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Preparation method of Idelalisib and intermediate thereof

A technology of idelaris and intermediates, applied in the direction of organic chemistry, can solve the problems of unfavorable environment, achieve the effect of reducing solid waste, avoiding genotoxic raw materials, improving safety and product yield

Active Publication Date: 2018-01-12
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This method uses diphenyl phosphite and pyridine, which are raw materials with a bad smell, which is not good for the environment.

Method used

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  • Preparation method of Idelalisib and intermediate thereof
  • Preparation method of Idelalisib and intermediate thereof
  • Preparation method of Idelalisib and intermediate thereof

Examples

Experimental program
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preparation example Construction

[0037] 3) The preparation of compound V is a ring-closing reaction, and the solvents are dichloromethane, chloroform, tetrahydrofuran, DME (ethylene glycol dimethyl ether), etc. Compound IV: solvent (mass ratio) = 1:5-1:10. The reaction raw materials are compound IV, iodine and HMDS (hexamethylsilazane), and the ratio of the reaction raw materials is compound IV: iodine: HMDS=1:0.8:2~1:1.2:5. The reaction temperature is 35~80°C. The reaction time is 24~48h. The reaction product can be purified by crystallization from isopropanol.

[0038] 4) Like the method in WO2015095601, hydrochloric acid can be used to depyran and sodium bicarbonate to adjust alkali to obtain the final product Idelalis.

Embodiment 1

[0040] The preparation of embodiment 1 chlorinated compound III:

[0041] In the flask, install N2 protection, install a thermometer, constant pressure dropping funnel and magnetic stirring. At room temperature, add 8 grams of phosphorus oxychloride to the reaction bottle, slowly add 30 g of triethylamine dropwise, keep the temperature at 5-40°C, after the drop is complete, react at 30-40°C for 0.5 hours, then add compound I in batches (X=Cl) 12.5g, stirred at 20-40°C for 3-4 hours. Concentrate under reduced pressure to remove part of excess hydrogen chloride. Add DME 30g and stir evenly, add to the constant pressure dropping funnel, set aside.

[0042] In another four-necked bottle, install N2 protection, a thermometer and the constant pressure dropping funnel of the above-mentioned acylated material. 15 g of compound II, 12 g of triethylamine, and 60 g of DME were added. The acylate in the above-mentioned pressure dropping funnel is added dropwise at a controlled tempera...

Embodiment 2

[0044] The preparation of embodiment 2 brominated compound III:

[0045]In the flask, install N2 protection, install a thermometer, constant pressure dropping funnel and magnetic stirring. At room temperature, add 10 g of phosphorus oxychloride to the reaction bottle, slowly add 25 g of triethylamine dropwise, keep the temperature at 5-40°C, after the drop is complete, react at 30-40°C for 0.5 hours, then add compound I in batches (X=Br) 15g, stirred at 20-40°C for 3-4 hours. Concentrate under reduced pressure to remove part of excess hydrogen chloride. Add DME 30g and stir evenly, add to the constant pressure dropping funnel, set aside.

[0046] In another four-necked bottle, install N2 protection, a thermometer and the constant pressure dropping funnel of the above-mentioned acylated material. 15.3 g of compound II, 10 g of triethylamine, and 60 g of DME were added. The acylate in the above-mentioned pressure dropping funnel is added dropwise at a controlled temperature ...

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Abstract

The invention discloses a preparation method of Idelalisib and an intermediate thereof. The method comprises the following steps: using 2-halogeno-6-fluorine-N-phenyl benzamide as a raw material, performing a reaction on the 2-halogeno-6-fluorine-N-phenyl benzamide and N-(9'-tetrahydropyrane-6'-purinyl)-L-2-aminobutyric acid, performing a reaction on a reaction product and ammonium carbonate or liquid ammonia to replace 2-halogeno with ammonia by cuprous oxide, copper and potassium carbonate or cesium carbonate, performing a ring-closure reaction under the existence of hexamethyl disilazane and iodine, and performing a reaction on a reaction product and hydrochloric acid solution to remove pyran finally, so as to generate an Idelalisib finished product. According to the process, the novelmethod is provided for synthesizing the Idelalisib; in the process, the easily available 2-halogeno-6-fluorobenzoic acid is used as a starting material, and zinc acetate pollution and the like can beprevented from being generated through reduction of nitro and the like with zinc powder in a synthesis process.

Description

technical field [0001] The invention relates to a preparation method of a PI3Kδ kinase inhibitor anticancer new drug idelalis and its intermediate, which belongs to the field of chemical synthesis technology. Background technique [0002] The structure of Idelalis as a new anticancer drug of PI3Kδ kinase inhibitor was first disclosed by Aikes Co., Ltd. in WO03 / 035075 (CN1606444). Aikes company has defined the Edelaris division structure in WO2005 / 113556 (CN101031569), and provides specific routes, specifically as follows: [0003] [0004] The raw material 5-fluoronitrobenzoic acid in this method is a genotoxic impurity, which is not easy to control; zinc powder is required for reduction, a small amount of hydrogen gas is generated, the safety is low, the reduction yield is low, and there are many waste solids; trifluoroacetic acid is required to remove BOC equipment The corrosion is heavy, and the operation is unsafe; finally, 6-bromopurine reaction is required, and the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34
Inventor 王志华颜剑波林义洪华斌
Owner ZHEJIANG LEPU PHARMA CO LTD
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