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A kind of preparation method of idelaris and its intermediate

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

Active Publication Date: 2020-01-10
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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  • A kind of preparation method of idelaris and its intermediate
  • A kind of preparation method of idelaris and its intermediate
  • A kind of preparation method of idelaris and its intermediate

Examples

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preparation example Construction

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

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

Embodiment 1

[0040] Example 1 Preparation of chlorinated compound III:

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

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

Embodiment 2

[0044] Example 2 Preparation of Bromo Compound III:

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

[0046] In another four-necked flask, install N2 protection, a thermometer and a constant pressure dropping funnel for the above-mentioned acylated materials. Add 15.3g of compound II, 10g of triethylamine, and 60g of DME. The acylate in the pressure dropping funnel is added dropwise at a controlled temperature of 5-30°C. Afte...

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PUM

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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 method for preparing a new anticancer drug ideraris of PI3Kδ kinase inhibitor and its intermediates, and belongs to the field of chemical synthesis technology. Background technique [0002] As a new anti-cancer drug of PI3Kδ kinase inhibitor, Idelaris was originally disclosed in WO03 / 035075 (CN1606444) by Ecos Co., Ltd. ACX has clarified the structure of Adelaris in WO2005 / 113556 (CN101031569), and gave a specific route, as follows: [0003] [0004] The raw material of this method, 5-fluoronitrobenzoic acid is a genotoxic impurity, which is not easy to control; it needs zinc powder reduction, a small amount of hydrogen is generated, low safety, low reduction yield, and a lot of waste and solid; it needs to use trifluoroacetic acid to remove BOC equipment The corrosion is heavy and the operation is unsafe; the final 6-bromopurine reaction is required, and the production cost is high. [0005] Gilead disclosed the following route in ...

Claims

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Application Information

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Patent Type & Authority Patents(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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