Ibrutinib amorpphis and preparation method thereof

A technology of ibrutinib and amorphous substances, which is applied in the field of medicine, can solve the problems of poor reproducibility and stability, and achieve the effect of simple operation and stable stability

Active Publication Date: 2016-06-01
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to provide a stable ibrutinib amorphous (i.e. amorphous) and preparation method thereof, which overcomes the problems of poor reproducibility and stability in the prior art, and the method of the present invention reproduces Good stability, the obtained ibrutinib amorphous substance has good stability and is suitable for industrial production

Method used

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  • Ibrutinib amorpphis and preparation method thereof
  • Ibrutinib amorpphis and preparation method thereof
  • Ibrutinib amorpphis and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 1.0 g of ibrutinib into 6.0 ml of methanol, heat to 50°C, and stir to dissolve. Add the above solution to 18g of ice-water mixture, control the temperature below 5°C, stir and solidify for 30 minutes, filter, and dry the filter cake at 50°C under reduced pressure to constant weight to obtain 0.96g of white solid, HPLC: 99.57%. Test its X-ray powder diffraction, its XRPD as figure 1 ; Test infrared spectrum such as figure 2 .

Embodiment 2

[0044] Add 5.0 g of ibrutinib into 25.0 ml of ethanol, heat to 65°C, and stir to dissolve. Add the above solution to 100g of ice and 30g of ethanol mixed solution, control the temperature between -20°C and 0°C, stir and solidify for 2 hours, filter, and dry the filter cake at 70°C under reduced pressure to constant weight to obtain 4.8g of white solid , HPLC: 99.77%. The X-ray powder diffraction test is the same as the XRPD of Example 1, and the infrared spectrum of the test is basically the same as that of Example 1, that is, the amorphous ibrutinib.

Embodiment 3

[0046] Add 1.0 g of ibrutinib into 10.0 ml of acetonitrile, heat to reflux, and stir to dissolve. Add the above solution to a mixture of 18 g of ice and 3.0 g of acetone, control the temperature below 0°C, stir and solidify for 4 hours, filter, and dry the filter cake at 60°C under reduced pressure to constant weight to obtain 0.87 g of a white solid, HPLC: 99.37 %. The X-ray powder diffraction test is the same as the XRPD of Example 1, and the infrared spectrum of the test is basically the same as that of Example 1, that is, the amorphous ibrutinib.

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Abstract

The invention discloses a method for preparing ibrutinib amorpphis. The method comprises the following steps: (1) adding ibrutinib into a high-quality organic solvent, and heating to completely dissolve the ibrutinib; (2) adding the solution into an anti-solvent, and performing stirring and curing, wherein in the adding process, the temperature of the anti-solvent system is maintained below 5 DEG C; (3) filtering, decompressing and drying solids to obtain the ibrutinib amorpphis. The ibrutinib amorpphis prepared by the method is stable and suitable for preparation production.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an amorphous ibrutinib and a preparation method thereof. Background technique [0002] The chemical name of Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidine- 1-yl]-1-piperidinyl]-2-propen-1-one, its structural formula is as follows. [0003] [0004] Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor used in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Both MCL and CLL belong to B-cell non-Hodgkin's lymphoma, which are refractory and easy to relapse. Commonly used chemoimmunotherapy is not targeted, and grade 3 or 4 adverse reactions often occur. Ibrutinib irreversibly inhibits BTK by selectively covalently binding to the cysteine ​​residue (Cys-481) in the active site of the target protein BTK, thereby effectively preventing tumors from migrating from B cells to adapting to tumor growth. Env...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/02A61P35/00
CPCA61K31/519C07D487/04
Inventor 罗斌左小勇雷皇书肖进迈
Owner CHONGQING PHARMA RES INST
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