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Novel crystal forms of ibrutinib and preparation method thereof

A technology of ibrutinib and crystal form, applied in the field of medicinal chemistry, can solve the problems of cumbersome operation, difficult to control the cooling speed, difficult to implement the industrialization of stirring, etc.

Inactive Publication Date: 2016-02-03
SHANGHAI ACEBRIGHT PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The operation of this method is cumbersome, there are repeated heating and cooling in the operation, and the production process is not easy to control
[0007] Suzhou Jingyun CN104327085A discloses another crystal form A (hereinafter referred to as crystal form A'), and its reported preparation method has three kinds: Method 1, dissolving the crude product of ibrutinib in a mixed solution of isopropanol and n-heptane In the method, crystal form A' was obtained by stirring at a speed of 750 revolutions per minute at room temperature. It is very difficult to industrialize such high-speed stirring; method 2, dissolving the crude ibrutinib in a mixed solvent of isopropanol and n-heptane , and at a cooling rate of 0.1 °C / min from 50 °C to 5 °C to obtain crystal form A, such a precise cooling rate is difficult to control; method 3, dissolve the crude ibrutinib in acetone, and then slowly add n-heptyl alkane, and stirred at a speed of 1000 rpm for 1 day to obtain Form A. This method requires a higher speed than Method 1, and it is more difficult to achieve industrialization.
When the inventor repeated these methods, he found that the reproducibility was poor, and the crystal form A disclosed in WO2013 / 184572 would be obtained if the control was not good.

Method used

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  • Novel crystal forms of ibrutinib and preparation method thereof
  • Novel crystal forms of ibrutinib and preparation method thereof
  • Novel crystal forms of ibrutinib and preparation method thereof

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preparation example Construction

[0101] The invention also provides a preparation method of the crystal.

[0102] The preparation method of the crystal form I described in the present invention, the preparation method comprises the following steps:

[0103] (i) dissolving crude ibrutinib I in an organic solvent, with a weight-to-volume ratio of about 1:1-1:20 g / ml;

[0104] (ii) after cooling down to 0-25°C, crystallize to obtain the crystal form I;

[0105] Wherein, the crude ibrutinib I is selected from the following group: crystal form A of ibrutinib, amorphous ibrutinib.

[0106] In another preferred example, the organic solvent in the step (i) is selected from the following group: ether solvents, ester solvents, alcohol solvents, mixed solvents of ketone solvents and water, mixed solvents of ester solvents and alkanes , a mixed solvent of an alcohol solvent and an alkane, or a combination thereof.

[0107] In another preferred example, the organic solvent in the step (i) is selected from the group con...

Embodiment 1

[0155] Embodiment 1 Preparation of ibrutinib crystal form I

[0156] Add ibrutinib amorphous (10.0 g) into 50 ml of isopropanol, and heat to reflux to dissolve. Continue stirring for 30 minutes after dissolving. Heating was stopped, and the temperature was lowered at a rate of about 1 °C / min, and solids were gradually precipitated. After cooling to room temperature, keep stirring for 2 hours, filter, rinse the filtrate with acetone, and vacuum-dry the filter cake at 50°C to obtain 8.8 g of the product.

[0157] Result: The powder X-ray diffraction pattern of the obtained solid is basically as figure 1 Characterized, the differential thermal scanning spectrum is basically as figure 2 As shown, the thermogravimetric analysis is basically as image 3 As shown, the infrared Fourier transform spectrum is basically as Figure 4 shown.

Embodiment 2

[0158] Embodiment 2 Preparation of ibrutinib crystal form I

[0159] Ibrutinib Form A (1.0 g) was added to 10 ml of isopropyl acetate, stirred overnight at room temperature, the resulting suspension was filtered, and vacuum-dried at 50° C. to constant weight to obtain 720 mg of a white solid.

[0160] Result: its powder X-ray diffraction pattern is basically as figure 1 As shown, the differential thermal scanning spectrum is basically as figure 2 As shown, the thermogravimetric analysis is basically as image 3 As shown, the infrared Fourier transform spectrum is basically as Figure 4 shown.

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Abstract

The invention provides two crystal forms of ibrutinib, a preparation method and applications thereof. Specifically, the invention provides crystal forms of 1-[(3R)-3-[4-amino-3-(4-phenoxylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl]-1-piperidyl]-2-propylene-1-one, a preparation method and applications thereof.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, specifically, the present invention relates to 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d A crystal form of ]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one, and a preparation method and use of the new crystal form. Background technique [0002] Ibrutinib (Ibrutinib) is jointly developed by American Pharmacyclics Company and Johnson & Johnson, the trade name is Imbruvica, and its chemical name is: 1-[(3R)-3-[4-amino-3-(4-phenoxybenzene Base)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, the structural formula is as follows: [0003] [0004] Ibrutinib is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor, which selectively co-activates cysteine ​​residues (Cys-481) in the active site of the target protein Btk. It binds to BTK and irreversibly inhibits BTK, thereby effectively preventing the migration of tumors from B cells to lymphoid tis...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04C07B2200/13
Inventor 李金亮杨勤刚任华森郭沛霖常彩风侯丽
Owner SHANGHAI ACEBRIGHT PHARMA GRP
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