Process for the production of eltrombopag olamine

Abstract

To provide a method capable of producing eltrombopag olamine with reduced residual solvent levels, ensuring ease of separation operation and a high yield.SOLUTION: A method for producing eltrombopag olamine includes following steps 1-2. A total amount of monoethanolamine used in step 1 is 2-200 moles relative to 1 mole of eltrombopag. (Step 1): reacting eltrombopag and monoethanolamine within a temperature range of 40-90°C, in the absence of a solvent. (Step 2): exposing the reaction product from step 1 to a lower alcohol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing eltrombopag olamine.

Background Art

[0002] Eltrombopag olamine is a medicine effective for chronic idiopathic thrombocytopenic purpura and aplastic anemia (Non-Patent Documents 1 and 2). As a method for producing such eltrombopag olamine, for example, a method of reacting eltrombopag and ethanolamine in the presence of tetrahydrofuran (THF) (Patent Document 1), a method of reacting eltrombopag and ethanolamine in the presence of ethyl acetate at around room temperature (Patent Document 2), and a method of heating and reacting eltrombopag and ethanolamine, cooling it at room temperature as it is, and then performing filtration and ethanol washing (Patent Document 3) are known.

[0003] In addition, three types of crystal polymorphs and amorphous forms have been confirmed in eltrombopag olamine (Patent Document 4). Among them, type I crystals having peaks at diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2°, and 23.0° ± 0.2° in the powder X-ray diffraction spectrum are useful for treating, for example, symptoms causing thrombocytopenia.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] Patent Document 1 describes, as the above method of reacting eltrombopag with ethanolamine in the presence of THF, a method (Example 2) in which eltrombopag is dissolved in THF at room temperature, and ethanolamine is added thereto for reaction. However, the residual solvent concentration was high, and it was not suitable as a pharmaceutical manufacturing method. Patent Document 1 also describes a method (Example 4) in which eltrombopag is completely dissolved in THF at room temperature, filtered and washed with THF to obtain an eltrombopag solution, while a mixed solution of ethanolamine and ethanol is distilled, and the above eltrombopag solution is dropped into the distilled ethanolamine at a dropping rate equal to or slightly slower than the distillation rate. However, in this method, a large amount of ethanol remained (1200 ppm). In addition, since it was necessary to make the distillation rate and the dropping rate substantially equal, the operation was complicated and it was not suitable as a manufacturing method on an industrial scale.

[0007] Also, when the inventors reacted eltrombopag with ethanolamine in the presence of ethyl acetate as described in Patent Document 2, the residual solvent concentration became extremely high, and there was a problem with the reproducibility of reducing the residual solvent concentration.

[0008] In particular, when THF or ethyl acetate remains in eltrombopag olamine, even if the drying process is carried out for a long time, the residual solvent concentration is hardly reduced. There is also a problem that when the drying temperature is increased, the amount of type II crystals produced increases instead of type I crystals.

[0009] Further, Patent Document 3 describes a method in which eltrombopag and ethanolamine are heated and reacted, and then cooled at room temperature as it is, followed by filtration and ethanol washing (Example 13). However, when the solid-liquid separation treatment was performed only by cooling the reaction product of eltrombopag and ethanolamine in this way, the yield was insufficient. The inventors also found through research that the viscosity of the reaction product is high and the separation operation requires a long time. Patent Document 3 also describes a method of reacting eltrombopag and ethanolamine at room temperature (Examples 14 and 19). However, the residual solvent concentration becomes high, leaving problems as a pharmaceutical manufacturing method.

[0010] An object of the present invention is to provide a method capable of producing eltrombopag olamine with a reduced residual solvent concentration by a simple separation operation and in a high yield.

Means for Solving the Problems

[0011] As a result of intensive studies, the inventors have found that by reacting a specific amount of monoethanolamine with eltrombopag in the range of 40 to 90 °C without a solvent and then bringing the reaction product into contact with a lower alcohol, eltrombopag olamine with a reduced residual solvent concentration can be produced by a simple separation operation and in a high yield.

[0012] That is, the present invention provides the following <1> to <10>. <1> A method for producing eltrombopag olamine, including the following steps 1 to 2, wherein the total amount of monoethanolamine used in step 1 is 2 to 200 moles per mole of eltrombopag (hereinafter, also referred to as the eltrombopag olamine production method of the present invention). (Step 1) A step of reacting eltrombopag with monoethanolamine within a range of 40 to 90 °C and without a solvent (Step 2) A step of bringing the reaction product obtained in Step 1 into contact with a lower alcohol

[0013] <2> The production method according to <1>, further comprising the following Step 3. (Step 3) A step of separating eltrombopag olamine from the slurry obtained in Step 2 <3> The production method according to <1> or <2>, wherein the reaction temperature in Step 1 is within a range of 45 to 80 °C. <4> The production method according to any one of <1> to <3>, wherein the total usage amount of monoethanolamine used in Step 1 is 4 to 100 moles relative to 1 mole of eltrombopag. <5> The production method according to any one of <1> to <4>, wherein the reaction time in Step 1 is 3 minutes to 24 hours.

[0014] <6> The production method according to any one of <1> to <5>, wherein the lower alcohol used in Step 2 is a linear or branched alcohol having 1 to 4 carbon atoms. <7> The production method according to any one of <1> to <6>, wherein the total usage amount of the lower alcohol used in Step 2 is 3 to 50 mL relative to 1 g of eltrombopag. <8> The production method according to any one of <1> to <7>, wherein Step 2 is a step of dropping a lower alcohol into the reaction product obtained in Step 1. <9> The production method according to any one of <1> to <8>, further comprising the following Step 4. (Step 4) A step of drying the eltrombopag olamine separated in Step 3 <10> The production method according to any one of <1> to <9>, wherein the eltrombopag olamine is a crystal having peaks at at least one selected from diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2° and 23.0° ± 0.2° in a powder X-ray diffraction spectrum.

Advantages of the Invention

[0015] According to the present invention, eltrombopag olamine with a reduced solvent residue concentration can be produced with a simple separation operation and in a high yield.

Brief Description of the Drawings

[0016]

Figure 1

Mode for Carrying Out the Invention

[0017] The method for producing eltrombopag olamine of the present invention includes the following steps 1 to 2, and is characterized in that the total amount of monoethanolamine used in step 1 is 2 to 200 moles per 1 mole of eltrombopag. (Step 1) A step of reacting eltrombopag with monoethanolamine without a solvent within a range of 40 to 90°C (Step 2) A step of bringing the reaction product obtained in step 1 into contact with a lower alcohol

[0018] (Step 1) The eltrombopag used in step 1 (chemical name: 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid) is the compound represented by the following formula (1)

[0019]

Chemical formula

[0020] It is a compound represented by. Specifically, it is the free form of eltrombopag, preferably the non-solvate of the free form of eltrombopag. The Eltron bopag used in Project 1 may be amorphous, crystalline, or a mixture of these. The crystalline form of the Eltron bopag can be confirmed by known methods such as X-ray diffraction measurement (specifically, powder X-ray diffraction measurement, etc.), thermal analysis measurement (specifically, differential thermal analysis (DTA), differential scanning calorimetry (DSC), etc.), solid-state NMR measurement, infrared spectroscopy (IR), etc. In this specification, the powder X-ray diffraction peak refers to the peak measured using Cu irradiation, and more specifically, the peak measured using Cu irradiation at 1.54 angstroms.

[0021] Examples of the crystal of Eltron bopag include a crystal having a peak at at least one selected from diffraction angles (2θ): 4.0° ± 0.2°, 7.3° ± 0.2°, 7.7° ± 0.2°, 12.1° ± 0.2°, and 16.1° ± 0.2° in the powder X-ray diffraction spectrum (Eltron bopag type I crystal); a crystal having a peak at at least one selected from diffraction angles (2θ): 9.2° ± 0.2°, 11.2° ± 0.2°, 12.2° ± 0.2°, and 14.0° ± 0.2° in the powder X-ray diffraction spectrum (Eltron bopag type III crystal (hydrate)); a crystal having a peak at at least one selected from diffraction angles (2θ): 5.9° ± 0.2°, 8.2° ± 0.2°, 10.5° ± 0.2°, and 12.5° ± 0.2° in the powder X-ray diffraction spectrum (Eltron bopag type V crystal (tetrahydrofuran / water solvate)); a crystal having a peak at at least one selected from diffraction angles (2θ): 7.1° ± 0.2°, 9.5° ± 0.2°, 13.9° ± 0.2°, 21.2° ± 0.2°, and 25.5° ± 0.2° in the powder X-ray diffraction spectrum (Eltron bopag type XVI crystal (monohydrate)).

[0022] As the eltrombopag type I crystal, those having peaks at at least two or more selected from diffraction angles (2θ): 4.0° ± 0.2°, 7.3° ± 0.2°, 7.7° ± 0.2°, 12.1° ± 0.2° and 16.1° ± 0.2° in the powder X-ray diffraction spectrum are preferred, those having peaks at diffraction angles (2θ): 4.0° ± 0.2°, 7.3° ± 0.2°, 7.7° ± 0.2°, 12.1° ± 0.2° and 16.1° ± 0.2° in the powder X-ray diffraction spectrum are more preferred, and those having peaks at 8.8° ± 0.2°, 14.6° ± 0.2°, 17.6° ± 0.2°, 24.3° ± 0.2° and 26.8° ± 0.2° in addition to these are particularly preferred. From another perspective, as the eltrombopag type I crystal, the solid phase 13 Those having peaks at 166.9 ± 0.2 ppm, 155.4 ± 0.2 ppm, 134.1 ± 0.2 ppm, 125.7 ± 0.2 ppm and 111.8 ± 0.2 ppm in the 13C NMR spectrum are preferred.

[0023] When the eltrombopag used in Step 1 contains the eltrombopag type I crystal, as the eltrombopag used in Step 1, the eltrombopag type I crystal having a chemical purity of 95% or more and 100% or less measured by HPLC is preferred, and the eltrombopag type I crystal having a chemical purity of 99% or more and 100% or less measured by HPLC is more preferred.

[0024] For eltrombopag, a commercially available product or a product obtained by synthesis according to a conventional method may be used.

[0025] The total amount of monoethanolamine used in Step 1 is 2 to 200 moles per 1 mole of eltrombopag. When the total amount of monoethanolamine used is less than 2 moles per 1 mole of eltrombopag, the eltrombopag monoethanolamine salt is likely to be formed, and the yield of eltrombopag olamine becomes insufficient. Also, when the total amount of monoethanolamine used exceeds 200 moles per 1 mole of eltrombopag, the yield of eltrombopag olamine becomes insufficient. The total amount of monoethanolamine used in Step 1 is preferably in the range of 4 to 100 moles, more preferably in the range of 5 to 70 moles, and particularly preferably in the range of 7 to 40 moles, per mole of eltrombopag, from the viewpoints of reaction efficiency, production cost, and reduction of the residual solvent concentration. When the total amount of monoethanolamine is in the range of 7 to 40 moles per mole of eltrombopag, the residual solvent concentration can be particularly reduced.

[0026] Step 1 is carried out without a solvent, and the total amount of eltrombopag and monoethanolamine is preferably 90 to 100% by mass, more preferably 95 to 100% by mass, and particularly preferably 99 to 100% by mass, based on the total amount of the liquid phase (excluding the product) in the reaction system. In Step 1, eltrombopag and monoethanolamine can be reacted, for example, by coexisting and stirring them. It should be noted that either monoethanolamine can be added to eltrombopag for reaction, or eltrombopag can be added to monoethanolamine for reaction.

[0027] The reaction temperature of Step 1 is in the range of 40 to 90°C. When the reaction temperature is less than 40°C, the residual solvent concentration increases, and when it exceeds 90°C, the impurities increase. From the viewpoint of reducing the residual solvent concentration, the reaction temperature of Step 1 is preferably 45 to 80°C, more preferably 45 to 70°C, still more preferably 45 to 65°C, still more preferably 45 to 60°C, still more preferably 45 to 55°C, and particularly preferably 45 to 50°C. When the reaction temperature of Step 1 is 45 to 80°C, the residual solvent is further reduced in concentration.

[0028] The reaction time of Step 1 is usually 3 minutes to 24 hours, and from the viewpoint of reducing the residual solvent concentration, it is preferably 10 minutes to 12 hours, more preferably 15 minutes to 6 hours, still more preferably 15 minutes to 2 hours, and particularly preferably 30 minutes to 2 hours.

[0029] (Step 2) Step 2 is a step of bringing the reaction product obtained in Step 1 into contact with a lower alcohol. This lower alcohol acts as a poor solvent and crystallizes eltrombopag olamine from the reaction product obtained in Step 1. As a result, the purity of eltrombopag olamine is improved. At the same time, since the crystals of eltrombopag olamine are dispersed in the lower alcohol (poor solvent), they can be easily separated by filtration or the like, and eltrombopag olamine can be recovered with a short separation operation and a high yield. Examples of the lower alcohol include linear or branched alcohols having 1 to 4 carbon atoms, preferably linear or branched monohydric alcohols having 1 to 4 carbon atoms, and more preferably linear or branched saturated monohydric alcohols having 1 to 4 carbon atoms. Examples of the lower alcohol include methanol, ethanol (EtOH), n-propanol, isopropanol, and butanol. Among these, from the viewpoints of safety and economy, EtOH and isopropanol are preferred, and EtOH is particularly preferred. From the viewpoints of reducing the concentration of the residual solvent and economy, the total amount of the lower alcohol used in Step 2 is preferably 3 to 50 mL, more preferably 5 to 40 mL, still more preferably 10 to 35 mL, and particularly preferably 15 to 30 mL per 1 g of eltrombopag.

[0030] From the viewpoint of reducing the concentration of the residual solvent, Step 2 is preferably a step of dropping the lower alcohol into the reaction product obtained in Step 1. The dropping may be by divided addition or continuous addition. Specifically, a method of charging the reaction product obtained in Step 1 into a reaction vessel in advance, setting a predetermined temperature if necessary, and then dropping the lower alcohol in a divided or continuous manner can be mentioned. In addition, the dropping may be carried out while stirring the reaction product obtained in Step 1. From the viewpoint of reducing the concentration of the residual solvent, the dropping rate is preferably 0.03 to 1.66 mL / min, more preferably 0.04 to 1.34 mL / min, and particularly preferably 0.12 to 1 mL / min per 1 g of eltrombopag. The stirring rate of the reaction product obtained in Step 1 when dropping the lower alcohol is usually 30 to 60 rpm, although it depends on the stirring device and the stirring vessel.

[0031] The contact temperature in Step 2 is preferably the same temperature as the reaction temperature in Step 1. That is, from the viewpoint of reducing the residual solvent concentration, the contact temperature in Step 2 is preferably 40 to 90°C, more preferably 45 to 80°C, still more preferably 45 to 70°C, still more preferably 45 to 65°C, still more preferably 45 to 60°C, still more preferably 45 to 55°C, and particularly preferably 45 to 50°C.

[0032] (Step 3) As the method for producing eltrombopag olamine of the present invention, in addition to Steps 1 to 2, a method including a step of separating eltrombopag olamine from the slurry obtained in Step 2 (Step 3) is preferred. Here, in this specification, the slurry refers to a mixture of a solid substance in a liquid. Examples of the separation operation in Step 3 include solid-liquid separation operations such as filtration (e.g., normal pressure filtration, pressure filtration, vacuum filtration, etc.), centrifugation, and decantation, and one or more of these solid-liquid separation operations can be combined and carried out. The separation temperature in Step 3 is usually 10 to 40°C, preferably 15 to 30°C. It is preferable to pre-age the slurry obtained in Step 2 at the above separation temperature prior to the separation operation in Step 3. The aging time is usually within the range of 0.15 to 12 hours. According to the present invention, eltrombopag olamine can be separated by such a simple method.

[0033] (Step 4) As the method for producing eltrombopag olamine of the present invention, in addition to Steps 1 to 3, a method including a step of drying the eltrombopag olamine separated in Step 3 (Step 4) is preferred. Note that prior to Step 4, the eltrombopag olamine may be washed with a lower alcohol. Examples of the lower alcohol used for washing include the same ones as those used in Step 2. Specific examples of the drying treatment method in Step 4 include, for example, heat drying, freeze drying, vacuum drying, vacuum drying, ventilation drying, spray drying, etc. The pressure during vacuum drying is preferably 0.1 to 4 kPa. As the drying temperature, 40 to 60°C is preferable, and 45 to 55°C is more preferable. As the drying time, 1 to 189 hours is preferable, and 17 to 100 hours is more preferable. The drying treatment can be carried out using, for example, a box dryer, a vacuum dryer, a vacuum drying machine, a ventilation dryer, a spray dryer, or the like.

[0034] According to the present invention, eltrombopag olamine with a reduced solvent residue concentration can be produced with a simple separation operation and a high yield. Eltrombopag olamine is an eltrombopag bisethanolamine salt. Eltrombopag olamine may be amorphous, crystalline, or a mixture thereof, but crystals are preferred. The crystal form of eltrombopag olamine can be confirmed by known methods such as X-ray diffraction measurement (specifically, powder X-ray diffraction measurement, etc.), thermal analysis measurement (specifically, differential thermal analysis (DTA), differential scanning calorimetry (DSC), etc.), solid-state NMR measurement, infrared spectroscopy (IR), etc. As described above, in this specification, the powder X-ray diffraction peak refers to the peak measured using Cu irradiation, and more specifically, the peak measured using Cu irradiation at 1.54 angstroms.

[0035] As the crystals of eltrombopag olamine, from the viewpoints of stability and bioavailability, crystals having peaks at at least one selected from diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2° and 23.0° ± 0.2° in the powder X-ray diffraction spectrum (eltrombopag olamine type I crystals) are preferred, those having peaks at at least two selected from diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2° and 23.0° ± 0.2° in the powder X-ray diffraction spectrum are more preferred, those having peaks at diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2° and 23.0° ± 0.2° in the powder X-ray diffraction spectrum are still more preferred, and those having peaks at 5.7° ± 0.2°, 11.4° ± 0.2°, 17.2° ± 0.2° and 26.7° ± 0.2° in addition to these are particularly preferred.

[0036] When the eltrombopag olamine obtained by the method for producing eltrombopag olamine of the present invention contains eltrombopag olamine type I crystals, as the eltrombopag olamine, eltrombopag olamine type I crystals having a chemical purity of 99% or more and 100% or less as measured by HPLC are preferred, and eltrombopag olamine type I crystals having a chemical purity of 99.5% or more and 100% or less as measured by HPLC are more preferred.

Examples

[0037] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[0038] 〔Example 1〕 (Step 1) 1.8 mL (29.8 mmol, 26.3 mol times) of monoethanolamine was added to 0.5 g (1.13 mmol) of eltrombopag, and the mixture was stirred at 40°C for 15 minutes. (Step 2) Then, 10 mL (20 v / w) of EtOH was added dropwise over 60 minutes, and then the mixture was cooled to room temperature and aged for 1 hour. After subjecting the slurry obtained in (Processes 3 to 4) to vacuum filtration, it was washed with 1.5 mL (3 v / w) of EtOH and dried under reduced pressure at 50 °C for 17 hours or more. The yield of the obtained eltrombopag olamine was determined.

[0039] [Examples 2 to 18 and Comparative Examples 1 to 4] The same operations as in Example 1 were carried out except that the stirring time and stirring temperature in Step 1 were changed to those shown in Tables 1 to 4. The time required for filtration and the yield are shown in Tables 1 to 4.

[0040] [Test Example 1] Using a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. 1 The residual EtOH concentration was measured by 1H NMR (400 MHz, DMSO-d6) and evaluated according to the following criteria (note that a residual EtOH concentration of 500 ppm or less is synonymous with 1 / 10 or less of the allowable residual solvent amount in the ICH guidelines). The results of the residual EtOH concentration measurement are shown in Tables 1 to 4.

[0041] (Residual EtOH Concentration Evaluation Criteria) AAA: 100 ppm or less AA: More than 100 ppm and 200 ppm or less A: More than 200 ppm and 500 ppm or less B: More than 500 ppm and 5000 ppm or less C: More than 5000 ppm

[0042] [Table 1]

[0043] [Table 2]

[0044] [Table 3]

[0045] [Table 4]

[0046] As shown in Tables 1 to 4, when the reaction temperature of eltrombopag and monoethanolamine was less than 40 °C (Comparative Examples 1 to 4), the residual solvent concentration became high.

[0047] [Examples 19 to 20] The same operations as in Example 1 were carried out except that the amount of monoethanolamine used per 1 mol of eltrombopag was as shown in Table 5, and the stirring time and stirring temperature in Step 1 were changed to 1 hour and 60 °C, respectively. Also, the EtOH residual concentration was measured and evaluated in the same manner as in Test Example 1. The EtOH residual concentration, the time required for filtration, and the yield are shown in Table 5.

[0048]

Table 5

[0049] [Examples 21 to 22] The same operations as in Example 1 were carried out except that the stirring time and stirring temperature in Step 1 were changed to 1 hour and 60 °C, respectively, and the EtOH used in Step 2 and washing was changed to methanol (Example 21) or isopropanol (Example 22). Also, using a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. 1 The residual solvent concentration was measured by 1H NMR (400 MHz, DMSO-d6) and evaluated according to the following criteria (note that a methanol residual concentration of 300 ppm or less and an isopropanol residual concentration of 500 ppm or less are synonymous with 1 / 10 or less of the allowable residual solvent amount in the ICH guideline). The residual solvent concentration, the time required for filtration, and the yield are shown in Table 6.

[0050] (Methanol residual concentration evaluation criteria) A: 300 ppm or less B: More than 300 ppm and 3000 ppm or less C: More than 3000 ppm

[0051] (Isopropanol residual concentration evaluation criteria) A: 500 ppm or less B: More than 500 ppm and 5000 ppm or less C: More than 5000 ppm

[0052]

Table 6

[0053] 〔Example 23〕 (Step 1) To 16.5 kg (37.3 mol) of eltrombopag with an HPLC purity of 99.7% was added 58 L (959 mol, 26-fold molar amount) of monoethanolamine, and the mixture was stirred at 50 °C for 1 hour. (Step 2) Then, 329 L (20 v / w) of EtOH was added dropwise over 40 minutes, and the mixture was cooled to room temperature and aged for 1 hour. (Steps 3 - 4) The obtained slurry was filtered under reduced pressure, washed with 49 L (3 v / w) of EtOH, and dried under reduced pressure at 50 °C for 88 hours to obtain 20.2 kg (yield 96.5%) of eltrombopag olamine with an HPLC purity of 99.9%. The residual solvent of EtOH by GC chromatography was 123 ppm. Also, the powder X-ray diffraction spectrum showed type I crystals having peaks at diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2°, and 23.0° ± 0.2° (Figure 1).

[0054] 〔Comparative Example 5〕 4 mL of monoethanolamine was dissolved in 15 mL of THF. 1 g of eltrombopag was added thereto, and the mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, it was aged for 1 hour. The obtained slurry was filtered under reduced pressure, washed with 3 mL (3 v / w) of THF, and dried under reduced pressure at 50 °C for 17 hours. The yield of the obtained eltrombopag olamine was determined. Also, using a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. 1 The residual solvent concentration was measured by 1H NMR (400 MHz, DMSO-d6) and evaluated according to the following criteria (note that a THF residual concentration of 72 ppm or less is synonymous with 1 / 10 or less of the allowable residual solvent amount in the ICH guideline). The solvent residual concentration, the time required for filtration, and the yield are shown in Table 7.

[0055] (THF Residual Concentration Evaluation Criteria) A: 72 ppm or less B: More than 72 ppm and 720 ppm or less C: More than 720 ppm

[0056] [Comparative Examples 6 - 7] The same production operations as in Comparative Example 5 were carried out except that THF was changed to ethyl acetate (Comparative Example 6) or EtOH (Comparative Example 7). Also, a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. was used 1 The solvent residual concentration was measured by 1H NMR (400 MHz, DMSO-d6). For ethyl acetate, it was evaluated according to the following criteria, and for EtOH, it was evaluated according to the same criteria as in Test Example 1 (Note that a residual ethyl acetate concentration of 500 ppm or less is synonymous with 1 / 10 or less of the allowable residual solvent amount in the ICH guidelines). In Comparative Example 6, due to the remaining monoethanolamine and crystal sticking, it could not be separated by filtration under reduced pressure, so the yield could not be calculated The solvent residual concentration, the time required for filtration, and the yield are shown in Table 7

[0057] (Ethyl Acetate Residual Concentration Evaluation Criteria) A: 500 ppm or less B: More than 500 ppm and 5000 ppm or less C: More than 5000 ppm

[0058] [Comparative Examples 8 - 9] The same production operations as in Comparative Example 5 were carried out except that THF was changed to water (Comparative Example 8) or dimethyl sulfoxide (Comparative Example 9). Also, a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. was used 1 The solvent residual concentration was measured by 1H NMR (400 MHz, DMSO-d6) The solvent residual concentration, the time required for filtration, and the yield are shown in Table 7. In Comparative Example 8, since water was used, no residual solvent was detected. In Comparative Example 9, eltrombopag olamine dissolved in dimethyl sulfoxide and could not be separated, so the solvent residual concentration could not be measured

[0059] [Comparative Example 10] 1 g of eltrombopag was added to 4 mL of monoethanolamine, and the mixture was stirred at 50 °C for 1 hour. After cooling to room temperature and aging for 1 hour, the resulting slurry was filtered under reduced pressure. The yield of eltrombopag olamine obtained was determined. Also, a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. was used 1 The residual solvent concentration was measured by 1H NMR (400 MHz, DMSO-d6). Since no solvent was used, no residual solvent was detected The residual solvent concentration, the time required for filtration, and the yield are shown in Table 7

[0060] [Table 7]

[0061] As shown in Table 7, when the reaction of eltrombopag and monoethanolamine was carried out in the presence of THF, ethyl acetate or EtOH (Comparative Examples 5 to 7), the residual solvent concentration became large Also, when the reaction of eltrombopag and monoethanolamine was carried out in the presence of water (Comparative Example 8), a long time was required for the separation operation Also, when the reaction of eltrombopag and monoethanolamine was carried out in the presence of dimethyl sulfoxide (Comparative Example 9), eltrombopag olamine could not be separated from dimethyl sulfoxide Also, when eltrombopag olamine was separated from the slurry without performing the contact operation with a lower alcohol after the reaction of eltrombopag and monoethanolamine (Comparative Example 10), a long time was required for the separation operation and the yield was also insufficient

[0062] [Comparative Examples 11 to 16] The same operations as in Example 11 were carried out except that the EtOH used in Step 2 and the washing was changed to ethyl acetate (Comparative Example 11), heptane (Comparative Example 12), tert-butyl methyl ether (Comparative Example 13), toluene (Comparative Example 14), N-methyl-2-pyrrolidone (Comparative Example 15) or water (Comparative Example 16) For Comparative Examples 11 to 14, sticking occurred, and eltrombopag olamine could not be separated by filtration, so the residual solvent concentration could not be measured. For Comparative Examples 15 to 16, eltrombopag olamine dissolved in N-methyl-2-pyrrolidone or water and could not be separated, so the residual solvent concentration could not be measured.

[0063] [Comparative Example 17] Purification was carried out using a mixture of eltrombopag olamine and THF or EtOH as a raw material instead of eltrombopag. That is, to 2 g of eltrombopag olamine, THF or EtOH was added to the concentration shown in Table 8 to prepare a raw material composition. 5.5 mL of monoethanolamine was added thereto, and the mixture was stirred at 50 °C for 1 hour. Then, 30 mL of EtOH was added dropwise over 60 minutes, and after cooling to room temperature, it was aged for 1 hour. The obtained slurry was filtered under reduced pressure, washed with 5 mL of EtOH, and dried under reduced pressure at 50 °C for 17 hours. The yield of the obtained eltrombopag olamine was determined. Also, using a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. 1 The residual solvent concentration was measured by 1H NMR (400 MHz, DMSO-d6). The residual solvent concentration and the yield are shown in Table 8.

[0064]

Table 8

[0065] [Test Example 2] Powder X-ray diffraction measurement was performed on the eltrombopag olamine obtained in Examples 1 to 22. That is, after crushing the sample, it was placed on a non-reflection test plate and powder X-ray diffraction measurement was performed (measurement apparatus: Rigaku Corporation MiniFlex600C, Cu irradiation source: 1.54 Å). The results are shown in Figure 1. (Scanning conditions) Angle range: 2 to 40° Step size: 0.02° Time per step: 10° / second

[0066] As a result of Test Example 2, it was confirmed that the eltrombopag olamine obtained in Examples 1 to 22 has peaks at 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2° and 23.0° ± 0.2° and is a type I crystal.

Claims

1. A method for producing eltrombopag olamine, comprising the following steps 1 to 2, wherein the total amount of monoethanolamine used in step 1 is 2 to 200 moles per mole of eltrombopag. (Step 1) A step of reacting eltrombopag and monoethanolamine without a solvent within a range of 40 to 90 °C (Step 2) A step of bringing the reaction product obtained in step 1 into contact with a lower alcohol

2. The production method according to claim 1, further comprising the following step 3. (Step 3) A step of separating eltrombopag olamine from the slurry obtained in step 2

3. The production method according to claim 1, wherein the reaction temperature in step 1 is within a range of 45 to 80 °C.

4. The production method according to claim 1, wherein the total amount of monoethanolamine used in step 1 is 4 to 100 moles per mole of eltrombopag.

5. The production method according to claim 1, wherein the reaction time in step 1 is 3 minutes to 24 hours.

6. The production method according to claim 1, wherein the lower alcohol used in step 2 is a linear or branched alcohol having 1 to 4 carbon atoms.

7. The production method according to claim 1, wherein the total amount of the lower alcohol used in step 2 is 3 to 50 mL per 1 g of eltrombopag.

8. The production method according to claim 1, wherein step 2 is a step of dropping a lower alcohol into the reaction product obtained in step 1.

9. The production method according to claim 2, further comprising the following step 4. (Step 4) A step of drying the eltrombopag olamine separated in step 3

10. The production method according to any one of claims 1 to 9, wherein the eltrombopag olamine is a crystal having peaks at at least one selected from diffraction angles (2θ): 7.5° ± 0.2°, 8.3° ± 0.2°, 14.0° ± 0.2° and 23.0° ± 0.2° in a powder X-ray diffraction spectrum.

Images