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Regorafenib salt, crystal thereof and preparation method of crystal

A technology of regorafenib and regorafenib ethyl sulfonate, applied in the field of regorafenib, can solve the problems of poor solubility of regorafenib monohydrate, limited application and the like, and achieves good stability and product quality. High utilization rate and good repeatability

Active Publication Date: 2014-07-16
药源生物科技(启东)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the poor solubility of regorafenib monohydrate limits its application in formulations

Method used

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  • Regorafenib salt, crystal thereof and preparation method of crystal
  • Regorafenib salt, crystal thereof and preparation method of crystal
  • Regorafenib salt, crystal thereof and preparation method of crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Embodiment 1 Preparation of the amorphous crystal form of regorafenib etetinate

Embodiment 11

[0123] Add 1.0 g of regorafenib to 10 ml of ethyl acetate and 1 ml of water, and heat up to 40°C to dissolve. Add 0.33g of 2-hydroxyethylsulfonic acid into the reaction solution, and react at not lower than 40°C for 2 hours. After cooling down to room temperature, no precipitation occurred, and the reaction solution was concentrated to dryness to obtain the amorphous form of regorafenib etetinate.

[0124] 1 H-NMR (400MHz, DMSO): δ2.65-2.68 (t, J = 2.8Hz, 2H), 2.80 (d, J = 4.8Hz, 3H), 3.64 (t, J = 2.8Hz, 2H), 6.71 (broads, 1H), 7.07-7.10 (dd, J 1 =8.8Hz,J 2 =1.2Hz, 1H), 7.26(t, J=2.8Hz, 1H), 7.34-7.37(dd, J 1 =11.6Hz,J 2 =2.8Hz,1H), 7.54(d,J=2.0Hz,1H), 7.63(s,2H), 8.16(m,2H), 8.57(d,J=5.6Hz,1H), 8.80(s,1H ), 8.91(s,1H), 9.57(s,1H).

Embodiment 12

[0126] The same method as in Example 1.1 was adopted, but 10 ml of the used solvent ethyl acetate was replaced by 20 ml of acetone.

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Abstract

The invention relates to two regorafenib organic acid salt as shown in formulas (I, II), namely 2-isethionate(isethionate) and esilate of regorafenib, and relates to two regorafenib isethionate (formula I) crystals named as a crystal A and a crystal B, two regorafenib esilate (formula II) crystals named as a crystal alpha and a crystal Beta and a novel regorafenib tosilate crystal named as a crystal N-1. The invention also relates to preparation methods of the regorafenib isethionate crystals A, B, the regorafenib esilate crystals alpha and beta and the novel regorafenib tosilate crystal N-1. The regorafenib isethionate crystals A, B, the regorafenib esilate crystals alpha and beta and the novel regorafenib tosilate crystal N-1 which are disclosed by the invention have X-ray powder diffraction characteristic absorption peaks and DSC (Differential Scanning Calorimeter) characteristic absorption peaks; and the regorafenib isethionate crystal A, the regorafenib esilate crystal beta and the novel regorafenib tosilate crystal N-1 which are disclosed by the invention have the advantages of stability, difficulty in moisture absorption and good solubility.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically relates to the drug commonly known as Regorafenib, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2-fluoro-(4-(2-(N- A pharmaceutically acceptable salt of methylcarbamoyl)-4-pyridyloxy)phenyl)urea, a crystal form and a preparation method thereof. Background technique [0002] The Chinese name of Regorafenib is: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2-fluoro-(4-(2-(N-methylammonia) Formyl)-4-pyridyloxy)phenyl)urea, English name: [0003] 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea. Trade name: Stivarga. The structural formula is as follows: [0004] [0005] Regorafenib is a new type of multikinase inhibitor, which can block various enzymes that promote tumor growth, and was discovered and developed by Bayer (Bayer). In September 2012, the US FDA approved it for the treatment of metastatic colorectal cancer. ...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 王元何训贵周岩锋梁晨冰
Owner 药源生物科技(启东)有限公司
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