Method for producing 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 technology]

[0002] Eltrombopag olamine is a medicine whose efficacy is chronic idiopathic thrombocytopenic purpura and aplastic anemia (Non-Patent Documents 1 and 2). Known methods for producing such eltrombopag olamine include, for example, a method of reacting eltrombopag with ethanolamine in the presence of tetrahydrofuran (THF) (Patent Document 1), a method of reacting eltrombopag with ethanolamine in the presence of ethyl acetate at around room temperature (Patent Document 2), and a method of reacting eltrombopag with ethanolamine by heating, cooling at room temperature, and then filtering and washing with ethanol (Patent Document 3).

[0003] Eltrombopagulamine has been identified as having three types of crystalline polymorphism and an amorphous form (Patent Document 4), and type I crystals, which have peaks at diffraction angles (2θ) of 7.5°±0.2°, 8.3°±0.2°, 14.0°±0.2°, and 23.0°±0.2° in a powder X-ray diffraction spectrum, are useful for treating conditions that cause, for example, thrombocytopenia. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2003 / 098992 [Patent Document 2] China Patent Publication No. 106966984 [Patent Document 3] US Patent Application Publication No. 2015 / 0087845 [Patent Document 4] WO2010 / 114943 [Non-patent literature]

[0005] [Non-Patent Document 1] Revolade (registered trademark) Tablets 12.5 mg Revolade (registered trademark) Tablets 25 mg Pharmaceutical Interview Form Novartis Pharma K.K. Revised November 2018 (10th edition) [Non-Patent Document 2] US Drug Package Insert PROMACTA® (eltrombopag) Tablets, URL: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2011 / 022291s006lbl.pdf Summary of the Invention [Problem to be solved by the invention]

[0006] Patent Document 1 describes a method for reacting eltrombopag with ethanolamine in the presence of THF in which eltrombopag is dissolved in THF at room temperature and ethanolamine is added thereto to cause a reaction (Example 2). However, this method results in a high residual solvent concentration and is not suitable as a method for producing pharmaceuticals. Patent Document 1 also describes a method (Example 4) in which eltrombopag is completely dissolved in THF at room temperature, and an eltrombopag solution is obtained by filtering and washing with THF, while a mixture of ethanolamine and ethanol is distilled and the eltrombopag solution is dropped into the distilled ethanolamine at the distillation rate or a rate slightly slower than the distillation rate. However, this method left a large amount of residual ethanol (1200 ppm), and the operation was complicated because the distillation rate and the dropping rate had to be approximately equal, making it unsuitable for an industrial-scale production process.

[0007] Furthermore, when the present 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 eltrombopagolamine, the residual solvent concentration is hardly reduced even if the drying treatment is performed for a long period of time, and there is also the problem that increasing the drying temperature increases the amount of crystals of type II rather than type I.

[0009] In addition, Patent Document 3 describes a method in which eltrombopag and ethanolamine are reacted by heating as described above, cooled to room temperature, and then filtered and washed with ethanol (Example 13). However, when the reaction product of eltrombopag and ethanolamine was subjected to solid-liquid separation treatment by simply cooling it in this manner, the yield was insufficient. Furthermore, the inventors of the present invention found that the viscosity of the reaction product was high, and the separation operation required a long time. Furthermore, Patent Document 3 also describes a method of reacting eltrombopag with ethanolamine at room temperature (Examples 14 and 19), but this results in a high residual solvent concentration, which poses a problem for use in the production of pharmaceutical products.

[0010] An object of the present invention is to provide a method for producing eltrombopag olamine having a reduced residual solvent concentration in a high yield through a simple separation procedure. [Means for solving the problem]

[0011] As a result of extensive research, 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 contacting the reaction product with a lower alcohol, eltrombopag olamine with a reduced residual solvent concentration can be produced with a simple separation procedure and in high yield.

[0012] That is, the present invention provides the following: <1> ~ <10> This provides: <1> A method for producing eltrombopag olamine, comprising the following steps 1 and 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 method for producing eltrombopag olamine of the present invention): (Step 1) Reacting eltrombopag with monoethanolamine at a temperature within the range of 40 to 90°C without using a solvent (Step 2) A step of contacting the reaction product obtained in step 1 with a lower alcohol

[0013] <2> The method further includes the following step 3: <1> The manufacturing method described in (Step 3) A step of separating eltrombopag olamine from the slurry obtained in step 2. <3> The reaction temperature in step 1 is within the range of 45 to 80°C. <1> or <2> The manufacturing method described in <4> The total amount of monoethanolamine used in step 1 is 4 to 100 moles per mole of eltrombopag. <1> ~ <3> 13. The method for producing a semiconductor device according to any one of the preceding claims. <5> The reaction time in step 1 is 3 minutes to 24 hours. <1> ~ <4> 13. The method for producing a semiconductor device according to any one of the preceding claims.

[0014] <6> The lower alcohol used in step 2 is a linear or branched alcohol having 1 to 4 carbon atoms. <1> ~ <5> 13. The method for producing a semiconductor device according to any one of the preceding claims. <7> The total amount of the lower alcohol used in step 2 is 3 to 50 mL per 1 g of eltrombopag. <1> ~ <6> 13. The method for producing a semiconductor device according to any one of the preceding claims. <8> Step 2 is a step of adding a lower alcohol dropwise to the reaction product obtained in step 1. <1> ~ <7> 13. The method for producing a semiconductor device according to any one of the preceding claims. <9> The method further includes the following step 4: <1> ~ <8> 13. The method for producing a semiconductor device according to any one of the preceding claims. (Step 4) A step of drying the eltrombopag olamine separated in step 3. <10> The eltrombopagolamine is a crystal having a peak at at least one or more diffraction angles (2θ) selected from 7.5°±0.2°, 8.3°±0.2°, 14.0°±0.2°, and 23.0°±0.2° in a powder X-ray diffraction spectrum. <1> ~ <9> 13. The method for producing a semiconductor device according to any one of the preceding claims. Effect of the Invention

[0015] According to the present invention, eltrombopag olamine having a reduced residual solvent concentration can be produced in high yield by a simple separation procedure. [Brief description of the drawings]

[0016] [Figure 1] FIG. 2 shows the powder X-ray diffraction (XRD) pattern of the compound prepared in Example 23. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The method for producing eltrombopag olamine of the present invention comprises the following steps 1 and 2, and is characterized in that the total amount of monoethanolamine used in step 1 is 2 to 200 mol per 1 mol of eltrombopag. (Step 1) Reacting eltrombopag with monoethanolamine at a temperature within the range of 40 to 90°C without using a solvent (Step 2) A step of contacting the reaction product obtained in step 1 with a lower alcohol

[0018] (Process 1) Eltrombopag (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) used in step 1 is represented by the following formula (1):

[0019] [ka]

[0020] Specifically, it is a free form of eltrombopag, and preferably a non-solvate of the free form of eltrombopag. Eltrombopag used in step 1 may be amorphous, crystalline, or a mixture thereof. The crystalline form of eltrombopag 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 used herein, powder X-ray diffraction peak refers to a peak measured using Cu irradiation, and more specifically, to a peak measured using Cu irradiation at 1.54 angstroms.

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

[0022] The eltrombopag type I crystals preferably have peaks in an X-ray powder diffraction spectrum at at least two or more angles selected from the group consisting of 4.0°±0.2°, 7.3°±0.2°, 7.7°±0.2°, 12.1°±0.2°, and 16.1°±0.2°, more preferably have peaks in an X-ray powder diffraction spectrum 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°, and particularly preferably have peaks in an X-ray powder diffraction spectrum at 8.8°±0.2°, 14.6°±0.2°, 17.6°±0.2°, 24.3°±0.2°, and 26.8°±0.2°. From another perspective, the solid phase of eltrombopag type I crystals 13 Preferred are 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 C NMR spectrum.

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

[0024] Eltrombopag may be a commercially available product or may be synthesized according to a conventional method.

[0025] The total amount of monoethanolamine used in step 1 is 2 to 200 moles per mole of eltrombopag. If the total amount of monoethanolamine used is less than 2 moles per mole of eltrombopag, eltrombopag monoethanolamine salt is easily produced, resulting in an insufficient yield of eltrombopag olamine. If the total amount of monoethanolamine used is more than 200 moles per mole of eltrombopag, the yield of eltrombopag olamine is insufficient. The total amount of monoethanolamine used in step 1 is preferably in the range of 4 to 100 mol, more preferably in the range of 5 to 70 mol, and particularly preferably in the range of 7 to 40 mol, per 1 mol of eltrombopag, from the viewpoints of reaction efficiency, production costs, and low concentration of residual solvents. When the total amount of monoethanolamine used is within the range of 7 to 40 mol per 1 mol 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 mass%, more preferably 95 to 100 mass%, and particularly preferably 99 to 100 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 them and stirring them. Note that monoethanolamine may be added to eltrombopag and reacted with each other, or eltrombopag may be added to monoethanolamine and reacted with each other.

[0027] The reaction temperature in step 1 is within the range of 40 to 90° C. If the reaction temperature is lower than 40° C., the concentration of residual solvent increases, whereas if it is higher than 90° C., impurities increase. From the viewpoint of reducing the concentration of the residual solvent, the reaction temperature in step 1 is preferably 45 to 80° C., more preferably 45 to 70° C., even more preferably 45 to 65° C., even more preferably 45 to 60° C., even more preferably 45 to 55° C., and particularly preferably 45 to 50° C. When the reaction temperature in step 1 is 45 to 80° C., the concentration of the residual solvent is further reduced.

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

[0029] (Process 2) Step 2 is a step of contacting the reaction product obtained in step 1 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, the crystals of eltrombopag olamine are dispersed in the lower alcohol (poor solvent), allowing easy separation by filtration or the like, and allowing eltrombopag olamine to be recovered in a high yield with a short separation operation. The lower alcohol includes linear or branched alcohols having 1 to 4 carbon atoms, preferably linear or branched monohydric alcohols having 1 to 4 carbon atoms, 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. The total amount of the lower alcohol used in step 2 is preferably 3 to 50 mL, more preferably 5 to 40 mL, even more preferably 10 to 35 mL, and particularly preferably 15 to 30 mL per g of eltrombopag, from the viewpoints of reducing the residual solvent concentration and economic efficiency.

[0030] From the viewpoint of reducing the concentration of the residual solvent, step 2 is preferably a step of adding a lower alcohol dropwise to the reaction product obtained in step 1. The dropwise addition may be divided or continuous. Specifically, the reaction product obtained in step 1 is charged in a reaction vessel in advance, and after the reaction vessel is heated to a predetermined temperature as necessary, the lower alcohol is added dropwise in divided portions or continuously. The reaction product obtained in step 1 may be added dropwise while being stirred. 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 the lower alcohol is dropped is usually 30 to 60 rpm, although it depends on the stirring device and stirring vessel.

[0031] The contact temperature in step 2 is preferably the same 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, even more preferably 45 to 70°C, even more preferably 45 to 65°C, even more preferably 45 to 60°C, even more preferably 45 to 55°C, and particularly preferably 45 to 50°C.

[0032] (Step 3) The method for producing eltrombopag olamine of the present invention preferably includes, in addition to steps 1 and 2, a step (step 3) of separating eltrombopag olamine from the slurry obtained in step 2. In this specification, the term "slurry" refers to a mixture of a solid substance in a liquid. The separation operation in step 3 includes solid-liquid separation operations such as filtration (e.g., atmospheric filtration, pressure filtration, reduced pressure filtration, etc.), centrifugation, decantation, etc., and one or more of these solid-liquid separation operations can be combined. The separation temperature in step 3 is usually 10 to 40° C., preferably 15 to 30° C. It is preferable to previously age the slurry obtained in step 2 at the above separation temperature prior to the separation operation in step 3. The ageing 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) The method for producing eltrombopag olamine of the present invention preferably includes, in addition to steps 1 to 3, a step (step 4) of drying the eltrombopag olamine separated in step 3. Prior to step 4, eltrombopag olamine may be washed with a lower alcohol. Examples of the lower alcohol used for washing include the same lower alcohols as those used in step 2. Specific examples of the drying method in step 4 include heat drying, freeze drying, reduced pressure drying, vacuum drying, aeration drying, spray drying, etc. The pressure during reduced pressure drying is preferably 0.1 to 4 kPa. The drying temperature is preferably from 40 to 60°C, and more preferably from 45 to 55°C. The drying time is preferably from 1 to 189 hours, and more preferably from 17 to 100 hours. The drying treatment can be carried out using, for example, a box dryer, a reduced pressure dryer, a vacuum dryer, a ventilation dryer, a spray dryer, or the like.

[0034] According to the present invention, eltrombopag olamine having a reduced residual solvent concentration can be produced in high yield by a simple separation procedure. Eltrombopag olamine is an eltrombopag bisethanolamine salt. Eltrombopag olamine may be amorphous, crystalline, or a mixture thereof, but is preferably crystalline. The crystalline 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 mentioned above, in this specification, powder X-ray diffraction peak refers to a peak measured using Cu irradiation, and more specifically, a peak measured using Cu irradiation at 1.54 angstroms.

[0035] From the viewpoints of stability and bioavailability, the crystals of eltrombopag olamine are preferably crystals having peaks at at least one or more angles selected from the diffraction angles (2θ) of 7.5°±0.2°, 8.3°±0.2°, 14.0°±0.2°, and 23.0°±0.2° in a powder X-ray diffraction spectrum (eltrombopag olamine type I crystals). More preferably, the powder X-ray diffraction spectrum has peaks at diffraction angles (2θ): 7.5°±0.2°, 8.3°±0.2°, 14.0°±0.2°, and 23.0°±0.2°, and further preferably, the powder X-ray diffraction spectrum has peaks at diffraction angles (2θ): 7.5°±0.2°, 8.3°±0.2°, 14.0°±0.2°, and 23.0°±0.2°, and particularly preferably, the powder X-ray diffraction spectrum has peaks at these angles as well as 5.7°±0.2°, 11.4°±0.2°, 17.2°±0.2°, and 26.7°±0.2°.

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

[0037] The present invention will be described in detail below 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-fold) 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) Next, 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. (Steps 3 and 4) The obtained slurry was filtered under reduced pressure, washed with 1.5 mL (3 v / w) of EtOH, and dried under reduced pressure for 17 hours or more at 50° C. The yield of the obtained eltrombopagolamine 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 times required for filtration and the yields are shown in Tables 1 to 4.

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

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

[0042] [Table 1]

[0043] [Table 2]

[0044] [Table 3]

[0045] [Table 4]

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

[0047] [Examples 19-20] The same procedure as in Example 1 was carried out, except that the amount of monoethanolamine used per mole 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. In addition, the residual EtOH concentration was measured and evaluated in the same manner as in Test Example 1. The residual EtOH concentration, the time required for filtration, and the yield are shown in Table 5.

[0048] [Table 5]

[0049] [Examples 21-22] The same procedure as in Example 1 was 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). 1 Residual solvent concentrations were measured by H NMR (400 MHz, DMSO-d6) and evaluated according to the following criteria (note that a residual methanol concentration of 300 ppm or less and a residual isopropanol concentration of 500 ppm or less are equivalent to 1 / 10 or less of the allowable residual solvent amount in the ICH guidelines). Table 6 shows the residual solvent concentration, the time required for filtration, and the yield.

[0050] (Methanol Residual Concentration Evaluation Standard) A: 300ppm or less B: More than 300ppm and less than 3000ppm C: More than 3000ppm

[0051] (Isopropanol Residual Concentration Evaluation Standard) A: 500ppm or less B: More than 500ppm and less than 5000ppm C: More than 5000ppm

[0052] [Table 6]

[0053] Example 23 (Step 1) 58 L (959 mol, 26 mol-fold) of monoethanolamine was added to 16.5 kg (37.3 mol) of eltrombopag with an HPLC purity of 99.7%, and the mixture was stirred at 50° C. for 1 hour. (Step 2) Next, 329 L (20 v / w) of EtOH was added dropwise over 40 minutes, and the mixture was then 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 (96.5% yield) of eltrombopagolamine with an HPLC purity of 99.9%. The residual solvent of EtOH was 123 ppm by GC chromatography. In addition, the powder X-ray diffraction spectrum showed type I crystals with 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 stirred at 50°C for 1 hour. The mixture was cooled to room temperature and aged for 1 hour. The resulting 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 resulting eltrombopag olamine was determined. In addition, a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. was used. 1 Residual solvent concentrations were measured by 1 H NMR (400 MHz, DMSO-d6) and evaluated according to the following criteria (note that a residual THF concentration of 72 ppm or less is equivalent to 1 / 10 or less of the allowable residual solvent amount in the ICH guidelines). The residual solvent concentration, the time required for filtration, and the yield are shown in Table 7.

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

[0056] [Comparative Examples 6 to 7] The same production procedure as in Comparative Example 5 was carried out, except that THF was replaced with ethyl acetate (Comparative Example 6) or EtOH (Comparative Example 7). 1 The residual solvent concentration was measured by H NMR (400 MHz, DMSO-d6), and ethyl acetate was evaluated according to the following criteria, and EtOH 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 equivalent to 1 / 10 or less of the allowable residual solvent amount in the ICH guidelines). Note that in Comparative Example 6, the yield could not be calculated because separation by reduced pressure filtration was not possible due to the remaining monoethanolamine and the adhesion of the crystals. The residual solvent concentration, the time required for filtration, and the yield are shown in Table 7.

[0057] (Ethyl acetate residual concentration evaluation standard) A: 500ppm or less B: More than 500ppm and less than 5000ppm C: More than 5000ppm

[0058] [Comparative Examples 8 to 9] The same production procedure as in Comparative Example 5 was carried out, except that THF was replaced with water (Comparative Example 8) or dimethyl sulfoxide (Comparative Example 9). 1 The residual solvent concentration was measured by H NMR (400 MHz, DMSO-d6). The residual solvent concentration, the time required for filtration, and the yield are shown in Table 7. In Comparative Example 8, the residual solvent was not detected because water was used. In Comparative Example 9, eltrombopag olamine was dissolved in dimethyl sulfoxide and could not be separated, so the residual solvent concentration could not be measured.

[0059] Comparative Example 10 1 g of eltrombopag was added to 4 mL of monoethanolamine and 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 the resulting eltrombopag olamine was determined. 1 The residual solvent concentration was measured by H 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 with monoethanolamine was carried out in the presence of THF, ethyl acetate, or EtOH (Comparative Examples 5 to 7), the residual solvent concentration was high. Furthermore, when the reaction between eltrombopag and monoethanolamine was carried out in the presence of water (Comparative Example 8), a long period of time was required for the separation procedure. Furthermore, when the reaction between eltrombopag and monoethanolamine was carried out in the presence of dimethyl sulfoxide (Comparative Example 9), eltrombopag olamine could not be separated from the dimethyl sulfoxide. Furthermore, when eltrombopag olamine was separated from the slurry without contacting it with a lower alcohol after the reaction of eltrombopag with monoethanolamine (Comparative Example 10), the separation operation took a long time and the yield was 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 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). In Comparative Examples 11 to 14, adhesion occurred, and eltrombopag olamine could not be separated by filtration, and the residual solvent concentration could not be measured. In Comparative Examples 15 to 16, eltrombopagolamine was 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 the raw material, rather than eltrombopag. That is, a raw material composition was prepared by adding THF or EtOH to 2 g of eltrombopag olamine to the concentration shown in Table 8. 5.5 mL of monoethanolamine was added thereto and stirred at 50°C for 1 hour. Next, 30 mL of EtOH was added dropwise over 60 minutes, and the mixture was cooled to room temperature and 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. In addition, a nuclear magnetic resonance apparatus manufactured by JEOL Ltd. was used. 1 The residual solvent concentration was measured by H NMR (400 MHz, DMSO-d6). The residual solvent concentrations and yields are shown in Table 8.

[0064] [Table 8]

[0065] [Test Example 2] The eltrombopag olamine obtained in Examples 1 to 22 was subjected to powder X-ray diffraction measurement. That is, the sample was ground, then placed on a non-reflective test plate and subjected to powder X-ray diffraction measurement (measuring device: Rigaku MiniFlex600C, Cu irradiation source: 1.54 Å). The results are shown in Figure 1. (Scanning conditions) Angle range: 2~40° Step size: 0.02° Time per step: 10° / sec

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

Claims

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

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

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

6. The 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 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 method according to claim 1, wherein step 2 is a step of adding a lower alcohol dropwise to the reaction product obtained in step 1.

9. The method according to claim 1 , further comprising the following step 4: (Step 4) A step of drying the eltrombopag olamine separated in step 3

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

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