Preparation method of fenerenone crystal form

Abstract

The invention relates to a method for preparing a crystal form of fenerenone. The invention provides the preparation method of the fenerenone crystal form I. The preparation method is simple and convenient to operate, high in yield and / or low in solvent residue, particularly, the dosage of ethanol for toluene denaturation is remarkably reduced, the complex distillation operation with the end point difficult to control is avoided, and the method is more environmentally friendly.

Description

Technical Field

[0001] The invention relates to a method for preparing a finerenone crystal form, and belongs to the field of drug crystal form preparation methods. Background Art

[0002] Diabetes is the main risk factor for chronic kidney disease (CKD), and about 50% of patients with type 2 diabetes mellitus (T2DM) will develop CKD. Domestic and international consensus and guidelines have proposed that attention should be paid to the screening of CKD in diabetic patients, so as to achieve early diagnosis and early treatment to delay the progression of CKD and reduce the occurrence of related cardiovascular events.

[0003] Mineralocorticoid receptors (MR) are expressed in the kidneys, heart, and blood vessels. Overactivation of MR in diabetic CKD patients mediates the occurrence and development of inflammation and fibrosis in renal and cardiac tissues, further leading to the occurrence of a variety of adverse renal and cardiac clinical outcomes. Blocking MR overactivation is crucial for preventing and treating adverse renal and cardiovascular outcomes. Previous studies have shown that Asian T2DM patients are more likely to have proteinuria and higher levels of urinary protein, which may be related to the salt-sensitive gene background and high-salt diet habits of the Asian population. One of the main mechanisms for salt sensitivity and high salt intake to cause kidney damage is MR overactivation.

[0004] The traditional steroid mineralocorticoid receptor antagonist (MRA) spironolactone has not been explored in depth in the field of CKD due to the risk of sex steroid receptor cross-reactivity and hyperkalemia. The new nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone ((4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide) has been proven to have a clear renal and cardiovascular protective effect on patients with diabetes and CKD. Long-term use can significantly reduce the urine albumin-to-creatinine ratio (UACR) level of patients, and has little effect on blood potassium. Indicated for use in adult patients with CKD associated with T2DM (with albuminuria) to reduce the risk of sustained decline in eGFR, end-stage renal disease, cardiovascular death, and hospitalization for heart failure.

[0005]

[0006] The Chinese patent with the authorization announcement number CN106795155B discloses a finerenone crystal form I and a preparation method thereof, wherein a large amount of ethanol denatured by toluene is used as a solvent, and after complex distillation and cooling crystallization steps, the finerenone crystal form I is obtained. This method has the disadvantages of large amount of solvent, complex operation, and difficult control of the distillation end point. Therefore, it is necessary to develop a preparation method of finerenone crystal form I with more convenient operation, higher yield and / or less residual solvent. Summary of the invention

[0007] In order to improve the above technical problems, the present invention provides a method for preparing finerenone crystal form I.

[0008] According to an embodiment of the present invention, the method for preparing the finerenone crystalline form I comprises: crystallizing finerenone in a mixture of methanol and water to obtain the finerenone crystalline form.

[0009] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0010] (1) mixing finerenone with methanol to obtain a mixture of finerenone and methanol;

[0011] (2) adding water to the mixture of finerenone and methanol obtained in step (1) to obtain a mixture of finerenone, methanol and water;

[0012] (3) crystallizing a mixture of the finerenone obtained in step (2) and methanol and water to obtain the finerenone crystalline form I.

[0013] According to an embodiment of the present invention, in step (1), finerenone is mixed and dissolved with methanol to obtain a methanol solution of finerenone.

[0014] According to an embodiment of the present invention, step (1) can be carried out under heating conditions. Preferably, the temperature at which finerenone and methanol are mixed can be selected from 30°C-65°C, such as 50°C-65°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C.

[0015] According to an embodiment of the present invention, in step (1), the finerenone may be in other forms other than crystalline form I, such as amorphous finerenone.

[0016] According to an embodiment of the present invention, in step (2), water is added to the methanol solution of finerenone obtained in step (1) to obtain a mixture of finerenone, methanol and water.

[0017] According to an embodiment of the present invention, the ratio of the weight of finerenone to the volume of methanol can be selected from 1g:(3-20)mL, for example 1g:(5-15)mL, such as 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL.

[0018] According to an embodiment of the present invention, the volume ratio of methanol to water can be selected from 1:(0.2-2), for example 1:(0.5-1.2), such as 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.

[0019] According to an embodiment of the present invention, the water may be added dropwise.

[0020] According to an embodiment of the present invention, the water is purified water.

[0021] According to an embodiment of the present invention, the temperature of step (2) can be selected from 5°C-65°C, for example 10°C-65°C, such as 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C.

[0022] According to an embodiment of the present invention, step (2) further comprises adding activated carbon before or after adding water.

[0023] According to an embodiment of the present invention, the weight ratio of activated carbon to finerenone is selected from 1:(10-200), for example 1:(20-100), such as 1:40, 1:50, 1:60, 1:70, 1:80.

[0024] According to an embodiment of the present invention, the reaction can be kept warm after the water is added, and the warming time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0025] According to an embodiment of the present invention, in step (3), the crystallization temperature can be selected from -15°C-50°C, for example, -10°C-20°C, such as -5°C, 0°C, 5°C, 10°C, 15°C, 20°C.

[0026] According to an embodiment of the present invention, the crystallization time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0027] According to an embodiment of the present invention, the X-ray powder diffraction pattern of finerenone or a pharmaceutically acceptable salt thereof has characteristic peaks at the following 2θ angles: 8.519±0.20°, 15.358±0.20°, 19.001±0.20°, 19.737±0.20°, 22.923±0.20°.

[0028] According to an embodiment of the present invention, the X-ray powder diffraction pattern of finerenone or a pharmaceutically acceptable salt thereof has characteristic peaks at the following 2θ angles: 8.519±0.20°, 14.020±0.20°, 15.358±0.20°, 19.001±0.20°, 19.737±0.20°, 22.923±0.20°, 23.877±0.20°, and 25.531±0.20°.

[0029] According to an embodiment of the present invention, the X-ray powder diffraction pattern of finerenone or a pharmaceutically acceptable salt thereof has characteristic peaks at the following 2θ angles: 8.519±0.20°, 11.365±0.20°, 14.020±0.20°, 15.358±0.20°, 17.161±0.20°, 19.001±0.20°, 19.737±0.20°, 22.923±0.20°, 23.877±0.20°, 25.531±0.20°, and 26.467±0.20°.

[0030] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 1 XRPD spectrum shown.

[0031] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 2 DSC spectrum shown.

[0032] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 3 TGA spectrum shown.

[0033] The present invention also provides a method for preparing the finerenone crystal form I, wherein the preparation method comprises mixing finerenone with an organic solvent, cooling and crystallizing to obtain the finerenone crystal form I.

[0034] According to an embodiment of the present invention, the preparation method comprises mixing and dissolving finerenone with an organic solvent, cooling and crystallizing to obtain the finerenone crystal form I.

[0035] According to an embodiment of the present invention, the organic solvent comprises at least one of methanol and isopropanol.

[0036] According to an embodiment of the present invention, the organic solvent is selected from methanol, isopropanol or a mixture thereof.

[0037] According to an embodiment of the present invention, the ratio of the weight of finerenone to the volume of the organic solvent can be selected from 1g:(3-50)mL, for example 1g:(5-35)mL, such as 1g:10mL, 1g:15mL, 1g:20mL, 1g:25mL, 1g:30mL, 1g:35mL.

[0038] According to an embodiment of the present invention, the preparation method can be carried out under heating conditions. Preferably, the temperature at which finerenone is mixed with the organic solvent can be selected from 30°C-90°C, such as 50°C-85°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C.

[0039] According to an embodiment of the present invention, the temperature during crystallization can be selected from -15°C-50°C, for example -10°C-20°C, such as -5°C, 0°C, 5°C, 10°C, 15°C, 20°C.

[0040] According to an embodiment of the present invention, the crystallization time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0041] Beneficial Effects

[0042] The invention provides a method for preparing finerenone crystal form I. The method has the advantages of simple operation, high yield and / or low residual solvent, and in particular, significantly reduces the amount of ethanol denatured by toluene, avoids a complex distillation operation with a difficult end point control, and is more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the XRPD spectrum of the phenarezone crystal form I prepared in Example 2.

[0044] Figure 2 This is the DSC spectrum of the phenaredonide crystal form I prepared in Example 2.

[0045] Figure 3 This is the TGA spectrum of phenarezone Form I prepared in Example 2.

[0046] Figure 4 This is a micrograph of the crystalline form I of phenerenone prepared in Example 2.

[0047] Figure 5 This is the dissolution curve diagram in Test Example 1. DETAILED DESCRIPTION

[0048] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0049] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0050] Source of reference preparation: Bayer, 10 mg finerenone, batch number BXK04F1.

[0051] The temperatures described in the present invention are all temperatures inside the reaction container.

[0052] Example 1

[0053] The experimental method of single solvent cooling crystallization is as follows: finerenone is added to a certain amount of organic solvent, the temperature is raised until the finerenone is completely dissolved, and then the temperature is slowly lowered to crystallize, and the filter cake is filtered and dried to obtain a finerenone solid.

[0054] Experimental method for mixed solvent anti-solvent crystallization: add finerenone to a certain amount of good solvent, heat until finerenone is completely dissolved, add poor solvent for crystallization, then slowly cool down, filter, and dry the filter cake to obtain finerenone solid.

[0055] (1) Screening of crystallization solvent

[0056] Firstly, the effects of commonly used single solvent cooling crystallization and mixed solvent anti-solvent crystallization on the crystal form and yield of finerenone were investigated. The experimental data are shown in Table 1.

[0057] Table 1 Screening investigation and results of crystallization solvents

[0058]

[0059] From the above data, it can be seen that when a single solvent is used for cooling crystallization, methanol is used in a smaller amount than ethanol and isopropanol, but the yield is also lower. This shows that methanol has better solubility for phenelenone. When a mixed solvent anti-solvent crystallization (the poor solvent is water or methyl tert-butyl ether) is used, only the mixed solvent of methanol and water has a higher yield and can obtain Form I.

[0060] (2) Screening of the amount of poor solvent water

[0061] The effect of water dosage on crystallization yield, crystal form and solvent residue was further studied. The experimental data are shown in Table 2 below.

[0062] Table 2 Investigation and results of poor solvent water usage

[0063]

[0064]

[0065] It can be seen from the above data that as the amount of water used gradually increases, the yield gradually increases, but the methanol residue also gradually increases (the solubility limit of methanol is 0.30%).

[0066] (3) Screening of the temperature for adding poor solvents

[0067] In order to study the effect of the system temperature when adding water on the crystallization yield, crystal form and solvent residue, the water dropping temperature was investigated. The experimental data are shown in Table 3.

[0068] Table 3 Investigation and results of poor solvent addition temperature

[0069] Serial number Good solvent water Water temperature Stirring temperature after crystallization Crystal form Methanol soluble residue Yield 1 Methanol (10V) 10V 15℃ Ice bath (0-10℃) Crystalline Form I 0.42％ 93.6％ 2 Methanol (10V) 10V 35℃ Ice bath (0-10℃) Crystalline Form I 0.24％ 93.6％ 3 Methanol (10V) 10V 50℃ Ice bath (0-10℃) Crystalline Form I 0.17％ 92.4％ 4 Methanol (10V) 10V 65℃ Ice bath (0-10℃) Crystalline Form I 0.12％ 92.8％

[0070] From the above data, it can be seen that as the temperature of the system gradually increases when water is added, the methanol residue gradually decreases, but the yield is relatively stable. In order to reduce the risk of methanol residue, the water addition temperature is selected to be 65±5℃.

[0071] (4) Screening of crystallization temperature

[0072] In order to study the effect of stirring temperature after crystallization on crystallization yield, crystal form and solvent residue, we investigated the crystallization temperature. The experimental data are shown in Table 4.

[0073] Table 4 Crystallization temperature investigation and results

[0074] Serial number Good solvent water Water temperature Stirring temperature after crystallization Crystal form Methanol soluble residue Yield 1 Methanol (10V) 10V 65℃ 10-20℃ Crystalline Form I 0.09％ 90.8％ 2 Methanol (10V) 10V 65℃ 0-10℃ Crystalline Form I 0.12％ 92.8％ 3 Methanol (10V) 10V 65℃ -10℃ Crystalline Form I 0.09％ 92.8％

[0075] From the above data, it can be seen that the methanol residue has no increasing trend as the crystallization temperature decreases. When the stirring temperature is reduced from 0-10°C to -10°C after crystallization, the refining yield does not continue to increase, and the crystallization temperature has little effect on the yield.

[0076] Example 2 Preparation of Finerenone Crystal Form I

[0077] Add phenarenalone (270 g) and methanol (2430 mL) to a 5L three-necked flask, heat to 65°C, reflux and stir until the sample is dissolved. Add activated carbon (5.40 g) and stir for 30 minutes. Filter while hot, rinse the reaction flask and funnel with methanol (270 mL), and transfer the filtrate to a 20L reactor. Turn on stirring, heat to 65°C, add purified water (2700 mL), and continue to keep warm and crystallize for 1 hour after the addition is complete. Slowly cool to 5°C and keep warm and crystallize for 1 hour. Filter by suction, rinse the filter cake with a methanol / water mixed solvent (V / V=1 / 1, 270 mL), and dry it in vacuo at 60°C overnight to obtain phenarenalone form I (239.95 g, yield 88.9%, methanol residual 0.04%). The XRPD spectrum of phenarenalone form I is shown in the following figure. Figure 1 As shown, the DSC spectrum is Figure 2 As shown in the TGA spectrum Figure 3 As shown in the micrographs Figure 4 shown.

[0078] Example 3 Preparation 1 containing finerenone crystalline form I

[0079] Table 5 Prescription composition of 10 mg finerenone preparation Preparation method:

[0080] Lactose monohydrate and microcrystalline cellulose are added into a fluidized bed, and then a binder prepared by hydroxypropyl methylcellulose and sodium lauryl sulfate is sprayed into the fluidized bed to granulate the soft material, which is then dried and sieved through a 20-mesh sieve to obtain granules a.

[0081] The finerenone crystal form I of Example 2 was crushed and added to the granule a material, passed through a 40-mesh sieve, and transferred to the total mixing tank together with the cross-linked sodium carboxymethyl cellulose to mix evenly. Magnesium stearate was added to the above-mentioned mixed material, mixed for 5 minutes, and the total mixed granules were obtained, which were compressed into tablets with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was then film-coated.

[0082] The finerenone crystal form I was subjected to air flow milling and mechanical milling to obtain API with the following particle size:

[0083] Table 6 Particle size of APIs in different pulverization methods

[0084] serial number Crushing method D10μm D50μm D90μm Example 2-1 Uncrushed 18.8 61.6 134 Example 2-2 Air flow milling 1bar 30rpm 2.07 4.41 7.63 Example 2-3 Air flow milling 2bar 30rpm 1.54 2.93 6.37 Embodiment 2-4 Air flow milling 3bar 30rpm 1.67 3.07 4.95 Embodiment 2-5 Mechanical crushing 15s 2.04 6.27 22.0 Embodiment 2-6 Mechanical crushing 30s 1.71 4.62 16.2

[0085] Comparative Example 1 Preparation of Finerenone Crystal Form I

[0086] Add finerenone (160.00 g) to a 2L three-necked flask, add ethanol (2720 mL) and toluene (80 mL), raise the temperature to reflux (78°C) until the sample is completely dissolved, transfer the filtrate to a single-necked flask and concentrate under reduced pressure until the solvent remains about 560 mL, and after the reduced pressure concentration is completed, cool to 0°C and stir for crystallization for 1h, filter, rinse the filter cake with ethanol, and vacuum dry at 60°C overnight to obtain finerenone Form I.

[0087] Comparative Example 2 Preparation containing finerenone crystal form I

[0088] The formulation prescription and preparation method are referred to Example 3, and the finerenone crystal form I is derived from Comparative Example 1.

[0089] Finerenone was subjected to air flow milling and mechanical milling to obtain API with the following particle sizes.

[0090] Table 7 Particle size of APIs in different pulverization methods

[0091] serial number Crushing method D10μm D50μm D90μm Comparative Example 2-1 Uncrushed 5.58 15.5 38.1 Comparative Example 2-2 Mechanical crushing 30s 1.44 4.7 12.5 Comparative Examples 2-3 Air flow milling 1bar 30rpm 1.50 3.53 8.36 Comparative Examples 2-4 Air flow milling 2bar 30rpm 1.37 2.52 5.04 Comparative Examples 2-5 Air flow milling 3bar 30rpm 1.54 2.83 4.81

[0092] Test Example 1: Dissolution Study of Samples with Different Particle Sizes (10 mg)

[0093] According to the dissolution method of the United States Pharmacopoeia and the second method of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, pH 4.5 acetate solution, 900mL is used as the dissolution medium, the speed is 75r / min, and at 5, 10, 15, 20, 30, 45, 60min, online filtration is performed, and 1.8mL of the solution is taken as the test solution. The dissolution results of Example 2-2, Example 2-3, Example 2-4, Example 2-5, Example 2-6, Comparative Example 2-2, Comparative Example 2-3, Comparative Example 2-5 and the reference preparation are shown in Table 8 and Figure 5 shown.

[0094] Table 8 Dissolution test results

[0095]

[0096] From the above data, it can be seen that the preparation prepared by using phenelenone crystal form I prepared by methanol / water recrystallization has a good dissolution effect and is consistent with the reference release.

[0097] The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A method for preparing finerenone crystal form I, wherein the preparation method comprises: Finerenone is crystallized in a mixture of methanol and water to obtain the finerenone crystal form I.

2. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: (1) mixing finerenone with methanol to obtain a mixture of finerenone and methanol; (2) adding water to the mixture of finerenone and methanol obtained in step (1) to obtain a mixture of finerenone, methanol and water; (3) crystallizing a mixture of the finerenone obtained in step (2) and methanol and water to obtain the finerenone crystalline form I.

3. The preparation method according to claim 1 or 2, characterized in that: In step (1), finerenone and methanol are mixed and dissolved to obtain a methanol solution of finerenone; Preferably, step (1) can be carried out under heating conditions; Preferably, the temperature at which finerenone and methanol are mixed may be selected from 30°C to 65°C.

4. The preparation method according to any one of claims 1 to 3, characterized in that In step (1), the finerenone may be in other forms other than crystalline form I, such as amorphous finerenone.

5. The preparation method according to any one of claims 2 to 4, characterized in that: In step (1), the ratio of the weight of finerenone to the volume of methanol can be selected from 1 g: (3-20) mL; Preferably, the volume ratio of methanol to water can be selected from 1:(0.2-2).

6. The preparation method according to any one of claims 2 to 5, characterized in that: The temperature of step (2) can be selected from 5°C to 65°C.

7. The preparation method according to any one of claims 2 to 6, characterized in that: Step (2) further comprises adding activated carbon before or after adding water; Preferably, the weight ratio of the activated carbon to finerenone is selected from 1:(10-200).

8. The preparation method according to any one of claims 2 to 7, characterized in that: After adding water, the reaction can be kept warm for a period of 0.5-5 hours.

9. The preparation method according to any one of claims 2 to 8, characterized in that: In step (3), the temperature during crystallization can be selected from -15°C to 50°C; Preferably, the crystallization time is selected from 0.5-5h.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The finerenone crystalline form I has an XRPD spectrum substantially as shown in FIG1 ; Preferably, the finerenone crystalline form I has a DSC spectrum substantially as shown in FIG2 ; Preferably, the finerenone crystalline form I has a TGA spectrum substantially as shown in FIG3 .

Images