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Preparation method of idelalisib intermediate

A technology for ederalix and intermediates, which is applied in the field of preparation of idelalix intermediates, can solve problems such as potential safety hazards and serious pollution, and achieve the effects of high reaction efficiency, less three wastes and fewer reaction steps.

Inactive Publication Date: 2018-08-17
南京法恩化学有限公司
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  • Claims
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Problems solved by technology

2) Use 2-fluoro-6-nitrobenzoic acid as a raw material, form an acid chloride with thionyl chloride, and directly react with aniline without treatment to obtain 2-fluoro-6-nitro-N-phenylbenzamide, after Thionyl chloride reacts with N-Boc-L-2-aminobutyric acid to obtain (S)-N-(2-Boc-aminobutyryl)-2-fluoro-6-nitro-N-phenylbenzamide , and then get the key intermediate 5-fluoro-3-phenyl-2-[(S)-1-Boc-aminopropyl]-4-(3H)-quinazolin-4-one through zinc powder reductive ring closure ; This route uses a large amount of thionyl chloride in the condensation and chlorination reaction, which is seriously polluted and has potential safety hazards

Method used

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  • Preparation method of idelalisib intermediate

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Effect test

preparation example Construction

[0024] A kind of preparation method of idelaris intermediate, such as figure 1 shown, including the following steps:

[0025] Step 1: Add 1L of dichloromethane to the reaction bottle, then add 100g of aniline and stir for 5 minutes, then add 225g of DCC, and then add 220g of N-Boc-L-2-aminobutyric acid and stir at 0°C to carry out the intermediate control reaction. After the reaction, add 300g of triethylamine, dropwise add 230g of 2-fluoro-5-nitrobenzoyl chloride, after the dropwise addition, stir and react for 5 hours, add the reaction solution into water, separate the liquid, concentrate the organic phase, Crystallization, filtration, and drying yielded 445 g of the intermediate (S)-N-(2-Boc-aminobutyryl)-2-fluoro-6-nitro-N-phenylbenzamide.

Embodiment 1

[0027] Add 400g (S)-N-(2-Boc-aminobutyryl)-2-fluoro-6-nitro-N-phenylbenzamide in the reaction flask, add 3L acetic acid in the reaction flask, and then batch Add 85g of zinc powder, stir for 30min, raise the temperature to 100°C, and carry out the central control reaction. After the reaction is completed, it is concentrated under reduced pressure, cooled, filtered, washed with water, and dried to obtain 292g of the product idelaris intermediate 5-fluoro -3-Phenyl-2-[(S)-1-Boc-aminopropyl]-4-(3H)-quinazolin-4-one.

Embodiment 2

[0029] Add 400g (S)-N-(2-Boc-aminobutyryl)-2-fluoro-6-nitro-N-phenylbenzamide in the reaction flask, add 3L acetic acid in the reaction flask, and then batch Add 32g of magnesium powder, stir for 30min, raise the temperature to 80°C, and carry out the central control reaction. After the reaction is completed, it is concentrated under reduced pressure, cooled, filtered, washed with water, and dried to obtain 286g of the product idelaris intermediate 5-fluoro -3-Phenyl-2-[(S)-1-Boc-aminopropyl]-4-(3H)-quinazolin-4-one.

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Abstract

The invention discloses a preparation method of an idelalisib intermediate, the idelalisib intermediate (S)-N-(2-Boc-aminobutyryl)-2-fluoro-6-N-phenyl benzamide is prepared from aniline, N-Boc-L-2-aminobutyric acid, DCC, triethylamine and 2-fluoro-5-nitrobenzoyl chloride as raw materials by a three-step reaction of condensation reaction, amidation reaction and ring closure reaction for one-pot synthesis, and the condensation reaction and the amidation reaction do not require separation. The preparation method is a preparation method with the advantages of high yield, low cost, less waste, easyoperation and suitable industrialization.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of an idelaris intermediate. Background technique [0002] Idelalisib is another successful new drug development model after the acquisition of Sovaldi, which is unique to Gilead Sciences. In particular, the efficacy of idelalisib is through the regulation of the immune system, which itself does not directly inhibit the growth of tumors, and the early clinical results are not impressive. Because of this, the early development of Idelalisib was full of hardships. After 20 failures, Mike Gallatin finally persuaded Frazier Healthcare to invest in this experimental drug that had been put on the shelf for several years by ICOS for the 21st time. Later, Frazier Healthcare’s $26 million investment grew to $600 million in just 3 years [0003] Idelalisib is the first marketed oral, selective phosphoinositide 3-kinase delta (PI3K-delta, P110-delta) inhibitor. P110-delta is...

Claims

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Application Information

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IPC IPC(8): C07D239/91
CPCC07D239/91
Inventor 王坤鹏韩月林
Owner 南京法恩化学有限公司
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