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The preparation method of Sorafenib tosylate crystal form III

A technology of fennel crystal form and toluenesulfonic acid, which is applied in the field of medicinal chemistry, can solve the problems of large phase difference, easily exceeding the standard of dissolution residue, complicated operation, etc.

Active Publication Date: 2021-07-27
SHANGHAI ACEBRIGHT PHARMA CO LTD
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  • Description
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Problems solved by technology

The raw material of this preparation process is crystal form II, so the premise of using this process is to prepare crystal form II first, the whole process cycle is long and the operation is complicated
Patent No. US9156789 (B2) discloses the method for preparing Sorafenib tosylate crystal form III: Sorafenib free base and p-toluenesulfonic acid are dissolved in DMF or DMA, crystallized by adding methanol , the obtained product is beaten in methanol, finally filtered, and dried to obtain the crystal form III of sorafenib tosylate, but the methanolate obtained by this method has a large particle size, and it is difficult to convert into the crystal form III during the drying and crystallization process. Easy to exceed the standard, the product is not suitable for making preparations
The same product has a low dissolution rate in medium pH 4.5, water, and pH 6.8 after it is made into a preparation
The dissolution result of the sorafenib tosylate crystal form III obtained in the prior art is quite different from that of the crystal form I

Method used

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  • The preparation method of Sorafenib tosylate crystal form III
  • The preparation method of Sorafenib tosylate crystal form III
  • The preparation method of Sorafenib tosylate crystal form III

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preparation example Construction

[0041] The preparation method of the present invention adopts the reverse drop technique, and the organic solvent of p-phenylmethanesulfonic acid and Sorafenib free base is added to crystallize in methanol, or the organic solvent of Sorafenib free base is added to p-phenylmethanesulfonic acid Crystallization in the methanol solution of acid can effectively control the residual solvent, and the small particle size of the product is conducive to drying into type III.

[0042] The main advantages of the present invention are:

[0043] 1. The preparation method of the present invention does not need to prepare other crystal forms in advance, the process cycle is short, and the operation is simple;

[0044] 2. The residual amount of organic solvents such as NMP, DMSO, DMF and the like in the crystal form III obtained by the preparation method of the present invention is low;

[0045] 3. The methanolate obtained by the preparation method of the present invention has a small particl...

Embodiment 1

[0052] Example 1: Preparation of Form III-1

[0053] Add 10 g of sorafenib free base and 6 g of p-benzenemethanesulfonic acid into 30 mL of N-N-dimethylformamide, stir and dissolve at room temperature, and filter to obtain filtrate A.

[0054] Take 180mL of methanol in a 500mL three-necked flask, and cool it to an internal temperature of 0-5°C with mechanical stirring in an ice-water bath. At this time, slowly add filtrate A to precipitate solids. After the addition of filtrate A is completed, keep stirring at 0-5°C for 1 hour, The resulting solid A was collected by filtration.

[0055] The obtained solid A was then added to 200 mL of methanol, slurried at room temperature for 1 h, and finally the obtained solid B was collected by filtration, and solid B was dried at 80° C. to obtain 12.45 g of crystal form III-1 with a molar yield of 91%.

[0056] After determination and analysis, the obtained crystal form III-1 has the following properties: figure 1 The XRD pattern shown. ...

Embodiment 2

[0057] Example 2: Preparation of Form III-2

[0058] Add 10 g of sorafenib free base to 30 mL of N-N-dimethylformamide, stir to dissolve at room temperature, filter, and obtain the filtrate as A.

[0059] Weigh 6g of p-phenylmethanesulfonic acid and dissolve it in 180mL of methanol, and use mechanical stirring to cool in an ice-water bath to an internal temperature of 0-5°C. At this time, slowly add filtrate A to precipitate solids, and keep warm at 0-5°C after the addition of filtrate A is completed. After stirring for 1 h, the resulting solid A was collected by filtration.

[0060] The obtained solid A was then added to 200 mL of methanol, slurried at room temperature for 1 h, and finally the obtained solid B was collected by filtration, and solid B was dried at 80° C. to obtain 12.45 g of crystal form III-2 with a molar yield of 91%.

[0061] After determination and analysis, the obtained crystal form III-2 has basically the following figure 1 The XRD spectrum shown.

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Abstract

The invention provides a preparation method of sorafenib tosylate crystal form III, adding an organic solvent of p-benzenemethanesulfonic acid and sorafenib free base to methanol for crystallization, or dissociating sorafenib The organic solvent of the base is added to the methanol solution of p-toluenesulfonic acid for crystallization to obtain the methanol solvate of sorafenib tosylate, and finally the crystal form III is obtained through desolventization. The methanolate obtained by this method has a small particle size and is easier to bake into crystal form III. Finally, crystal form III has the characteristics of good fluidity, high purity, qualified quality and dissolution similar to crystal form I, and the method is simple to operate and high in yield. Suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular, the invention relates to a preparation method of Sorafenib tosylate crystal form III. Background technique [0002] Compound 4-[4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureide]-phenoxy]-pyridine-2-carboxylic acid methylamine-4-toluenesulfonate Structure is as shown in formula I: [0003] [0004] The compound of formula I was developed by Bayer HealthCare Co., Ltd. In October 2007, the European Medicines Evaluation Agency (EMEA) approved Sorafenib Tosylate (Nexavar) for the treatment of hepatocellular carcinoma. In November 2007, the US Food and Drug Administration approved Nexavar for the treatment of unresectable hepatocellular carcinoma. [0005] Among the known crystalline forms, crystalline form I is the most thermodynamically stable form, and crystalline form III can be used in pharmaceutical preparations. In the prior art, the crystal form III cannot be di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81
CPCC07B2200/13C07D213/81
Inventor 安晓霞胡猛申淑匣詹小兰修平
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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