WO2023088394A2 - New crystal forms of lurbinectedin and preparation thereof - Google Patents

Abstract

The present invention relates to a new crystal form C and a new crystal form D of Lurbinectedin; an XRPD spectrum of crystal form C has characteristic Bragg angles at 4.0 degrees, 7.8 degrees, 10.1 degrees, 11.9 degrees, 18.2 degrees and 25.4 degrees; and an XRPD spectrum of crystal form D has characteristic Bragg angles at 4.7 degrees, 7.9 degrees, 9.4 degrees, 11.9 degrees, 13.0 degrees, 16.8 degrees, 20.3 degrees, 24.6 degrees and 25.5 degrees.

Description

New crystal form of rupidine and its preparation

This application claims the priority of the Chinese patent application with the application number 202111398172.5 submitted to the China Patent Office on November 19, 2021, and the invention title is "New Crystal Form of Rubitidine and Its Preparation Method", the entire contents of which are incorporated herein by reference. Applying.

technical field

The invention relates to a new crystal form of rupitidine and a preparation method thereof.

Background technique

Lurbinectedin (Lurbinectedin, PM01183, CAS: 497871-47-3) was developed by the Spanish company PharmaMar SA and was first launched in the United States in 2020 as a therapeutic drug for small cell lung cancer. Lurbinectedin’s The mechanism of action is the inhibitor of RNA polymerase II, combined with the minor groove on the DNA double helix structure, causing tumor cells to distort and apoptosis during mitosis, and ultimately reduce cell proliferation, which belongs to phosphodiesterase inhibitors. Platinum-based chemotherapy (platinum-based compounds + irinotecan/etoposide, etc.) is generally used as first-line therapy for small cell lung cancer. These active substances are effective in most patients during the initial phase of treatment, and the patient's condition can be stabilized for a period of time. But then most patients will relapse and must switch to second-line drug therapy. In foreign countries, some phase III clinical studies currently use PD-L1 inhibitors combined with platinum-based chemotherapy to improve the first-line treatment effect of SCLC (atezolizumb+irinotecan+platinum). Clinical data show that platinum-based chemotherapy combined with PD-L1 is effective for a small number of patients and can significantly reduce mortality, but has no significant effect on most cases. And almost all cases recur. In other words, if standard therapy is adopted, almost every patient with small cell lung cancer will undergo platinum-based chemotherapy (including combining with PD-L1), and after chemotherapy, the next second-line drug therapy will be clinically used for the treatment of heart failure . In the past, topotecan has been the standard second-line treatment for small cell lung cancer. It was not until the FDA accelerated approval of rupidine in 2020 that doctors had a new second-line treatment for SCLC. Rubitedin is a broad-spectrum anti-cancer drug. At present, there are many clinical studies abroad using Rubitedin to treat various solid tumors.

The chemical name of this product is: (1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6',9-dimethoxy-4,10,23-trimethyl Base-19-oxo-2',3',4',6,7,9',12,13,14,16-decahydro-6aH-spiro[7,13-imino-6,16-(Table Thiopropoxymethylene)[1,3]dioxo[7,8]isoquinoline[3,2-b][3]benzacine-20,1'-pyrido[3,4 -b] indol]-5-yl acetate.

There are two kinds of crystalline forms for the preparation of rupitidine publicly reported at present. Patent WO2021/099635A1 found that there are two different crystal forms of rupitidin, which are defined as crystal form A and crystal form B respectively. Form A is amorphous; the Bragg angles (2θ) characterized by XRPD of Form B are 6.2±0.2°, 7.6±0.2°, 9.0±0.2°, 10.9±0.2°, 14.9±0.2°, 15.3±0.2°( The corresponding densities are 79±6%, 100±3%, 63±3%, 100±3%, 76±3% and, 75±3%); this crystal form has no melting point and completely decomposes at around 172°C; It has the following typical IR characteristic peaks: 2928, 1755, 1626, 1485, 1456, 1370, 1197, 1150, 1088, 1003, 959, 916 and 587cm ^-1 .

During the preparation and storage of rupitidin, various impurities can be produced, such as deacylated impurities (“Impurity D”), isomer impurities (“Impurity I”), oxidation impurities (“Impurity O”), etc. , the structures of the identified impurities are as follows. These impurities need to be controlled within an acceptable range in the composition of rupidine. Compositions of rupitidin as pharmaceutical formulations need to ensure that they are stable for long-term storage, retain their therapeutic effectiveness and exhibit minimal chemical degradation during long-term storage. Deacylation of rubitidine produces rubitidine degradation products. Patent WO2021/098992A1 provides a storage freeze-dried rupidinedine composition, which can control the content of the degradation product impurity D of rupitidine after long-term storage, and the use of partially crystallized rupitidin can better control the impurity and/or degradation The product, wherein partially crystalline rupitidine is in crystalline Form B.

Simultaneously, since rupitidine is easy to degrade or react with solvents in conventional crystallization solvents, for example, chemical structure changes will occur in dimethyl sulfoxide, tetrahydrofuran, methanol, N,N-dimethylformamide, Therefore, it is difficult to prepare rupitidine in a relatively single crystalline form. Patent WO2021099635A1 provides a preparation method for the preparation of crystalline form of rupitidine, preparing an acidic aqueous solution containing rupitidine or its protonated form; then basifying the resulting acidic aqueous solution with alkali or buffer to precipitate form B of rupitidine Certainly.

Contents of the invention

The key of the present invention lies in the newly discovered new crystal form C and new crystal form D of rupitidine, which are used for the research of drug biological activity, bioavailability and the like.

The invention provides rupitidine crystal form C and crystal form D with high crystal purity and crystallization into a single crystal form, and a preparation method thereof.

The X-ray powder diffraction (XRPD) data of the new crystal form of rupitidine of the present invention, measuring instrument is the EMPYREAN type X-ray derivatization instrument of PANalyltical company, relevant test parameter is as follows: 45KV, 40mA, ray wavelength CuKa

Scanning range 3-40°, Step Size=0.0167[°2Th], Scan Step Time=17.85(s).

The infrared absorption spectrum (IR) data testing conditions of the new crystal form of rupitidine of the present invention are as follows: resolution: 4.000, sampling gain: 1.0, detector: DTGS KBr, beam splitter: KBr, infrared light source, sample Number of scans: 32, Number of background scans: 32.

The method parameters of the thermogravimetric analysis (TGA) of the new crystal form of rupitidine according to the present invention are as follows: heating from 30°C to 400°C, heating rate: 10°C/min, protective gas: nitrogen.

The test conditions of differential scanning calorimetry (DSC) of the new crystal form of rupitidine in the present invention are as follows: heating from 30°C to 400°C at a speed of 10°C/min; detection environment conditions: room temperature: 21°C.

The XRPD spectrum of Form C shows (Fig. 1), this crystal form has characteristic Bragg angles at 4.0°, 7.8°, 10.1°, 11.9°, 18.2° and 25.4°; typically, the XRPD spectrum is at 4.0°, 7.6°, 7.8°, 10.1°, 11.9°, 18.2°, 19.9°, 24.8°, and 25.4° have characteristic Bragg angles.

The relevant spectrum signals of Form C are as follows:

Table 1 XPRD diffraction peak data of rubitidine crystal form C

The infrared absorption (IR) spectrum of Form C has obvious characteristic signals at 2928, 1755, 1726, 1589, 1433, 1373, 1252, 1291, 1147, 1086, 1040, 1004, 957, 801, and 587 cm ^-1 .

The XRPD pattern of crystal form D shows (Figure 2), this crystal form has characteristic Bragg angles at 4.7°, 7.9°, 9.4°, 11.9°, 13.0°, 16.8°, 20.3°, 24.6° and 25.5°, typically, The XRPD pattern has characteristic Bragg angles at 4.7°, 7.9°, 9.0°, 9.4°, 11.9°, 13.0°, 16.8°, 18.2°, 19.0°, 20.3°, 24.6° and 25.5°.

The relevant spectrum signal of crystal form D is as follows:

Table 2 XPRD diffraction peak data of rubitidine crystal form D

The infrared absorption (IR) spectrum of Form D has obvious characteristic signals at 2927, 1754, 1739, 1591, 1457, 1359, 1194, 1168, 1146, 1083, 999, 729, and 585 cm ^-1 .

Process for the preparation of rupitidine in crystalline form

The present invention also provides a process for the preparation of the crystalline form of rupitidine. Rubitidine compounds are prone to decompose or react with solvents in conventional solvents. Therefore, the prior art lacks a simple method for preparing crystalline forms of rupidine with high crystal purity. The invention provides a method for preparing rupidinedine in crystalline form, which is more suitable for large-scale preparation and treatment, and can prepare rupitedine in crystalline form with high purity, low solvent residue and low impurity.

In some embodiments, the solid mixture of rupitidine C or crystalline form C of rupitidine with high crystal purity can be prepared by the preparation method of the present invention. The preparation method of the rupitidine crystal form C or the solid mixture of the rupitidine crystal form C comprises the following steps:

The crude product of rupitidine is added into an ester solvent, heated, stirred and/or beaten, and dried to obtain a solid.

The ester solvent is selected from one or more of ethyl acetate, ethyl formate, butyl formate, and isopropyl acetate; preferably, the solvent is ethyl acetate.

In some embodiments, the rupitidine crystal form D or a solid mixture of rupitidine crystal form D with high crystal purity can be prepared by the preparation method of the present invention. The preparation method of the rupitidine crystal form D or the solid mixture of the rupitidine crystal form D comprises the following steps:

Add the crude product of rupitidine to the first solvent, dissolve it and add the second solvent to precipitate a solid.

Preferably, the first solvent is selected from halogenated alkanes solvents; preferably one or more of dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; more preferably dichloromethane .

Preferably, the second solvent is selected from alkane solvents; preferably one or more of n-pentane, n-hexane, n-heptane and n-octane; more preferably n-pentane.

In some embodiments, the preparation method of the rupitidine crystal form D or the solid mixture of the rupitidine crystal form D further includes a step of adding an ester solvent for beating, and adding the solid obtained after beating into the first solvent. The ester solvent is selected from one or more of ethyl acetate, ethyl formate, butyl formate, and isopropyl acetate; preferably, the solvent is ethyl acetate.

low solvent residue

The rupitidine crystal form D prepared by the method of the present invention can advantageously control residual solvents. In one embodiment, the rupitidine crystalline form D comprises no more than 5000 ppm residual solvent, preferably no more than 3000 ppm residual solvent, preferably no more than 1000 ppm residual solvent, preferably no more than 600 ppm residual solvent, preferably substantially No residual solvent was detected.

low impurity content

In one embodiment, the rupitidine crystalline form C prepared by the method of the present invention may have a purity measurement (%) in the range of 94.0%-102.0% and a total impurity level ≤ 1.0%. The specified impurity limit level of any single type can be ≤0.15%, further, the limit can be impurity G (≤0.05%), impurity D (≤0.02%), impurity C (≤0.02%), impurity I ( ≤0.05%) and/or impurity O (≤0.05%). Any other individual non-specified impurity may have a limit of < 0.15%, preferably any other individual non-specified impurity may have a limit of < 0.05%.

In one embodiment, the crystalline form D of rupitidine prepared by the method of the present invention may have a purity measurement (%) in the range of 94.0%-102.0% and a total impurity level ≤ 1.0%. The specified impurity limit level of any single type can be ≤0.15%, further, the limit can be impurity G (≤0.05%), impurity D (≤0.02%), impurity C (≤0.02%), impurity I ( ≤0.05%) and/or impurity O (≤0.05%). Any other individual non-specified impurity may have a limit of < 0.15%, preferably any other individual non-specified impurity may have a limit of < 0.05%.

Storage-stable single crystal form

In one embodiment, the present invention provides a solid mixture form comprising crystalline form C or crystalline form D of rupitidine, wherein the content of crystalline form C or crystalline form D of rupitidine is in the range of 95.0%-102.0%, Preferably, the content of crystalline form C or crystalline form D of rupitidine is in the range of 98.0%-101.0%, and the amount of various impurities and the amount of total impurities in the rupitidine solid mixture can be controlled during long-term storage. In some embodiments, after storage at about -5°C ± 3°C for 1 month, 2 months, and 3 months, the total impurity level in the rupitidine solid mixture is ≤ 1.0%, and the specified impurity and its limit can be Impurity G (≤0.05%), Impurity D (≤0.02%), Impurity C (≤0.02%), Impurity I (≤0.05%) and/or Impurity O (≤0.05%). Any other individual non-specified impurity may have a limit of < 0.10%, preferably any other individual non-specified impurity may have a limit of < 0.05%.

pharmaceutical composition

The present invention also provides a pharmaceutical composition, which comprises crystalline form C or D of rupitidin in combination with one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of an active pharmaceutical ingredient in admixture with a pharmaceutically acceptable excipient, wherein the active pharmaceutical ingredient comprises a detectable amount of rupitidine or rupitidine in a crystalline form of the invention. fixed solvates.

The application of the pharmaceutical composition in the preparation of medicines for treating and/or preventing diseases related to RNA polymerase II.

definition

As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which this term applies, or one or more symptoms of such a disorder or condition. A condition or one or more symptoms of such a disorder or condition. As used herein, unless otherwise stated, the term "treatment" refers to the act of "treating" as defined immediately above.

As used herein, the term "substantially pure" when referring to a particular crystalline or non-crystalline form means that the crystalline or non-crystalline form of the compound comprises less than 10% by weight, preferably less than 5% by weight, preferably less than 2% by weight, preferably less than 1% by weight of any other physical form of the compound. The term "purity" as used herein means the content of the compound after removal of residues, moisture and residues.

As used herein, the term "substantially the same" when referring to X-ray powder diffraction peak positions is meant to take into account typical peak positions and intensity variability. For example, those skilled in the art understand that peak positions (2Θ) will show some variability, typically as much as ±0.10° to ±0.20°, depending on the solvent used and the device used to measure the diffraction. Furthermore, those skilled in the art understand that relative peak intensities will exhibit inter-instrument variability as well as variability due to crystallinity, preferred orientation, sample surface prepared, and other factors known to those skilled in the art , specifically reflected in the horizontal displacement error range of ±0.20°.

Similarly, "substantially the same" as used herein in reference to infrared spectroscopy is intended to also encompass the variability associated with these analytical techniques, which variability is known to those skilled in the art. For example, infrared spectral shifts typically have a variability of about ±5 cm ⁻¹ .

The term "pharmaceutical composition" refers to a combination comprising one or more polymorphic forms of the compounds described herein and chemical components such as physiologically/pharmaceutically acceptable carriers, diluents, vehicles and/or excipients things. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism such as a human or other mammal.

The term "pharmaceutically acceptable", "carrier", "diluent", "vehicle" or "excipient" refers to a material which can be included with a particular pharmaceutical substance to form a pharmaceutical composition and which can be solid or liquid . Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Likewise, the carrier or diluent may include time delay or sustained release materials known in the art, such as glyceryl monostearate or glyceryl distearate (alone or mixed with a wax), ethylcellulose, Hydroxypropyl methylcellulose, methyl methacrylate, and the like.

Technical effect of the present invention:

Compared with the crystalline form of rubitidine in the prior art, the crystalline form of rubitidine prepared by the present invention has good thermal stability, high crystalline form purity, and no solvent residue; the preparation method is simple, and the obtained product has high HPLC purity, The content of various specified impurities such as acyl impurities, isomer impurities, and oxidation impurities is low; it has good thermal stability, crystal form stability, and chemical stability, and has good storage stability under high temperature or light conditions, making it It has the performance that is more suitable for the application of preparing medicine, and it does not need to be prepared as freeze-dried powder for storage under a specific solvent system.

The crystal form of rupitidine of the present invention also has advantages in terms of physical and chemical properties, preparation processing performance and bioavailability, such as melting point, solubility, purification, adhesion, compressibility, fluidity, dissolution in vivo and in vitro, There is an advantage in at least one of aspects such as bioavailability.

Description of drawings

Fig. 1 is the XRPD spectrum of rupitidine crystal form C;

Fig. 2 is the XRPD spectrum of rupitidine crystal form D;

Figure 3 is the XRPD pattern of rupitidine crystal form D stored at high temperature for 30 days;

Figure 4 is the XRPD pattern of Rubitidine crystal form D stored under light conditions for 30 days;

Detailed ways

The present invention can be understood more specifically through the following examples, but they are intended to illustrate rather than limit the scope of the present invention.

The crude rupitidine was prepared according to the methods disclosed in WO2003/014127 or WO2021/099635 patents.

Example 1 Preparation of Rubitidine Form C

Rubitidine (0.5g) was added to ethyl acetate (10mL), heated and stirred for 2h, filtered while hot, and the resulting solid was vacuum-dried at 25°C to give Rubitidine Form C. The product yield of crystal form C is 95%, and the HPLC purity is 99.9%.

As shown in Figure 1, the XRPD spectrum of this crystal form has characteristic Bragg angles at 4.0°, 7.8°, 10.1°, 11.9°, 18.2° and 25.4°; the infrared absorption (IR) spectrum of this crystal form is shown at 2928, 1755 , 1726, 1589, 1433, 1373, 1252, 1291, 1147, 1086, 1040, 1004, 957, 801, 587cm ^-1 have obvious characteristic signals.

At least 10 mg of the sample was analyzed under a nitrogen blanket at a heating rate of 10°C/min at a temperature ranging from 30°C to about 400°C.

Rubitidine crystal form C prepared in Example 1, its TGA/DSC test results show that rupitidine crystal form C is an ethyl acetate solvate, and thermogravimetric analysis shows that there is about 11.48% weight loss in the range of 60-100°C , Decomposition occurs at about 170-210°C; its differential scanning calorimetry spectrum has an endothermic peak in the range of 60-100°C, and the thermal decomposition peak is about 201°C.

Example 2 Preparation of Rubitidine Crystal Form D Method 1

Rubitidine (1.5g) was added to dichloromethane (50mL), stirred at room temperature to dissolve, slowly added n-pentane (40mL) dropwise to precipitate a solid, stirred for 1h after dropping, filtered, and the obtained solid was vacuum-dried at 25°C Rubitidine Form D was obtained.

As shown in Figure 2, the XRPD spectrum of the Rubitidine crystal form D prepared in Example 2 has characteristic Bragg at 4.7°, 7.9°, 9.4°, 11.9°, 13.0°, 16.8°, 20.3°, 24.6° and 25.5° angle; the infrared absorption (IR) spectrum of this crystal form shows that there are obvious characteristic signals at 2927, 1754, 1739, 1591, 1457, 1359, 1194, 1168, 1146, 1083, 999, 729, 585cm ^-1 .

The crystal form D of rupitidine prepared in Example 2 decomposes at 170-220°C; its differential scanning calorimetry (DSC) spectrum has a thermal decomposition peak at about 202°C.

Compared with the rupitidine crystal form B in WO2021/099635, the rupitidine crystal form D prepared in Example 2 of this patent has a higher thermal decomposition temperature and shows better stability.

Example 3 Preparation of Rubitidine Form D Method Two

Before the step of adding dichloromethane, ethyl acetate (10 mL) was added to the crude product (0.5 g), and after heating, stirring and/or beating, the steps of Example 2 were carried out to prepare the solid form D of rupitidine, Its XRD spectrogram and infrared spectrum are identical with the product that embodiment 2 obtains. The step of heating, stirring and/or beating the crude product in ethyl acetate can remove impurities well, and obtain a crystalline product with high purity.

According to the method of the above-mentioned Example 2 or Example 3, three batches of rupitidine crystal form D solids were prepared, the HPLC purity was 98.9%, 98.4% and 99.9%, respectively, the residual dichloromethane solvent was less than 600ppm, and the n-pentane solvent The residue is less than 5000ppm.

The three batches of rupitidine prepared had low total impurity content and low single impurity content including deacylation impurity D, isomerization impurity I, oxidation impurity O and other specific impurities. The crystalline form D of rupitidine prepared in three batches can be stored stably for 90 days at -5°C±3°C (Table 3 to Table 5).

table 3

LOQ: limit of quantification

Table 4

LOQ: limit of quantification

table 5

LOQ: limit of quantification

Stability of Rubitidine Form D under high temperature (5°C) or light conditions

The XRPD patterns of Rubitidine crystalline form D stored at high temperature (5°C) or under light conditions for 5 days, 10 days, and 30 days are shown in Figure 5 and Figure 6, respectively. Rubitidine crystal form D can keep the crystal form stable under high temperature or light conditions, and can be stored stably for a long time.

Claims (25)

1. Rubitidine Form C has characteristic Bragg angles at 4.0°, 7.8°, 10.1°, 11.9°, 18.2° and 25.4° in the XRPD pattern.
2. The crystal form C of claim 1, the XRPD pattern has characteristic Bragg angles at 4.0°, 7.6°, 7.8°, 10.1°, 11.9°, 18.2°, 19.9°, 24.8° and 25.4°.
3. The crystal form C according to claim 1 or 2, which has an XRPD pattern substantially consistent with that shown in FIG. 1 .
4. The crystal form C as claimed in claim 1 or 2, the infrared absorption spectrum has ^obvious characteristic signal.
5. The crystal form C according to claim 1 or 2, at a heating rate of 10°C/min, its thermogravimetric analysis (TGA) spectrum decomposes at 170-210°C; and/or, its differential scanning calorimetry (DSC) The spectrum has endothermic peaks in the range of 60-100°C and in the range of 200-210°C.
6. The crystal form C according to claim 1 or 2, wherein the mass content of the total impurities is ≤ 1%, and the mass content of the single impurity is ≤ 0.15%, preferably, the mass content of the single impurity is ≤ 0.05%.
7. The rupitidine crystal form C as claimed in claim 6, wherein the mass content of the deacylated impurity D is ≤0.02%.
8. A method for preparing the rupitidine crystal form C according to any one of claims 1-7, comprising: adding crude rupitidine to an ester solvent, heating, stirring and/or beating, and drying to obtain a solid.
9. The preparation method as claimed in claim 8, the ester solvent is selected from one or more of ethyl acetate, ethyl formate, butyl formate, isopropyl acetate; preferably, the solvent is ethyl acetate ester.
10. A solid mixture of rupitidine crystal form C, wherein the rupitidine crystal form C according to any one of claims 1 to 7 accounts for more than 90% of the weight of the solid mixture, preferably, crystal form C accounts for 90% of the weight of the solid mixture More than 95%, preferably, crystal form C accounts for more than 98% by weight of the solid mixture.
11. Rubitidine crystal form D has characteristic Bragg angles at 4.7°, 7.9°, 9.4°, 11.9°, 13.0°, 16.8°, 20.3°, 24.6° and 25.5° in the XRPD pattern.
12. The crystal form D of claim 11, the XRPD spectrum has characteristic Bragg at 4.7°, 7.9°, 9.0°, 9.4°, 11.9°, 13.0°, 16.8°, 18.2°, 19.0°, 20.3°, 24.6° and 25.5° horn.
13. The crystal form D of claim 11, which has an XRPD pattern substantially consistent with that shown in FIG. 2 .
14. The crystal form D according to any one of claims 11-13, the infrared absorption spectrum has ^obvious characteristic signal.
15. The crystal form D according to any one of claims 11-13, at a heating rate of 10°C/min, its thermogravimetric analysis (TGA) spectrum decomposes in the range of 170-220°C; and/or, its difference The scanning calorimetry (DSC) spectrum has an endothermic peak in the range of 200-210°C.
16. Rubitidine crystal form D according to any one of claims 11-13, wherein the mass content of the total impurities is ≤1%, and the mass content of the single impurity is ≤0.15%, preferably, the mass content of the single impurity is ≤ 0.05%.
17. The crystalline form D of rupitidine according to claim 16, wherein the mass content of the deacylated impurity D is ≤0.02%.
18. A method for preparing the rupitidine crystal form D according to any one of claims 11-17, comprising: adding the crude rupitidine to the first solvent, and adding the second solvent after dissolving to precipitate a solid.
19. The preparation method according to claim 18, the first solvent is selected from halogenated alkanes solvents; preferably one or more of dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane ; More preferably dichloromethane.
20. The preparation method according to claim 18, the second solvent is selected from alkane solvents; preferably one or more of n-pentane, n-hexane, n-heptane and n-octane; more preferably n-pentane .
21. The preparation method as claimed in claim 18, further comprising the step of adding an ester solvent to heat and stir and/or beating, and the ester solvent is selected from the group consisting of ethyl acetate, ethyl formate, butyl formate, and isopropyl acetate. One or more; Preferably, the solvent is ethyl acetate.
22. A solid mixture of rupitidine crystal form D, wherein the rupitidine crystal form D according to any one of claims 11 to 17 accounts for more than 90% of the weight of the solid mixture, preferably, crystal form D accounts for more than 90% of the weight of the solid mixture. More than 95% by weight of the solid mixture, preferably, crystal form D accounts for more than 98% by weight of the solid mixture.
23. A pharmaceutical composition, containing the solid mixture of the rupitidine crystal form C described in any one of claims 1-7 or the rupitidine crystal form C described in claim 10, and a pharmaceutically acceptable carrier, diluted agent, medium and/or excipient.
24. A pharmaceutical composition, containing the solid mixture of the rupitidine crystal form D described in any one of claims 11-17 or the rupitidine crystal form D described in claim 22, and a pharmaceutically acceptable carrier, diluted agent, medium and/or excipient.
25. The application of the pharmaceutical composition described in any one of claims 23-24 in the preparation of medicines for treating diseases related to RNA polymerase II.

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