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I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase

A technology of tinib dibenzene sulfonate and patinib dibenzene sulfonate, which is applied to the I-type crystallization of lapatinib dibenzene sulfonate and the field of preparation thereof, and can solve the problems of easy agglomeration and poor product stability , difficult to filter and other problems, to achieve the effect of repeatable and controllable production process, good crystal stability, and stable production process

Inactive Publication Date: 2015-07-22
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] This type of medicine that has been listed now has erlotinib (erlotinib), gefitinib (gefitinib) and lapatinib, and GlaxoSmithKline has developed lapatinib (chemical name: N-{3-chloro Substitute-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4 - quinazoline amine) bis-p-toluenesulfonate monohydrate, the dihydrochloride salt was initially screened and found to be problematic when it is used in pharmaceutical form, it may be exposed to humidity (for example, 20- 75% relative humidity (RH)), it will absorb a lot of water
Generally speaking, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase
  • I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase
  • I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of lapatinib dibenzenesulfonate:

[0044] Lapatinib (2g, 3.44mmol, prepared according to the method provided by CN1134438C), was dissolved in 20ml of tetrahydrofuran, and a solution of benzenesulfonic acid (1.35g, 8.52mmol) in tetrahydrofuran (20ml) was added dropwise at room temperature, and the drop was completed, and stirred at room temperature for 12h . After filtering, the filter cake was washed with 5ml×2 tetrahydrofuran, and dried under vacuum at 50°C for 4h to obtain 3.00g of a yellow solid, yield: 97.1%.

Embodiment 2

[0046] Lapatinib dibenzenesulfonate (1g, 1.11mmol) prepared according to the method of Example 1 was added to 30ml of tetrahydrofuran / water (4:1) mixed solution, heated to reflux at 100°C to dissolve, stop heating, cool, Stirring and crystallization for 12h. After suction filtration, the filter cake was vacuum-dried at 50° C. for 12 hours to obtain 0.71 g of yellow crystals, yield: 71.0%. The X-ray diffraction spectrum pattern of this crystalline sample can be found in figure 1. The crystallization at about 6.21 (14.23), 10.02 (8.82), 12.11 (7.30), 13.26 (6.67), 13.55 (6.53), 13.79 (6.42), 14.88 (5.95), 6.70 (5.31), 17.59 (5.04), 18.26 (4.86), 18.93(4.68), 19.61(4.52), 20.71(4.29), 21.06(4.21), 22.19(4.00), 23.60(3.77), 24.20(3.68), 24.58(3.62), 25.10(3.55), 25.85 There are characteristic peaks at (3.44), 26.75(3.33), 30.83(2.90) and 32.89(2.72). DSC spectrum see figure 2 , there is a characteristic absorption peak at about 260°C, defining this crystal form as I crystal ...

Embodiment 3

[0048] Add lapatinib dibenzenesulfonate (1g, 1.11mmol) into 60ml of ethanol / water (2:3) mixture, heat to reflux at 100°C to dissolve, stop heating, cool down, stir and crystallize for 12h. After suction filtration, the filter cake was vacuum-dried at 50° C. for 12 hours to obtain 0.85 g of yellow crystals, yield: 85.0%. The X-ray diffraction and DSC spectrograms of the crystalline sample are studied and compared, and it is determined that the product is the I crystal form.

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Abstract

The invention relates to a I-type crystal of dibenzenesulfonate of an inhibitor of protein tyrosine kinase. Specifically, the invention relates to a I-type crystal of lapatinib dibenzenesulfonate. The crystal, radiated by Cu-K<alpha>, has the following characteristic peaks, represented by a 2theta angle and an inter-planar distance in an X-ray powder diffraction pattern: 6.21(14.23), 10.02(8.82), 12.11(7.30), 13.26(6.67), 13.55(6.53), 13.79(6.42), 14.88(5.95), 6.70(5.31), 17.59(5.04), 18.26(4.86), 18.93(4.68), 19.61(4.52), 20.71(4.29), 21.06(4.21), 22.19(4.00), 23.60(3.77), 24.20(3.68), 24.58(3.62), 25.10(3.55), 25.85(3.44), 26.75(3.33), 30.83(2.90), and 32.89(2.72). According to the invention, the I-type crystal of lapatinib dibenzenesulfonate has better stability, and can be preferably used for clinic treatment.

Description

technical field [0001] The present invention relates to a type I crystal of diphenylsulfonate salt of protein tyrosine kinase inhibitor. In particular, the present invention relates to type I crystals of lapatinib dibenzenesulfonate and its preparation method and use. Background technique [0002] In recent years, the mortality rate of cancer in our country has shown an obvious upward trend. Cancer is a serious threat to people's life and quality of life. Therefore, finding high-efficiency and low-toxic anti-tumor drugs is a very challenging and significant topic in today's life sciences. Receptor tyrosine kinases are a class of transmembrane proteins involved in signal transduction. Studies have shown that more than 50% of proto-oncogenes and oncogene products have tyrosine kinase activity, and their abnormal expression will lead to tumorigenesis. Aberrant protein tyrosine kinase (PTK) activity has been implicated in a number of disorders including psoriasis, rheumatoid a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04A61K31/517A61P35/00A61P15/14
CPCC07D405/04A61K31/517C07B2200/13
Inventor 孙飘扬武乖利韦艳丽吴玉霞沈灵佳
Owner JIANGSU HENGRUI MEDICINE CO LTD
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