POLYCRYSTALLINE FORM OF DEHYDROPHENYLAHISTIN-LIKE COMPOUND, AND MANUFACTURING AND PURIFICATION METHOD AND APPLICATION THEREOF

• US 20190177302A1
• Filed: 07/24/2017
• Published: 06/13/2019
• Est. Priority Date: 08/12/2016
• Status: Active Grant

• Current Assignee: Shenzhen Huahong Marine Biomedicine Company Limited (Yee Hop Holdings Ltd.)
• Original Assignee: Marine Biomedical Research Institute Of Qingdao Co., Ltd.
• Inventors: LI, Wenbao, WANG, Shixiao, DING, Zhongpeng, HOU, Yingwei, GUAN, Huashi
• Granted Patent: US 10,851,086 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A polycrystalline form of a dehydrophenylahistin-like compound, and a manufacturing and purification method and application thereof. A (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)deuteromethylene]piperazine-2,5-dione monohydrate crystal and a (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)methylene]piperazine-2,5-dione monohydrate crystal are more competitive crystalline forms with stable quality. The manufacturing and purification method is simple and easy to operate, and can effectively control the generation of a trans-isomer contaminant to obtain a high purity product. The polycrystalline form of the dehydrophenylahistin-like compound has a certain value in an application for manufacturing an antitumor pharmaceutical product.

Claims

1. A crystalline form of (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)deuteromethylene]piperazine-2,5-dione as shown in Formula (I), wherein the crystalline form is selected from the group consisting of α

-crystalline form, β

-crystalline form, γ

-crystalline form and δ

-crystalline form, wherein,

the α

-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 8.415°

±

0.2°

, 11.512°

±

0.2°

, 14.824°

±

0.2°

, 17.087°

±

0.2°

, 17.278°

±

0.2°

, 19.461°

±

0.2°

, 21.350°

±

0.2°

, 22.344°

±

0.2°

or 27.621°

±

0.2°

;

the β

-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 7.629°

±

0.2°

, 8.052°

±

0.2°

, 12.967°

±

0.2°

, 15.327°

±

0.2°

, 16.195°

±

0.2°

, 23.194°

±

0.2°

, 23.760°

±

0.2°

, 24.129°

±

0.2°

, 24.419°

±

0.2°

, 26.465°

±

0.2°

or 29.213°

±

0.2°

;

the γ

-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 8.075°

±

0.2°

, 12.986°

±

0.2°

, 16.217°

±

0.2°

, 19.709°

±

0.2°

or 24.441°

±

0.2°

;

the δ

-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 8.075°

±

0.2°

, 12.988°

±

0.2°

, 16.201°

±

0.2°

, 17.545°

±

0.2°

, 19.084°

±

0.2°

, 19.724°

±

0.2°

, 23.710°

±

0.2°

, 24.422°

±

0.2°

, 26.485°

±

0.2°

or 29.234°

±

0.2°

;

2. The crystalline form according to claim 1, wherein the X-ray powder diffraction pattern of the α

-crystalline form is consistent with FIG. 1.

4. The crystalline form according to claim 1, wherein the X-ray powder diffraction pattern of the β

-crystalline form is consistent with FIG. 2.

6. The crystalline form according to claim 1, wherein the X-ray powder diffraction pattern of the γ

-crystalline form is consistent with FIG. 4.

8. The crystalline form according to claim 1, wherein the δ

-crystalline form is a monohydrate of (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)deuteromethylene]piperazine-2,5-dione.

9. The crystalline form according to claim 1, wherein the X-ray powder diffraction pattern of the δ

-crystalline form is consistent with FIG. 6.

10. The crystalline form according to claim 9, wherein the δ

-crystalline form is cultivated into a single crystal which is determined by X-ray single crystal diffraction analysis as monoclinic single crystal and has a space group of P2(1)/n and whose analytical structure is consistent with FIG. 7, and the melting point is 263°

C. to 267°

C.

15. An anti-tumor method, comprising the step of administrating the crystalline form according to claim 1 to a subject in need thereof.

3. (canceled)

5. (canceled)

7. (canceled)

11. A method of preparing the δ

-crystalline form, wherein the method of preparing the δ

-crystalline form comprises the following steps;

using a mixed solvent of water and an organic solvent as crystallization solvent, wherein the organic solvent is selected from at least one of an alkane saturated alcohol, an unsaturated alcohol, an alkane saturated amine and an unsaturated amine;

recrystallizing (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)deuteromethylene]piperazine-2,5-dione in the mixed solvent, cooling and stirring, and precipitating to obtain the δ

-crystalline form.

12. The method according to claim 11, wherein the composition of the organic solvent and the mixed solvent is any one of the followings:

1) the organic solvent is methanol, and the mixed solvent comprises water and methanol with a volume ratio of V_water;

V_methanol ranging from 1;

100 to 10;

1;

or

2) the organic solvent is ethanol, and the mixed solvent comprises water and ethanol with a volume ratio of V_water;

V_ethanol ranging from 1;

100 to 10;

1;

or

3) the organic solvent is isopropanol, and the mixed solvent comprises water and isopropanol with a volume ratio of V_water;

V_isopropanol ranging from 1;

100 to 10;

1.

13. The method according to claim 11, comprising the following steps:

placing (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)deuteromethylene]piperazine-2,5-dione in a reaction vessel in the absence of light, adding isopropanol as solvent and heating till dissolving completely, then adding water with a volume ratio of V_water to V_isopropanol ranging from 1;

100 to 1;

1, keeping at −

10°

C. to 30°

C., stirring and cooling to precipitate, suction filtering, washing and drying to obtain the δ

-crystalline form.

14. The method according to claim 13, wherein the volume ratio of V_water to V_isopropanol is 2:

5, preferably keeping at −

5°

C. to 10°

C., stirring and cooling to precipitate.

16. A crystalline form of (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)methylene]piperazine-2,5-dione as shown in Formula (II), wherein the crystalline form is selected from the group consisting of b-crystalline form, c-crystalline form and d-crystalline form, wherein

the b-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 7.670°

±

0.2°

, 9.069°

±

0.2°

, 15.383°

±

0.2°

, 16.668°

±

0.2°

, 17.468±

0.2°

, 18.109°

±

0.2°

, 19.960°

±

0.2°

, 23.307°

±

0.2°

, 23.836°

±

0.2°

, 24.462°

±

0.2°

, 28.046°

±

0.2°

or 28.827°

±

0.2°

;

the c-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 7.918°

±

0.2°

, 9.168°

±

0.2°

, 12.014°

±

0.2°

, 12.985°

±

0.2°

, 18.382°

±

0.2°

, 18.616°

±

0.2°

, 23.367°

±

0.2°

, 25.203°

±

0.2°

or 27.771°

±

0.2°

;

the d-crystalline form has at least three X-ray powder diffraction characteristic peaks at 2θ

diffraction angle of 8.073°

±

0.2°

, 13.005°

±

0.2°

, 17.544°

±

0.2°

, 18.382°

±

0.2°

, 19.082°

±

0.2°

, 19.707°

±

0.2°

, 22.766°

±

0.2°

, 23.759°

±

0.2°

, 24.438°

±

0.2°

, 25.277°

±

0.2°

, 26.486°

±

0.2°

or 29.234°

±

0.2;

17. The crystalline form according to claim 16, wherein the X-ray powder diffraction pattern of the b-crystalline form is consistent with FIG. 11.

19. The crystalline form according to claim 16, wherein the X-ray powder diffraction pattern of the c-crystalline form is consistent with FIG. 13.

21. The crystalline form according to claim 16, wherein the d-crystalline form is a monohydrate of (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)methylene]piperazine-2,5-dione.

22. The crystalline form according to claim 16, wherein the X-ray powder diffraction pattern of the d-crystalline form is consistent with FIG. 15.

18. (canceled)

20. (canceled)

23. A method of preparing the d-crystalline form, comprising the following steps:

using a mixed solvent of water and an organic solvent as crystallization solvent, wherein the organic solvent is selected from at least one of an alkane saturated alcohol, an unsaturated alcohol, an alkane saturated amine and an unsaturated amine;

recrystalling (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)methylene]piperazine-2, 5-dione in the mixed solvent, cooling and stirring to precipitate to obtain the d-crystalline form.

24. The method according to claim 23, wherein the mixed solvent comprises water and isopropanol with a volume ratio of V_water:

V_isopropanol ranging from 1;

100 to 99;

100.

25. The method according to claim 24, wherein the mixed solvent has a volume ratio of V_water:

V_isopropanol ranging from 1;

10 to 9;

10.

26. The method according to claim 23, wherein the method comprises the following steps:

placing (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazole-4-yl)methylene]piperazine-2,5-dione in a reaction vessel in the absence of light, adding isopropanol as solvent, heating till dissolving completely, then adding water with a volume ratio of isopropanol to water ranging from 1;

10 to 100;

1, keeping at −

15°

C. to 30°

C., stirring and cooling to precipitate, suction filtering, washing and drying to obtain the d-crystalline form.

27. The method according to claim 26, wherein the volume ratio of isopropanol to water is 5:

2, preferably keeping at −

5°

C. to 10°

C., stirring and cooling to precipitate.

28. A method of preparing and purifying a dehydrophenyl ahistin-like compound with high purity, wherein the method comprises the following steps:

placing a crude product of the dehydrophenyl ahistin-like compound in a reaction vessel in the absence of light, adding isopropanol or methanol or ethanol or n-butanol upon heating till dissolving completely, then adding water resulting in no crystalline form precipitation, keeping at 15°

C. to 30°

C., stirring and cooling to precipitate, suction filtering, washing and drying to obtain the dehydrophenyl ahistin-like compound with high purity.