New crystal form of LEE011 intermediate 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 substance crystal form of the LEE011 intermediate, and the anhydrous substance crystal form is named as Form N; the dihydrate crystal form of the LEE011 intermediate is named as Form I; the crystal form of the monohydrate of the LEE011 intermediate is named as Form P. The crystal form provided by the invention is stable in chemical property, easy to preserve and suitable for being prepared into various preparations. The preparation process is simple and feasible and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a new crystal form of LEE011 intermediate and a preparation method thereof. Background Art

[0002] Ribociclib (trade name: Kisqali) is an oral targeted CDK4 / 6 inhibitor, which can selectively inhibit cyclin-dependent kinases 4 / 6 (CDK4 / 6), restore cell cycle control, and block the proliferation of tumor cells.

[0003] The LEE011 intermediate, with the chemical name of 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, has the following structural formula:

[0004] 。

[0005] The LEE011 intermediate is the free base of Kisqali. The original patent CN103201275 protects a hydrate crystal form and an anhydrous crystal form of the LEE011 intermediate monosuccinate. EP3156406 discloses the free base Form 1 of the LEE011 intermediate, which has a low crystal purity, contains impurities, and is not a pure Form 1 (a mixed crystal containing other crystal forms).

[0006] Therefore, it is necessary to further develop a crystal form with good stability, suitable for storage and industrial production, so as to meet the subsequent development of the drug. Summary of the Invention

[0007] The purpose of the present invention is to provide various crystal forms of the LEE011 intermediate and a preparation method thereof.

[0008] The present invention provides a method for preparing the anhydrous Form N of the LEE011 intermediate, comprising the following steps:

[0009] (1) Dissolving the LEE011 intermediate solid in water to form an aqueous solution, and adjusting the pH with an acid to form a sample solution;

[0010] (2) Mixing the sample solution with an alcoholic solution of a base, and controlling the temperature at 40 - 60 °C;

[0011] (3) Cooling the mixed solution to 0 - 10 °C for crystallization;

[0012] (4) Filtering the precipitated solid by suction and drying.

[0013] Among them, the mass-volume ratio of the LEE011 intermediate solid to water in the step (1) ranges from 1:10 to 15 g / mL.

[0014] Among them, the alcohol is methanol, and the mass-volume ratio of the LEE011 intermediate solid to methanol in the step (2) ranges from 1:7.3 to 14.9 g / mL.

[0015] Among them, the acid in the step (1) is an organic acid or an inorganic acid, and preferably hydrochloric acid. The base in the step (2) is an organic base or an inorganic base, and preferably potassium carbonate, sodium carbonate, etc.

[0016] Among them, the anhydrous Form N of the LEE011 intermediate

[0017] ,

[0018] Its X-ray diffraction pattern includes peaks at 2θ of 6.8, 8.1, 12.4, 12.6, 12.8, 13.3, 13.6, 14.8, 15.2, 15.7, 18.0, 18.3, 18.6, 18.7, 20.1, 20.4, 21.4, 21.8, 22.6, 22.9, 23.8, 26.2, 27.0 and 29.3 ± 0.2 degrees.

[0019] Specifically, the differential scanning calorimetry thermogram of the anhydrous Form N of the LEE011 intermediate contains endotherms starting at about 37.5 °C and 200.1 °C.

[0020] Specifically, the thermogravimetric analysis thermogram of the anhydrous Form N of the LEE011 intermediate contains a weight loss of about 2.4% when heated from about 30 °C to about 170 °C.

[0021] The present invention provides a dihydrate Form I of the LEE011 intermediate.

[0022] Specifically, for Form I provided by the present invention, its X-ray diffraction pattern includes peaks at 2θ of 8.4, 9.7, 10.9, 11.3, 12.7, 12.9, 15.2, 15.5, 16.9, 17.2, 19.1, 19.4, 19.6 and 20.4 ± 0.2 degrees.

[0023] Specifically, for Form I provided by the present invention, its differential scanning calorimetry thermogram contains endotherms starting at about 53.1 °C and 194.1 °C.

[0024] Specifically, for Form I provided by the present invention, its thermogravimetric analysis thermogram contains a weight loss of about 7.4% when heated from about 30 °C to about 150 °C.

[0025] The present invention provides a method for preparing the dihydrate Form I of the LEE011 intermediate, comprising the following steps:

[0026] 1) Dissolve the solid of the LEE011 intermediate in an alcohol and water, and then filter;

[0027] 2) Volatilize the alcohol and water solution of the LEE011 intermediate at room temperature;

[0028] Wherein, the alcohol is methanol, and the volume ratio of methanol to water in step 1) is 1:10 - 15, and more preferably 1:13.75.

[0029] Wherein, the volatilization temperature in step 2) is 20 - 30 °C, and the more preferred temperature is 25 °C.

[0030] The present invention provides a monohydrate Form P of the LEE011 intermediate.

[0031] Specifically, for the Form P provided by the present invention, its X-ray diffraction pattern includes peaks at 2θ of 6.5, 8.4, 9.3, 11.3, 11.4, 11.6, 12.9, 13.2, 15.2, 15.5, 16.9, 17.2, 17.9, 19.0, 19.4, 19.6, 19.9, 20.4, 20.7, 21.1, 21.3, 22.5, 23.6, 26.8, 28.2 and 28.4 ± 0.2 degrees.

[0032] Specifically, for the Form P provided by the present invention, its differential scanning calorimetry thermogram includes endotherms starting at about 37.5 °C and 200.1 °C.

[0033] Specifically, for the Form P provided by the present invention, its thermogravimetric analysis thermogram includes a weight loss of about 2.4% when heated from about 30 °C to about 170 °C.

[0034] The present invention provides a method for preparing the monohydrate Form P of the LEE011 intermediate, comprising the following steps:

[0035] 1) Dissolve the solid of the LEE011 intermediate in water to form an aqueous solution, adjust the pH with an acid to form a sample solution;

[0036] 2) Mix the sample solution with an alcoholic solution of a base, and control the temperature at 40 - 60 °C;

[0037] 3) Cool the mixed solution to 0 - 10 °C to crystallize;

[0038] 4) Filter the precipitated solid by suction and dry it.

[0039] Wherein, the alcohol reagent mentioned in the above preparation method is more preferably methanol.

[0040] The mass-volume ratio of the LEE011 intermediate solid to methanol in step 2) ranges from 1:2.3 to 5.9 g / mL.

[0041] The excellent effects of the present invention are as follows: The present invention provides various crystal forms of the LEE011 intermediate and its preparation method. The crystal forms provided by the present invention have stable chemical properties, are easy to store, and are suitable for being made into various preparations. The preparation process is simple and feasible, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 It is the PXRD pattern of the anhydrous form N of the LEE011 intermediate obtained in Example 1.

[0043] Figure 2 It is the DSC pattern of the anhydrous form N of the LEE011 intermediate obtained in Example 1.

[0044] Figure 3 It is the TGA pattern of the anhydrous form N of the LEE011 intermediate obtained in Example 1.

[0045] Figure 4 It is the PXRD pattern of the dihydrate form I of the LEE011 intermediate obtained in Example 2.

[0046] Figure 5 It is the DSC pattern of the dihydrate form I of the LEE011 intermediate obtained in Example 2.

[0047] Figure 6 It is the TGA pattern of the dihydrate form I of the LEE011 intermediate obtained in Example 2.

[0048] Figure 7 It is the PXRD pattern of the monohydrate form P of the LEE011 intermediate obtained in Example 3.

[0049] Figure 8 It is the DSC pattern of the monohydrate form P of the LEE011 intermediate obtained in Example 3.

[0050] Figure 9 It is the TGA pattern of the monohydrate form P of the LEE011 intermediate obtained in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0051] In order to further understand the present invention, the following examples are used to elaborate in detail on the new crystal forms of the LEE011 intermediate provided by the present invention and its preparation method. It should be understood that these descriptions of the examples are only for further elaborating on the features of the present invention, rather than limiting the scope of the present invention or the scope of the claims of the present invention.

[0052] The PXRD pattern of the present invention was collected on a Bruker D8 Advance X-ray diffractometer, and the specific parameters are as follows:

[0053] Light source: Cu Ka (1.5406 Å)

[0054] Tube voltage: 40 kV

[0055] Tube current: 40 mA

[0056] Divergence slit: 0.6 mm

[0057] Receiving slit: 3.0 mm

[0058] Anti-air-scattering slit (knife edge): 1.0 mm

[0059] 2θ scanning range: 3° to 40°

[0060] Scanning rate per step: 0.2 s / step

[0061] Step size: 0.02°

[0062] Example 1: Preparation of anhydrous form N of LEE011 intermediate

[0063] Add 23 g of water to 2 g of solid LEE011 intermediate, adjust the pH to 2.8 with concentrated hydrochloric acid to form a sample solution. Add 1.8 g of potassium carbonate to the reaction kettle, add about 5.3 g of water and 1.8 g of methanol, stir until dissolved and clear, add 4 g of methanol, and heat to 60 °C. After heating the sample solution to 40 °C, add it dropwise to the reaction kettle, and stir at 60 °C for 1 hour after dropping. Cool down to 10 °C, cool down for 5 hours, and stir overnight at 10 °C to form a crystal solution. Filter by suction and dry in vacuum at 60 °C overnight.

[0064] Table 1 PXRD peak table of anhydrous form N of LEE011 intermediate: Peak Name Diffraction Angle d Value Relative Intensity Peak #1 6.819 12.95326 18.20% Peak #2 8.135 10.86042 12.00% Peak #3 12.391 7.13745 38.90% Peak #4 12.606 7.01635 62.10% Peak #5 12.827 6.8957 11.30% Peak #6 13.252 6.67563 29.90% Peak #7 13.63 6.49125 24.80% Peak #8 14.826 5.97028 24.70% Peak #9 15.172 5.83513 11.40% Peak #10 15.718 5.63344 19.00% Peak #11 18.045 4.91192 59.30% Peak #12 18.321 4.83852 88.40% Peak #13 18.553 4.77852 46.40% Peak #14 18.735 4.73253 36.70% Peak #15 20.081 4.41827 36.50% Peak #16 20.444 4.34069 100.00% Peak #17 21.376 4.15349 21.10% Peak #18 21.82 4.06999 37.10% Peak #19 22.627 3.92659 28.20% Peak #20 22.902 3.88002 50.00% Peak #21 23.771 3.74005 18.80% Peak #22 26.245 3.39287 11.40% Peak #23 26.97 3.30332 31.00% Peak #24 29.316 3.04409 19.90%

[0065] Example 2: Preparation of dihydrate form I of LEE011 intermediate

[0066] Add 5.5 mL of methanol and 0.4 mL of water to 40 mg of solid LEE011 intermediate, dissolve and filter, and volatilize the filtrate at 25 °C to collect the solid.

[0067] Table 2 PXRD peak table of dihydrate form I of LEE011 intermediate: Peak Name Diffraction Angle d Value Relative Intensity Peak #1 8.374 10.55037 100.00% Peak #2 9.737 9.0767 8.60% Peak #3 10.899 8.11148 3.10% Peak #4 11.285 7.83479 4.70% Peak #5 12.715 6.95651 2.00% Peak #6 12.875 6.87042 9.20% Peak #7 15.183 5.83086 3.80% Peak #8 15.481 5.71927 4.00% Peak #9 16.865 5.25292 78.00% Peak #10 17.205 5.14986 23.00% Peak #11 19.052 4.65463 8.80% Peak #12 19.402 4.57134 2.50% Peak #13 19.566 4.53346 62.10% Peak #14 20.42 4.34564 10.00% Peak #15 21.098 4.20761 38.10%

[0068] Example 3: Preparation of LEE011 Intermediate Monohydrate Form P

[0069] Add 23 g of water to 2 g of LEE011 intermediate solid, and adjust the pH to 2.8 with concentrated hydrochloric acid. Add 1.8 g of potassium carbonate to the reaction kettle, add about 5.3 g of water and 1.8 g of methanol, stir until dissolved and clear, add 4 g of water, and heat to 70 °C. After heating the sample solution to 40 °C, add it dropwise to the reaction kettle. After the addition is complete, stir at 60 °C for 1 hour. Cool down to 10 °C over 5 hours, and stir overnight at 10 °C. Filter by suction and dry under vacuum at 60 °C overnight.

[0070] Table 3 PXRD Peak Table of LEE011 Intermediate Monohydrate Form P: Peak Name Diffraction Angle d Value Relative Intensity Peak #1 6.535 13.51468 70.40% Peak #2 8.37 10.55539 30.20% Peak #3 9.253 9.54996 18.70% Peak #4 11.284 7.83545 21.00% Peak #5 11.411 7.74819 16.90% Peak #6 11.554 7.65257 12.20% Peak #7 12.868 6.87383 16.00% Peak #8 13.177 6.71342 19.10% Peak #9 15.202 5.82335 10.70% Peak #10 15.471 5.72274 27.60% Peak #11 16.867 5.25212 24.90% Peak #12 17.194 5.15307 14.40% Peak #13 17.948 4.93838 11.00% Peak #14 19.036 4.65828 28.30% Peak #15 19.395 4.57293 26.80% Peak #16 19.576 4.53113 22.10% Peak #17 19.87 4.46475 33.70% Peak #18 20.418 4.34603 25.30% Peak #19 20.682 4.29115 19.70% Peak #20 21.097 4.2077 100.00% Peak #21 21.317 4.16484 12.00% Peak #22 22.536 3.94217 39.40% Peak #23 23.573 3.77106 12.20% Peak #24 26.816 3.3219 17.10% Peak #25 28.239 3.15762 24.50% Peak #26 28.423 3.13764 12.70%

Claims

1. A method for preparing the anhydrous form N of the LEE011 intermediate, characterized in that, It includes the following steps: (1) Dissolve the LEE011 intermediate solid in water to form an aqueous solution, and adjust the pH with an acid to form a sample solution; (2) Mix the sample solution with an alcoholic solution of a base, and control the temperature at 40 - 60 °C; (3) Cool the mixed solution to 0 - 10 °C to crystallize; (4) Filter the precipitated solid by suction and dry it.

2. The preparation method according to claim 1, characterized in that, The mass - volume ratio of the LEE011 intermediate solid to water in step (1) ranges from 1:10 to 15 g / mL.

3. The preparation method according to claim 1, characterized in that, The alcohol in step (2) is methanol, and the mass - volume ratio of the LEE011 intermediate solid to methanol ranges from 1:7.3 to 14.9 g / mL.

4. The preparation method according to claim 1, characterized in that, The acid in step (1) is an organic acid or an inorganic acid, and the base in step (2) is an organic base or an inorganic base.

5. The preparation method according to claim 1, characterized in that, The anhydrous crystalline form of the LEE011 intermediate is Form N, ， whose X - ray diffraction pattern includes peaks at 6.8, 8.1, 12.4, 12.6, 12.8, 13.3, 13.6, 14.8, 15.2, 15.7, 18.0, 18.3, 18.6, 18.7, 20.1, 20.4, 21.4, 21.8, 22.6, 22.9, 23.8, 26.2, 27.0 and 29.3 ± 0.2 degrees 2θ.

6. The preparation method according to claim 1 or 2, characterized in that, The differential scanning calorimetry thermogram of the anhydrous crystalline form of the LEE011 intermediate, Form N, contains endotherms starting at 37.5 °C and 200.1 °C.

7. The preparation method according to claim 1 or 2, characterized in that, The thermogravimetric analysis thermogram of the anhydrous crystalline form of the LEE011 intermediate, Form N, contains a weight loss of approximately 2.4% when heated from about 30 °C to about 170 °C.

8. The dihydrate crystal form Form I of LEE011 intermediate, characterized in that, Its X - ray diffraction pattern includes peaks at 8.4, 9.7, 10.9, 11.3, 12.7, 12.9, 15.2, 15.5, 16.9, 17.2, 19.1, 19.4, 19.6 and 20.4 ± 0.2 degrees 2θ.

9. The crystalline form according to claim 8, wherein Its differential scanning calorimetry thermogram contains endotherms starting at 53.1 °C and 194.1 °C.

10. The crystalline form according to claim 8, wherein Its thermogravimetric analysis thermogram contains a weight loss of approximately 7.4% when heated from about 30 °C to about 150 °C.

11. A method for preparing LEE011 intermediate dihydrate Form I, characterized in that, It includes the following steps: 1) Dissolve the LEE011 intermediate solid in alcohol and water and then filter; 2) Let the alcoholic and aqueous solution of the LEE011 intermediate evaporate at room temperature.

12. The preparation method according to claim 11, wherein The alcohol is methanol, and the volume ratio of methanol to water in step 1) ranges from 1:10 to 15.

13. The preparation method according to claim 11, characterized in that, The evaporation temperature in step 2) is 20 - 30 °C.

14. A monohydrate crystalline form Form P of LEE011 intermediate, characterized in that, Its X - ray diffraction pattern includes peaks at 6.5, 8.4, 9.3, 11.3, 11.4, 11.6, 12.9, 13.2, 15.2, 15.5, 16.9, 17.2, 17.9, 19.0, 19.4, 19.6, 19.9, 20.4, 20.7, 21.1, 21.3, 22.5, 23.6, 26.8, 28.2 and 28.4 ± 0.2 degrees 2θ.

15. The crystalline form according to claim 14, wherein Its differential scanning calorimetry thermogram contains endotherms starting at 37.5 °C and 200.1 °C.

16. The crystalline form according to claim 14, wherein Its thermogravimetric analysis thermogram contains a weight loss of approximately 2.4% when heated from about 30 °C to about 170 °C.

17. A method for preparing the monohydrate Form P of LEE011 intermediate, characterized in that, It includes the following steps: 1) Dissolve the solid of LEE011 intermediate in water to form an aqueous solution, and adjust the pH with an acid to form a sample solution; 2) Mix the sample solution with an alcoholic solution of a base, and control the temperature at 40~60 °C; 3) Cool the mixed solution to 0~10 °C to crystallize; 4) Filter the precipitated solid by suction and dry it; Among them, the alcoholic solution in step 2) is methanol, and the mass-volume ratio range of the LEE011 intermediate solid to methanol in step 2) is 1: 2.3~5.9 g / mL.

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