New crystal form of LEE011 key raw material and preparation method thereof

Abstract

The invention provides various crystal forms of an LEE011 intermediate and a preparation method thereof. Specifically, the invention provides an anhydrous crystal form of the LEE011 intermediate, namely Form A; the crystal form of the LEE011 intermediate is Form B; the crystal form of the LEE011 intermediate is Form C; the crystal form of the LEE011 intermediate is Form D; the crystal form of the LEE011 intermediate is Form E. The crystal form provided by the invention is stable in chemical property and easy to preserve, and the filtering performance is far better than that of a mixed crystal sample obtained by a current process. The preparation process is simple and feasible and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, specifically relating to a new crystal form of LEE011 key raw material and its preparation method. Background Technology

[0002] Recent studies have found that different drug crystal forms can alter their physicochemical properties (density, hardness, solubility, stability, optical properties, and electrical properties, etc.), production and processing properties (compression resistance, filtration performance, and chemical stability, etc.), dissolution rate, and biological effects. Therefore, the study of drug crystal forms has important practical value in medicine.

[0003] Kisqali (rebocinib) is an oral targeted CDK4 / 6 inhibitor that selectively inhibits cyclin-dependent kinase 4 / 6 (CDK4 / 6), restores cell cycle control, and blocks tumor cell proliferation.

[0004] Kisqali (LEE011) intermediate, chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester, its structural formula is as follows:

[0005] .

[0006] This compound is a key raw material for the synthesis of Kisqali. Existing recrystallization processes yield mixed crystals of this compound, resulting in significant mother liquor entrainment during filtration and separation, severely impacting separation, purification, and production efficiency. Currently, there are no studies or reports on the crystal form of this compound. Summary of the Invention

[0007] To overcome the shortcomings of existing technologies, the purpose of this invention is to provide a new crystal form of LEE011 intermediate and its preparation method.

[0008] This invention provides a Form A crystal form of the LEE011 intermediate shown in Formula (I) (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester).

[0009] .

[0010] Specifically, the Form A crystal form provided by the present invention has an X-ray diffraction pattern including peaks at 5.9, 7.8, 11.2, 11.6, 13.9, 14.8, 16.5, 17.0, 17.8, 18.1, 20.2 and 27.1 ± 0.2 degrees 2θ.

[0011] Specifically, the Form A crystal form provided by the present invention has a differential scanning calorimetry (DSC) chart containing endothermic signals at approximately 199.4°C and 219.8°C.

[0012] Specifically, the thermogravimetric analysis (TGA) diagram of the Form A crystal form provided by this invention includes a weight loss of approximately 0.09% when heated from approximately 30°C to approximately 120°C.

[0013] This invention provides a method for preparing LEE011 intermediate (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate) Form A crystal form, comprising the following steps:

[0014] 1) Dissolve the LEE011 intermediate solid in anisole and then filter.

[0015] 2) Cool the LEE011 intermediate anisole solution to a low temperature to induce crystallization;

[0016] 3) Filter and dry the precipitated solid.

[0017] In step 1), the mass-to-volume ratio of LEE011 intermediate solid to anisole is 1:15~25 g / mL, with a preferred mass-to-volume ratio of 1:20 g / mL.

[0018] In step 2), the cooling and crystallization temperature is 30~40℃.

[0019] This invention provides a Form B crystal form of the LEE011 intermediate shown in formula (I) (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester).

[0020] .

[0021] Specifically, the Form B crystal form provided by the present invention has an X-ray diffraction pattern including peaks at 6.2, 10.4, 12.2, 15.8, 17.1, 18.9, 19.1, 19.5, 20.2, 21.4 and 22.7 ± 0.2 degrees 2θ.

[0022] Specifically, the Form B crystal form provided by the present invention has a differential scanning calorimetry (DSC) pattern containing an exothermic signal at approximately 198.5°C and an endothermic signal at approximately 219.8°C.

[0023] Specifically, the Form B crystal form provided by the present invention has a thermogravimetric analysis diagram showing a weight loss of approximately 0.48% when heated from approximately 30°C to approximately 120°C.

[0024] This invention provides a method for preparing LEE011 intermediate (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate) Form B crystal form, comprising the following steps:

[0025] 1) Dissolve the LEE011 intermediate solid in methanol / dichloromethane and then filter.

[0026] In step 1), the volume ratio of methanol to dichloromethane is 1:1~2.

[0027] In step 1), the mass-to-volume ratio of the LEE011 intermediate solid to the mixed solvent of methanol and dichloromethane is 1:10 g / mL.

[0028] This invention provides a Form C crystal form of the LEE011 intermediate shown in formula (I) (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester).

[0029] .

[0030] Specifically, the X-ray diffraction pattern of the Form C crystal form provided by the present invention includes peaks at 10.0, 11.9, 14.2, 15.2, 17.7, 18.4, 19.1, 20.0, 20.4, 21.9, 22.7 and 23.2 ± 0.2 degrees 2θ.

[0031] Specifically, the Form C crystal form provided by the present invention has a differential scanning calorimetry (DSC) pattern containing exothermic signals at approximately 47.7°C, 114.6°C, and 219.6°C, and endothermic signals at approximately 119.2°C and 158.6°C.

[0032] Specifically, the Form C crystal form provided by the present invention has a thermogravimetric analysis diagram showing a weight loss of about 2.6% when heated from about 30°C to about 120°C.

[0033] This invention provides a method for preparing LEE011 intermediate (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate) Form C crystal form, comprising the following steps:

[0034] 1) Dissolve the LEE011 intermediate solid in acetonitrile by stirring until clear, then filter.

[0035] 2) Cool and stir the acetonitrile solution of the LEE011 intermediate to allow crystals to precipitate;

[0036] 3) Filter and dry the precipitated solid.

[0037] In step 1), the mass-to-volume ratio of LEE011 intermediate solid to acetonitrile ranges from 1:25 to 35 g / mL, with a preferred mass-to-volume ratio of 1:30 g / mL.

[0038] In step 2), the cooling temperature for crystallization is 30~40℃.

[0039] This invention provides a Form D crystal form of the LEE011 intermediate shown in Formula (I) (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester).

[0040] .

[0041] Specifically, the Form D crystal form provided by the present invention has an X-ray diffraction pattern including peaks at 6.3, 6.9, 11.3, 12.2, 12.9, 13.6, 13.8, 15.5, 17.0, 17.3, 17.7, 18.7, 20.1, 20.9, 21.4, 22.8, 23.2 and 23.7 ± 0.2 degrees 2θ.

[0042] Specifically, the Form D crystal form provided by the present invention contains an endothermic signal at approximately 219.2°C in its differential scanning calorimetry (DSC) curve.

[0043] Specifically, the Form D crystal form provided by the present invention has a thermogravimetric analysis diagram showing a weight loss of approximately 0.74% when heated from approximately 30°C to approximately 120°C.

[0044] This invention provides a method for preparing LEE011 intermediate (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate) Form D crystal form, comprising the following steps:

[0045] 1) Dissolve the LEE011 intermediate solid in tetrahydrofuran by stirring until clear, then filter.

[0046] 2) Slowly evaporate the tetrahydrofuran solution of the LEE011 intermediate;

[0047] 3) Filter and dry the precipitated solid.

[0048] In step 1), the mass-to-volume ratio of LEE011 intermediate solid to tetrahydrofuran ranges from 1:15 to 25 g / mL, with a preferred mass-to-volume ratio of 1:20 g / mL.

[0049] In step 2), the temperature for slow evaporation is 20~30℃.

[0050] This invention provides a Form E crystal form of the LEE011 intermediate shown in formula (I) (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester).

[0051] .

[0052] Specifically, the Form E crystal form provided by the present invention has an X-ray diffraction pattern including peaks at 6.0, 7.5, 10.3, 12.2, 12.3, 13.3, 13.5, 14.7, 15.7, 15.9, 16.9, 18.0, 18.9, 19.4, 19.6, 20.2, 21.4, 22.5, and 22.7 ± 0.2 degrees 2θ.

[0053] Specifically, the Form E crystal form provided by the present invention has a differential scanning calorimetry (DSC) pattern containing an exothermic signal at approximately 199.9°C and an endothermic signal at approximately 219.6°C.

[0054] Specifically, the Form E crystal form provided by the present invention has a thermogravimetric analysis diagram showing a weight loss of approximately 0.33% when heated from approximately 30°C to approximately 120°C.

[0055] This invention provides a method for preparing LEE011 intermediate (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate) in Form E crystal form, comprising the following steps:

[0056] 1) The LEE011 intermediate solid was suspended and stirred in methanol / purified water at 30°C;

[0057] 2) Filter the precipitated solid and dry it.

[0058] In step 1), the volume ratio of methanol to purified water ranges from 5.2 to 13.7:1.

[0059] This invention provides a series of crystal forms of the LEE011 intermediate (chemical name: tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid ester) and their preparation methods. These crystal forms are chemically stable, easy to store, and exhibit significantly better filtration performance than mixed-crystal samples obtained using current methods. The preparation process is simple and easy to implement, suitable for industrial production. Attached Figure Description

[0060] Figure 1 The image shows the PXRD pattern of the anhydrous form A of the LEE011 intermediate obtained in Example 1.

[0061] Figure 2 The image shows the DSC spectrum of the anhydrous form A of the LEE011 intermediate obtained in Example 1.

[0062] Figure 3 The TGA spectrum is shown for the anhydrous form A of the LEE011 intermediate obtained in Example 1.

[0063] Figure 4 The image shows the PXRD pattern of Form B, the intermediate of LEE011 obtained in Example 3.

[0064] Figure 5 The DSC spectrum of Form B, the intermediate of LEE011 obtained in Example 3.

[0065] Figure 6 The TGA map of Form B, the intermediate of LEE011 obtained in Example 3.

[0066] Figure 7 The image shows the PXRD pattern of Form C, the LEE011 intermediate obtained in Example 4.

[0067] Figure 8The DSC spectrum of Form C, the intermediate of LEE011 obtained in Example 4.

[0068] Figure 9 The TGA map of Form C, the intermediate of LEE011 obtained in Example 4.

[0069] Figure 10 The image shows the PXRD pattern of Form D, the LEE011 intermediate obtained in Example 5.

[0070] Figure 11 The DSC spectrum of the LEE011 intermediate Form D obtained in Example 5 is shown.

[0071] Figure 12 The TGA map of Form D, the LEE011 intermediate obtained in Example 5.

[0072] Figure 13 The image shows the PXRD pattern of Form E, the intermediate of LEE011 obtained in Example 6.

[0073] Figure 14 The DSC spectrum of Form E, the intermediate of LEE011 obtained in Example 6.

[0074] Figure 15 The TGA map of Form E, the intermediate of LEE011 obtained in Example 6. Detailed Implementation

[0075] To further understand the present invention, the following detailed description, in conjunction with embodiments, illustrates the novel crystal form of the LEE011 key raw material and its preparation method. It should be understood that these embodiments are merely for further detailing the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.

[0076] The X-ray powder diffraction testing instrument and testing conditions involved in this invention are as follows:

[0077] Instrument Model: Bruker D8 Advance

[0078] Light source: Cu Ka (1.5406 Å)

[0079] Pipe pressure: 40KV

[0080] Pipe current: 40mA

[0081] Diverging slit: 0.6mm

[0082] Receiving slit: 3.0mm

[0083] Air-scattering slit (blade edge): 1.0mm

[0084] 2θ scan range: 3°~40°

[0085] Scan rate per step: 0.2 s / step

[0086] Step size: 0.02°

[0087] The TGA / DSC thermal analysis test conditions for the LEE011 intermediate crystal form described in this invention are as follows:

[0088] Mettler Toledo TGA / DSC Thermal Analyzer (Model: TGA2 / DSC3+)

[0089] Dynamic temperature range: 30~300℃

[0090] Heating rate: 10℃ / min

[0091] Gas in program segment: N2

[0092] Flow rate: 50 ml / min

[0093] Crucibles: TGA quartz crucible; DSC aluminum crucible 40μl

[0094] Example 1: Preparation of anhydrous Form A, an intermediate of LEE011

[0095] Add 1g of LEE011 intermediate solid to 20 ml of anisole, heat to 50℃, stir to dissolve, filter, slowly cool to 35℃, add 10 mg of crystal form A as seed crystal, keep warm at 35℃ and stir for 2 h, continue to cool to 20℃, keep warm and stir for 3 h, filter, and vacuum dry the filter cake at 40℃ overnight to obtain Form A sample.

[0096] Example 2: Preparation of anhydrous Form A, an intermediate of LEE011

[0097] Add 10 ml of methyl tert-butyl ether to 2 g of LEE011 intermediate solid, keep it at 30°C and stir for 1 day, filter, and dry the filter cake under vacuum at 40°C overnight to obtain Form A sample.

[0098] Table 1. PXRD Peak Table of LEE011 Intermediate Form A Sample

[0099] peak Diffraction angle / degree d value relative strength #1 5.879 15.02199 2.30% #2 7.776 11.35995 6.60% #3 9.338 9.46364 0.60% #4 11.169 7.91537 7.20% #5 11.559 7.64976 14.30% #6 12.665 6.98384 0.50% #7 13.438 6.58384 0.70% #8 13.872 6.37868 14.60% #9 14.307 6.18586 0.80% #10 14.773 5.99174 4.90% #11 15.654 5.65633 2.70% #12 15.874 5.57842 0.70% #13 16.209 5.46406 1.50% #14 16.508 5.36574 6.10% #15 17.005 5.20979 8.50% #16 17.809 4.97645 34.10% #17 18.052 4.91007 16.30% #18 18.299 4.84431 6.80% #19 18.738 4.73171 9.20% #20 19.24 4.60935 0.60% #21 19.563 4.53418 2.60% #22 20.153 4.40261 100.00% #23 20.663 4.29504 2.50% #24 21.113 4.2046 0.50% #25 21.656 4.10031 4.80% #26 22.164 4.00757 2.00% #27 22.702 3.91383 5.50% #28 23.594 3.76781 2.60% #29 24.209 3.67349 3.40% #30 24.991 3.56018 4.20% #31 25.499 3.49045 2.30% #32 25.88 3.43991 1.90% #33 26.623 3.34561 4.10% #34 27.08 3.29018 14.20% #35 28.054 3.17812 0.40% #36 28.541 3.12497 1.30% #37 29.168 3.05917 0.60% #38 30.073 2.96918 1.30% #39 30.272 2.95013 0.90% #40 30.827 2.89825 1.60% #41 31.175 2.86666 1.00% #42 31.63 2.82649 0.90% #43 31.858 2.80676 0.70% #44 32.956 2.71568 0.60% #45 33.344 2.68495 0.60% #46 33.834 2.64717 0.60%

[0100] The endothermic reaction of the DSC begins at approximately 199.42°C and 219.80°C.

[0101] TGA contains approximately 0.09% weight loss when heated from approximately 30°C to approximately 120°C.

[0102] Example 3: Preparation of LEE011 intermediate Form B

[0103] Add 10 mL of methanol / dichloromethane (V methanol / V dichloromethane = 1 / 1) to 1 g of LEE011 intermediate solid, stir to dissolve at 25°C, concentrate under reduced pressure at 35°C until no obvious distillate is obtained to obtain Form B sample.

[0104] Table 2. PXRD Peak Table of LEE011 Intermediate Form B Sample

[0105] peak Diffraction angle / degree d value relative strength #1 6.162 14.3321 80.30% #2 7.502 11.77431 19.40% #3 8.996 9.82274 11.60% #4 10.38 8.51582 56.70% #5 12.199 7.24928 32.00% #6 12.39 7.13814 26.90% #7 13.436 6.58471 25.60% #8 14.346 6.16916 11.00% #9 14.797 5.98209 45.70% #10 15.127 5.85218 25.40% #11 15.779 5.61182 100.00% #12 17.073 5.18939 44.10% #13 17.397 5.09349 7.40% #14 17.972 4.9317 9.70% #15 18.368 4.82637 5.10% #16 18.903 4.69081 47.80% #17 19.144 4.63226 36.20% #18 19.459 4.55816 27.20% #19 19.905 4.45702 13.20% #20 20.228 4.38654 24.80% #21 20.829 4.26132 11.30% #22 21.403 4.14818 42.00% #23 21.652 4.10106 29.70% #24 22.514 3.94604 44.80% #25 22.701 3.91396 62.40% #26 23.324 3.81077 11.20% #27 23.82 3.73257 16.00% #28 24.229 3.6705 13.70% #29 24.601 3.61576 6.20% #30 25.207 3.53026 9.30% #31 26.442 3.36809 20.00% #32 27.033 3.29579 6.90% #33 27.637 3.22512 9.30% #34 29.384 3.03716 3.40% #35 29.904 2.98559 4.00% #36 30.493 2.92918 3.20% #37 31.687 2.82149 4.50% #38 31.952 2.79869 3.70%

[0106] The exothermic onset point of DSC is approximately 198.48℃, and the endothermic onset point is approximately 219.76℃.

[0107] TGA includes approximately 0.48% weight loss when heated from 30°C to 120°C.

[0108] Example 4: Preparation of LEE011 intermediate Form C

[0109] Add 30 ml of acetonitrile to 2 g of LEE011 intermediate solid, heat to 60 °C, stir to dissolve, filter, slowly cool the filtrate to 40 °C, add 10 mg of Form C as seed crystals, keep warm at 40 °C and stir for 2 h, continue to cool to 20 °C, keep warm and stir for 12 h, filter, and vacuum dry the filter cake at 40 °C overnight to obtain the Form C sample.

[0110] Table 3. PXRD Peak Table of LEE011 Intermediate Form C Sample

[0111] peak Diffraction angle / degree d value relative strength #1 7.21 12.25101 8.30% #2 8.44 10.46784 3.10% #3 9.971 8.86347 62.10% #4 11.268 7.84654 1.90% #5 11.672 7.5754 7.80% #6 11.912 7.42338 16.20% #7 13.051 6.77809 5.00% #8 13.562 6.52399 7.60% #9 13.955 6.34104 4.00% #10 14.196 6.23393 23.00% #11 15.163 5.8385 40.70% #12 15.905 5.56753 5.30% #13 16.766 5.2838 5.30% #14 17.749 4.9933 68.60% #15 18.393 4.81989 11.20% #16 19.145 4.63216 14.90% #17 19.272 4.6019 8.50% #18 20.02 4.4315 14.10% #19 20.383 4.35358 31.80% #20 21.085 4.21011 12.90% #21 21.383 4.15212 100.00% #22 21.94 4.04788 17.30% #23 22.74 3.90724 12.60% #24 23.163 3.83688 13.00% #25 24.528 3.62633 3.10% #26 25.544 3.48443 9.20% #27 26.696 3.33664 2.40% #28 26.963 3.30411 3.50% #29 27.355 3.25766 5.40% #30 28.251 3.15638 8.20% #31 28.622 3.11624 2.60% #32 29.542 3.02134 5.00% #33 29.998 2.97639 2.90% #34 30.687 2.91115 5.00% #35 32.211 2.77679 4.70% #36 32.951 2.71611 2.00% #37 33.433 2.67805 1.90% #38 36.024 2.49115 1.10% #39 39.095 2.30225 1.30% #40 39.689 2.26913 0.70%

[0112] The endothermic reaction of the DSC begins at approximately 47.75 °C, 114.63 °C, and 219.58 °C, while the exothermic reaction begins at approximately 119.23 °C and 158.59 °C.

[0113] TGA contains approximately 2.59% weight loss when heated from approximately 30°C to approximately 120°C.

[0114] Example 5: Preparation of LEE011 intermediate Form D

[0115] Add 20 ml of tetrahydrofuran to 2 g of LEE011 intermediate solid, stir and dissolve at 30 °C, filter, place the filtrate in a 20 ml sample bottle, seal with sealing film, punch holes, volatilize, crystallize for 3 days, filter, and vacuum dry the filter cake at 25 °C to constant weight to obtain LEE011 intermediate Form D crystal form.

[0116] Table 4. PXRD Peak Table of Form D Crystal Form of LEE011 Intermediate

[0117] peak Diffraction angle / degree d value relative strength #1 6.254 14.12089 54.70% #2 6.857 12.88058 84.70% #3 10.832 8.16143 4.40% #4 11.159 7.92266 6.50% #5 11.305 7.82046 12.20% #6 12.162 7.27136 30.00% #7 12.59 7.0255 8.40% #8 12.894 6.86039 30.80% #9 13.624 6.49409 16.20% #10 13.836 6.3953 24.80% #11 15.193 5.82695 7.00% #12 15.502 5.71153 54.90% #13 16.56 5.34881 4.10% #14 17.009 5.20878 100.00% #15 17.284 5.12648 26.90% #16 17.73 4.99856 43.30% #17 18.685 4.7451 26.70% #18 19.214 4.61553 2.20% #19 19.781 4.48471 6.70% #20 20.149 4.40355 20.10% #21 20.522 4.32422 8.50% #22 20.922 4.2426 13.00% #23 21.36 4.15645 92.40% #24 21.845 4.06539 2.30% #25 22.205 4.0003 4.00% #26 22.424 3.96157 9.80% #27 22.768 3.90252 48.70% #28 23.196 3.83146 27.20% #29 23.737 3.74539 12.70% #30 24.327 3.65589 3.90% #31 24.499 3.63066 6.50% #32 25.384 3.50595 12.80% #33 25.77 3.45428 11.50% #34 27.403 3.25204 11.40% #35 27.838 3.20219 6.40% #36 28.048 3.17872 5.00% #37 28.48 3.1315 1.60% #38 28.678 3.11031 2.50% #39 29.173 3.05872 2.70% #40 29.354 3.04021 2.50% #41 30.276 2.94968 1.60% #42 30.76 2.90436 3.40% #43 31.584 2.83045 2.00% #44 32.144 2.78243 5.90% #45 32.712 2.73536 2.00% #46 33.361 2.68363 1.40%

[0118] The DSC begins to absorb heat at approximately 219.18°C.

[0119] TGA contains approximately 0.74% weight loss when heated from approximately 30 °C to approximately 120 °C.

[0120] Example 6: Preparation of LEE011 intermediate Form E

[0121] Add 5 ml of methanol to 1 g of LEE011 intermediate solid, suspend and stir at 30°C for 3 days, filter, and dry the filter cake under vacuum at 25°C to constant weight to obtain LEE011 intermediate Form E crystal form.

[0122] Example 7: Preparation of LEE011 intermediate Form E

[0123] Add 5 ml of methanol / purified water (V methanol / V purified water = 13.7 / 1) to 1 g of LEE011 intermediate solid, suspend and stir at 30°C for 3 days, filter, and vacuum dry the filter cake at 25°C to constant weight to obtain LEE011 intermediate Form E crystal form.

[0124] Example 8: Preparation of LEE011 intermediate Form E

[0125] Add 5 ml of methanol / purified water (V methanol / V purified water = 5.2 / 1) to 1 g of LEE011 intermediate solid, suspend and stir at 30 ℃ for 3 days, filter, and vacuum dry the filter cake at 25 ℃ to constant weight to obtain LEE011 intermediate Form E crystal form.

[0126] Table 5. PXRD Peak Table of Form E Crystal Form of LEE011 Intermediate

[0127] peak Diffraction angle / degree d value relative strength #1 4.593 19.22225 2.90% #2 6.047 14.60369 40.50% #3 7.459 11.84196 20.70% #4 8.966 9.85468 7.70% #5 10.317 8.56713 31.40% #6 11.245 7.86208 3.10% #7 12.158 7.27417 20.70% #8 12.332 7.17178 16.30% #9 12.898 6.85839 2.40% #10 13.315 6.64433 28.30% #11 13.509 6.54953 11.50% #12 14.277 6.1988 8.30% #13 14.674 6.03186 43.40% #14 15.025 5.8919 10.00% #15 15.731 5.62902 100.00% #16 15.887 5.5739 72.20% #17 16.273 5.44245 2.50% #18 16.93 5.23292 25.00% #19 17.352 5.10658 4.60% #20 17.988 4.92725 28.10% #21 18.327 4.83685 3.50% #22 18.902 4.69122 29.00% #23 19.094 4.64442 12.90% #24 19.391 4.57394 32.50% #25 19.595 4.52666 22.50% #26 19.917 4.45429 12.10% #27 20.207 4.39102 47.10% #28 21.096 4.20786 6.60% #29 21.384 4.15197 62.20% #30 21.552 4.11992 20.50% #31 22.506 3.94743 62.10% #32 22.669 3.91937 92.40% #33 23.13 3.84234 5.70% #34 23.445 3.79132 24.20% #35 23.796 3.73628 17.80% #36 24.223 3.67137 23.00% #37 24.223 3.62156 6.20% #38 24.561 3.53785 19.80% #39 25.152 3.37308 21.70% #40 26.402 3.35195 21.10% #41 26.571 3.29608 7.40% #42 27.03 3.26418 11.60% #43 27.299 3.21605 14.60% #44 27.716 3.1714 7.00% #45 28.114 3.04801 6.30% #46 29.277 2.99053 3.00% #47 30.42 2.93605 7.20% #48 30.886 2.89283 1.90% #49 31.948 2.79901 3.90% #51 32.605 2.74416 1.50% #52 32.89 2.721 6.60% #53 33.403 2.6804 6.30%

[0128] The peak exothermic temperature of the DSC is approximately 199.97°C, and the endothermic temperature begins at approximately 219.59°C.

[0129] TGA contains approximately 0.33% weight loss when heated from approximately 30°C to approximately 120°C.

[0130] Comparative Example 1: Preparation of LEE011 intermediate using existing processes

[0131] Add 40 ml of tetrahydrofuran to 5 g of LEE011 intermediate solid, heat to 70°C and stir to dissolve, filter, concentrate the filtrate under reduced pressure at 70°C to obtain about 20 ml of tetrahydrofuran, cool to 40°C, add 20 ml of n-heptane and seed crystals, continue to cool to 10°C, keep warm and stir for 1 h, filter, and vacuum dry the filter cake at 40°C overnight to obtain mixed crystal sample.

[0132] Filtration performance evaluation test

[0133] The weights of the LEE011 intermediate solid samples prepared in Examples 1, 4, 5, and Comparative Example 1 after filtration and after vacuum drying were recorded, and the differences in the ratios were compared. The results are shown in the table below.

[0134] Table 6. Comparison of Dry and Wet Weights and Ratios of LEE011 Intermediate Solid Samples

[0135] As shown in the table, the wet-dry ratio of the Form A crystal sample obtained in Example 1 is greater than that of the mixed crystal sample obtained in Comparative Example 1, Form C obtained in Example 4, and Form D obtained in Example 5, indicating that the Form A crystal obtained in this invention has the best filtration performance among all the crystal forms discovered.

Claims

1. The Form A crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Its X-ray diffraction pattern includes peaks at 5.9, 7.8, 11.2, 11.6, 13.9, 14.8, 16.5, 17.0, 17.8, 18.1, 20.2, and 27.1 ± 0.2 degrees 2θ.

2. The crystal form according to claim 1, characterized in that, The differential scanning calorimetry (DSC) plot contains endothermic signals at 199.4 °C and 219.8 °C.

3. The crystal form according to claim 1, characterized in that, Its thermogravimetric analysis plot includes a weight loss of 0.09% when heated from 30°C to 120°C.

4. A method for preparing the Form A crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Includes the following steps: 1) Dissolve the LEE011 intermediate solid in anisole and then filter. 2) Cool the LEE011 intermediate anisole solution to a low temperature to induce crystallization; 3) Filter and dry the precipitated solid.

5. The preparation method according to claim 4, characterized in that, In step 1), the mass-to-volume ratio of LEE011 intermediate solid to anisole is in the range of 1:15~25 g / mL.

6. The preparation method according to claim 4, characterized in that, In step 2), the cooling and crystallization temperature is 30~40℃.

7. The Form B crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Its X-ray diffraction pattern includes peaks at 6.2, 10.4, 12.2, 15.8, 17.1, 18.9, 19.1, 19.5, 20.2, 21.4 and 22.7 ± 0.2 degrees 2θ.

8. The crystal form according to claim 7, characterized in that, Its differential scanning calorimetry (DSC) plot includes an exothermic signal at 198.5 °C and an endothermic signal at 219.8 °C.

9. The crystal form according to claim 7, characterized in that, Its thermogravimetric analysis plot includes a weight loss of 0.48% when heated from 30°C to 120°C.

10. A method for preparing the Form B crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, This includes the step of dissolving the LEE011 intermediate solid with methanol / dichloromethane and then filtering it.

11. The preparation method according to claim 10, characterized in that, The volume ratio of methanol to dichloromethane is 1:1~2.

12. The preparation method according to claim 10, characterized in that, The mass-to-volume ratio of the LEE011 intermediate solid to the methanol and dichloromethane mixed solvent is 1:10 g / mL.

13. The Form C crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Its X-ray diffraction pattern includes peaks at 10.0, 11.9, 14.2, 15.2, 17.7, 18.4, 19.1, 20.0, 20.4, 21.9, 22.7 and 23.2 ± 0.2 degrees 2θ.

14. The crystal form according to claim 13, characterized in that, Its differential scanning calorimetry (DSC) plot contains exothermic signals at 47.7 °C, 114.6 °C, and 219.6 °C, and endothermic signals at 119.2 °C and 158.6 °C.

15. The crystal form according to claim 13, characterized in that, Its thermogravimetric analysis plot includes a 2.6% weight loss when heated from 30°C to 120°C.

16. A method for preparing the Form C crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Includes the following steps: 1) Dissolve the LEE011 intermediate solid in acetonitrile by stirring until clear, then filter. 2) Cool and stir the acetonitrile solution of the LEE011 intermediate to allow crystals to precipitate; 3) Filter and dry the precipitated solid.

17. The preparation method according to claim 16, characterized in that, In step 1), the mass-to-volume ratio of LEE011 intermediate solid to acetonitrile is in the range of 1:25~35 g / mL.

18. The preparation method according to claim 16, characterized in that, In step 2), the cooling temperature for crystallization is 30~40℃.

19. The Form D crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Its X-ray diffraction pattern includes peaks at 6.3, 6.9, 11.3, 12.2, 12.9, 13.6, 13.8, 15.5, 17.0, 17.3, 17.7, 18.7, 20.1, 20.9, 21.4, 22.8, 23.2, and 23.7 ± 0.2 degrees 2θ.

20. The crystal form according to claim 19, characterized in that, Its differential scanning calorimetry (DSC) plot contains the endothermic signal at 219.2 °C.

21. The crystal form according to claim 19, characterized in that, Its thermogravimetric analysis plot includes a weight loss of 0.74% when heated from 30°C to 120°C.

22. A method for preparing the Form D crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Includes the following steps: 1) Dissolve the LEE011 intermediate solid in tetrahydrofuran by stirring until clear, then filter. 2) Slowly evaporate the tetrahydrofuran solution of the LEE011 intermediate; 3) Filter and dry the precipitated solid.

23. The preparation method according to claim 22, characterized in that, In step 1), the mass-to-volume ratio of LEE011 intermediate solid to tetrahydrofuran is in the range of 1:15~25 g / mL.

24. The preparation method according to claim 22, characterized in that, The temperature at which the slow evaporation occurs in step 2) is 20~30℃.

25. The Form E crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Its X-ray diffraction pattern includes peaks at 6.0, 7.5, 10.3, 12.2, 12.3, 13.3, 13.5, 14.7, 15.7, 15.9, 16.9, 18.0, 18.9, 19.4, 19.6, 20.2, 21.4, 22.5, and 22.7 ± 0.2 degrees 2θ.

26. The crystal form according to claim 25, characterized in that, The differential scanning calorimetry (DSC) curve contains an exothermic signal at 199.9 °C and an endothermic signal at 219.6 °C.

27. The crystal form according to claim 25, characterized in that, Its thermogravimetric analysis plot includes a weight loss of 0.33% when heated from 30°C to 120°C.

28. A method for preparing the Form E crystal form of the LEE011 intermediate shown in formula (I), ， Its features are, Includes the following steps: 1) The LEE011 intermediate solid was suspended and stirred in methanol / purified water at 30°C; 2) Filter the precipitated solid and dry it.

29. The preparation method according to claim 28, characterized in that, In step 1), the volume ratio of methanol to purified water ranges from 5.2 to 13.7:1.

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