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The preparation method of Eritinib

A technology of eritinib and tinib, which is applied in the field of preparation of drug eritinib, can solve problems such as difficult acquisition of reaction raw materials and intermediates, complicated reaction process, and increased side reactions, and achieves easy-to-obtain raw materials, simple process, and promote The effect of development

Active Publication Date: 2016-10-05
鄄城泰瑞化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the two substrates forming the ring contain multiple functional groups such as halogen, carbonyl, carboxyl, amino, and cyano, the reaction process is quite complicated, with more side reactions and difficult purification, and most of the raw materials and intermediates involved are difficult to obtain.

Method used

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  • The preparation method of Eritinib
  • The preparation method of Eritinib
  • The preparation method of Eritinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add 6-cyano-1H-indole-3-carboxylic acid methyl ester (II) (2.0g, 10mmol), 4-ethyl-3-(4-morpholin-4-yl-piperidine in the reaction flask -1-yl)-α,α-dimethylbenzyl alcohol (III) (3.3g, 10mmol) and 50mL of dichloromethane, cooled to 0-5°C, added trifluoroacetic acid (0.12g, 1mmol), stirred and reacted After 30 minutes, it was raised to room temperature, and the reaction was continued for 2-4 hours, and the reaction was detected by TLC. The reaction system was washed with water, 10% sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and a solid precipitated out. The obtained crude product was recrystallized from n-hexane and ethyl acetate (1:1, V / V). Dry in vacuo to obtain off-white solid 6-cyano-2-[2-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl]propan-2-yl] - 1H-indole-3-carboxylic acid methyl ester (IV) 4.1 g, yield 79.8%; mass spectrum (EI): m / z 515 (M+H).

Embodiment 2

[0033]In the reaction flask, add 6-cyano-1H-indole-3-carboxylic acid ethyl ester (II) (2.2g, 10mmol), 4-ethyl-3-(4-morpholin-4-yl-piperidine -1-yl)-α,α-dimethylbenzyl alcohol (III) (3.3g, 10mmol) and 50mL of tetrahydrofuran, cooled to 0-5°C, added boron trifluoride (1.4g, 10mmol) ether solution, Stir the reaction for 30 minutes, rise to room temperature, continue the reaction for 2-4 hours, and TLC detects that the reaction is complete. The reaction was quenched with water, extracted three times with dichloromethane, the organic phase was washed with water, 10% sodium bicarbonate solution and saturated brine respectively, dried over anhydrous sodium sulfate, concentrated, and solids were precipitated, and the obtained crude product was washed with n-hexane and ethyl acetate ( 1:1, V / V) recrystallized and dried in vacuo to give off-white solid 6-cyano-2-[2-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1- yl)phenyl]propan-2-yl]-1H-indole-3-carboxylic acid ethyl ester (IV) 3.82g, yield...

Embodiment 3

[0035] In a nitrogen atmosphere, add 6-cyano-2-[2-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl]propane-2 -yl]-1H-indole-3-carboxylic acid methyl ester (IV) (2.57g, 5mmol) and trifluoroethanol 15mL, 2mL of trimethylchlorosilane was added at 5-10°C, and the reaction was stirred for 3 hours. 15 mL of acetone was added, 9 mL of 1M sodium hydroxide solution and 3 mL of 1M potassium dihydrogen phosphate solution were added dropwise, and solids were precipitated under slow stirring. Filtration, the resulting solid was washed with water and acetone (1:1, V / V), and dried in vacuo to give an off-white solid 6-cyano-2-[2-[4-ethyl-3-(4-morpholine-4- Base-piperidin-1-yl)phenyl]propan-2-yl]-1H-indole-3-carboxylic acid (V) 2.36g, yield 94.4%; mass spectrum (EI): m / z 501 (M +H).

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Abstract

A method for preparing Alectinib (Alectinib, I), comprising the preparation steps: subjecting 6-cyano-1H-indole-3-carboxylate and 4-ethyl-3-(4-morpholine-4-yl-piperidine-1-yl)-α,α-dimethylbenzyl alcohol to condensation, hydrolyzing and cyclization reaction so as to prepare Alectinib (I). The preparation method has easily available raw materials and a simple process, and is economical and environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and the preparation of raw materials and intermediates, and in particular relates to a preparation method of alritinib, a drug for treating non-small cell lung cancer. Background technique [0002] Alectinib is a new anaplastic lymphoma kinase (ALK) inhibitor developed by Chugai Pharmaceutical, a subsidiary of Roche. preparation , for the treatment of non-small cell lung cancer patients with ALK gene rearrangement, because it is still effective in patients who are resistant to crizotinib (Crizotinib), and can significantly reduce brain metastases, the drug was granted " "Breakthrough Therapy" status and was approved for marketing in Japan in July 2014. Because the drug does not yet have a standard Chinese translation, the applicant here transliterates it as "Eritinib". [0003] The chemical name of Alectinib is: 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 许学农
Owner 鄄城泰瑞化工有限公司