CN116621817A - A kind of crystalline form of enciatevir fumarate and its preparation method, pharmaceutical composition and application - Google Patents

Abstract

The invention provides a crystal form of enclave fumarate and its preparation method, pharmaceutical composition and application, belonging to the technical field of medicine and chemical industry. The crystal form of the present invention is the crystal form of Encetevir fumarate shown in formula I, which uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ value ± 0.2° include 6.63, 9.67, 10.92 , 12.04, 12.18, 12.78, 13.27, 13.48, 16.22, 17.57, 18.35, 19.93, 21.78, 22.10, 22.39, 23.72, 24.06, 25.67, 28.03, 28.03, 32.99. The present invention achieves the goals of high yield, high purity, less impurities, good quality and controllable reaction of the new crystal form of Enclave fumarate, and the preparation method has the advantages of low cost, less waste, green and environmental protection, and is also conducive to industrial scale-up production , the application prospect is broad.

Description

A kind of crystalline form of enciatevir fumarate and its preparation method, pharmaceutical composition and use

technical field

The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a crystal form of enclave fumarate, a preparation method, a pharmaceutical composition and an application thereof.

Background technique

Drug molecules usually have different solid forms, including salts, polycrystals, co-crystals, amorphous forms, hydrates and solvates, etc.; different crystal forms of the same drug molecule usually have different physical properties, including solubility, hygroscopicity, etc. Sex, fluidity, stability and bioavailability, etc. These differences can directly affect the efficacy and developability of drugs. A stable crystal form is beneficial to increase the safety of the drug in clinical application. Therefore, in the commercial production of drugs, a drug molecule with high crystal stability, convenient production and pharmaceutical acceptance should be provided as much as possible.

Enclave fumarate, Chinese name: (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl- 1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione Fumarate; English name: Ensitrelvir Fumaric Acid; CAS: 2757470-18-9; Molecular formula: C ₂₂ H ₁₇ ClF ₃ N ₉ O ₂ ·C ₄ H ₄ O ₄ ; Molecular weight: 647.96; Show:

Ensitrelvir was jointly developed by Hokkaido University and Shionogi Pharmaceutical. It is a new coronavirus 3CL protease inhibitor. , for the treatment of novel coronavirus. It blocks the proliferation of the new coronavirus by selectively inhibiting the 3CL protease. This mechanism of action is consistent with the previously approved Pfizer's new crown oral drug Nematevir. According to Yaozhi data and drug clinical public data, compared with other companies’ new crown drugs, Ensitrelvir is currently the drug with the best effectiveness, the highest safety, and the longest duration of action. It has excellent performance in nucleic acid negative conversion, virus clearance, hospitalization rate, and mortality. The launch of the drug has undoubtedly brought huge benefits to the control and treatment of the new coronavirus.

The international patent application (publication number is WO2023027198A1) discloses a crystalline form of enciatevir fumarate, which is prepared by adding fumaric acid and ethyl acetate to enciatevir free base, and After stirring at room temperature, the solid was collected by filtration and dried. However, the purity and stability of the crystal form of Enclave fumarate obtained in this way are unknown. The Chinese patent (publication number CN114591304B) discloses two crystal forms of enciatevir fumarate. The preparation method of its crystal form A is to add enciatevir fumarate into a solvent to prepare a suspension, and suspend at room temperature After stirring for 3-7 days, the suspension was separated and dried. The preparation time of this crystal form is long, the production efficiency is low, and it is not conducive to industrial scale-up production, and through data comparison, this patent is consistent with the crystal form obtained in the international patent application (publication number WO2023027198A1). Another crystalline form is the crystalline form B obtained by stirring Encetevir free base and fumaric acid in ethyl acetate and filtering, but the purity of the crystalline form obtained by this method is not high (97%), and the patent data shows that its Poor stability, micro-caking or agglomeration under high humidity conditions, unstable under light, and color change. Therefore, it is necessary to study the new crystal form of enclave fumarate and its preparation method to meet the commercial production of the pharmaceutical market.

Contents of the invention

In order to overcome the problems existing in the existing crystal form of enciatevir fumarate, the present invention provides a crystal form of enciatevir fumarate and its preparation method, pharmaceutical composition and application. The crystal form of enclave fumarate provided by the present invention is completely different from the crystal form A and crystal form B disclosed in the prior art. The present invention prepares the new crystal form C of encedentevir fumarate in a more economical, simpler and reproducible method. The crystal form C obtained by the method has high purity and excellent product stability, and is suitable for industrial production.

The present invention provides the crystalline form of enclave fumarate shown in formula I, which uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ value ± 0.2° include 6.63, 9.67, 10.92, 12.04, 12.18, 12.78, 13.27, 13.48, 16.22, 17.57, 18.35, 19.93, 21.78, 22.10, 22.39, 23.33, 23.72, 24.20, 24.56, 25.67, 26.05, 28.03, 32.99;

Formula I.

Further, it uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ value ± 0.2° also include 15.09, 19.13, 20.64, 26.38, 28.40, 30.40, 34.15, 35.52, 37.47, 39.21.

Further, the X-ray powder diffraction pattern of the crystal form is shown in FIG. 1 .

Further, the differential scanning calorimetry spectrum of the crystal form is shown in Figure 2;

There are two endothermic peaks in the differential scanning calorimetry spectrum, an endothermic peak with a peak value of 233±2°C and an endothermic peak with a peak value of 268°C±2°C.

Further, the molar ratio of enclave and fumaric acid in the crystal form is 1:1; the purity of the crystal form is above 99%, and/or the content of a single impurity is less than 0.1%.

The present invention also provides a method for preparing the aforementioned crystal form, which comprises the following steps:

Dissolve the solid of Encytevir in a solvent, add fumaric acid and stir, use a poor solvent to precipitate crystals, and dry to obtain the product.

Further, the solvent is dioxane, butanone, acetonitrile, ethyl formate, ethyl acetate, butyl formate, dichloromethane, chloroform, ethylene glycol dimethyl ether, methyl tert-butyl ether, toluene , one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 4-methyl-2-pentanone and/or tetrahydrofuran;

And/or, described poor solvent is one or more in methylene chloride, methanol, ethyl acetate;

And/or, the drying temperature is 60-100°C.

Preferably, the solvent is dimethylsulfoxide;

And/or, the poor solvent is dichloromethane, methanol or ethyl acetate.

The present invention also provides a pharmaceutical composition, which includes the aforementioned crystal form and a pharmaceutically acceptable carrier.

Further, in the pharmaceutical composition, the weight percentage of the aforementioned crystalline form is 0.1%-85%.

The present invention also provides the use of the aforementioned crystal form or the aforementioned pharmaceutical composition in the preparation of a drug for treating novel coronavirus.

Compared with prior art, the beneficial effect of the present invention is:

The invention provides a new crystal form of enciatevir fumarate and a preparation method thereof. The method for preparing the new crystal form of enciatevir fumarate is simple and convenient, reduces the amount of reaction solvent, reduces reaction time, and simplifies post-processing process and increase the reaction yield. In addition, the obtained enciatevir fumarate crystal form has high purity (HPLC > 98.5%), high melting point, better stability compared with the existing enciatevir fumarate crystal form, and meets ICHQ3C solvent limit requirements. Higher, the Enclave fumarate crystal form obtained in the present invention can effectively extend the validity period of the drug as a drug raw material, and can meet the pharmaceutical requirements of production, processing, transportation, and storage, and is also conducive to storage and quality control at room temperature. The present invention achieves the goals of high yield, high purity, less impurities, good quality and controllable reaction of the new crystal form of Enclave Fumarate, and the preparation method has the advantages of low cost, less waste, green and environmental protection, and is also conducive to industrial scale-up production , the application prospect is broad.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern of Enclave fumarate crystal form C prepared in Example 1, the abscissa in the figure is 2θ [º], and the ordinate is intensity (count).

Fig. 2 is the differential scanning calorimetry (DSC) spectrogram of enclave fumarate crystal form C prepared in Example 1.

Fig. 3 is the X-ray powder diffraction pattern of Enclave fumarate crystal form C prepared in Example 2, the abscissa in the figure is 2θ [º], and the ordinate is the intensity (count).

Fig. 4 is the X-ray powder diffraction pattern of Enclave fumarate crystal form C prepared in Example 3, the abscissa in the figure is 2θ [º], and the ordinate is the intensity (count).

Fig. 5 is the X-ray powder diffraction pattern of Enclave fumarate crystal form A prepared in Comparative Example 1, the abscissa in the figure is 2θ [º], and the ordinate is intensity (count).

Fig. 6 is the X-ray powder diffraction pattern of Enclave fumarate crystal form B prepared in Comparative Example 3, in which the abscissa in the figure is 2θ [º], and the ordinate is the intensity (count).

Fig. 7 is the X-ray powder diffraction pattern of Enclave fumarate crystal form C prepared in Example 1 after 6 months of accelerated stability experiments, in which the abscissa is 2θ [°], and the ordinate is intensity ( count).

Fig. 8 is the HPLC spectrogram of enclave fumarate crystal form C prepared in Example 1.

Fig. 9 is the HPLC spectrogram of Enclave fumarate crystal form C prepared in Example 1 after 6-month accelerated stability test.

Fig. 10 is the differential scanning calorimetry (DSC) spectrogram of Enclave Fumarate Form C prepared in Example 1 after 6-month accelerated stability test.

Fig. 11 is the solvent residual GC spectrum of enclave fumarate crystal form C prepared in Example 1.

Fig. 12 is the solvent residual GC spectrum of Enclave Fumarate Form A prepared in Comparative Example 1.

Detailed ways

The compounds or reagents used in the specific embodiments of the present invention can be purchased from commercial sources, or prepared by conventional methods known to those skilled in the art; the experimental instruments used can be purchased from commercial sources.

Test equipment used in the experiment:

1. X-ray powder diffraction spectrum

Instrument model: PANalyticalEmpyrean (PANalytical, NL)

Rays: monochromatic Cu-Ka rays

Scanning mode: q/2q, scanning range: 2 ~50

Voltage: 45kV; Current: 40mA

2. DSC spectrum

Instrument model: TADiscovery2500 (TA, US)

Purge gas: Nitrogen

Heating rate: 10.0 K/min

Temperature range: 30~350℃

3. High performance liquid chromatography (HPLC)

Instrument model: Agilent Technologies 1260Infinity

Chromatographic column: C18 column

Injection volume: 10μl

Mobile phase: water + acetonitrile; the volume ratio of water and acetonitrile is 95:5 for 5 minutes → the volume ratio of water and acetonitrile is 10:90 for 15 minutes → the volume ratio of water and acetonitrile is 95:5 for 5 minutes

Flow rate: 1.0ml/min

Column temperature: 30°C

Detection wavelength: 260nm

4. Gas chromatography (GC-RES)

Detector: FID

Chromatographic column: Agilent DB-624, 30m*0.32mm*1.80μm

Heating program: keep at 40°C for 0min, rise to 240°C at 20°C/min and keep for 5min

Injection port temperature: 250°C

Detector temperature: 300°C

Carrier gas: _N2

Pressure: (Constant Pressure)/Flow (Constant Flow) 7.8 Psi (Constant Pressure)

Split ratio: 30:1

Heating box temperature: 80°C

Quantitative loop temperature: 90°C

Transfer line temperature: 100°C

Injection vial equilibration time: 15min

GC cycle time: 25min

Embodiment 1, the preparation of enclave fumarate crystal form C of the present invention

Take (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione solid (1.0g) was added to 3.0ml dimethyl Dissolved liquid in base sulfoxide, heated to dissolve, added 0.22g fumaric acid while hot, stirred for 30min, cooled to room temperature, added dropwise 3.0ml dichloromethane, precipitated white solid, dried to obtain crystal form C ( 1.16g), the yield was 95%, the HPCL purity was >99.9%, and the single impurity content was less than 0.1%.

Enclave fumarate crystal form C of the present invention uses Cu-Ka radiation, and the obtained X-ray powder diffraction pattern is shown in Figure 1, represented by 2θ angle ± 2 and interplanar spacing (d), and its specific diffraction peak parameters As shown in Table 1.

Table 1. Specific diffraction peak parameters of enclave fumarate crystal form C

serial number 2θ[°] d value Relative Strength% 1 6.63 13.32 34.93 2 8.77 10.09 3.07 3 9.67 9.14 56.62 4 10.92 8.09 12.58 5 12.04 7.35 11.69 6 12.18 7.26 6.93 7 12.78 6.92 13.68 8 13.27 6.67 14.12 9 13.48 6.56 24.65 10 14.08 6.28 3.59 11 15.09 5.86 5.38 12 16.22 5.46 100.00 13 16.77 5.28 3.18 14 17.57 5.04 48.51 15 18.35 4.83 29.96 16 19.13 4.63 8.26 17 19.37 4.57 4.76 18 19.93 4.45 19.59 19 20.64 4.30 5.75 20 20.87 4.25 1.98 twenty one 21.78 4.07 19.59 twenty two 22.10 4.02 13.64 twenty three 22.39 3.97 24.13 twenty four 23.33 3.81 41.98 25 23.72 3.75 10.21 26 24.20 3.67 43.08 27 24.56 3.62 24.97 28 24.97 3.56 42.88 29 25.67 3.46 92.69 30 26.05 3.41 25.05 31 26.38 3.37 6.44 32 26.72 3.33 3.07 33 27.16 3.28 3.15 34 28.03 3.18 53.52 35 28.40 3.14 9.82 36 28.84 3.09 3.23 37 29.62 3.01 1.49 38 30.05 2.97 2.82 39 30.40 2.94 9.45 40 30.94 2.89 1.16 41 31.40 2.84 4.16 42 31.68 2.82 3.86 43 32.29 2.77 3.05 44 32.58 2.74 4.02 45 32.99 2.71 20.13 46 33.50 2.67 4.54 47 34.15 2.62 5.98 48 34.66 2.58 1.13 49 34.94 2.56 2.22 50 35.52 2.52 6.44 51 35.97 2.49 1.15 52 36.33 2.47 1.27 53 36.80 2.44 1.74 54 36.99 2.42 2.43 55 37.47 2.39 4.85 56 37.77 2.37 1.25 57 38.22 2.35 1.81 58 39.21 2.29 5.72

The differential scanning calorimetry (DSC) spectrogram of enciatevir fumarate crystal form C of the present invention is as shown in Figure 2, has two endothermic peaks in the spectrogram, and peak is the endothermic peak of 233 ± 2 ℃ and The peak is an endothermic peak at 268°C±2°C.

Embodiment 2, the preparation of enclave fumarate crystal form C of the present invention

Take (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione solid (1.0g) was added to 1.0ml dimethyl Dissolved clear liquid in sulfoxide, heated to dissolve, added 0.22g fumaric acid while hot, stirred for 30min, cooled to room temperature, added dropwise 6.0ml methanol, precipitated white solid, dried to obtain crystal form C (1.16g ), the yield was 95%, and the HPCL purity was 99.9%. The XRD pattern of the crystal form C obtained in this example (see Figure 3) is consistent with that of Example 1, and it can be proved that the obtained crystal form C of encedentevir fumarate is indeed.

Embodiment 3, the preparation of enclave fumarate crystal form C of the present invention

Take (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione solid (1.0g) was added to 1.0ml dimethyl Dissolved liquid in base sulfoxide, heated to dissolve, added 0.22g fumaric acid while hot, stirred for 30min, cooled to room temperature, added dropwise 6.0ml ethyl acetate, precipitated white solid, dried to obtain crystal form C (1.14 g), the yield is 94%, and the HPCL purity is 99.9%. The XRD pattern of the crystal form C obtained in this example (see Figure 4) is consistent with that in Example 1, and it can be proved that the obtained crystal form C of enciatevir fumarate is indeed.

Embodiment 4, kilogram grade product production

Take (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione solid (3.4kg) was added to 9.12L dimethyl Dissolved clear liquid in sulfoxide, heated to dissolve, added 967.40g fumaric acid while hot, stirred for 30min, cooled to room temperature, added dropwise 9.12L dichloromethane, precipitated white solid, dried to obtain crystal form C ( 3.8kg), the yield was 92%, the HPCL purity was >99.9%, and the single impurity content was less than 0.1%. The XRD spectrum of the crystal form C obtained in this example is consistent with that in Example 1, and it can be proved that the obtained crystal form C of enciatevir fumarate is indeed.

Comparative example 1, preparation of other crystal forms of Enclave fumarate

Take (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione solid (1.0g) was added to 1.0ml dimethyl Dissolved clear liquid in sulfoxide, heated to dissolve, added 0.22g fumaric acid while hot, stirred for 30min, cooled to room temperature, added dropwise 6.0ml purified water, precipitated white solid, dried to obtain crystal form A (1.12g ), the yield was 92%, and the HPCL purity was 99.9%. The X-ray powder diffraction pattern of the obtained crystal form A is shown in FIG. 5 .

Comparing Examples 1 to 3 with Comparative Example 1, it is found that the solvents used are different, and the crystal forms of Enclave fumarate obtained are different, such as using dimethyl sulfoxide as a solvent to form a salt, using methanol, dichloromethane (DCM) and ethyl acetate (EA) were used as poor solvents for crystallization to obtain crystal form C, but purified water was used as a poor solvent for crystallization to obtain crystal form A.

Comparative example 2, the preparation method of crystal form A in the patent whose announcement number is CN114591304B

Take (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione fumaric acid amorphous powder (15.2 mg) Add 1.0 mL ethyl acetate to prepare a suspension, suspend and stir at room temperature for 3-7 days, separate the suspension, and dry the solid in vacuo to obtain a white solid, which is Enclave fumarate crystal form A (13.45 mg). is 88.5%, and the HPCL purity is 99.9%. The XRD pattern of the crystal form A obtained in this comparative example is consistent with that of comparative example 1, which can prove that the crystal form A of enclave fumarate is indeed obtained.

Comparative example 3, the preparation method of crystal form B in the patent with the announcement number CN114591304B

(6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazole -3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione (2.0g) and fumaric acid (475.10 mg) in ethyl acetate (10 mL) and stirred at room temperature for 45 min. The suspension was filtered to give (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1 as a white solid ,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione fumaric acid Form B (2.10g), the yield was 85%, and the HPCL purity was 98%. The X-ray powder diffraction pattern of the obtained crystal form B is shown in FIG. 6 .

The beneficial effects of the present invention are demonstrated through specific test examples below.

Test Example 1. Stability study of each crystal form of Enclave fumarate

(1) The crystalline form C of enciatevir fumarate prepared in Example 1 was subjected to a 6-month accelerated stability experiment, and the crystalline form C of enciatevir fumarate was stored at a temperature of 40±2°C and a humidity of: In an environment of 75%±5%, its properties, moisture, melting point, and purity were tested before the accelerated stability test (0 month) and after 6 months (accelerated 6 months), and X-ray powder diffraction was performed Observe its crystal form, the results are shown in Table 2.

Table 2. The results of the 6-month accelerated stability test of Enclave fumarate crystal form C prepared in Example 1

The results in Table 2 show that: Enclave fumarate crystal form C prepared in Example 1 has good stability after the 6-month accelerated stability test, and its appearance and purity are basically the same as 0 months, and the 6-month accelerated stability test The final crystal form is still crystal form C, without dissociation or crystal transformation. The differential scanning calorimetry (DSC) spectrogram of the Enclave fumarate crystal form C prepared in Example 1 after the 6-month accelerated stability test is shown in Figure 10, and the results are consistent with Figure 2, which also illustrates the present invention. The crystal form C of enclave fumarate prepared by the invention has good stability.

(2) For the crystal form C of Enclave fumarate prepared in Example 1, the crystal form A of Enclave fumarate prepared in Comparative Example 1 and the crystal form of Enclave fumarate prepared in Comparative Example 3 The stability of B was studied. Divide Enclave fumarate crystal form A, crystal form B and crystal form C evenly into open petri dishes with a thickness of about 5mm, and place them in high temperature (60°C) and high humidity (92.5%, 25°C) respectively. ) and light (4500lx±500lx), samples were taken at 5 days, 10 days and 30 days respectively, the appearance was observed and the purity was tested, and compared with the results on day 0, the crystal form A, crystal form B and crystal form C The stability comparison results are shown in Table 3.

Table 3. Stability comparison results of Form A, Form B and Form C

The results in Table 3 show that Enclave Fumarate Form C has good stability under high temperature, high humidity and light, and maintains a stable appearance and purity within 30 days. Although the appearance of the Encciotevir fumarate crystal form A has no obvious change, the purity has decreased, which shows that the stability of the Encetermine fumarate fumarate crystal form C in the present invention is better than that of the Encetermine fumarate fumarate crystal form A. Enclave fumarate crystal form B exhibits micro-agglomeration or agglomeration under high-humidity conditions, is unstable under light, changes color, and has the worst stability.

From the above results, it can be seen that compared with other crystal forms of Enccitravir fumarate, the Enclave Fumarate Crystal Form C prepared by the present invention has very good stability, which is beneficial to the preparation, transportation and storage of medicines , to ensure the effectiveness and safety of drug use.

(3) For the crystal form C of Enclave fumarate prepared in Example 1, the crystal form A of Enclave fumarate prepared in Comparative Example 1 and the crystal form of Enclave fumarate prepared in Comparative Example 3 B conducted an accelerated stability test for 6 months, and stored each crystal form in an environment with a temperature of 40±2°C and a humidity of 75%±5%. The appearance and purity of each crystal form were detected before the experiment (0 month), 1 month, 2 months and 6 months after the experiment. The results are shown in Table 4.

Table 4. 6-month accelerated stability test results of Form A, Form B and Form C

The results in Table 4 show that Enclave Fumarate Form C has good stability at 40±2°C and 75%±5% relative humidity (RH), and maintains a stable appearance and purity within 6 months. Comparing the accelerated 6-month purity data of encampovir fumarate crystal form A and encetermine fumarate fumarate crystal form B, it can be seen that the stability of crystal form C is better than that of encetermine fumarate fumarate crystal form A and fumarate Enclave acid crystal form B.

(4) The present invention also investigates the solvent residues of Enclave Fumarate Form C prepared in Examples 1-3, and detects them by gas chromatography. The results of solvent residue detection are shown in Table 5. Fig. 11 is the solvent residue spectrum of enclave fumarate crystalline form C prepared in Example 1.

Table 5. Solvent residual test results of enclave fumarate crystal form C of the present invention

The results in Table 5 show that the Enclave fumarate crystal form C prepared by the present invention has a solvent residue limit lower than the ICHQ3C limit requirement and meets the quality requirements of the raw material drug. Fig. 12 is the solvent residue spectrum of Enclave Fumarate Form A prepared in Comparative Example 1. The solvent residue of the product obtained in Comparative Example 1 is too high to meet the quality requirements of the raw material drug, which fully demonstrates that the preparation method of crystal form C is more superior.

The results of the above test example 1 illustrate: compared with the existing enciatevir fumarate crystal form A and fumarate encedentevir crystal form B, the stability of the enciatevir fumarate crystal form C prepared by the present invention excellent. Simultaneously, the solvent residue of Enclave fumarate crystal form C prepared by the present invention meets the quality requirements of raw materials. In addition, compared with the existing method for preparing the crystal form of Enciatevir fumarate, the method of the present invention for preparing the crystal form C of Enciatevir fumarate adopts a smaller volume of reaction solvent, simpler operation, and convenient post-processing , The reaction time is greatly shortened, the yield is higher, and the product quality is better.

In summary, the present invention provides a new crystal form of enciatevir fumarate and a preparation method thereof. The method for preparing the new crystal form of enciatevir fumarate in the present invention is simple and convenient, reduces the amount of reaction solvent, reduces the reaction time, and simplifies The post-treatment process is improved, and the reaction yield is improved. In addition, the obtained enciatevir fumarate crystal form has high purity (HPLC > 98.5%), high melting point, better stability compared with the existing enciatevir fumarate crystal form, and meets ICHQ3C solvent limit requirements. Higher, the Enclave fumarate crystal form obtained in the present invention can effectively extend the validity period of the drug as a drug raw material, and can meet the pharmaceutical requirements of production, processing, transportation, and storage, and is also conducive to storage and quality control at room temperature. The present invention achieves the goals of high yield, high purity, less impurities, good quality and controllable reaction of the new crystal form of Enclave Fumarate, and the preparation method has the advantages of low cost, less waste, green and environmental protection, and is also conducive to industrial scale-up production , the application prospect is broad.

Claims (10)

1. The crystal form of Enclave fumarate shown in formula I is characterized in that: it uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ value ± 0.2 ° include 6.63, 9.67, 10.92, 12.04, 12.18, 12.78, 13.27, 13.48, 16.22, 17.57, 18.35, 19.93, 21.78, 22.10, 22.39, 23.33, 23.72, 24.20, 24.56, 25.67, 26.05, 28.03, 3 2.99; Formula I. 2. The crystal form according to claim 1, characterized in that: it uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ value ± 0.2° also include 15.09, 19.13, 20.64, 26.38, 28.40, 30.40, 34.15, 35.52, 37.47, 39.21. 3. The crystal form according to claim 1 or 2, characterized in that: the X-ray powder diffraction pattern of the crystal form is shown in Figure 1 . 4. The crystal form according to claim 1 or 2, characterized in that: there are two endothermic peaks in the differential scanning calorimetry spectrum, the endothermic peak at 233±2°C and the endothermic peak at 268°C±2°C Endothermic peak at 2°C. 5. The crystalline form according to claim 1 or 2, characterized in that: the molar ratio of enclave and fumaric acid in the crystalline form is 1:1; the purity of the crystalline form is more than 99%, And/or the single impurity content is less than 0.1%. 6. The preparation method of the crystal form described in any one of claims 1 to 5, characterized in that: it comprises the steps of: Dissolve the solid of Encytevir in a solvent, add fumaric acid and stir, use a poor solvent to precipitate crystals, and dry to obtain the product. 7. preparation method according to claim 6 is characterized in that: described solvent is dioxane, butanone, acetonitrile, ethyl formate, ethyl acetate, butyl formate, dichloromethane, chloroform, ethylene glycol Alcohol dimethyl ether, methyl tert-butyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 4-methyl-2-pentanone and / or one or more of tetrahydrofuran; And/or, described poor solvent is one or more in methylene chloride, methanol, ethyl acetate; And/or, the drying temperature is 60-100°C. 8. A pharmaceutical composition, characterized in that it comprises the crystal form according to any one of claims 1-5 and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to claim 8, characterized in that: in the pharmaceutical composition, the weight percentage of the crystalline form according to any one of claims 1-5 is 0.1%-85%. 10. Use of the crystal form according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 8 or 9 in the preparation of a medicament for the treatment of novel coronavirus.