Crystalline forms of pyrrolopyridine derivatives

Abstract

The present invention relates to a crystalline polymorph of a pyrrolopyridine derivative, which is a non-catalytic site integrase inhibitor, and a method for producing the same. The novel crystalline polymorph of the present invention exhibits excellent non-absorption and stability, making it suitable for pharmaceutical formulations.

Description

[Technical Field]

[0001] The present invention relates to a crystalline form of a pyrrolopyridine derivative that is a non-catalytic site integrase inhibitor, and further to a method for producing the crystalline form of the pyrrolopyridine derivative. [Background technology]

[0002] AIDS (Acquired Immunodeficiency Syndrome; AIDS) is induced by infection with the Human Immunodeficiency Virus (HIV). To treat AIDS, enzyme inhibitors have been developed based on the mechanism of action of HIV. They are classified according to their mode of action into nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors, and integrase inhibitors. Reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors have problems such as side effects, drug interactions, and the development of drug resistance, so active development of integrase inhibitors is underway.

[0003] Integrase inhibitors are classified into catalytic site inhibitors and non-catalytic site inhibitors based on their mechanism. Raltegravir is a representative catalytic site integrase inhibitor. The non-catalytic site integrase inhibitor mechanism was introduced by Zeger Debyser et al. (Frauke Christ, Zeger Debyser et al., Nature Chemical Biology, 2010, Vol. 6, 442), but no drug has yet been successfully developed.

[0004] However, it has been found that drug resistance also develops with raltegravir, a catalytic site integrase inhibitor. When HIV treatment is discontinued, latent HIV is reactivated, resulting in resistance, and the currently administered treatment is no longer effective. Therefore, efforts are being made to develop non-catalytic site integrase inhibitors as treatments that can solve the problem of drug resistance. In particular, pyrrolopyridine derivatives of the following formula I are known as non-catalytic site integrase inhibitors. [ka]

[0005] When designing a suitable dosage form for the pharmaceutical manufacturing process, it is important to select the physical state of the pharmaceutical raw material, i.e., crystalline or amorphous. However, crystalline raw materials have low solubility, which can reduce bioavailability per unit weight, and amorphous raw materials are unstable, which can make it difficult to control drug release and blood concentration.

[0006] Therefore, it is necessary to develop a new crystalline form of the pyrrolopyridine derivative of formula I that simultaneously solves these problems and exhibits excellent physicochemical properties. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a crystalline form of a pyrrolopyridine derivative which is non-absorbable, has excellent stability, and can improve solubility and bioavailability, and a method for producing the same. [Means for solving the problem]

[0008] In order to achieve the above object, the inventors have conducted extensive research and development, and as a result have produced the following crystalline forms A to D, which have been confirmed to exhibit excellent effects, thereby completing the present invention.

[0009] Crystalline form A and its manufacturing method The present invention provides a crystalline form A of a compound represented by formula I below, which has peaks in a powder X-ray diffraction pattern at diffraction angles (2θ±0.2°) of 9.26°, 10.47°, 12.76°, 14.70°, 15.83°, and 16.61°:

[0010] [ka] According to an embodiment of the present invention, the crystalline form A may further include one or more peaks at diffraction angles (2θ±0.2°) of 17.57°, 18.50°, 20.15°, 21.06°, 22.17°, 23.98°, or 27.05° in the powder X-ray diffraction pattern.

[0011] According to an embodiment of the present invention, the crystalline form A may further include one or more peaks at diffraction angles (2θ±0.2°) of 8.02°, 8.39°, 8.72°, 13.92°, 16.40°, 17.79°, 19.33°, 23.38°, 24.36°, 24.90°, 25.59°, 25.99°, 26.70°, 27.85°, 29.37°, 29.98°, 30.77°, or 31.59° in a powder X-ray diffraction pattern.

[0012] According to a specific example of the present invention, the crystalline form A may have a DSC (Differential Scanning Calorimetry) endothermic transition peak at 208 to 215° C. when the heating rate is 10° C. / min.

[0013] The present invention also provides a method for preparing crystalline form A. Specifically, the method includes the following steps: (A-1) adding the compound represented by formula I to toluene, ethyl acetate or isopropanol and stirring; and (A-2) A step of filtering and drying the produced solid.

[0014] Crystalline form B and its manufacturing method The present invention provides crystalline form B of the compound represented by formula I, which has peaks at diffraction angles (2θ±0.2°) of 9.24°, 12.79°, 15.43°, 16.32°, 17.83°, and 19.35° in a powder X-ray diffraction pattern.

[0015] According to an embodiment of the present invention, the crystalline form B may further include one or more peaks at diffraction angles (2θ±0.2°) of 20.18°, 23.35°, 23.84°, 24.46°, 26.03°, 29.66°, or 30.53° in the powder X-ray diffraction pattern.

[0016] According to an embodiment of the present invention, the crystalline form B may further include one or more peaks at diffraction angles (2θ±0.2°) of 7.94°, 10.03°, 11.65°, 14.63°, 16.80°, 17.55°, 18.63°, 21.58°, 22.67°, 23.62°, 25.29°, 27.15°, 28.13°, 29.38°, 30.68°, 31.61°, 32.05°, 33.04°, 34.41°, 35.50°, or 36.26° in a powder X-ray diffraction pattern.

[0017] According to a specific example of the present invention, the crystalline form B may have a DSC (Differential Scanning Calorimetry) endothermic transition peak at 213 to 218°C when the heating rate is 10°C / min.

[0018] The present invention also provides a method for preparing crystalline form B. Specifically, the method may include the following steps: (B-1) adding the compound represented by formula I to ethanol and stirring; and (B-2) A step of filtering and drying the produced solid.

[0019] Crystalline form C and its manufacturing method The present invention provides crystalline form C of the compound represented by formula I, which has peaks at diffraction angles (2θ±0.2°) of 7.62°, 8.61°, 10.10°, 12.06°, 13.52°, and 15.72° in a powder X-ray diffraction pattern.

[0020] According to an embodiment of the present invention, the crystalline form C may further include one or more peaks at diffraction angles (2θ±0.2°) of 17.35°, 18.73°, 19.62°, 22.60°, 23.50°, or 25.57° in the powder X-ray diffraction pattern.

[0021] According to an embodiment of the present invention, the crystalline form C may further include one or more peaks at diffraction angles (2θ±0.2°) of 9.23°, 9.73°, 11.36°, 12.85°, 15.37°, 16.16°, 17.85°, 20.34°, 21.00°, 23.96°, 24.37°, 25.21°, 26.24°, 27.33°, 27.84°, 29.70°, 30.32°, 31.08°, 33.94°, or 35.18° in a powder X-ray diffraction pattern.

[0022] According to a specific example of the present invention, the crystalline form C may have DSC (Differential Scanning Calorimetry) endothermic transition peaks at 124 to 143°C and 207 to 213°C when the heating rate is 10°C / min.

[0023] The present invention also provides a method for preparing crystalline form C. Specifically, the method includes the following steps: (C-1) adding the compound represented by formula I to methanol and stirring; and (C-2) A step of filtering and drying the produced solid.

[0024] Crystalline form D and its preparation method The present invention provides crystalline form D of the compound represented by formula I, which has peaks at diffraction angles (2θ±0.2°) of 8.70°, 11.42°, 13.62°, 15.51°, 16.70°, and 21.58° in a powder X-ray diffraction pattern.

[0025] According to an embodiment of the present invention, the crystalline form D may further include one or more peaks at diffraction angles (2θ±0.2°) of 7.52°, 9.37°, 9.89°, 18.59°, or 23.84° in the powder X-ray diffraction pattern.

[0026] According to an embodiment of the present invention, the crystalline form D may further include one or more peaks at diffraction angles (2θ±0.2°) of 8.24°, 10.72°, 12.02°, 12.38°, 15.01°, 15.93°, 17.95°, 19.91°, 20.62°, 21.29°, 22.71°, or 27.10° in the powder X-ray diffraction pattern.

[0027] According to an embodiment of the present invention, the crystalline form D may have a DSC (Differential Scanning Calorimetry) endothermic transition peak at 204 to 209° C. when the heating rate is 10° C. / min.

[0028] The present invention also provides a method for preparing crystalline form D. Specifically, the method may include the following steps: (D-1) adding a compound represented by the following formula I to acetone and water and stirring under reflux; (D-2) filtering insoluble matter, adding water and stirring; and (D-3) A step of filtering and drying the produced solid. [Effects of the Invention]

[0029] The crystalline form of the present invention has low absorbability, excellent stability under accelerated and long-term storage conditions, and can be stably maintained without any change in content for a long period of time, making it advantageous for pharmaceutical preparations.

[0030] Furthermore, the crystalline form of the present invention has high solubility and bioavailability and can be usefully used as a raw material for pharmaceuticals. [Brief explanation of the drawings]

[0031] [Figure 1] 1 shows the results of powder X-ray diffraction analysis (PXRD) of crystalline form A according to Example 1 of the present invention. [Figure 2] 1 shows the results of differential scanning calorimetry (DSC) thermogram of crystalline form A according to Example 1 of the present invention. [Figure 3] 1 shows the results of powder X-ray diffraction analysis (PXRD) of crystalline form B according to Example 2 of the present invention. [Figure 4] 1 shows the results of differential scanning calorimetry (DSC) thermogram of crystalline form B according to Example 2 of the present invention. [Figure 5] 1 shows the results of powder X-ray diffraction analysis (PXRD) of crystalline form C according to Example 3 of the present invention. [Figure 6] 1 shows the results of differential scanning calorimetry (DSC) thermogram of crystalline form C according to Example 3 of the present invention. [Figure 7] 1 shows the results of powder X-ray diffraction analysis (PXRD) of crystalline form D according to Example 4 of the present invention. [Figure 8] 1 shows the results of differential scanning calorimetry (DSC) thermogram of crystalline form D according to Example 4 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] In order to facilitate understanding of the present invention, the present invention will be described in detail below with reference to examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples and experimental examples of the present invention are provided to enable those skilled in the art to more completely understand the present invention.

[0033] Unless otherwise specified, the reagents and solvents described below were purchased from Sigma-Aldrich Korea, TCI, and Daejung Chemicals & Metals. HLPC was measured using an Agilent Technologies 1000 series.

[0034] In addition, various solid forms of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid prepared in the following examples were confirmed by X-ray diffraction patterns measured by X-ray diffractometry and DSC patterns measured by a differential scanning calorimeter (DSC).

[0035] Specifically, powder X-ray diffraction analysis was performed using a BRUKER D8 Focus equipped with a rotational detector and a solid-state detector, using Cu-Kα radiation under the conditions of an analysis range of 5° to 50°, a step of 0.020°, and a step time of 171.6 seconds. Additionally, differential scanning calorimetry (DSC) measurements were performed using a METTLER TOLEDO DSC3, with the temperature rising at a rate of 10°C / min, and values ​​were measured from 50 to 300°C.

[0036] Preparation Example: Preparation of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid [ka]

[0037] (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (13.5 g, 25.8 mmol) was diluted in 108 mL of tetrahydrofuran and 27 mL of methanol. Sodium hydroxide (3.1 g, 77.4 mmol) was added and the mixture was stirred at 40-45°C for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and 120 mL of dichloromethane and 60 mL of purified water were added. The mixture was cooled to 0-5°C and the pH was adjusted to 4.5-5.0 with 2N aqueous hydrochloric acid. The organic layer was separated, washed with 60 mL of purified water, dehydrated over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To the resulting residue, 30 mL of acetonitrile was added, and the mixture was cooled to 5 to 10°C and stirred for 3 hours. The precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (9.25 g, 72%, ee: 99%) as a fair-white solid.

[0038] Example 1. Preparation of Crystalline Form A 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid prepared in Preparation Example of the present invention was added to various solvents listed in Table 1 below and stirred at room temperature overnight. The resulting solid was filtered and dried in a hot air dryer at 50°C to obtain Crystalline Form A.

[0039] [Table 1]

[0040] The powder X-ray diffraction (PXRD) peak and differential scanning calorimetry (DSC) endothermic peak of the solid were analyzed, and the results are shown in Figures 1 and 2, respectively.

[0041] As seen in FIG. 1, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 9.26°, 10.47°, 12.76°, 14.70°, 15.83°, and 16.61°.

[0042] Furthermore, as can be seen from FIG. 2, the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 208 to 215° C. when the heating rate was 10° C. / min.

[0043] Example 2. Preparation of Crystalline Form B 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid prepared in Preparation Example of the present invention was added to ethanol (5 mL, 5 V) and stirred at room temperature overnight. The resulting solid was filtered and dried in a hot air dryer at 50°C to obtain crystalline form B (0.71 g, 71%).

[0044] The powder X-ray diffraction (PXRD) peak and differential scanning calorimetry (DSC) endothermic peak of the solid were analyzed, and the results are shown in Figures 3 and 4, respectively.

[0045] As seen in FIG. 3, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 9.24°, 12.79°, 15.43°, 16.32°, 17.83°, and 19.35°.

[0046] Furthermore, as can be seen from FIG. 4, the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 213 to 218° C. when the heating rate was 10° C. / min.

[0047] Example 3. Preparation of crystalline form C 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid prepared in Preparation Example of the present invention was added to methanol (5 mL, 5 V) and stirred at room temperature overnight. The resulting solid was filtered and dried in a hot air dryer at 50°C to obtain crystalline form C (0.71 g, 76%).

[0048] The powder X-ray diffraction (PXRD) peak and differential scanning calorimetry (DSC) endothermic peak of the solid were analyzed, and the results are shown in Figures 5 and 6, respectively.

[0049] As seen in FIG. 5, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 7.62°, 8.61°, 10.10°, 12.06°, 13.52°, and 15.72°.

[0050] Furthermore, as can be seen in Figure 6, the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 124 to 143°C when the heating rate was 10°C / min. The exothermic peak that appeared after the endothermic peak (melting) indicated that crystals were precipitated. After the crystals were precipitated (exothermic peak), another endothermic peak appeared at 206 to 213°C.

[0051] Example 4. Preparation of Crystalline Form D 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid prepared in Preparation Example of the present invention was diluted in a mixed solvent of 10 mL of acetone and 0.4 mL of purified water, and the mixture was refluxed and stirred for 1 hour. The insoluble matter was filtered, and 10 mL of purified water was added dropwise to the filtrate and stirred for 10 minutes. The resulting solid was stirred at room temperature for 30 minutes, filtered, and dried in a hot air dryer at 50°C to obtain crystalline form D (0.91 g, 91%).

[0052] The powder X-ray diffraction (PXRD) peak and differential scanning calorimetry (DSC) endothermic peak of the solid were analyzed, and the results are shown in Figures 7 and 8, respectively.

[0053] As seen in FIG. 7, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 8.70°, 11.42°, 13.62°, 15.51°, 16.70° and 21.58°.

[0054] Furthermore, as can be seen from FIG. 8, the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 204 to 209° C. when the heating rate was 10° C. / min.

[0055] Experimental example 1. Absorbency (DVS) measurement experiment Absorbability was tested using the crystalline forms prepared in the examples of the present invention.

[0056] a. Equipment used in the experiment -Model name: DVS Intrinsic (Surface Measurement Systems) -Specifications Temperature Range: 20~40℃ Temperature stability:±0.2℃ Humidity range: 0~98% RH RH Accuracy: ±1% RH Typical gas(Nitrogen+water vapor)flow rate:200sccm Sample chamber:40mm wide×50mm deep×50mm high Heating system:Peltier+Cartridge b. Sample information Experiments were carried out on the crystalline forms of the above examples. c. Experimental conditions -Temperature: 25℃ -Humidity: Initial 0% Max. 95% -Solvent:Water d. Experimental method A certain amount (10-20 mg) of the crystalline form prepared in the examples was placed in a sample pan in the sample chamber, and nitrogen was passed through a tube connected to the sample chamber for the first hour to remove moisture from the chamber and the sample. The humidity in the chamber was adjusted by adjusting the water vapor, and the target relative humidity was increased stepwise from the initial 0% by approximately 10%, and the moisture content of the crystalline form was measured. The mass of the sample was measured (from 0% RH to 95% RH), and the change in sample weight due to the increase or decrease in humidity was graphed.

[0057] The changes in water content of the crystalline forms according to the examples are as shown in Table 2 below.

[0058] [Table 2]

[0059] As a result of the analysis, it was observed that the crystalline form of the present invention has excellent non-absorbability with almost no change in water content, as shown in Table 2. This indicates that the crystalline form of the present invention is pharmaceutical superior in pre-processes such as production, storage, and formulation of the active ingredient.

[0060] Experimental Example 2: Accelerated Stability Test The crystalline powder according to the present invention was double-packed in a PE bag and then triple-packed in an aluminum bag, and left at 40±2°C and RH75±5% for 0 and 6 months, after which impurities were measured using HPLC. The results are shown in Table 3 below.

[0061] [Table 3]

[0062] From the results in Table 3, it was confirmed that the crystalline form of the present invention maintained its crystalline form without any significant change in soft substance and content. Therefore, it was found that the crystalline form of the present invention has excellent stability because it can stably maintain high purity for 6 months under accelerated conditions, and has very little change in water content and extremely low absorbency.

[0063] Experimental Example 3: Long-term stability test The crystalline powder according to the present invention was double-packed in a PE bag and then triple-packed in an aluminum bag, and left at 25±2°C and RH 60±5% for 0 and 12 months, after which impurities were measured using HPLC. The results are shown in Table 4 below.

[0064] [Table 4]

[0065] As shown in Table 4, the crystalline form of the present invention was confirmed to maintain its crystalline form without significant changes in softening agent and content. Therefore, the crystalline form of the present invention was found to have excellent stability by stably maintaining high purity for 12 months, with little change in water content and extremely low absorbency.

Claims

1. Crystalline Form A of the compound represented by formula I below, having peaks at diffraction angles (2θ±0.2°) of 9.26°, 10.47°, 12.76°, 14.70°, 15.83°, and 16.61° in a powder X-ray diffraction pattern: 【Chemistry 1】

2. 2. The crystalline form A of claim 1, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 17.57°, 18.50°, 20.15°, 21.06°, 22.17°, 23.98°, or 27.05° in a powder X-ray diffraction pattern.

3. 3. The crystalline form A of claim 2, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 8.02°, 8.39°, 8.72°, 13.92°, 16.40°, 17.79°, 19.33°, 23.38°, 24.36°, 24.90°, 25.59°, 25.99°, 26.70°, 27.85°, 29.37°, 29.98°, 30.77°, or 31.59° in a powder X-ray diffraction pattern.

4. 2. The crystalline form A of claim 1, which has a DSC (Differential Scanning Calorimetry) endothermic transition peak at 208-215°C when the heating rate is 10°C / min.

5. (A-1) adding a compound represented by the following formula I to toluene, ethyl acetate or isopropanol and stirring; and (A-2) filtering and drying the produced solid; A method for preparing crystalline form A of compound of formula I according to claims 1 to 4, comprising: 【Chemistry 2】

6. Crystalline Form B of the compound represented by formula I below, having peaks at diffraction angles (2θ±0.2°) of 9.24°, 12.79°, 15.43°, 16.32°, 17.83°, and 19.35° in a powder X-ray diffraction pattern: 【Transformation 3】

7. 7. The crystalline form B of claim 6, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 20.18°, 23.35°, 23.84°, 24.46°, 26.03°, 29.66°, or 30.53° in a powder X-ray diffraction pattern.

8. 8. The crystalline form B of claim 7, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 7.94°, 10.03°, 11.65°, 14.63°, 16.80°, 17.55°, 18.63°, 21.58°, 22.67°, 23.62°, 25.29°, 27.15°, 28.13°, 29.38°, 30.68°, 31.61°, 32.05°, 33.04°, 34.41°, 35.50°, or 36.26° in a powder X-ray diffraction pattern.

9. 7. The crystalline form B of claim 6, which has a DSC (Differential Scanning Calorimetry) endothermic transition peak at 213-218°C when the heating rate is 10°C / min.

10. (B-1) adding a compound represented by the following formula I to ethanol and stirring; and (B-2) filtering and drying the produced solid; A method for preparing crystalline form B of compound of formula I according to claims 6 to 9, comprising: 【Chemistry 4】

11. Crystalline form C of the compound represented by formula I below, having peaks at diffraction angles (2θ±0.2°) of 7.62°, 8.61°, 10.10°, 12.06°, 13.52°, and 15.72° in a powder X-ray diffraction pattern: 【Transformation 5】

12. 12. The crystalline form C of claim 11, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 17.35°, 18.73°, 19.62°, 22.60°, 23.50°, or 25.57° in a powder X-ray diffraction pattern.

13. 13. The crystalline form C of claim 12, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 9.23°, 9.73°, 11.36°, 12.85°, 15.37°, 16.16°, 17.85°, 20.34°, 21.00°, 23.96°, 24.37°, 25.21°, 26.24°, 27.33°, 27.84°, 29.70°, 30.32°, 31.08°, 33.94°, or 35.18° in a powder X-ray diffraction pattern.

14. 12. The crystalline form C of claim 11, which has DSC (Differential Scanning Calorimetry) endothermic transition peaks at 124-143°C and 207-213°C when the heating rate is 10°C / min.

15. (C-1) adding a compound represented by the following formula I to methanol and stirring; and (C-2) filtering and drying the resulting solid; A method for preparing crystalline form C of compound of formula I according to claims 11 to 14, comprising: 【Transformation 6】

16. Crystalline form D of the compound represented by formula I below, having peaks at diffraction angles (2θ±0.2°) of 8.70°, 11.42°, 13.62°, 15.51°, 16.70°, and 21.58° in a powder X-ray diffraction pattern: 【Transformation 7】

17. 17. The crystalline form D of claim 16, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 7.52°, 9.37°, 9.89°, 18.59°, or 23.84° in a powder X-ray diffraction pattern.

18. 18. The crystalline form D of claim 17, further comprising one or more peaks at diffraction angles (2θ±0.2°) of 8.24°, 10.72°, 12.02°, 12.38°, 15.01°, 15.93°, 17.95°, 19.91°, 20.62°, 21.29°, 22.71°, or 27.10° in a powder X-ray diffraction pattern.

19. 17. The crystalline form D of claim 16, which has a DSC (Differential Scanning Calorimetry) endothermic transition peak at 204-209°C when the heating rate is 10°C / min.

20. (D-1) adding a compound represented by the following formula I to acetone and water and stirring under reflux; (D-2) filtering insoluble matter, adding water, and stirring; and (D-3) filtering and drying the resulting solid; A method for preparing crystalline form D of compound of formula I according to claims 16 to 19, comprising: 【Transformation 8】

21. An antiviral pharmaceutical composition comprising crystalline form A according to claims 1 to 4, crystalline form B according to claims 6 to 9, crystalline form C according to claims 11 to 14, or crystalline form D according to claims 16 to 19.

22. The anti-human immunodeficiency virus (HIV) pharmaceutical composition according to claim 21.

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