone, resulting in a reduction in impurity levels at the expense of significantly lower yields. Furthermore, acetone is highly flammable, highly reactive, and harmful to human health, so it is not a convenient solvent for industrial applications.

[0008] Document WO 2017 / 001907 discloses a method for preparing vilanterol triphenylacetate, wherein vilanterol tartrate is converted into triphenylacetate by a base (by adding the corresponding acid) in a multi-step process. It is said that the method allows to obtain a product with relatively high purity, in particular a low amount of impurity A of the following formula:

[0009]

[0010] Vilanterol Impurity A

[0011] However, the method is carried out in a mixture of DCM, MTBE and EtOH and requires tedious clean-up.

[0012] Therefore, there is still a need to find new processes that allow the preparation of vilanterol triphenylacetate in high yield and purity and at the same time are easy to apply industrially. Summary of the invention

[0013] The present inventors have discovered a new method for purifying vilanterol triphenylacetate, which overcomes the disadvantages of the methods disclosed in the prior art. Surprisingly, they found that by crystallizing vilanterol triphenylacetate from certain specific ketone solvents, a solid product was obtained in high yield and high purity.

[0014] Therefore, one aspect of the present disclosure relates to a method for purifying vilanterol triphenylacetate of formula (I),

[0015]

[0016] The method comprises crystallizing vilanterol triphenylacetate from a ketone solvent selected from the group consisting of methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone, and mixtures thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Shown is a SEM image of vilanterol triphenylacetate crystals obtained from MEK by Ostwald ripening at a magnification of 2550X.

[0018] Figure 2 Shown is a SEM image of vilanterol triphenylacetate crystals obtained from MIK by Ostwald ripening at a magnification of 2500 times.

[0019] Figure 3 Shown is a SEM image of vilanterol triphenylacetate crystals obtained from ethanol by Ostwald ripening at a magnification of 2500 times. DETAILED DESCRIPTION OF THE INVENTION

[0021] Unless otherwise specified, all terms used in the specification should be understood according to their ordinary meanings known in the art.

[0022] The term "V" preceded by a number means the multiple by which the amount of one substance exceeds a given amount of another substance by volume. For example, given 7.5 g of vilanterol trifenac, adding 8 V of MEK means adding 60 mL of MEK.

[0023] The term "seeding" refers to the addition of crystalline material to promote crystallization. In the context of the present disclosure, seeding is performed using crystals of vilanterol trifenac.

[0024] The term "Ostwald ripening" refers to the growth of larger crystals from smaller crystals by temperature cycling, which have a higher solubility than the larger crystals. During the process, many of the small crystals that form at the beginning slowly disappear, and only a few small crystals grow larger and larger at the expense of other small crystals. Smaller crystals serve as fuel for the growth of larger crystals. Ostwald ripening is a key process in the digestion of precipitates. The digested precipitate is usually purer, more uniform and easier to clean and filter.

[0025] The term "room temperature" refers to about 20°C-25°C.

[0026] The term "about" includes the experimental error range that may occur in the measurement. Specifically, when referring to a value, it means plus or minus 5% of the given value, and when referring to a range, it means plus or minus 5% of the outer value.

[0027] The processes of the prior art attempt to obtain vilanterol triphenylacetate in the highest possible purity. In particular, there is an interest in providing a process that allows minimizing the presence of the above-mentioned impurity A in the final product. The inventors have realised that said mentioned impurities prove difficult to remove, even with subsequent recrystallization from the solvents disclosed in the prior art for this purpose, which does not allow obtaining a final product with the desired purity level and physical properties.

[0028] After extensive experiments, the inventors have surprisingly found that crystallization of vilanterol triphenylacetate from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone or mixtures thereof allows achieving the mentioned objectives.

[0029] Therefore, one aspect of the present disclosure relates to a method for purifying vilanterol triphenylacetate, the method comprising crystallizing vilanterol triphenylacetate from at least one of the ketone solvents mentioned above. Specifically, the ketone solvent is selected from MEK, MIK or a mixture thereof.

[0030] In a specific embodiment, the purification process is carried out in MEK as ketone solvent.

[0031] In another specific embodiment, the purification method is carried out in MIK as ketone solvent.

[0032] In one embodiment, optionally in combination with one or more features of the specific embodiments defined above, the method for purifying vilanterol triphenylacetate comprises:

[0033] a) providing a solution of vilanterol triphenylacetate in a suitable amount of the ketone solvent at a temperature below the boiling point of the ketone solvent, for example 55 to 70° C.;

[0034] b) cooling the solution to a temperature from room temperature to 0° C., in particular to room temperature, to crystallize vilanterol triphenylacetate; and

[0035] c) isolating the crystallized solid.

[0036] The term "suitable amount" of the ketone solvent refers to the amount of ketone solvent required to crystallize the vilanterol triphenylacetate when the cooling of step b) is performed. Specifically, the amount of the ketone solvent is such that the vilanterol triphenylacetate is dissolved in the specific solvent at the highest concentration at the mentioned temperature, i.e., the solution is a saturated solution of the vilanterol triphenylacetate.

[0037] Specifically, the method for purifying vilanterol triphenylacetate in MEK comprises:

[0038] a) providing a solution of vilanterol triphenylacetate in MEK, e.g., about 8V to 10V MEK, at a temperature of 55°C to 70°C;

[0039] b) cooling the solution at room temperature to crystallize vilanterol triphenylacetate; and

[0040] c) isolating the crystallized solid.

[0041] Specifically, the method for purifying vilanterol triphenylacetate in MIK comprises:

[0042] a) providing a solution of vilanterol triphenylacetate in MIK, e.g., about 30 V to about 35 V MIK, at a temperature of 55° C. to 70° C.;

[0043] b) cooling the solution at room temperature to crystallize vilanterol triphenylacetate; and

[0044] c) isolating the crystallized solid.

[0045] One way to improve the crystallization method of the present invention, in particular to promote crystallization in a controlled manner, is to seed with some crystals of the product. Therefore, in another embodiment, optionally in combination with one or more features of the specific embodiments defined above or below, the method comprises seeding with crystals of vilanterol triphenylacetate to start the crystallization. Specifically, after obtaining a solution of vilanterol triphenylacetate, the solution is cooled to a temperature above room temperature, for example 45°C to 60°C, then seeded with crystals of vilanterol triphenylacetate, and cooled to a temperature of room temperature to 0°C, in particular room temperature, to crystallize vilanterol triphenylacetate.

[0046] The separation of the vilanterol triphenylacetate crystals obtained according to the method of the present disclosure can be carried out according to methods known in the art, including but not limited to filtration, particularly vacuum filtration. Then, the crystalline solid can be washed with the crystallization solvent at a temperature from room temperature to 0°C, particularly at room temperature, and then dried for a suitable period of time at a temperature of 50°C to 60°C until constant weight. A suitable period of time can be, for example, 10 to 20 hours, for example, about 16 hours. The drying can be carried out according to methods known in the art, including but not limited to drying under reduced pressure.

[0047] In a more specific embodiment, optionally in combination with one or more features of the specific embodiments defined above or below, the method comprises a preliminary step comprising adding triphenylacetic acid to a solution of vilanterol free base in the ketone solvent to form a solution of vilanterol triphenylacetate in the ketone solvent. Vilanterol free base can be obtained by any method known in the art, in particular a method in which impurity A is formed.

[0048] In a more specific embodiment, optionally in combination with one or more features of the specific embodiments defined above or below, the method comprises a preliminary step comprising mixing vilanterol triphenylacetate with a suitable amount of the ketone solvent and heating the mixture until dissolved.

[0049] In another particular embodiment of the method of the present disclosure, optionally in combination with one or more features of the particular embodiments defined above or below, the solution of vilanterol triphenylacetate is a saturated solution.

[0050] In another embodiment, optionally in combination with one or more features of the specific embodiments defined above or below, the method for purifying vilanterol triphenylacetate further comprises recrystallizing vilanterol triphenylacetate from the same or different solvent, wherein the solvent is a ketone solvent selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone and mixtures thereof.

[0051] The purification by recrystallization can be carried out according to methods known in the art, in particular by dissolving the vilanterol triphenylacetate in at least one of the mentioned ketone solvents by heating, and then cooling the resulting solution to precipitate the product. In a more specific embodiment, optionally in combination with one or more features of the specific embodiments defined above or below, the method comprises seeding with vilanterol triphenylacetate crystals to start the recrystallization. The vilanterol triphenylacetate crystals for seeding can be obtained by any method known in the art, in particular by the crystallization and / or recrystallization method disclosed herein.

[0052] In a specific embodiment, the recrystallization is carried out in MEK.

[0053] Specifically, the recrystallization of vilanterol triphenylacetate in MEK involves:

[0054] a) suspending vilanterol triphenylacetate in MEK, e.g., about 8V to 10V MEK;

[0055] b) heating the suspension at a temperature of, for example, 55° C. to 60° C. until a solution is obtained;

[0056] c) cooling the solution at a temperature of 46° C. to 55° C.;

[0057] d) seeding the solution with vilanterol triphenylacetate crystals;

[0058] e) cooling the mixture at a temperature of 20° C. to 25° C. to crystallize vilanterol triphenylacetate; and

[0059] f) isolating the crystallized solid.

[0060] In another specific embodiment, the recrystallization is carried out in MIK as ketone solvent.

[0061] Specifically, the recrystallization of vilanterol triphenylacetate in MIK involves:

[0062] a) suspending vilanterol triphenylacetate in MIK, e.g., about 30 V to about 35 V MIK;

[0063] b) heating the suspension at a temperature of, for example, 65° C. to 70° C. until a solution is obtained;

[0064] c) cooling the solution at a temperature of 54° C. to 62° C.;

[0065] d) seeding the solution with vilanterol triphenylacetate crystals;

[0066] e) cooling the mixture at a temperature of 20° C. to 25° C. to crystallize vilanterol triphenylacetate; and

[0067] f) isolating the crystallized solid.

[0068] Furthermore, in an attempt to further improve the purity of the final product, the present inventors realized that by using the mentioned ketone solvents for recrystallization of vilanterol triphenylacetate by Ostwald ripening, no aggregates were formed, as opposed to other solvents such as ethanol. Furthermore, the size of the crystals produced from the mentioned ketone solvents was more convenient upon micronization than the crystals produced from ethanol.

[0069] Therefore, in another embodiment, optionally in combination with one or more features of the specific embodiments defined above or below, the recrystallization is carried out by Ostwald ripening. Specifically, Ostwald ripening comprises:

[0070] a) providing a suspension of vilanterol triphenylacetate in a ketone solvent;

[0071] b) heating the suspension of step a) until a solution is obtained;

[0072] c) cooling the solution to a first temperature above room temperature;

[0073] d) seeding the solution with vilanterol triphenylacetate crystals to obtain a suspension;

[0074] e) cooling the suspension to a second temperature between the first temperature and room temperature under stirring; heating the suspension to the first temperature under stirring; and repeating step e) at least once more;

[0075] f) cooling the suspension at a temperature of 20°C to 25°C; and

[0076] g) separating the vilanterol triphenylacetate crystals from the suspension of step f) at room temperature.

[0077] In a specific embodiment, Ostwald ripening is carried out in MEK and the method comprises the following steps:

[0078] a) providing a suspension of vilanterol triphenylacetate in MEK;

[0079] b) heating the suspension of step a) until a solution is obtained;

[0080] c) cooling the solution to 46°C-52°C, preferably 49°C;

[0081] d) seeding the solution with vilanterol triphenylacetate crystals to obtain a suspension;

[0082] e) cooling the suspension to 37°C-43°C, preferably 40°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0083] Heating the suspension to 46°C-52°C, preferably 49°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0084] Cooling the suspension to 37°C-43°C, preferably 40°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0085] heating the suspension to 46-52°C, preferably 49°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes; and

[0086] f) cooling the suspension at a temperature of 20°C to 25°C; and

[0087] g) separating the vilanterol triphenylacetate crystals from the suspension of step f).

[0088] In another specific embodiment, Ostwald ripening is carried out in MIK and the method comprises the following steps:

[0089] a) providing a suspension of vilanterol triphenylacetate in MIK;

[0090] b) heating the suspension of step a) until a solution is obtained;

[0091] c) cooling the solution to 54°C-60°C, preferably 57°C;

[0092] d) seeding the solution with vilanterol triphenylacetate crystals to obtain a suspension;

[0093] e) cooling the suspension to 44-50°C, preferably 47°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0094] Heating the suspension to 54-60°C, preferably 57°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0095] Cooling the suspension to 44-50°C, preferably 47°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0096] Heating the suspension to 54-60°C, preferably 57°C, while stirring at this temperature for 10-30 minutes, preferably 15 minutes;

[0097] f) cooling the suspension at a temperature of 20°C to 25°C; and

[0098] g) separating the vilanterol triphenylacetate crystals from the suspension of step f).

[0099] Throughout this specification and claims, the word "comprising" and variations of the word are not intended to exclude other technical features, additives, components or steps. In addition, the word "comprising" covers the situation of "consisting of..."

[0100] The following examples and figures are provided for illustration and are not intended to limit the present invention.In addition, the present invention covers all possible combinations of particular and preferred embodiments described herein. Example

[0101] HPLC analysis was performed on the following columns and conditions:

[0102]

[0103]

[0104] HLPC values ​​are area %.

[0105] Example 1. Preparation of Vilanterol Triphenylacetate

[0106] Vilanterol triphenylacetate was prepared according to the following reaction scheme:

[0107]

[0108]

[0109] As shown below, both the vilanterol base (II) in solution and the crystalline vilanterol triphenylacetate (I) contain impurity A in undesirable amounts.

[0110] 40.0 g (59.1 mmol) of compound (III) was stirred at 4° C. for 48 h in a mixture of 253 mL ACN and 355 mL HCl 0.5 N (177.4 mmol, 3.0 eq.). Then 344 mL of dichloromethane and 200 mL of K2CO3 20% were added and the phases were separated. The aqueous phase was extracted with 130 mL of dichloromethane.

[0111] The obtained organic phase containing compound (II) (HPLC=98.44%) and impurity A (HPLC=0.45%) was divided into 4 equal parts (parts 1 to 4). Each part was used in Examples 2 and 3 and Comparative Examples 1 and 2 below.

[0112] Example 2. Crystallization of Vilanterol Triphenylacetate from MEK

[0113] The solvent of part 1 obtained in Example 1 was distilled off under reduced pressure and replaced with methyl ethyl ketone (MEK). The obtained residue (compound (II)) was dissolved in 88 mL MEK. 4.3 g (14.8 mmol, 1.0 eq) of solid triphenylacetic acid was added immediately at one time. The solution was heated to 55 ° C and cooled to 20-25 ° C for 3 h. The obtained white solid was filtered out and washed twice with 11 mL MEK. The white solid was dried at 20-25 ° C for 16 h under reduced pressure and at 55 ° C for 1 h under reduced pressure. 9.2 g (11.9 mmol) of vilanterol triphenylacetate (I) (yield = 80%) (HPLC = 99.38%, impurity A = 0.19%) was obtained.

[0114] Example 3. Crystallization of Vilanterol Triphenylacetate from MIK

[0115] The solvent of part 2 obtained in Example 1 was distilled off under reduced pressure and replaced with methyl isobutyl ketone (MIK). The obtained residue (compound (II)) was dissolved in 88 mL MIK. 4.3 g (14.8 mmol, 1.0 eq) of solid triphenylacetic acid was immediately added at one time. The solution was heated to 55° C. and cooled to 20-25° C. for 3 h. The obtained white solid was filtered out and washed twice with 11 mL MIK. The white solid was dried at 20-25° C. for 16 h under reduced pressure and at 55° C. for 1 h under reduced pressure. 10.4 g (13.4 mmol) of vilanterol triphenylacetate (I) (yield = 91%) (HPLC = 99.28%, impurity A = 0.23%) was obtained.

[0116] Comparative Example 1. Crystallization of Vilanterol Triphenylacetate from Acetone

[0117] The solvent of part 3 obtained in Example 1 was distilled off under reduced pressure and replaced with acetone. The obtained residue (compound (II)) was dissolved in 88 mL of acetone. 4.3 g (14.8 mmol, 1.0 eq) of solid triphenylacetic acid was immediately added at one time. The solution was heated to 55° C. and cooled to 20-25° C. for 3 h. The obtained white solid was filtered out and washed twice with 11 mL of acetone. The white solid was dried at 20-25° C. for 16 h under reduced pressure and at 55° C. for 1 h under reduced pressure. 7.1 g (9.2 mmol) of vilanterol triphenylacetate (I) (yield = 62%) (HPLC = 99.47%, impurity A = 0.14%) was obtained.

[0118] Comparative Example 2. Crystallization of Vilanterol Triphenylacetate from Ethanol

[0119] The solvent of part 4 obtained in Example 1 was distilled off under reduced pressure and replaced with ethanol. The obtained residue (compound (II)) was dissolved in 88 mL of ethanol. 4.3 g (14.8 mmol, 1.0 eq) of solid triphenylacetic acid was added immediately at one time. The solution was heated to 55 ° C and cooled to 20-25 ° C for 3 h. The obtained white solid was filtered out and washed twice with 11 mL of ethanol. The white solid was dried at 20-25 ° C for 16 h under reduced pressure and dried at 55 ° C for 1 h under reduced pressure. 9.3 g (12.0 mmol) of vilanterol triphenylacetate (I) (yield = 81%) (HPLC = 99.11%, impurity A = 0.28%) was obtained.

[0120] Example 4. Crystallization of Vilanterol Triphenylacetate from MEK

[0121] Vilanterol triphenylacetate was obtained according to Example 2. After filtering and washing with MEK, the white solid was dried under reduced pressure at 20-25° C. for 16 h and at 55° C. for 1 h. 36.3 g (46.8 mmol) of vilanterol triphenylacetate (I) (yield = 79%) were obtained (HPLC = 99.37%, impurity A = 0.18%).

[0122] Example 5. Recrystallization of Vilanterol Triphenylacetate in MEK

[0123] 9.0 g (11.6 mmol) of the vilanterol triphenylacetate obtained in Example 4 was stirred with 72 mL of MEK at 20-25 ° C. The suspension was heated at 55-60 ° C until a solution was obtained. The solution was cooled to 50-55 ° C, seeded with vilanterol triphenylacetate crystals, and cooled to 20-25 ° C for 3 h. The obtained white solid was filtered out and washed twice with 9 mL of MEK. The white solid was dried at 55 ° C for 16 h under reduced pressure. 8.1 g (10.5 mmol) of vilanterol triphenylacetate (I) (yield = 90%) was obtained (HPLC = 99.60%, impurity A = 0.08%).

[0124] Example 6. Recrystallization of Vilanterol Triphenylacetate in MIK

[0125] 9.0 g (11.6 mmol) of the vilanterol triphenylacetate obtained in Example 4 were stirred with 270 mL of MIK at 20-25° C. The suspension was heated at 65-67° C. until a solution was obtained. The solution was cooled to 60-62° C., seeded with vilanterol triphenylacetate crystals and cooled to 20-25° C. for 3 h. The obtained white solid was filtered off and washed twice with 9 mL of MIK. The white solid was dried at 55° C. for 16 h under reduced pressure. 7.8 g (10.1 mmol) of vilanterol triphenylacetate (I) were obtained (yield = 87%) (HPLC = 99.54%, impurity A = 0.09%).

[0126] Comparative Example 3. Recrystallization of Vilanterol Triphenylacetate in Acetone

[0127] 9.0 g (11.6 mmol) of the vilanterol triphenylacetate obtained in Example 4 were stirred with 90 mL of acetone at 20-25 ° C. The suspension was heated at 55-56 ° C until a solution was obtained. The solution was cooled to 50-52 ° C, seeded with vilanterol triphenylacetate crystals, and cooled to 20-25 ° C for 3 h. The obtained white solid was filtered out and washed twice with 9 mL of acetone. The white solid was dried at 55 ° C for 16 h under reduced pressure. 5.5 g (7.1 mmol) of vilanterol triphenylacetate (I) (yield = 61%) (HPLC = 99.57%, impurity A = 0.09%) were obtained.

[0128] Comparative Example 4. Recrystallization of Vilanterol Triphenylacetate in Ethanol

[0129] 9.0 g (11.6 mmol) of the vilanterol triphenylacetate obtained in Example 4 were stirred with 90 mL of ethanol at 20-25 ° C. The suspension was heated at 55-60 ° C until a solution was obtained. The solution was cooled to 50-55 ° C, seeded with vilanterol triphenylacetate crystals, and cooled to 20-25 ° C for 3 h. The obtained white solid was filtered out and washed twice with 9 mL of ethanol. The white solid was dried at 55 ° C for 16 h under reduced pressure. 7.9 g (10.2 mmol) of vilanterol triphenylacetate (I) (yield = 88%) was obtained (HPLC = 99.44%, impurity A = 0.17%).

[0130] Example 7. Ostwald Ripening Experiment Using MEK

[0131] Vilanterol triphenylacetate (100 g, 129 mmol) was suspended in MEK (850 mL). The suspension was heated to 55°C until a solution was observed. The system was then cooled to 49°C, seeded with vilanterol triphenylacetate crystals, and then followed the following Ostwald ripening process:

[0132] 1. Cool the suspension to 40°C and stir at this temperature for 15 minutes;

[0133] 2. Heat the suspension to 49°C and stir at this temperature for 15 minutes;

[0134] 3. Cool the suspension to 40°C and stir at this temperature for 15 minutes; and

[0135] 4. The suspension was heated to 49 ° C and stirred at this temperature for 15 minutes.

[0136] The resulting suspension was cooled to 20° C. and stirred at this temperature for 1 h. The resulting white solid was filtered off and dried at 55° C. under reduced pressure for 24 h. 88 g (114 mmol) of vilanterol triphenylacetate (I) were obtained (yield = 88%).

[0137] The SEM image of the obtained crystal is shown in Figure 1 , where it can be seen that no aggregates are formed when MEK is used.

[0138] Example 8. Ostwald Ripening Experiment Using MIK

[0139] Vilanterol triphenylacetate (20 g, 25.8 mmol) was suspended in MIK (600 mL). The suspension was heated to 65-68°C until a solution was observed. The system was then cooled to 57°C, seeded with vilanterol triphenylacetate crystals, and then followed the following Ostwald ripening process:

[0140] 1. Cool the suspension to 47°C and stir at this temperature for 15 minutes;

[0141] 2. Heat the suspension to 57°C and stir at this temperature for 15 minutes;

[0142] 3. Cool the suspension to 47°C and stir at this temperature for 15 minutes; and

[0143] 4. Heat the suspension to 57°C and stir at this temperature for 15 minutes.

[0144] The obtained suspension was cooled to 20° C. and stirred at this temperature for 1 h. The obtained white solid was filtered off and dried at 55° C. under reduced pressure for 16 h. 17 g (21.9 mmol) of vilanterol triphenylacetate (I) were obtained (yield = 85%).

[0145] The SEM image of the obtained crystal is shown in Figure 2 , where it can be seen that no aggregates are formed when MIK is used.

[0146] Comparative Example 5. Ostwald Ripening Experiment Using Ethanol

[0147] Vilanterol triphenylacetate (20 g, 25.8 mmol) was suspended in ethanol (210 mL). The suspension was heated to 55-56°C until a solution was observed. The system was then cooled to 49°C, seeded with vilanterol triphenylacetate crystals, and then followed the following Ostwald ripening process:

[0148] 1. Cool the suspension to 37°C and stir at this temperature for 15 minutes;

[0149] 2. Heat the suspension to 47°C and stir at this temperature for 15 minutes;

[0150] 3. Cool the suspension to 37°C and stir at this temperature for 15 minutes; and

[0151] 4. Heat the suspension to 47°C and stir at this temperature for 15 minutes.

[0152] The obtained suspension was cooled to 10° C. and stirred at this temperature for 1 h. The obtained white solid was filtered off and dried at 55° C. under reduced pressure for 16 h. 18 g (23.2 mmol) of vilanterol triphenylacetate (I) were obtained (yield = 90%).

[0153] The SEM image of the obtained crystal is shown in Figure 3 In the figure, it can be seen that aggregates are formed.

[0154] The above examples and comparative examples carried out by Ostwald ripening show that, advantageously, no aggregates are formed from MEK or MIK, in contrast to ethanol, and that the size of the crystals produced from MEK or MIK is more adequate upon micronization than from ethanol.

[0155] Citation List

[0156] WO 2003 / 024439

[0157] WO 2014 / 041565

[0158] WO 2017 / 001907

Claims

1. A method for purifying the vilanterol triphenylacetate of formula (I), The invention comprises crystallizing vilanterol triphenylacetate from a solution of vilanterol triphenylacetate in a ketone solvent, wherein the ketone solvent is selected from methyl ethyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone and a mixture thereof.

2. The method according to claim 1, wherein the crystallization comprises: a) providing a solution of vilanterol triphenylacetate in a suitable amount of the ketone solvent at a temperature below the boiling point of the ketone solvent; b) cooling the solution to a temperature from room temperature to 0°C to crystallize vilanterol triphenylacetate; and c) isolating the crystallized solid.

3. The process according to claim 1, wherein the crystallization is carried out from methyl ethyl ketone or methyl isobutyl ketone.

4. The method of claim 1, wherein the method comprises seeding with vilanterol triphenylacetate crystals to initiate the crystallization.

5. The method of claim 1, wherein the method comprises a preliminary step comprising adding triphenylacetic acid to a solution of vilanterol free base in the ketone solvent to form a solution of vilanterol triphenylacetate in the ketone solvent.

6. The method according to claim 1, wherein the method comprises a preliminary step comprising mixing vilanterol triphenylacetate with a suitable amount of the ketone solvent and heating the mixture until dissolved.

7. The method of claim 1, wherein the solution of vilanterol triphenylacetate is a saturated solution.

8. The method according to any one of claims 1 to 7, further comprising recrystallizing the vilanterol triphenylacetate obtained in any one of claims 1 to 6 from a ketone solvent selected from methyl ethyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone and a mixture thereof.

9. The method of claim 8, wherein the method comprises seeding with vilanterol triphenylacetate crystals to initiate the recrystallization.

10. The process according to claim 8, wherein the recrystallization is carried out from methyl ethyl ketone.

11. The process according to claim 8, wherein the recrystallization is carried out from methyl isobutyl ketone.

12. The process according to claim 1, wherein the crystallization is carried out by Ostwald ripening.

13. The method according to claim 8, wherein the recrystallization is performed by Ostwald ripening.

14. The method according to claim 12 or 13, wherein Ostwald ripening comprises the following steps: a) providing a suspension of vilanterol triphenylacetate in a ketone solvent; b) heating the suspension of step a) until a solution is obtained; c) cooling the solution to a first temperature above room temperature; d) seeding the solution with vilanterol triphenylacetate crystals to obtain a suspension liquid; e) cooling the suspension to a temperature between the first temperature and room temperature under stirring. heating the suspension to the first temperature under stirring; and repeating step e) at least once more; f) cooling the suspension at a temperature of 20°C to 25°C; and g) separating vilanterol triphenylethylene from the suspension of step f) at room temperature Salt crystals.

15. The method according to claim 14, wherein the ketone solvent is methyl ethyl ketone or methyl isobutyl ketone.

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