A polymorph of a fgfr4 protein kinase inhibitor and methods of making the same

Abstract

The present application relates to a kind of polymorphs of FGFR4 protein kinase inhibitor and its preparation method.N-(2-(4-cyclopropylpiperazine-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo [1,2-a][1,6] naphthyridin-8-yl)-4-methoxyphenyl) acrylamide is a kind of FGFR4 protein kinase inhibitor, it can high selectivity inhibit FGFR4 tyrosine kinase, and the inhibitory effect of FGFR1-3 is weak, so it can safely, effectively treat the liver cancer patient of FGFR4 high expression.

Description

Technical Field

[0001] This invention relates to polymorphs of pharmaceutical compounds, specifically to polymorphs of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide and their preparation methods. Background Technology

[0002] N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide is an FGFR4 protein kinase inhibitor that selectively inhibits FGFR4 tyrosine kinase while having a weaker inhibitory effect on FGFR1-3, thus providing a safe and effective treatment for liver cancer patients with high FGFR4 expression. The structural formula is as follows:

[0003]

[0004] The synthetic method for this compound is disclosed in CN111662292 A, but it does not cover the compound's crystal form, and no other literature reports its crystal form. Polymorphism of a drug is significant for its physical properties, bioavailability, formulation quality, and processing. Differences in physicochemical properties between different crystal forms of a polymorphic drug affect its stability, and different crystal forms of the same drug may exhibit significant differences in bioavailability. Different crystal forms affect the drug's dissolution rate, and differences in surface free energy between different crystal forms result in varying binding forces between crystal particles, affecting the drug's flowability, particle uniformity, content uniformity, and physical stability. The compound obtained using the method in CN111662292 A is amorphous, and its stability does not meet the requirements for drug use. Therefore, a systematic study of its crystal form is needed to find a stable crystal form suitable for drug use. Attached Figure Description

[0005] Figure 1 The image shows the X-ray diffraction powder pattern of crystal form A.

[0006] Figure 2 The image shows the X-ray diffraction powder pattern of crystal form B.

[0007] Figure 3 The image shows the X-ray diffraction powder pattern of crystal form C.

[0008] Figure 4 The image shows the X-ray diffraction powder pattern of crystal form D.

[0009] Figure 5 The image shows the X-ray diffraction powder pattern of crystal form E.

[0010] Figure 6 The image shows the X-ray diffraction powder pattern of crystal form F.

[0011] Figure 7 The image shows the X-ray diffraction powder pattern of crystal form G.

[0012] Figure 8 The image shows the X-ray diffraction powder pattern of crystal form H.

[0013] Figure 9 This is the differential scanning calorimetry (DSC) curve for crystal form A.

[0014] Figure 10 This is the TGA image of crystal form A.

[0015] Figure 11 This is a differential scanning calorimetry (DSC) image of crystal form B.

[0016] Figure 12 This is the TGA image of crystal form B.

[0017] Figure 13 This is a differential scanning calorimetry (DSC) image of crystal form C.

[0018] Figure 14 This is the TGA image of crystal form C.

[0019] Figure 15 This is the differential scanning calorimetry (DSC) image of crystal form E.

[0020] Figure 16 This is the TGA image of crystal form E.

[0021] Figure 17 This is a differential scanning calorimetry (DSC) image of crystal form G.

[0022] Figure 18 This is the TGA image of crystal form G. Summary of the Invention

[0023] This invention relates to the polymorphs of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide. Due to the poor stability of this compound, the crystal forms obtained with conventional solvents are unstable and easily degrade during storage, failing to meet pharmaceutical requirements. To address the stability issue, extensive experimental and systematic studies were conducted, revealing eight crystal forms: A, B, C, D, E, F, G, and H. Only crystal form A is stable and meets pharmaceutical requirements; the remaining crystal forms B, C, D, E, F, G, and H all exhibit stability problems.

[0024] This invention provides polymorph A of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, which has the following properties: Figure 1 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 1.

[0025] Table 1. d-values ​​and 2θ angles of polymorph A

[0026] d- 2θ angle relative strength 12.93 6.8387 28.06 10.57 8.3621 36.70 8.11 10.9062 42.19 6.85 12.9179 58.88 6.30 14.0539 21.60 6.17 14.3607 19.27 5.53 16.0282 57.16 5.41 16.3859 65.38 4.98 17.7991 49.86 4.87 18.2037 100.00 4.55 19.5279 17.37 4.41 20.1368 33.71 4.04 22.0160 65.11 3.90 22.8108 56.71 3.81 23.3330 78.57 3.73 23.8665 12.35 3.47 25.7043 11.86 3.39 26.3103 85.65 3.27 27.2912 40.25

[0027] This invention relates to polymorph B of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, which has the following properties: Figure 2 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 2.

[0028] Table 2. d-values ​​and 2θ angles of polymorph B

[0029]

[0030]

[0031] This invention relates to polymorph C of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, wherein the crystalline form of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide has the following properties: Figure 3 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 3.

[0032] Table 3. d-values ​​and 2θ angles of polymorphic C

[0033]

[0034]

[0035] This invention relates to polymorph D of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, wherein the crystalline form of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide has the following properties: Figure 4 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 4.

[0036] Table 4. d-values ​​and 2θ angles of polymorph D

[0037]

[0038]

[0039] This invention relates to polymorph E of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, wherein the crystalline form of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide has the following properties: Figure 5 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 5.

[0040] Table 5. d-values ​​and 2θ angles of polymorphic E

[0041]

[0042]

[0043] This invention relates to polymorph F of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, wherein the crystalline form of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide has the following properties: Figure 6 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 6.

[0044] Table 6. d-values ​​and 2θ angles of polymorphic F

[0045] d- 2θ angle relative strength 11.26 7.8539 41.78 10.92 8.0935 100.00 7.59 11.6644 8.87 5.52 16.0637 27.59 5.41 16.3831 42.85 5.07 17.5009 19.05 5.00 17.7592 10.77 4.80 18.4932 31.26 4.72 18.7960 29.82 4.66 19.0554 59.98 4.37 20.3033 27.38 4.16 21.3486 17.98 3.98 22.3498 44.80 3.94 22.5580 29.37 3.79 23.4992 42.57 3.61 24.6357 31.38 3.19 27.9598 11.48 3.01 29.6908 18.46

[0046] This invention relates to polymorph G of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, wherein the crystalline form of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide has the following properties: Figure 7 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 7.

[0047] Table 7. d-values ​​and 2θ angles of polymorph G

[0048] d- 2θ angle relative strength 11.10 7.9662 29.79 8.30 10.6659 32.63 7.86 11.2637 17.69 7.60 11.6391 48.98 6.93 12.7671 13.60 6.24 14.1978 33.75 6.13 14.4347 100.00 5.83 15.1868 23.57 5.68 15.5945 57.01 5.53 16.0338 10.16 5.37 16.5135 10.65 5.05 17.5482 42.88 4.60 19.2766 26.05 4.46 19.9271 13.85 4.30 20.6451 87.28 4.19 21.6288 62.95 4.00 22.2217 38.22 3.91 22.7179 70.46 3.79 23.4918 60.98 3.68 24.2036 30.74 3.60 24.7640 23.41 3.40 26.2350 13.19 3.06 29.1843 10.70

[0049] This invention relates to polycrystalline form H of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide, wherein the crystalline form N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide has the following properties: Figure 8 The X-ray powder diffraction pattern shown has a measurement error of ±0.10 degrees for 2θ and contains multiple characteristic peaks between 0 and 50 degrees, as shown in Table 8.

[0050] Table 8. d-values ​​and 2θ angles of polymorph H

[0051]

[0052]

[0053] The relative intensities expressed numerically in the eight tables above are defined as follows:

[0054] relative strength definition 80-100 VS (Very Strong) 60-80 S (Strong) 30-60 M (Medium) 5-30 W(weak)

[0055] This invention also provides methods for preparing polymorphs A, B, C, D, E, F, G, and H of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide, and methods for preparing N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide. The eight polymorphs were synthesized according to the method of patent CN111662292A. The preparation method of the eight polymorphs used N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide purified by column chromatography with an HPLC purity of 98.84%, which was an off-white solid.

[0056] The preparation method of polymorph A is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is dissolved in trifluoroethanol, ethanol is added dropwise at 76-78℃, heating is turned off, and the mixture is allowed to cool naturally with stirring to crystallize.

[0057] The preparation method of polymorph B is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is placed in a mixed solvent of dichloromethane and acetonitrile, heated until dissolved, then the heating is turned off and the mixture is allowed to cool naturally to 20-30℃, and stirred to crystallize.

[0058] The preparation method of polymorph C is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is placed in tetrahydrofuran, heated until dissolved, then the heating is turned off, and the mixture is allowed to cool naturally to 20-30℃, and stirred to crystallize.

[0059] The preparation method of polymorph D is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is dissolved in dimethyl sulfoxide, and n-propanol is added dropwise at 95-110℃. Then, the heating is turned off, and the mixture is allowed to cool naturally with stirring to crystallize.

[0060] The preparation method of polymorph E is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is placed in methanol and stirred and slurried at room temperature (20-30℃) to transform it into crystals.

[0061] The preparation method of polymorph F is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is dissolved in trifluoroethanol, ethanol is added dropwise at room temperature, and crystals are stirred to precipitate.

[0062] The preparation method of polymorph G is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is placed in n-propanol, heated under reflux (95-97°C) for 2 hours, the heating is turned off, and the mixture is allowed to cool naturally with stirring to crystallize.

[0063] The preparation method of polymorph H is as follows: N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide is dissolved in N,N-dimethylformamide, ethyl acetate is added dropwise at 85-88℃, after the addition is complete, the solution becomes clear, the heating is turned off, and the solution is allowed to cool naturally with stirring to crystallize.

[0064] In the preparation method of the polymorphs A, B, C, D, E, F, G, and H, after crystallization, the mixture is filtered and dried to remove solvent and moisture.

[0065] The aforementioned polymorph A can be obtained by crystallization or stirring in one or more mixed solvents such as trifluoroethanol and ethanol, trifluoroethanol and tert-butanol, tert-butanol, n-butanol, n-pentanol, and trifluoroethanol, ethanol and tert-butanol. X-ray powder diffraction analysis of the products obtained from different solvent systems showed that the number of different 2θ angles was less than one-third, and all of them contained the characteristic peaks listed in Table 1. Therefore, it is considered that N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide obtained from several solvent systems belong to the same polymorph.

[0066] This invention experimentally discovered that N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide exists in polymorphs A, B, C, D, E, F, G, and H. These eight polymorphs were obtained by recrystallization or stirring and slurry precipitation in different solvents. The stability of the eight polymorphs was investigated under conditions of 40±2℃ and 75±5% relative humidity. The results showed that only polymorph A exhibited good stability, while the other polymorphs showed poor stability.

[0067] The present invention will be further described in detail below with reference to specific embodiments.

[0068] Example 1: Preparation of polymorph A of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0069] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and trifluoroethanol (2 mL) were added to a 50 mL single-necked flask and dissolved by magnetic stirring. The solution was heated in an oil bath at a temperature of T = 76–78 °C, and ethanol (8 mL) was added dropwise. After the addition was complete, the solution became clear. The heating was turned off, and the solution was allowed to cool naturally with stirring to induce crystallization. The solution was filtered, and the filter cake was dried at room temperature to obtain 0.33 g of a light yellow solid. The yield was 66.0%.

[0070] HPLC test showed a purity of 99.07%.

[0071] DSC detection chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 9 As shown.

[0072] TGA test chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 10 As shown.

[0073] Example 2, Preparation of polymorph B of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0074] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and acetonitrile (25 mL) were added to a 100 mL three-necked flask. The mixture was heated to reflux (~81 °C) in an oil bath, and the mixture was stirred and crystallized for 1 hour. The heating was turned off, and the mixture was allowed to cool naturally with stirring to induce crystallization. The mixture was filtered, and the filter cake was dried at room temperature to obtain 0.49 g of a light yellow solid. The yield was 98.0%.

[0075] HPLC test showed a purity of 99.35%.

[0076] DSC detection chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 11 As shown.

[0077] TGA test chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 12 As shown.

[0078] Example 3, Preparation of polymorph C of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0079] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and tetrahydrofuran (25 mL) were added to a 100 mL three-necked flask and heated to reflux until the solid was completely dissolved. The heating was turned off, and the mixture was allowed to cool naturally with stirring to induce crystallization. The mixture was filtered, and the filter cake was dried at room temperature to obtain 0.25 g of a light yellow solid. Yield: 50.0%.

[0080] HPLC test showed a purity of 99.50%.

[0081] DSC detection chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 13 As shown.

[0082] TGA test chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 14 As shown.

[0083] Example 4, Preparation of polymorph D of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0084] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and dimethyl sulfoxide (5 mL) were added to a 100 mL three-necked flask. The mixture was heated in an oil bath at T = 97 °C until the solid was completely dissolved. The temperature was maintained between T = 97 and 110 °C. 15 mL of n-propanol was added dropwise. After the addition was complete, the solution became clear. The heating was turned off, and the mixture was allowed to cool naturally with stirring to induce crystallization. The solution was filtered, and the filter cake was dried at room temperature to obtain 0.34 g of a light yellow solid. The yield was 68.0%.

[0085] HPLC test showed a purity of 98.56%.

[0086] Example 5, Preparation of polymorph E of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0087] The compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide (18.7 g) and methanol (100 mL) were added to a 250 mL three-necked flask. The mixture was stirred and crystallized at room temperature for 2 hours. The mixture was then filtered, and the filter cake was dried at room temperature to obtain 17.0 g of a light yellow solid. The yield was 90.9%.

[0088] HPLC analysis showed a purity of 98.83%.

[0089] DSC detection chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 15 As shown.

[0090] TGA test chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 16 As shown.

[0091] Example 6, Preparation of polymorph F of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0092] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and trifluoroethanol (2 mL) were added to a 100 mL three-necked flask and dissolved by magnetic stirring. Ethanol (8 mL) was added dropwise at room temperature. After the addition was complete, a large amount of solid precipitated out. The mixture was stirred and crystallized for another hour at room temperature. The mixture was then filtered, and the filter cake was dried at room temperature to obtain 0.47 g of a light yellow solid. The yield was 94.0%.

[0093] HPLC analysis showed a purity of 99.11%.

[0094] Example 7, Preparation of polymorph G of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0095] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and n-propanol (25 mL) were added to a 100 mL three-necked flask, heated to reflux (97–99 °C), stirred and slurried for 2 hours, the heating was turned off, and the mixture was allowed to cool naturally with stirring to crystallize. The mixture was filtered, and the filter cake was dried at room temperature to obtain 0.46 g of a light yellow solid, yield: 92.0%.

[0096] HPLC test showed a purity of 99.20%.

[0097] DSC detection chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 17 As shown.

[0098] TGA test chart (starting temperature 30℃, ending temperature 350℃, heating rate 10℃ / min) is shown below. Figure 18 As shown.

[0099] Example 8, Preparation of polymorph H of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthidin-8-yl)-4-methoxyphenyl)acrylamide

[0100] Compound N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide (0.5 g) and N,N-dimethylformamide (4 mL) were added to a 100 mL three-necked flask. The mixture was heated in an oil bath at T = 85 °C until the solid was completely dissolved. The temperature was then maintained between T = 85 and 88 °C. Ethyl acetate (8 mL) was added dropwise. After the addition was complete, the solution became clear. The heating was turned off, and the mixture was allowed to cool naturally with stirring to induce crystallization. The solution was filtered, and the filter cake was dried at room temperature to obtain 0.36 g of a light yellow solid. The yield was 72.0%.

[0101] HPLC test showed a purity of 99.59%.

[0102] Stability studies: Stability investigation of polymorphs A, B, C, D, E, F, G, and H of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthid-8-yl)-4-methoxyphenyl)acrylamide.

[0103] The polymorphs A, B, C, D, E, F, G, and H prepared in Examples 1-8 were subjected to stability testing at 40±2℃ and 75±5% relative humidity. Purity was determined by HPLC. The purity values ​​and stability study results are as follows:

[0104] Stability of polymorph A.

[0105]

[0106]

[0107] Stability of polymorph B

[0108] Time (days) purity 0 99.35％ 10 99.25％ 20 98.98％ 30 97.98％ 60 97.75％

[0109] Stability of polycrystalline C

[0110] Time (days) purity 0 99.50％ 10 99.27％ 20 98.90％ 30 98.06％ 60 97.75％

[0111] Stability of polymorph D

[0112] Time (days) purity 0 98.56％ 30 97.86％ 60 97.73％ 90 91.71％

[0113] Stability of polymorph E

[0114] Time (days) purity 0 98.83％ 10 98.39％ 20 97.85％ 30 97.45％ 60 97.19％

[0115] Stability of polymorph F

[0116]

[0117]

[0118] Stability of polymorphic G

[0119] Time (days) purity 0 99.20％ 10 98.87％ 20 95.35％ 30 91.00％

[0120] Stability of polymorphic H

[0121] Time (days) purity 0 99.59％ 10 99.57％ 20 99.60％ 30 99.03％ 90 98.90％

[0122] Stability conclusion: The stability study data above shows that crystal form A has good long-term stability over 3 months and is a suitable crystal form for drug development. The other crystal forms B, C, D, E, F, G and H all have stability issues.

Claims

1. Polymorph Form A of N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5- dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8-yl)-4-methoxyphenyl)acrylamide characterized by, It melts and decomposes at 280±5°C, and its X-ray powder diffraction pattern has characteristic peaks at the following positions in terms of 2 theta: 6.8387, 8.3621, 10.9062, 12.9179, 14.0539, 14.3607, 16.0282, 16.3859, 17.7991, 18.2037, 19.5279, 20.1368, 22.0160, 22.8108, 23.3330, 23.8665, 25.7043, 26.3103, 27.2912.

2. The polymorph form A of claim 1, characterized by, The X-ray powder diffraction pattern is shown in FIG.

1.

3. Process for the preparation of polymorph form A according to any one of claims 1-2, characterized in that, N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8-yl)-4-methoxyphenyl)acrylamide was recrystallized or stirred to recrystallize in a mixed solvent of trifluoroethanol and ethanol, a mixed solvent of trifluoroethanol and tert-butanol, or a mixed solvent of trifluoroethanol, ethanol and tert-butanol to obtain polymorph A.

4. The method of claim 3, wherein, N-(2-(4-cyclopropylpiperazin-1-yl)-5-(4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8-yl)-4-methoxyphenyl)acrylamide was dissolved in trifluoroethanol, ethanol was added dropwise at 76 to 78°C, heating was turned off, and the mixture was stirred to crystallize naturally to obtain polymorph A.

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