Purification method of vilanterol trifenate

Abstract

The present invention relates to a process for purifying vilanterol trifenatate of formula (I), comprising crystallizing vilanterol trifenatate 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. [Formula 1] TIFF2023535575000008.tif50155

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of European Patent Application No. 20382677.1, filed on July 27, 2020.

[0002] The present invention relates to a method for purifying vilanterol trifenatate.

Background Art

[0003] Vilanterol trifenatate is the common name of the compound (R)-4-(2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-hydroxyethyl)-2-(hydroxymethyl)phenol 2,2,2-triphenylacetate having the following chemical structure.

Chemical formula

[0004] Vilanterol trifenatate is a selective long - acting β2 - adrenergic agonist. It is administered by inhalation as a dry powder formulation in combination with umeclidinium bromide and / or fluticasone furoate for the treatment of chronic obstructive pulmonary disease (COPD) and asthma.

[0005] Vilanterol trifenatate was first disclosed in Patent Document 1, which discloses a method of crystallizing vilanterol trifenatate in ethanol. Nevertheless, the product is obtained with undesirably high levels of impurities.

[0006] Patent Document 2 discloses the crystallization of vilanterol trifenatate in acetone, by which the impurity level is reduced, but the yield is significantly low. Furthermore, acetone is highly flammable, highly reactive, and harmful to human health, so it is not a solvent convenient for industrial use.

[0007] Patent Document 3 discloses a method for preparing vilanterol trifenate, in which vilanterol tartrate is converted into the trifenate salt via a base (by addition of the corresponding acid) in a multi-step process. By this method, the product can be obtained in relatively high purity, especially with a small amount of impurity A of the following formula: [Chemical formula]

[0008] However, this method is carried out in a mixture of DCM, MTBE and EtOH and requires laborious post-treatment. [Prior Art Documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2003 / 024439 [Patent Document 2] International Publication No. 2014 / 041565 [Patent Document 3] International Publication No. 2017 / 001907 [Summary of the Invention] [Problems to be Solved by the Invention]

[0010] Therefore, there is still a need to find a new method that enables the preparation of vilanterol trifenate in good yield and purity, while being industrially easy to use. [Means for Solving the Problems]

[0011] The inventors have found a new method for the purification of vilanterol trifenate that overcomes the drawbacks of the methods disclosed in the prior art. The inventors have surprisingly found that by crystallizing vilanterol trifenate from some specific ketone solvents, a solid product can be obtained in both good yield and high purity.

[0012] Accordingly, one aspect of the present disclosure is a method for purifying vilanterol trifenatate of formula (I), comprising

Chemical formula

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0014] Detailed Description of the Invention All terms used herein should be understood in their ordinary meaning as known in the art, unless otherwise indicated.

[0015] The term "V" preceded by a number means how many times the volume-based amount of a substance is of the given weight-based amount of another substance. For example, in 7.5 g of vilanterol trifenatate, adding 8 V of MEK means adding 60 mL of MEK.

[0016] The term "seeding" refers to the addition of a crystalline material to promote crystallization. In the context of the present disclosure, seeding is performed using crystals of vilanterol trifenate.

[0017] The term "Ostwald ripening" refers to the growth of larger crystals from smaller-sized crystals that have a higher solubility than the larger crystals by temperature cycling. In this method, many of the small crystals formed initially disappear slowly, but a few grow larger, replacing the small crystals. The small crystals act as fuel for the growth of the large crystals. Ostwald ripening is an important method in the digestion of precipitates. The digested precipitate is generally purer, more uniform, and easier to wash and filter.

[0018] The term "room temperature" refers to about 20°C to 25°C.

[0019] The term "about" includes the range of experimental error that can occur in measurements. In particular, when referring to a value, "about" means plus or minus 5% of a given value, and when referring to a range, it means plus or minus 5% of the end values.

[0020] Prior art methods attempt to obtain vilanterol trifenate with the highest possible purity. In particular, there is an interest in providing a method that minimizes the presence of the above-mentioned impurity A in the final product. The inventors have found that the removal of the above-mentioned impurities is difficult, and have recognized that even subsequent recrystallization from the solvents disclosed in the prior art for this purpose did not result in a final product having the desired purity level and physical properties.

[0021] After extensive experiments, the inventors have surprisingly found that the above-mentioned object can be achieved by crystallizing vilanterol trifenate from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone, or a mixture thereof.

[0022] Accordingly, one aspect of the present disclosure relates to a method for purifying vilanterol trifenatate, which comprises crystallizing vilanterol trifenatate from at least one of the above ketone solvents. In particular, the ketone solvent is selected from MEK, MIK or a mixture thereof.

[0023] In certain embodiments, the purification method is carried out in MEK as the ketone solvent.

[0024] In another specific embodiment, the purification method is carried out in MIK as the ketone solvent.

[0025] In one embodiment, the method for purifying vilanterol trifenatate is optionally combined with one or more features of the specific embodiments defined above, a) preparing a solution of vilanterol trifenatate with an appropriate amount of the ketone solvent at a temperature lower than the boiling point of the solvent, such as 55 °C to 70 °C, b) cooling the solution to room temperature to 0 °C, particularly to room temperature, to crystallize vilanterol trifenatate, and c) isolating the crystallized solid is included.

[0026] The term "appropriate amount" of the ketone solvent relates to the amount of the ketone solvent required for vilanterol trifenatate to crystallize when the cooling in step b) is carried out. In particular, the amount of the ketone solvent is such that vilanterol trifenatate is dissolved in a specific solvent at its maximum concentration, that is, the solution is a saturated solution of vilanterol trifenatate at the above temperature.

[0027] In particular, the method for purifying vilanterol trifenatate in MEK is a) preparing a MEK solution of vilanterol trifenatate, for example, a MEK solution of about 8V to 10V, at a temperature of 55 °C to 70 °C, b) cooling the solution to room temperature to crystallize vilanterol trifenatate, and c) Isolating the crystallized solid comprises.

[0028] In particular, the method for purifying vilanterol trifenate in MIK comprises a) preparing a solution of vilanterol trifenate in MIK, for example a solution of MIK at about 30V to 35V, at a temperature of 55°C to 70°C; b) cooling the solution to room temperature to crystallize vilanterol trifenate; and c) isolating the crystallized solid comprises.

[0029] Means for improving the crystallization method of the present invention, in particular means for promoting crystallization by controlled means, are by seeding some crystals of the product. Thus, in another embodiment, the method comprises seeding vilanterol trifenate crystals to initiate crystallization, optionally in combination with one or more features of the specific embodiments defined above or below. In particular, after obtaining a solution of vilanterol trifenate, the solution is cooled to a temperature higher than room temperature, for example 45°C to 60°C, then seeded with vilanterol trifenate crystals, and cooled to room temperature to 0°C, in particular to room temperature, to crystallize vilanterol trifenate.

[0030] Isolation of the vilanterol trifenate 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, in particular filtration under vacuum. The crystalline solid can then be washed with a crystallization solvent at a temperature of room temperature to 0°C, in particular at room temperature, and dried to a constant weight over a suitable period of time at a temperature of 50°C to 60°C. A suitable period can be, for example, 10 to 20 hours, for example about 16 hours. Drying can be carried out according to methods known in the art, including but not limited to drying under reduced pressure.

[0031] In a more specific embodiment, the method includes a preceding step that, optionally in combination with one or more features of the specific embodiments defined above or below, comprises adding triphenylacetic acid to a vilanterol free base solution in a ketone solvent to form a vilanterol triphenate solution in the ketone solvent. The vilanterol free base can be obtained by any method known in the art, particularly a method that forms impurity A.

[0032] In a more specific embodiment, the method includes a preceding step that, optionally in combination with one or more features of the specific embodiments defined above or below, comprises mixing vilanterol triphenate with an appropriate amount of a ketone solvent and heating the mixture until it dissolves.

[0033] In another specific embodiment of the method of the present disclosure, optionally in combination with one or more features of the specific embodiments defined above or below, the vilanterol triphenate solution is a saturated solution.

[0034] In another embodiment, the method for purifying vilanterol triphenate further comprises recrystallizing vilanterol triphenate from the same or a different solvent, which is 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, optionally in combination with one or more features of the specific embodiments defined above or below.

[0035] Purification by recrystallization can be carried out according to methods known in the art, in particular by heating and dissolving vilanterol trifenate in at least one of the above ketone solvents and then cooling the resulting solution to precipitate the product. In more specific embodiments, including, optionally, in combination with one or more features of the specific embodiments defined above or below, seeding with vilanterol trifenate crystals to initiate recrystallization is included. The vilanterol trifenate crystals used for seeding can be obtained by any method known in the art, in particular by the crystallization and / or recrystallization methods of the present disclosure.

[0036] In certain embodiments, recrystallization is carried out in MEK.

[0037] In particular, the recrystallization of vilanterol trifenatate in MEK a) suspending vilanterol trifenate in MEK (e.g., about 8V - 10V of MEK); b) heating the suspension at a temperature such as 55°C - 60°C until a solution is obtained; c) cooling the solution at a temperature of 46°C - 55°C; d) seeding the solution with vilanterol trifenate crystals; e) cooling the mixture at a temperature of 20°C - 25°C to crystallize vilanterol trifenate; and f) isolating the crystallized solid is included.

[0038] In another specific embodiment, recrystallization is carried out in MIK as the ketone solvent. In particular, the recrystallization of vilanterol trifenatate in MIK a) suspending vilanterol trifenate in MIK (e.g., about 30V - 35V of MIK); b) heating the suspension at a temperature such as 65°C - 70°C until a solution is obtained; c) cooling the solution at a temperature of 54°C - 62°C; d) Seeding the solution with vilanterol trifenate crystals; e) Cooling the mixture at a temperature of 20°C to 25°C to crystallize vilanterol trifenate; and f) Isolating the crystallized solid. It includes.

[0039] Furthermore, in an attempt to further increase the purity of the final product, the inventors recognized that by recrystallizing vilanterol trifenate by Ostwald ripening using the above-mentioned ketone solvent, in contrast to other solvents such as ethanol, no aggregates are formed. Furthermore, the size of the crystals produced from the above-mentioned ketone solvent is convenient when micronized compared to those produced from ethanol.

[0040] Therefore, in another embodiment, recrystallization is carried out by Ostwald ripening, optionally in combination with one or more features of the specific embodiments defined above or below. In particular, Ostwald ripening is a) Preparing a suspension of vilanterol trifenate in a ketone solvent; b) Heating the suspension of step a) until a solution is obtained; c) Cooling the solution to a first temperature higher than room temperature; d) Seeding the solution with vilanterol trifenate crystals to obtain a suspension; e) Cooling the suspension with stirring to a second temperature between the first temperature and room temperature, and heating the suspension with stirring to the first temperature, and repeating step e) at least one more time; f) Cooling the suspension at a temperature of 20°C to 25°C; and g) Isolating vilanterol trifenate crystals from the suspension of step f) at room temperature. It includes.

[0041] In a particular embodiment, Ostwald ripening is carried out in MEK, and the method is as follows: a) Preparing a MEK suspension of vilanterol trifenate; b) Heating the suspension of step a) until a solution is obtained; c) Cooling the solution to 46°C to 52°C, preferably 49°C; d) Seeding the solution with vilanterol trifenate crystals to obtain a suspension; e) Cooling the suspension to 37°C to 43°C, preferably 40°C, and stirring at this temperature for 10 to 30 minutes, preferably 15 minutes; Heating the suspension to 46°C to 52°C, preferably 49°C, and stirring at this temperature for 10 to 30 minutes, preferably 15 minutes; Cooling the suspension to 37°C to 43°C, preferably 40°C, and stirring at this temperature for 10 to 30 minutes, preferably 15 minutes; Heating the suspension to 46°C to 52°C, preferably 49°C, and stirring at this temperature for 10 to 30 minutes, preferably 15 minutes, and f) Cooling the suspension to a temperature of 20°C to 25°C, and g) Isolating vilanterol trifenate crystals from the suspension of step f) are included.

[0042] In another specific embodiment, Ostwald ripening is carried out in MIK, and the method is as follows: a) Preparing a MIK suspension of vilanterol trifenate; b) Heating the suspension of step a) until a solution is obtained; c) Cooling the solution to 54°C to 60°C, preferably 57°C; d) Seeding the solution with vilanterol trifenate crystals to obtain a suspension; e) Cooling the suspension to 44°C to 50°C, preferably 47°C, and stirring at this temperature for 10 to 30 minutes, preferably 15 minutes; Heating the suspension to 54°C to 60°C, preferably 57°C, and stirring at this temperature for 10 to 30 minutes, preferably 15 minutes; Cool the suspension from 44 °C to 50 °C, preferably to 47 °C, while stirring at this temperature for 10 to 30 minutes, preferably for 15 minutes, A step of heating the suspension from 54 °C to 60 °C, preferably to 57 °C, while stirring at this temperature for 10 to 30 minutes, preferably for 15 minutes, f) A step of cooling the suspension to a temperature of 20 °C to 25 °C, and g) A step of isolating vilanterol trifenate crystals from the suspension of step f) is included.

[0043] Throughout the specification and the claims, the term "comprise" and variations of that term are not intended to exclude other technical features, additives, components or steps. Further, the term "comprise" includes the case of "consisting of".

[0044] The following examples and drawings are provided for illustration purposes and are not intended to limit the present invention. Further, the present invention encompasses all conceivable combinations of the specific preferred embodiments described herein.

Example

[0045] HPLC analysis was performed under the following columns and conditions:

Table 1

[0046] Example 1 Preparation of Vilanterol Trifenate

[0047] Vilanterol trifenate was prepared according to the following reaction scheme:

Chemical formula

[0048] As shown below, both the dissolved vilanterol base (II) and the crystallized vilanterol triphenate (I) contain an undesirable amount of impurity A.

[0049] 40.0 g (59.1 mmol) of compound (III) was stirred at 4 °C for 48 hours in a mixture of 253 mL of ACN and 355 mL of 0.5 N HCl (177.4 mmol, 3.0 equivalents). Then, 344 mL of methylene chloride and 200 mL of 20% K2CO3 were added, and the phases were separated. The aqueous phase was extracted with 130 mL of methylene chloride.

[0050] The obtained organic phase containing compound (II) (HPLC = 98.44%) and impurity A (HPLC = 0.45%) was divided into four equal parts (parts 1 to 4). Each part was used in Examples 2, 3, Comparative Examples 1, and 2 below.

[0051] Example 2 Crystallization of Vilanterol Triphenate from MEK

[0052] The solvent of part 1 obtained in Example 1 was distilled off under reduced pressure and exchanged with methyl ethyl ketone (MEK). The obtained residue (compound (II)) was dissolved in 88 mL of MEK. 4.3 g (14.8 mmol, 1.0 equivalent) of solid triphenylacetic acid was added all at once. The solution was heated to 55 °C and cooled to 20 - 25 °C over 3 hours. The obtained white solid was filtered and washed twice with 11 mL of MEK. The white solid was dried at 20 - 25 °C for 16 hours under reduced pressure and at 55 °C for 1 hour under reduced pressure. 9.2 g (11.9 mmol) of vilanterol triphenate (I) was obtained (yield = 80%) (HPLC = 99.38%, impurity A = 0.19%).

[0053] Example 3 Crystallization of Vilanterol Triphenate from MIK

[0054] The solvent of Part 2 obtained in Example 1 was distilled off under reduced pressure and exchanged with methyl isobutyl ketone (MIK). The obtained residue (Compound (II)) was dissolved in 88 mL of MIK. 4.3 g (14.8 mmol, 1.0 equivalent) of solid triphenylacetic acid was added all at once. The solution was heated to 55 °C and cooled to 20 - 25 °C over 3 hours. The obtained white solid was filtered and washed twice with 11 mL of MIK. The white solid was dried at 20 - 25 °C for 16 hours under reduced pressure and at 55 °C for 1 hour under reduced pressure. 10.4 g (13.4 mmol) of vilanterol triphenate (I) was obtained (yield = 91%) (HPLC = 99.28%, impurity A = 0.23%).

[0055] Comparative Example 1 Crystallization of Vilanterol Triphenate from Acetone

[0056] The solvent of Part 3 obtained in Example 1 was distilled off under reduced pressure and exchanged with acetone. The obtained residue (Compound (II)) was dissolved in 88 mL of acetone. 4.3 g (14.8 mmol, 1.0 equivalent) of solid triphenylacetic acid was added all at once. The solution was heated to 55 °C and cooled to 20 - 25 °C over 3 hours. The obtained white solid was filtered and washed twice with 11 mL of acetone. The white solid was dried at 20 - 25 °C for 16 hours under reduced pressure and at 55 °C for 1 hour under reduced pressure. 7.1 g (9.2 mmol) of vilanterol triphenate (I) was obtained (yield = 62%) (HPLC = 99.47%, impurity A = 0.14%).

[0057] Comparative Example 2 Crystallization of Vilanterol Triphenate from Ethanol

[0058] The solvent of Part 4 obtained in Example 1 was distilled off under reduced pressure and exchanged with ethanol. The obtained residue (Compound (II)) was dissolved in 88 mL of ethanol. 4.3 g (14.8 mmol, 1.0 equivalent) of solid triphenylacetic acid was added all at once. The solution was heated to 55 °C and cooled to 20 - 25 °C over 3 hours. The obtained white solid was filtered and washed twice with 11 mL of ethanol. The white solid was dried at 20 - 25 °C for 16 hours under reduced pressure and at 55 °C for 1 hour under reduced pressure. 9.3 g (12.0 mmol) of vilanterol triphenate (I) was obtained (yield = 81%) (HPLC = 99.11%, impurity A = 0.28%).

[0059] Example 4 Crystallization of Vilanterol Triphenate from MEK

[0060] Vilanterol triphenarate was obtained according to Example 2. After filtration and washing with MEK, the white solid was dried at 20 - 25 °C for 16 hours under reduced pressure and at 55 °C for 1 hour under reduced pressure. 36.3 g (46.8 mmol) of vilanterol triphenate (I) was obtained (yield = 79%) (HPLC = 99.37%, impurity A = 0.18%).

[0061] Example 5 Recrystallization of Vilanterol Triphenate in MEK

[0062] 9.0 g (11.6 mmol) of vilanterol triphenate obtained in Example 4 was stirred with 72 mL of MEK at 20 - 25 °C. The suspension was heated to 55 - 60 °C until a solution was obtained. The solution was cooled to 50 - 55 °C, seeded with vilanterol triphenate crystals, and cooled to 20 - 25 °C over 3 hours. The obtained white solid was filtered and washed twice with 9 mL of MEK. The white solid was dried at 55 °C for 16 hours under reduced pressure. 8.1 g (10.5 mmol) of vilanterol triphenate (I) was obtained (yield = 90%) (HPLC = 99.60%, impurity A = 0.08%).

[0063] Example 6 Recrystallization of Vilanterol Triphenate in MIK

[0064] 9.0 g (11.6 mmol) of vilanterol trifenate obtained in Example 4 was 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 trifenate crystals, and cooled to 20 - 25°C over 3 hours. The resulting white solid was filtered and washed twice with 9 mL of MIK. The white solid was dried under reduced pressure at 55°C for 16 hours. 7.8 g (10.1 mmol) of vilanterol trifenate (I) was obtained (yield = 87%) (HPLC = 99.54%, impurity A = 0.09%).

[0065] Comparative Example 3 Recrystallization of vilanterol trifenate in acetone

[0066] 9.0 g (11.6 mmol) of vilanterol trifenate obtained in Example 4 was 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 trifenate crystals, and cooled to 20 - 25°C over 3 hours. The resulting white solid was filtered and washed twice with 9 mL of acetone. The white solid was dried under reduced pressure at 55°C for 16 hours. 5.5 g (7.1 mmol) of vilanterol trifenate (I) was obtained (yield = 61%) (HPLC = 99.57%, impurity A = 0.09%).

[0067] Comparative Example 4 Recrystallization of vilanterol trifenate in ethanol

[0068] 9.0 g (11.6 mmol) of vilanterol trifenate obtained in Example 4 was 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 trifenate crystals, and cooled to 20 - 25°C over 3 hours. The resulting white solid was filtered and washed twice with 9 mL of ethanol. The white solid was dried under reduced pressure at 55°C for 16 hours. 7.9 g (10.2 mmol) of vilanterol trifenate (I) was obtained (yield = 88%) (HPLC = 99.44%, impurity A = 0.17%).

[0069] Example 7 Ostwald ripening experiment using MEK

[0070] Vilanterol trifenate (100 g, 129 mmol) was suspended in MEK (850 mL). The suspension was heated to 55°C until a solution was observed. Then, the system was cooled to 49°C, seeded with vilanterol trifenate crystals, and then followed the following Ostwald ripening process: 1. The suspension was cooled to 40°C and stirred at this temperature for 15 minutes. 2. The suspension was heated to 49°C and stirred at this temperature for 15 minutes. 3. The suspension was cooled to 40°C and stirred at this temperature for 15 minutes, and 4. The suspension was heated to 49°C and stirred at this temperature for 15 minutes.

[0071] The resulting suspension was cooled to 20°C and stirred at this temperature for 1 hour. The resulting white solid was filtered and dried under reduced pressure at 55°C for 24 hours. 88 g (114 mmol) of vilanterol trifenate (I) was obtained (yield = 88%).

[0072] The SEM image of the obtained crystals is shown in Figure 1, and it can be seen that no aggregates were formed by MEK.

[0073] Example 8 Ostwald ripening experiment using MIK

[0074] Vilanterol trifenate (20 g, 25.8 mmol) was suspended in MIK (600 mL). The suspension was heated to 65 - 68 °C until a solution was observed. Subsequently, the system was cooled to 57 °C, seeded with vilanterol trifenate crystals, and then followed the following Ostwald ripening process: 1. The suspension was cooled to 47 °C and stirred at this temperature for 15 minutes. 2. The suspension was heated to 57 °C and stirred at this temperature for 15 minutes. 3. The suspension was cooled to 47 °C and stirred at this temperature for 15 minutes, and 4. The suspension was heated to 57 °C and stirred at this temperature for 15 minutes.

[0075] The resulting suspension was cooled to 20 °C and stirred at this temperature for 1 hour. The obtained white solid was filtered and dried under reduced pressure at 55 °C for 16 hours. 17 g (21.9 mmol) of vilanterol trifenate (I) was obtained (yield = 85%).

[0076] The SEM image of the obtained crystals is shown in Figure 2, and it can be seen that no aggregates were formed by MIK.

[0077] Comparative Example 5 Ostwald ripening experiment using ethanol

[0078] Vilanterol trifenate (20 g, 25.8 mmol) was suspended in ethanol (210 mL). The suspension was heated to 55 - 56 °C until a solution was observed. Subsequently, the system was cooled to 49 °C, seeded with vilanterol trifenate crystals, and then followed the following Ostwald ripening process: 1. The suspension was cooled to 37 °C and stirred at this temperature for 15 minutes. 2. The suspension was heated to 47 °C and stirred at this temperature for 15 minutes. 3. The suspension was cooled to 37 °C and stirred at this temperature for 15 minutes, and 4. The suspension was heated to 47 °C and stirred at this temperature for 15 minutes.

[0079] The resulting suspension was cooled to 10 °C and stirred at this temperature for 1 hour. The obtained white solid was filtered and dried under reduced pressure at 55 °C for 16 hours. 18 g (23.2 mmol) of vilanterol trifenate (I) was obtained (yield = 90%).

[0080] The SEM image of the obtained crystals is shown in Figure 3, from which it can be seen that aggregates are formed.

[0081] The above Examples and Comparative Examples carried out by Ostwald ripening advantageously show that, in contrast to ethanol, no aggregates are formed from MEK or MIK, and the size of the crystals produced from MEK or MIK is more suitable during micronization than the size of the crystals from ethanol.

[0082] Cited References Pamphlet of International Publication No. WO 2003 / 024439 Pamphlet of International Publication No. WO 2014 / 041565 Pamphlet of International Publication No. WO 2017 / 001907

Claims

1. A method for purifying vilanterol trifenate of formula (I), comprising: 【Chemical 1】 crystallization of the vilanterol trifenate from a solution of vilanterol trifenate in 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, a method for purifying vilanterol trifenate of formula (I).

2. The crystallization comprises: a) preparing a solution of vilanterol trifenate with an appropriate amount of the ketone solvent at a temperature lower than the boiling point of the solvent, such as 55°C to 70°C; b) cooling the solution to a temperature from room temperature to 0°C to crystallize vilanterol trifenate; and c) isolating the crystallized solid. The method according to claim 1.

3. The method according to claim 1, wherein the crystallization is carried out from MEK or MIK.

4. The method according to claim 1, comprising seeding the vilanterol trifenate crystals to initiate the crystallization.

5. The method according to claim 1, comprising a preceding step of adding triphenylacetic acid to a solution of vilanterol free base in the ketone solvent to form a solution of vilanterol trifenate in the ketone solvent.

6. The method according to claim 2, comprising a preceding step of mixing vilanterol trifenate with an appropriate amount of the ketone solvent and heating the mixture until it dissolves.

7. The method according to claim 1, wherein the solution of vilanterol trifenate is a saturated solution.

8. The method according to any one of claims 1 to 7, further comprising recrystallizing the vilanterol trifenate 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.

9. The method according to claim 8, comprising seeding the vilanterol trifenate crystals to initiate the recrystallization.

10. The method according to claim 8, wherein the recrystallization is carried out from MEK or MIK.

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

12. The method according to claim 8, wherein the recrystallization is carried out by Ostwald ripening.

13. The Ostwald ripening is as follows a) preparing a suspension of vilanterol trifenate in the ketone solvent; b) heating the suspension of step a) until a solution is obtained; c) cooling the solution to a first temperature higher than room temperature; d) seeding the solution with vilanterol trifenate crystals to obtain a suspension; e) cooling the suspension to a second temperature between the first temperature and room temperature while stirring the suspension, and heating the suspension to the first temperature while stirring the suspension, and repeating step e) at least one more time; f) cooling the suspension to a temperature of 20°C to 25°C, and g) isolating vilanterol trifenate crystals from the suspension of step f) at room temperature. The method according to claim 11 or 12, comprising the steps of:

14. The method according to claim 13, wherein the ketone solvent is MEK or MIK.

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