PREPARATION METHODS FOR PALBOCICLIB FREE BASE CRYSTAL FORM A AND CRYSTAL FORM B

• US 20180319790A1
• Filed: 11/02/2016
• Published: 11/08/2018
• Est. Priority Date: 11/02/2015
• Status: Active Grant

• Current Assignee: Shanghai SynCores Technologies, Inc. (Zhejiang Huahai Pharmaceutical Company Limited), Zhejiang Huahai Pharmaceutical Company Limited
• Original Assignee: Shanghai SynCores Technologies, Inc. (Zhejiang Huahai Pharmaceutical Company Limited), Zhejiang Huahai Pharmaceutical Company Limited
• Inventors: Fan, Haisheng, Guo, Xiaowen, Huang, Luning, Gu, Hong
• Granted Patent: US 10,329,290 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B01D 9/0054 Use of anti-solvent
• CPC Class Codes: B01D 9/0063 Control or regulation control per se G05
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed is a preparation method for a Palbociclib free base crystal form A as shown in Formula I, comprising the following steps: treating a Palbociclib free base and/or a Palbociclib salt compound by using an inorganic base in a water solvent at the temperature of 35 to 100° C. to obtain a Palbociclib free base crystal form A, the water solvent being water or mixed solvent obtained by water and an organic solvent capable of being mixed and disclosed in the water. Also disclosed is a preparation method for a Palbociclib free base crystal form B, comprising the following steps: treating a Palbociclib salt compound by using an inorganic base in a water solvent at the temperature of 0 to 20° C. to obtain a Palbociclib free crystal form B, the water solvent being water or a mixed solvent obtained by water and an organic solvent capable of being mixed and dissolved in the water. The method is safe and convenient in operation and low in pollution, and facilitates industrial production.

Claims

1. A preparation method for a crystal form A of palbociclib free base as shown in Formula I, the method comprising the following step:

treating a palbociclib free base and/or a palbociclib salt compound with an inorganic base in an aqueous solvent at a temperature of 35°

C. to 100°

C. to obtain the crystal form A of palbociclib free base, wherein the aqueous solvent is water or a mixed solvent of water and water-miscible organic solvent,

2. The method according to claim 1, the method comprising the following steps:

1) treating a palbociclib free base with an inorganic base in an aqueous solvent at a temperature of 35°

C. to 100°

C. to obtain a crystal form A of palbociclib free base;

or

2) dissolving a palbociclib salt compound and optionally palbociclib free base in an aqueous solvent to form a solution, then treating the solution with an inorganic base water solution at a temperature of 35°

C. to 100°

C. to obtain a crystal form A palbociclib free base;

wherein the aqueous solvent is water or a mixed solvent of water and water-miscible organic solvent.

3. The method according to claim 1, characterized in that the palbociclib salt compound is selected from the group consisting of palbociclib isethionate, palbociclib hydrochloride, palbociclib sulfate, and palbociclib methane sulfonate or a combination thereof.

4. The method according to claim 1, characterized in that the palbociclib free base is in the form of palbociclib free base itself, or in a crystal form B of palbociclib free base, or a mixed crystal of the crystal form B and the crystal form A.

5. The method according to claim 1, characterized in that a volume ratio of water and the organic solvent in the aqueous solvent is 1:

(0-20).

6. The method according to claim 1, characterized in that the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, isopropanol and tetrahydrofuran.

7. The method according to claim 1, characterized in that the inorganic base is aqueous ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

8. The method according to claim 1, characterized in that the treatment is performed at a temperature of 35-100°

C. at a pH of >

8.0.

16. The method according to claim 1, characterized in that a volume ratio of water and the organic solvent in the aqueous solvent is 1:

(0-2).

17. The method according to claim 8, characterized in that the treatment is performed at a temperature of 50-70°

C.

9. A preparation method for a crystal form B of palbociclib free base, the method comprising the following step:

treating a palbociclib salt compound with an inorganic base in an aqueous solvent at a temperature of 0-20°

C. to obtain a crystal form B of palbociclib free base, wherein the aqueous solvent is water or a mixed solvent of water and water-miscible organic solvent.

10. The method according to claim 9, the method comprising the following steps:

dissolving a palbociclib salt compound in an aqueous water solution to form a solution, then treating the solution with an inorganic base solution at a temperature of 0-20°

C. to obtain a crystal form B of palbociclib free base, wherein the aqueous solvent is water or a mixed solvent of water and water-miscible organic solvent.

11. The method according to claim 9, characterized in that the palbociclib salt compound is selected from the group consisting of palbociclib isethionate, palbociclib hydrochloride, palbociclib sulfate, and palbociclib methane sulfonate or a combination thereof.

12. The method according to claim 9, characterized in that a volume ratio of water and the organic solvent in the mixed solvent is 1:

(0-20).

13. The method according to claim 9, characterized in that the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, isopropanol and tetrahydrofuran.

14. The method according to claim 9, characterized in that the inorganic base is aqueous ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

15. The method according to claim 9, characterized in that the treatment is performed at a temperature of 0-20°

C. at a pH of >

8.0.

18. The method according to claim 9, characterized in that a volume ratio of water and the organic solvent in the mixed solvent is 1:

(0-2).

19. The method according to claim 9, characterized in that the treatment is performed at a temperature of 5-15°

C.