Crystal forms of azetidinone compounds and preparing methods thereof

Patent metadata

Field	Value
Publication number	US-9802891-B2
Application number	US-201615386349-A
Country	US
Kind code	B2
Filing date	Dec 21, 2016
Priority date	Sep 5, 2012
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

The present invention provides crystal forms of the compound of (3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybut-2(Z)-enyl]-1-(4-fluorophenyl)-2-azetidinone (formula A). The crystal forms can be characterized by X-ray powder diffraction (XRPD) spectra, differential scanning calorimetry (DSC) spectra, infrared absorption spectra and so on. Meanwhile, the present invention also provides methods for preparing the crystal forms of the compound of formula A, pharmaceutical compositions and uses thereof.

First claim

The invention claimed is:

1. A crystal form III of the compound of formula A structured as follows,

wherein an X-ray powder diffraction spectrum radiated by Cu-Kα and characterized in degrees 2θ has following characteristic peaks at 8.16±0.20°, 12.02±0.20°, 14.38±0.20°, 17.60±0.20°, 18.36±0.20° and 20.98±0.20°.

2. The crystal form III according to claim 1 , wherein the X-ray powder diffraction spectrum characterized in degrees 2θ further has following characteristic peaks at: 6.06±0.20°, 8.74±0.20°, 10.32±0.20°, 13.22±0.20°, 14.78±0.20°, 15.36±0.20°, 16.12±0.20°, 16.52±0.20°, 17.08±0.20°, 18.70±0.20°, 19.04±0.20°, 20.06±0.20°, 21.52±0.20°, 22.36±0.20°, 22.84±0.20°, 23.50±0.20°, 24.20±0.20°, 24.84±0.20°, 25.10±0.20°, 26.18±0.20°, 26.66±0.20°, 27.12±0.20°, 27.44±0.20°, 28.44±0.20°, 29.02±0.20°, 29.62±0.20°, 30.62±0.20°, 31.16±0.20°, 31.58±0.20°, 33.47±0.20° and 33.73±0.20°.

3. A preparation method of the crystal form III of the compound of formula A according to claim 1 , comprising the following steps of:
1) adding the compound of formula A into a mixed solvent of C 4 -C 10 alcohol and ethanol, optionally heating to dissolve the compound and obtain a solution, wherein the ratio of the volume of ethanol to the volume of C 4 -C 10 alcohol is less than or equal to 0.2;
2) adding water more than one time of the volume of the foregoing mixed solvent into the foregoing solution; and
3) crystallizing out the crystals, filtrating, and optionally drying to obtain the crystals in form III.

4. The preparation method according to claim 3 , wherein the C 4 -C 10 alcohol is tert-butyl alcohol.

5. The preparation method according to claim 3 , wherein the volume of the water added in step 2) is 2-10 times of the volume of the mixed solvent.

6. The preparation method according to claim 3 , wherein the ratio of the mass of the compound of formula A in g to the volume of the C 4 -C 10 alcohol in mL in step 1) is 1:8-15.

7. The preparation method according to claim 3 , comprising the following steps of: adding the compound of formula A in g into a mixed solvent of tert-butyl alcohol and 0.3 portion of ethanol in mL, completely dissolving at the normal temperature to obtain a solution, adding water in mL into the foregoing solution, crystallizing out the crystals, filtrating, and drying at the normal temperature and pressure to obtain the crystals in form III, wherein the ratio of the mass of the compound of formula A in g to the volume of the tert-butyl alcohol in mL to the volume of the ethanol in mL to the volume of the water in mL is 0.4:4:0.3:10.

8. A preparation method of the crystal form III of the compound of formula A according to claim 1 , comprising the following steps of: adding the compound of formula A in g into a crystallizer, then adding tert-butyl alcohol in mL thereinto, dissolving at 50° C., then naturally cooling to the room temperature to crystallize out solids, filtrating the solid, and drying at the normal temperature and pressure, thus obtaining the crystals in form III, wherein the ratio of the mass of the compound of formula A in g to the volume of the tert-butyl alcohol in mL is 1:15.

9. A pharmaceutical composition, comprising a therapeutically effective amount of the crystal form III according to claim 1 .

10. A method for reducing plasma cholesterol contents, comprising the steps of administering to a sufferer in need the therapeutically effective amount of the crystal form III according to claim 1 .

11. A method for reducing plasma cholesterol contents, comprising the steps of administering to a sufferer in need the therapeutically effective amount of the pharmaceutical composition according to claim 9 .

12. The preparation method according to claim 3 , wherein the volume of the water added in step 2) is 2-3 times of the volume of the mixed solvent.

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Wei Hongyuan
• Liu Chongjun
• Zhao Xuyang
• Xu Xiaojie
• Bai Hua
• Zhang Yuncai

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/397

  having four-membered rings, e.g. azetidine · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• C07D205/08 Primary

  with one oxygen atom directly attached in position 2, e.g. beta-lactams · CPC title