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Method for preparing deuterated diphenyl urea

A kind of technology of diphenylurea and trideuterated methyl group is applied in the field of intermediates for preparing deuterated diphenylurea, which can solve the problems of low yield, high cost, difficult separation and the like

Active Publication Date: 2012-09-19
SUZHOU ZELGEN BIOPHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, Sorafenib has various side effects such as high blood pressure, weight loss, skin rash, etc.
[0005] However, the existing technology for preparing deuterated diphenylurea compounds is still immature, and has disadvantages such as high cost, low yield, low product purity or difficult separation, so there is an urgent need in this field to develop new and efficient preparation of high-purity diphenyl urea compounds. Process for diphenylurea compounds

Method used

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  • Method for preparing deuterated diphenyl urea
  • Method for preparing deuterated diphenyl urea
  • Method for preparing deuterated diphenyl urea

Examples

Experimental program
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Effect test

preparation example 1

[0118] (1) Synthesis of intermediate N-(1,1,1-trideuteromethyl)benzosuccinimide

[0119]

[0120] 1: Preparation of 4-methylbenzenesulfonic acid-(1,1,1-trideuteromethyl)ester

[0121] Sodium hydroxide (180g, 4.5mol, 5.0eq) was added to water (288mL), at 0°C, deuterated methanol (32.4g, 900mmol, 1.0eq) was added, and p-toluenesulfonyl chloride (206g , 1.1 mmol, 1.2 eq) in tetrahydrofuran (288 mL). Warm to room temperature and stir overnight. Add acetic acid (206g) dropwise below 25°C to neutralize, filter the reaction mixture, separate the layers, extract the water layer with ethyl acetate (100mL), dissolve the filter cake with water (300mL), and extract with ethyl acetate ( 200 mL) and the organic phase was washed with saturated sodium carbonate (100 mL), washed with saturated brine (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound as light yellow liquid 160.5 g, ...

preparation example 2

[0130] Preparation of intermediate N-(1,1,1-trideuteromethyl)benzosuccinimide

[0131]

[0132] 1: Preparation of N-(1,1,1-trideuteromethyl)benzosuccinimide

[0133] Step 2 of Example 1 was repeated, except that the potassium phthalimide salt was replaced with phthalimide (5.9 g, 40 mmol, 2.0 eq), and hydroxide was added in batches at 0° C. Potassium solid (2.2g, 40mmol, 2.0eq), after stirring for 30 minutes, 4-methylbenzenesulfonic acid-(1,1,1-trideuteromethyl)ester (3.8g, 20mmol, 1.0eq) was added dropwise DMF (10 mL) solution, the temperature was raised to 60° C. and stirred for 30 minutes after the dropwise addition. Filtration, washing and vacuum drying were performed in the same manner to obtain the title compound as a white solid, 2.1 g, with a purity of 81%, and a yield of about 62%.

preparation example 3

[0135]

[0136] 1: Preparation of N-(1,1,1-trideuteromethyl)benzosuccinimide

[0137] Step 2 of Example 1 was repeated except that phthalimide potassium salt was replaced with phthalimide (5.9 g, 40 mmol, 2.0 eq), and sodium hydride was added in batches at 0° C. (80%, 1.2g, 40mmol, 2.0eq), after stirring for 30 minutes, 4-methylbenzenesulfonic acid-(1,1,1-trideuteromethyl)ester (3.8g, 20mmol, 1.0eq ) in DMF (10 mL), after the dropwise addition was completed, the temperature was raised to 60° C. and stirred for 30 minutes. Filtration, washing and vacuum drying were performed in the same manner to obtain the title compound as a white solid, 2.7 g, with a purity of 86% and a yield of 80%.

[0138] It can be seen from the above experiments that the above three methods can all prepare the new intermediate N-(1,1,1-trideuteromethyl)benzosuccinimide. However, using phthalimide potassium salt as an intermediate, compared with the production process using phthalimide+potassium hyd...

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Abstract

The invention relates to a method for preparing deuterated diphenyl urea. Specifically, the invention provides an intermediate N-(1, 1, 1-3 deuterated methyl) benzo succinimide which can be used for preparing a deuterated diphenyl urea compound and an application of the intermediate in the preparation of the deuterated diphenyl urea compound. The method can be used for conveniently preparing the intermediate with the high purity and various deuterated diphenyl urea compounds in high efficiency.

Description

technical field [0001] The invention relates to the field of chemical synthesis, and more specifically relates to an intermediate that can be used to prepare deuterated diphenylurea and a synthesis method and application of the intermediate. Background technique [0002] Known ω-diphenylurea derivatives are c-RAF kinase active compounds. For example, WO2000 / 042012 discloses a class of ω-carboxyaryl substituted diphenylureas and their use in the treatment of cancer and related diseases. [0003] ω-Diphenylurea compounds such as Sorafenib were first discovered as inhibitors of c-RAF kinase, and subsequent studies have found that it can also inhibit MEK and ERK signaling pathways, vascular endothelial growth factor-2 (VEGFR-2), vascular endothelial growth factor-3 (VEGFR-3), and platelet-derived growth factor-β (PDGFR-β) tyrosine kinase activity (Curr Pharm Des 2002; 8: 2255-2257), Therefore it is called a multi-kinase inhibitor with dual anti-tumor effects. [0004] Sorafen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B59/00C07D209/48C07D213/81C07D213/89C07C211/04C07C209/62
Inventor 冯卫东高小勇代晓俊
Owner SUZHOU ZELGEN BIOPHARML
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