A kind of preparation method of alectinib

A technology of alectinib and piperidine, which is applied in the field of medicinal chemical synthesis, can solve the problems of short technological process, difficult to obtain, and use a large amount of solvents, and achieves the effects of reasonable technical solution, simplified operation and less impurities

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

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Embodiment 1

[0041] A) Preparation of 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal:

[0042] 2-{4-Bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal (6.0g, 13.7mmol) was dissolved in tetrahydrofuran (80mL) , cooled to -78°C, slowly added a toluene solution of bis(2-methoxyethoxy) sodium aluminum hydride (3.9g, 19.3mmol) dropwise, kept at -78°C and stirred for 2 hours, then evaporated to dryness under reduced pressure , added dilute hydrochloric acid to adjust to neutrality, extracted with ethyl acetate, washed with water and dried, rotary evaporated to dryness under reduced pressure, and recrystallized from isopropanol to obtain 2-{4-bromo-3-[4-(morpholine-4- yl)piperidin-1-yl]phenyl}-2-methylpropanal, pale yellow solid (4.5g), yield 83%.

[0043] B) Preparation of tert-3-chloro-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-2-oxopentanoic acid Butyl esters:

[0044] 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-meth...

Embodiment 2

[0054] A) Preparation of 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal:

[0055] 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal (10.0g, 22.8mmol) dissolved in 1,4- Dioxane (150mL), cooled to -78°C, slowly added diisobutylaluminum hydride (3.9g, 27.4mmol) in n-hexane solution dropwise, kept at -78°C and stirred for 3 hours, then evaporated to dryness under reduced pressure , added dilute hydrochloric acid to adjust to neutrality, extracted with ethyl acetate, washed with water and dried, rotary evaporated to dryness under reduced pressure, and recrystallized from isopropanol to obtain 2-{4-bromo-3-[4-(morpholine-4- yl)piperidin-1-yl]phenyl}-2-methylpropanal, light yellow solid (8.7g), yield 97%.

[0056] B) Preparation of tert-3-chloro-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-2-oxopentanoic acid Butyl esters:

[0057]2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal (8.5g, 21.5mmo...

Embodiment 3

[0067] A) Preparation of 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal:

[0068] 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal (8.5g, 19.3mmol) dissolved in methyl tert-butyl Diisobutylaluminum hydride (4.3g, 30.2mmol) in n-hexane solution was slowly added dropwise, stirred and reacted at -68°C for 1 hour, then rotary evaporated to dryness under reduced pressure, added Adjust dilute hydrochloric acid to neutrality, extract with ethyl acetate, wash with water and dry, evaporate to dryness under reduced pressure, and recrystallize from isopropanol to obtain 2-{4-bromo-3-[4-(morpholin-4-yl) Piperidin-1-yl]phenyl}-2-methylpropanal, pale yellow solid (7.0 g), yield 92%.

[0069] B) Preparation of tert-3-chloro-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-2-oxopentanoic acid Butyl esters:

[0070] 2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropanal (7.0g, 17.7mmol) and 2,2-di Tert-butyl ch...

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Abstract

The invention discloses a preparation method for alectinib. The preparation method comprises the following steps: with 2-{4-bromo-3[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylethyl propionate as a raw material, carrying out a reduction reaction to reduce the raw material into aldehyde; then subjecting the prepared aldehyde and tert-butyl 2,2-dichloroacetate to an addition-rearrangement reaction; then subjecting obtained 3-chloro-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-tert-butyl 2-oxovalerate to a substitution reaction; carrying out a cyclization reaction and a hydrolysis reaction on prepared 3-(3-cyanophenylamino)ethyl-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-tert-butyl 2-oxovalerate; subjecting obtained 6-cyano-2-{2-[4-bromo-3-(4-(morpholin-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H-indole-3-carboxylic acid to a cyclization reaction; and successively carrying out a boric acid reaction and a catalytic coupling reaction on obtained 9-bromo-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile 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 宁婷童明李涛
Owner 湖南润星制药有限公司
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