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Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof

A technology of di-p-toluenesulfonic acid and lapatinib, which is applied in the preparation of organic compounds, chemical instruments and methods, organic chemistry, etc., and can solve problems such as fluidity and static electricity difference

Inactive Publication Date: 2014-07-02
SHANGHAI ACEBRIGHT PHARMA GRP +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other crystal forms, including the anhydrate crystal form reported in the above literature, are needle-shaped, and have poor properties in terms of fluidity and static electricity.

Method used

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  • Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof
  • Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof
  • Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0060] The present invention provides a preferred method for preparing the polymorphic form of lapatinib di-p-toluenesulfonate N-methylpyrrolidone solvate according to the present invention, comprising the steps of:

[0061] (1) A mixture of lapatinib di-p-toluenesulfonate crude product and N-methylpyrrolidone is provided, the temperature of the mixture is raised to 35-50°C (preferably 35-40°C), and stirred until dissolved, thereby forming a mixture containing N-methylpyrrolidone solution of lapatinib di-p-toluenesulfonate;

[0062] (2) keep the temperature of step (1) (such as 35-50 ° C; preferred 35-40 ° C), in the N-methylpyrrolidone solution containing lapatinib di-p-toluenesulfonate in step (1) Add the eluent dropwise to precipitate crystals;

[0063] (3) Separating the separated crystals to obtain the polymorphic form of lapatinib di-p-toluenesulfonate N-methylpyrrolidone solvate according to the present invention.

[0064] In another preference, the step (2) is: at 35...

Embodiment 1 2

[0079] Example 1 Preparation of lapatinib di-p-toluenesulfonate NMP solvate crystal form A

[0080] Add 20g lapatinib di-p-toluenesulfonate crude product and 250ml NMP in reaction bottle, be warming up to 35-40 ℃, stir, until solid dissolves completely, obtain bright yellow solution, keep stirring for 30 minutes. Then maintain the temperature of solution to be 35-40 DEG C, drip acetone 600ml with the speed of 2ml / min, begin to separate out crystal. After the dropwise addition, slowly drop to 15°C. Filter and wash the filter cake 2-3 times with 90ml acetone. Vacuum drying at 45° C. for 12 hours yielded 21.3 g of light yellow di-p-toluenesulfonate lapatinib NMP solvate crystals. The HPLC detection purity was 99.6%, and the crystal form purity was about 100%. 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 shown. ima...

Embodiment 2 2

[0081] Example 2 Preparation of lapatinib di-p-toluenesulfonate NMP solvate crystal form A

[0082] Add 10g lapatinib di-p-toluenesulfonate crude product and 180ml NMP in reaction bottle, be warming up to 35 ℃, stir, until solid dissolves completely, keep stirring for 1 hour. Then maintain the temperature of solution to be 35 DEG C, drip acetone 550ml with the speed of 2.5ml / min, begin to separate out crystal. After the dropwise addition, slowly drop by 10°C. Filter and wash the filter cake 2-3 times with 30ml acetone. Vacuum drying at 55° C. for 8 hours gave 9.6 g of pale yellow lapatinib di-p-toluenesulfonate NMP solvate crystals. The HPLC detection purity was 99.8%, and the crystal form purity was about 100%. Its XRD figure, DSC figure, TGA figure are basically consistent with embodiment 1.

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Abstract

The invention discloses a poly-crystal-form substance of lapatinib ditosylate solvate as well as a preparation method and application thereof. Particularly, the invention discloses a poly-crystal-form substance of the lapatinib ditosylate solvate with stable thermodynamic and dynamical properties, namely a crystal form A. The crystal form A is easy in storage and transportation, also can be conveniently prepared into coalescent lapatinib ditosylate anhydride, so that great improvement on the aspects of fluidity and static electricity and the like is achieved.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically, the present invention relates to lapatinib di-p-toluenesulfonate N-methylpyrrolidone solvate polymorph and its preparation method and use. Background technique [0002] The chemical name of lapatinib (Lapat inibditosylate) is N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(((2 -(methylsulfonyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine di-p-toluenesulfonic acid, its molecular structural formula is as follows: [0003] [0004] Lapatinib is a tyrosinase inhibitor (TKI) developed by GlaxoSmithKline in the United Kingdom. It is combined with capecitabine (Capecitabine) for the treatment of ErbB-2 overexpression. It has previously received treatment including anthracycline Paclitaxel, advanced or metastatic breast cancer treated with trastuzumab (Herceptin), was approved for marketing by the US FDA on March 13, 2007, and the active ingredient of the marketed pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07C309/30C07C303/44
CPCC07D405/04
Inventor 安晓霞李祯祖远远
Owner SHANGHAI ACEBRIGHT PHARMA GRP
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