Crystal forms of azetidinone compounds and preparing methods thereof

Patent metadata

Field	Value
Publication number	US-9776959-B2
Application number	US-201615386147-A
Country	US
Kind code	B2
Filing date	Dec 21, 2016
Priority date	Sep 5, 2012
Publication date	Oct 3, 2017
Grant date	Oct 3, 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. The crystal form II 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 5.20±0.20°, 7.46±0.20°, 8.70±0.20°, 10.60±0.20°, 11.84±0.20°, 17.14±0.20°, 20.36±0.20° and 26.48±0.20°.

2. The crystal form II according to claim 1 , wherein the X-ray powder diffraction spectrum characterized in degrees 2θ further has following characteristic peaks at: 6.29±0.20°, 6.96±0.20°, 12.82±0.20°, 13.28±0.20°, 14.21±0.20°, 15.02±0.20°, 15.40±0.20°, 16.40±0.20°, 17.61±0.20°, 18.34±0.20°, 18.62±0.20°, 19.06±0.20°, 19.58±0.20°, 20.02±0.20°, 21.50±0.20°, 22.18±0.20°, 22.74±0.20°, 23.41±0.20, 24.06±0.20°, 24.34±0.20°, 24.70±0.20°, 25.16±0.20°, 27.34±0.20°, 28.00±0.20°, 28.88±0.20°, 29.36±0.20°, 31.39±0.20°, 32.02±0.20°, 32.60±0.20° and 34.42±0.20°.

3. A preparation method of the crystal form II of the compound of formula A according to claim 1 , comprising the following steps of:
1) adding the compound of formula A into C 1 -C 3 alcohol, optionally heating to dissolve the compound and obtain a solution, wherein the ratio of the mass of the compound of formula A in g to the volume of the C 1 -C 3 alcohol in mL is 1:2-10;
2) adding water into the foregoing solution and ensuring that no crystal is crystallized out; and
3) naturally volatilizing the solvent at the normal temperature and the normal pressure, and collecting solids that are crystallized out, thus obtaining the crystals in form II.

4. The preparation method according to claim 3 , wherein the C 1 -C 3 alcohol is ethanol or iso-propanol.

5. The preparation method according to claim 3 , wherein the ratio of the volume of the water added in step 2) to the volume of the C 1 -C 3 alcohol is 10:1-6.

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 1 -C 3 alcohol in mL in step 1) is 1:2-5.

7. The preparation method according to claim 6 , comprising the following steps of: adding the compound of formula A in g into a crystallizer, then adding ethanol in mL thereinto, heating to 50° C. for complete dissolving, then adding water in mL thereinto, stopping heating, cooling naturally, volatilizing the solvent at the normal temperature and pressure, crystallizing out crystals, filtrating, and drying the crystals at the normal temperature to obtain the crystals in form II, wherein the ratio of the mass of the compound of formula A in g to the volume of the ethanol in mL to the volume of the water in mL is 0.7:1.7:1.

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

9. 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 II 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 pharmaceutical composition according to claim 8 .

11. The preparation method according to claim 3 , wherein the ratio of the volume of the water added in step 2) to the volume of the C 1 -C 3 alcohol is 10:2.

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

• C07D205/08 Primary

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K31/397

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