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Novel sorafenib TsOH crystal form as well as preparation method and application thereof

A technology of sorafenib p-toluenesulfonate and p-toluenesulfonic acid, which is applied in the field of medicine and can solve problems such as the possibility of increasing solvent residues

Inactive Publication Date: 2016-05-18
BIOCOMPOUNDS PHARMACEUTICAL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN104177292A provides a kind of reflux in acetone-acetonitrile mixed solvent to form salt, cool down and crystallize to obtain the preparation method of polymorph I sorafenib p-toluenesulfonate, the method adopts mixed solvent, which increases the possibility of solvent residue in medicine , although the method is simple, the obtained polymorphic form I is still

Method used

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  • Novel sorafenib TsOH crystal form as well as preparation method and application thereof
  • Novel sorafenib TsOH crystal form as well as preparation method and application thereof
  • Novel sorafenib TsOH crystal form as well as preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0059] Preparation of the formula (II) compound of sorafenib p-toluenesulfonate monohydrate type E crystal:

[0060] Dissolve 2g of sorafenib free base in 15ml of 1,4-dioxane and 5ml of deionized water, stir, heat up to 78°C, add 1g of 1,4-p-toluenesulfonic acid monohydrate after the system dissolves quickly Dioxane solution 3ml, keep stirring for 30 minutes. The system was naturally cooled to room temperature, then cooled to -5-0°C with freezing liquid, and continued to stir and crystallize for 20 hours. Suction filtration, wash with 1,4-dioxane, collect filter cake, blow dry at 50°C for 72 hours, measure moisture after drying to 3.0, and obtain 2.4g of sorafenib p-toluenesulfonate monohydrate, yield 88%, purity 98.79%, melting point: 127.3~134.8℃, X-ray powder diffraction pattern as figure 1 As shown, the TGA graph is shown as figure 2 shown.

Embodiment 2

[0062] Preparation of the formula (II) compound of sorafenib p-toluenesulfonate monohydrate type E crystal:

[0063] Dissolve 2.2g of sorafenib free base in 44ml of 1,4-dioxane and 4.4ml of deionized water, stir, heat up to 76°C, and add 1g of p-toluenesulfonic acid monohydrate after the system dissolves rapidly. , 4 dioxane solution 3ml, continue to stir for 30 minutes. Naturally cool down to room temperature, then cool down to -5-0°C, and continue to stir and crystallize for 25 hours. Filter with suction, wash the filter cake with 1,4-dioxane, and collect the filter cake. Air-drying at 60°C for 16 hours, the measured water content after drying was 3.22, and 2.5 g of sorafenib p-toluenesulfonate monohydrate was obtained with a yield of 84%. Purity: 98.59%, melting point: 126.0~135.1℃.

Embodiment 3

[0065] Preparation of the formula (II) compound of sorafenib p-toluenesulfonate monohydrate type E crystal:

[0066] Dissolve 1g of sorafenib free base in 8ml of 1,4-dioxane and 2ml of deionized water, stir, heat up to 76°C, add 0.4g of p-toluenesulfonic acid monohydrate 1, 4 dioxane solution 2ml, continue to stir for 1 hour. Cool down to room temperature (15-18°C) naturally, and stir and crystallize for 17 hours. Filter with suction, wash the filter cake with 1,4-dioxane, and collect the filter cake. Air-dried at 60°C for 6 hours, and measured moisture content after drying was 3.20 to obtain 0.9 g of sorafenib p-toluenesulfonate monohydrate with a yield of 90%. Purity 98.86%, melting point: 133.2-136.9°C, X-ray powder diffraction pattern is as follows image 3 as shown, 1 H-NMR detection results such as Figure 7 Shown (DMSO-d 6 ,400MHzδppm=2.29(s,1.5H),2.83(s,3H),5.79(br,2.5H),7.17~7.21(m,3H),7.25~7.27(m,1H),7.58~7.70(m, 6H), 8.14(d,1H), 8.57(d,1H), 9.03(d,1H), 9.27(s...

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Abstract

The invention relates to the technical field of medicine, in particular to a novel sorafenib TsOH crystal form as well as a preparation method and an application thereof, and provides a type E crystal of a sorafenib TsOH monohydrate. In an X-ray powder diffraction pattern, the type E crystal of the sorafenib TsOH monohydrate displays characteristic diffraction peaks when 2-theta is about 8.961 degrees plus / minus 0.2 degrees,13.379 degrees plus / minus 0.2 degrees, 13.939 degrees plus / minus 0.2 degrees, 19.718 degrees plus / minus 0.2 degrees, 20.658 degrees plus / minus 0.2 degrees, 22.761 degrees plus / minus 0.2 degrees, 23.561 degrees plus / minus 0.2 degrees, 24.080 degrees plus / minus 0.2 degrees and 24.881 degrees plus / minus 0.2 degrees. A compound shown in a formula (II) of the type E crystal of the sorafenib TsOH monohydrate is high in product yield and excellent in product quality and has the advantages of good stability, high crystal purity, convenience in storage and the like.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a new crystal form of sorafenib p-toluenesulfonate and its preparation method and application. Background technique [0002] Sorafenib p-toluenesulfonate (SorafenibTsOH, molecular formula C 28 h 24 CIF 3 N 4 o 6 S, molecular weight 637.03) has the structure shown in formula I, and its chemical name is 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy}pyridine-2-methyl Amide p-toluenesulfonic acid. A new multi-target anti-tumor drug (trade name: Nexavar, Nexavar) developed and marketed by German Bayer and Onyx. In December 2005, sorafenib p-toluenesulfonate was quickly approved by the US FDA as a first-line drug for the treatment of advanced renal cancer. In June 2006, sorafenib p-toluenesulfonate was granted fast-track approval by the FDA for the treatment of metastatic liver cancer. In August 2009, China's State Food and Drug Administration approved Bayer Pharmac...

Claims

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Application Information

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IPC IPC(8): C07D213/81A61P35/00
CPCC07D213/81C07B2200/13
Inventor 杨世琼康立涛李倩赵爱平
Owner BIOCOMPOUNDS PHARMACEUTICAL INC
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