Crystal form of azetidinone compound and preparation method thereof

A compound and crystal form technology, applied in the field of chemistry, can solve the problem of no crystal form of the compound of formula A, etc.

Active Publication Date: 2016-12-07
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, there is no report on th

Method used

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  • Crystal form of azetidinone compound and preparation method thereof
  • Crystal form of azetidinone compound and preparation method thereof
  • Crystal form of azetidinone compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1: (3R, 4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybutyl-2(Z)-ene]-1-( Preparation of 4-fluorophenyl)-2-azetidinone (compound of formula A)

[0132] The preparation of the compound of formula A refers to the method of WO2011017907A1, specifically as follows:

[0133]

[0134] Step 1: Add 32.5 mmoles of compound II (Formula Z), 250 mL of methanol, and 4.89 g (35.8 mmoles) of potassium carbonate to a 500 mL reaction flask, and stir at room temperature for 30 minutes. After the reaction was completed, it was extracted three times with ethyl acetate (300 mL×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and kept for later use.

[0135] Step 2: Dissolve the product of step 1 in 200 mL of tetrahydrofuran, adjust the pH to about 1 with 6 mol / L hydrochloric acid, stir and react at room temperature for 30 minutes, then extract 3 times with ethyl acetate (250 mL×3), combi...

Embodiment 2

[0137] Embodiment 2: the preparation of crystal form I

[0138] At room temperature, 1 g of the compound of formula A was dissolved in 1 mL of methanol to prepare its saturated solution, and then 10 mL of water was added to the saturated solution at one time, and the obtained solid was filtered out immediately, and dried in a vacuum drying oven (the drying temperature was 35 ~40° C.), the dried solid is the crystal form I, the yield is 0.73 g, and the yield is 73%.

[0139] Its XRPD pattern is as follows figure 1 shown.

[0140] DSC spectrum such as figure 2 shown. Display: the melting point is 154.8°C.

[0141] Infrared spectrum such as image 3 shown.

Embodiment 3

[0142] Embodiment 3: the preparation of crystal form I

[0143] The operation process is the same as in Example 2, except that methanol is replaced by tetrahydrofuran, isopropanol, acetone, n-propanol, acetic acid, n-butanol, ethyl acetate, acetonitrile and N, N-dimethylformamide, respectively to obtain The crystal form I. The XRPD spectrum of the obtained crystal form I is consistent with the XRPD spectrum of the crystal form I in Example 2.

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Abstract

The present invention provides (3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybutyl-2(Z)-ene]-1-( 4-fluorophenyl)-2-azetidinone (formula A) compound crystal form, which can be identified by X-powder diffraction (XRPD) spectrum, differential scanning calorimetry (DSC) spectrum, infrared spectrum, etc. characterization. At the same time, the present invention also provides the preparation method of the crystal form of the compound of formula A, their pharmaceutical composition and application.

Description

technical field [0001] The invention belongs to the field of chemistry, more specifically, the invention relates to (3R, 4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybutyl-2 A crystal form of (Z)-en]-1-(4-fluorophenyl)-2-azetidinone and a preparation method thereof. Background technique [0002] The azetidinone compound having the structure of the following formula A, the chemical name is: (3R, 4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxyl Butyl-2(Z)-ene]-1-(4-fluorophenyl)-2-azetidinone. The compound of formula A is a plasma cholesterol-lowering agent, which is used for lowering plasma cholesterol levels and thus for treating diseases associated with high plasma cholesterol levels. WO2011017907 discloses the compound of formula A and its preparation method and use. [0003] [0004] Currently, there is no report on the crystal form of the compound of formula A. The present inventor obtained the crystal form of the compound of formula A through a ...

Claims

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Application Information

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IPC IPC(8): C07D205/08A61K31/397A61P3/06
CPCC07B2200/13C07D205/08A61K31/397A61P3/06
Inventor 卫宏远刘崇峻赵旭阳徐肖杰白骅张云才
Owner ZHEJIANG HISUN PHARMA CO LTD
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