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A kind of preparation method of alectinib

A technology of alectinib and ethyl, which is applied in the field of medicinal chemical synthesis, can solve the problems of unfavorable industrial production promotion, expensive starting materials, and the use of a large amount of solvents, and achieve effective control of reaction conditions, cheap raw materials, and easy access to raw materials. The effect

Active Publication Date: 2019-09-20
湖南润星制药有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The starting materials of the above two synthetic routes are relatively expensive and difficult to obtain, so they need to be synthesized and prepared; because the intermediate products and final products of the two synthetic routes contain many impurities and by-products, a large amount of solvents are required for purification, and the operation is cumbersome , the yield is low, which is not conducive to the promotion of industrial production. Therefore, it is necessary to explore the preparation method of Alectinib which is suitable for industrial production due to its short process flow, simple operation and low cost.

Method used

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  • A kind of preparation method of alectinib
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  • A kind of preparation method of alectinib

Examples

Experimental program
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Effect test

Embodiment 1

[0037] A) Preparation of 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal:

[0038] 2-{4-Ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanoic acid ethyl ester (5.0g, 12.9mmol) dissolved in tetrahydrofuran (80mL), cooled to -78°C, slowly added diisobutylaluminum hydride (18.0mmol) tetrahydrofuran solution dropwise, kept at -78°C and stirred for 2 hours, evaporated to dryness under reduced pressure, added dilute hydrochloric acid to adjust to neutral , extracted with ethyl acetate, washed with water and dried, evaporated to dryness under reduced pressure, and recrystallized from isopropanol to obtain 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidine-1- Base]phenyl}-2-methylpropanal, pale yellow solid (4.1g), yield 92%.

[0039] B) Preparation of 3-chloro-4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-2-oxopentanoic acid tert-butyl ester:

[0040] 2-{4-Ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal (4.0g, 11.6...

Embodiment 2

[0048] A) Preparation of 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal:

[0049] 2-{4-Ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanoic acid ethyl ester (10.0g, 25.7mmol) was dissolved in 1 , 4-dioxane (120mL), cooled to -78°C, slowly added dropwise a solution of bis(2-methoxyethoxy)aluminum hydride (41.0mmol) in 1,4-dioxane, and kept warm Stir and react at -75°C for 3 hours, rotary evaporate to dryness under reduced pressure, adjust to neutrality by adding dilute hydrochloric acid, extract with ethyl acetate, wash with water and dry, rotary evaporate to dryness under reduced pressure, recrystallize from isopropanol to obtain 2-{4 -Ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal, pale yellow solid (8.0 g), yield 90%.

[0050] B) Preparation of 3-chloro-4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-2-oxopentanoic acid tert-butyl ester:

[0051] 2-{4-Ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phen...

Embodiment 3

[0059] A) Preparation of 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal:

[0060] 2-{4-Ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanoic acid ethyl ester (2.3g, 5.9mmol) was dissolved in methanol Methyl tert-butyl ether (30mL), cooled to -78°C, slowly added diisobutylaluminum hydride (7.5mmol) in methyl tert-butyl ether solution dropwise, kept at -68°C and stirred for 1 hour, then rotary evaporated under reduced pressure To dryness, add dilute hydrochloric acid to adjust to neutrality, extract with ethyl acetate, wash with water and dry, rotary evaporate to dryness under reduced pressure, and recrystallize from isopropanol to obtain 2-{4-ethyl-3-[4-(morpholine -4-yl)piperidin-1-yl]phenyl}-2-methylpropanal, light yellow solid (1.7g), yield 83%.

[0061] B) Preparation of 3-chloro-4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-2-oxopentanoic acid tert-butyl ester:

[0062]2-{4-Ethyl-3-[4-(morpholin-4-yl)piperidin-1-y...

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Abstract

The invention discloses a preparation method for alectinib. The preparation method comprises the following steps: subjecting 2-4-{4-ethyl-3[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylethyl propionate to a reduction reaction; then subjecting prepared 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropionaldehyde and tert-butyl 2,2-dichloroacetate to an addition-rearrangement reaction; then subjecting obtained 3-chloro-4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-tert-butyl 2-oxovalerate and m-aminobenzonitrile to a substitution reaction; then carrying out a cyclization reaction and a hydrolysis reaction on prepared 3-(3-cyanophenylamino)ethyl-4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-tert-butyl 2-oxovalerate; and subjecting obtained 6-cyano-2-{2-[4-ethyl-3-(4-(morpholin-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H-indole-3-carboxylic acid to a cyclization reaction so as to obtain alectinib. The method has the advantages of simple operation and low cost, and is a green environment-friendly process suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of alectinib. Background technique [0002] The chemical name of Alectinib, a novel anaplastic lymphoma kinase (ALK) inhibitor, is 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidine -1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, its chemical structure is: [0003] [0004] Alectinib is an innovative drug invented by Chugai Pharmaceutical, a subsidiary of Roche Pharmaceuticals. It has been approved as a breakthrough drug by the US FDA and has been approved for accelerated approval as a new oral anti-lung cancer drug for the treatment of advanced (metastatic) ALK gene mutations. Non-small cell lung cancer (NSCLC), or the treatment of patients resistant to crizotinib. [0005] Patents US20130143877 and WO2012023597A1 disclose a synthetic route for the preparation of Alectinib: starting from 7-methoxy-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
Inventor 宁婷黄伟张建国
Owner 湖南润星制药有限公司
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