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Preparation method of alectinib intermediate

A technology for intermediates and tinib, which is applied in the field of preparation of alectinib intermediates, can solve the problems of cumbersome operation, difficulty in obtaining, and low yield, and achieve the effects of reasonable technical scheme, simplified operation, and high yield

Inactive Publication Date: 2017-06-30
HUNAN BOAODE BIOPHARML TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • 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

Method used

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  • Preparation method of alectinib intermediate
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  • Preparation method of alectinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] A) Preparation of 6-ethyl-7-bromo-3,4-dihydro-2-naphthone:

[0035] 6-Ethyl-3,4-dihydro-2-naphthalenone (4.5g, 25.9mmol) was dissolved in 1,2-dichloroethane (25mL), and N-bromosuccinimide (5.1 g, 28.7mmol), the reaction mixture was stirred and reacted at 30°C for 5 hours, TLC spotting confirmed the completion of the reaction, slowly added water (10mL), cooled to -10°C for crystallization for 3 hours, filtered, recrystallized from isopropanol, and obtained 6- Ethyl-7-bromo-3,4-dihydro-2-naphthone, off-white solid (6.3g), yield 95.5%.

[0036] B) Preparation of 6-ethyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-3,4-dihydro-2-naphthone:

[0037] 6-Ethyl-7-bromo-3,4-dihydro-2-naphthone (6.0g, 23.7mmol) was dissolved in 1,4-dioxane (25mL), and 4-(4-piperidinyl ) morpholine (7.3g, 42.7mmol), sodium isopropoxide (4.3g, 52.2mmol), the reaction mixture was stirred and reacted at 90°C for 12 hours, TLC spot plate confirmed that the reaction was complete, the reaction solution was coo...

Embodiment 2

[0041] A) Preparation of 6-ethyl-7-bromo-3,4-dihydro-2-naphthone:

[0042]6-Ethyl-3,4-dihydro-2-naphthalenone (4.5g, 25.8mmol) was dissolved in tetrahydrofuran (25mL), and N-bromosuccinimide (5.4g, 30.3mmol) was added slowly, and the reaction The mixture was stirred and reacted at 35°C for 2 hours. After the reaction was confirmed by TLC spotting, water (15 mL) was slowly added, cooled to -10°C for crystallization for 5 hours, filtered, and recrystallized from isopropanol to obtain 6-ethyl-7-bromo- 3,4-Dihydro-2-naphthone, off-white solid (6.4g), yield 98%.

[0043] B) Preparation of 6-ethyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-3,4-dihydro-2-naphthone:

[0044] 6-Ethyl-7-bromo-3,4-dihydro-2-naphthone (6.0g, 23.7mmol) was dissolved in 1,4-dioxane (25mL), and 4-(4-piperidinyl ) morpholine (7.3g, 42.9mmol), sodium isopropoxide (4.3g, 52.4mmol), the reaction mixture was stirred and reacted at 95°C for 18 hours, TLC spot plate confirmed that the reaction was complete, the reactio...

Embodiment 3

[0048] A) Preparation of 6-ethyl-7-bromo-3,4-dihydro-2-naphthone:

[0049] 6-Ethyl-3,4-dihydro-2-naphthalenone (4.5g, 25.8mmol) was dissolved in toluene (20mL), bromine water (4.4g, 27.5mmol) was slowly added, and the reaction mixture was stirred at 20°C for 6 hours , TLC spot plate confirmed that the reaction was complete, slowly added water (15mL), cooled to -10 ° C for 4 hours, filtered, and recrystallized from isopropanol to obtain 6-ethyl-7-bromo-3,4-dihydro- 2-Naphthone, off-white solid (6.5g), yield 99%.

[0050] B) Preparation of 6-ethyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-3,4-dihydro-2-naphthone:

[0051] 6-Ethyl-7-bromo-3,4-dihydro-2-naphthone (6.0g, 23.7mmol) was dissolved in N,N-dimethylacetamide (25mL), and 4-(4-piperidine Base) morpholine (10.8g, 63.4mmol), sodium ethoxide (4.8g, 70.5mmol), the reaction mixture was stirred and reacted at 110°C for 8 hours, TLC was spotted to confirm that the reaction was complete, the reaction solution was cooled to room tempe...

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Abstract

The invention discloses a preparation method of 1,1-dimethyl-6-ethyl-7-[4-(morpholine-4-yl)piperidine-1-yl]-3,4-dihydro-2-naphthalenone which is an alectinib intermediate. The method comprises: carrying out a bromination reaction between 6-ethyl-3,4-dihydro-2-naphthalenone and a bromination reagent; allowing the obtained 6-ethyl-7-bromine-3,4-dihydro-2-naphthalenone and 4-(4-piperidyl)morpholine to undergo a substitution reaction; and allowing obtained 6-ethyl-7-[4-(morpholine-4-yl)piperidine-1-yl]-3,4-dihydro-2-naphthalenone and iodomethane to undergo a dimethylation reaction to obtain 1,1-dimethyl-6-ethyl-7-[4-(morpholine-4-yl)piperidine-1-yl]-3,4-dihydro-2-naphthalenone. The preparation method is relatively short in steps, simplified in operation, and low is cost, is a green eco-friendly technical method, and is 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 an alectinib intermediate. 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 certified 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) non-cancerous patients with ALK gene mutations. Small cell lung cancer (NSCLC), or the treatment of patients resistant to crizotinib. [0005] Patents US20130143877 and WO2012023597A1 disclose a synthetic route for the preparati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 李兴民钟云健
Owner HUNAN BOAODE BIOPHARML TECH DEV
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