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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 short process flow, difficulty in obtaining, and low yield, and achieve the effects of reasonable technical scheme, simplified operation, and high yield

Inactive Publication Date: 2017-07-07
HUNAN BOAODE BIOPHARML TECH DEV
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  • 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. 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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  • Preparation method of Alectinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] A) Preparation of ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate:

[0045] Dissolve ethyl 2-(4-ethyl-3-methoxyphenyl)acetate (12.0g, 54.0mmol) in methanol (250mL), slowly add sodium methoxide (7.3g, 135.1mmol), and cool to -5°C Left and right, methyl iodide (19.2g, 135.3mmol) was added dropwise, and the reaction mixture was stirred at 70°C for 4 hours. Dried over magnesium, concentrated to dryness by rotary evaporation, and recrystallized from methanol to obtain ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate, off-white solid (12.8g), yield 95%.

[0046] B) Preparation of ethyl 2-(4-ethyl-3-hydroxyphenyl)-2-methylpropionate:

[0047] Add ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate (12.5g, 49.9mmol) and 48% hydrobromic acid solution (101.0g, 599.1mmol) by mass percentage In the reaction flask, the reaction mixture was added to 100°C, refluxed and stirred for 24 hours, the reaction solution was lowered to 0-5°C, slowly added 50% sodium hydroxide sol...

Embodiment 2

[0057] A) Preparation of ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate:

[0058] Dissolve ethyl 2-(4-ethyl-3-methoxyphenyl)acetate (4.5g, 20.2mmol) in ethanol (120mL), add sodium ethoxide (4.1g, 60.2mmol) slowly, and cool to about 0°C , dropwise added iodomethane (8.6g, 60.6mmol), the reaction mixture was stirred and reacted at 60°C for 6 hours, the reaction solution was cooled to room temperature, adjusted to neutrality by adding dilute hydrochloric acid, concentrated to dryness by rotary evaporation, extracted with ethyl acetate, magnesium sulfate Dry, concentrate to dryness by rotary evaporation, and recrystallize from methanol to obtain ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate, off-white solid (4.5g), yield 89 %.

[0059] B) Preparation of ethyl 2-(4-ethyl-3-hydroxyphenyl)-2-methylpropionate:

[0060] 2-(4-Ethyl-3-methoxyphenyl)-2-methylpropionic acid ethyl ester (4.0g, 16.0mmol) and 48% concentration of hydrobromic acid aqueous solution (14.8g, 87.8mm...

Embodiment 3

[0070] A) Preparation of ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate:

[0071] 2-(4-Ethyl-3-methoxyphenyl)ethyl acetate (5.0g, 22.5mmol) was dissolved in isopropanol (120mL), slowly added sodium isopropoxide (3.7g, 45.1mmol), cooled To about 0°C, methyl iodide (6.4g, 45.1mmol) was added dropwise, the reaction mixture was stirred and reacted at 80°C for 2 hours, the reaction solution was cooled to room temperature, adjusted to neutrality by adding dilute hydrochloric acid, concentrated to dryness by rotary evaporation, and ethyl acetate was added Extracted, dried over magnesium sulfate, concentrated to dryness by rotary evaporation, and recrystallized from methanol to obtain ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropionate as off-white solid (4.7g) , yield 83%.

[0072] B) Preparation of ethyl 2-(4-ethyl-3-hydroxyphenyl)-2-methylpropionate:

[0073] 2-(4-Ethyl-3-methoxyphenyl)-2-methylpropionic acid ethyl ester (4.5g, 18.1mmol) and 48% concentration of hydrobromi...

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Abstract

The invention discloses a preparation method of an Alectinib intermediate, namely tert-butyl 4-{4-ethyl-3-[4-(morpholine-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate. The method comprises the steps that ethyl 2-(4-ethyl-3-methoxyphenyl)acetate and iodomethane are subjected to a bis-methylation reaction; obtained ethyl 2-(4-ethyl-3-methoxyphenyl)-2-methylpropanoate is subjected to a hydrolysis reaction; obtained ethyl 2-(4-ethyl-3-hydroxyphenyl) -2-methylpropanoate is subjected to a trifluoromethanesulfonic acid esterification reaction; obtained 5-[2-( ethyloxylcarbonyl)prop-2-yl]-2-ethylphenyl trifluoromethanesulfonate is subjected to a substitution reaction; obtained ethyl 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidin-1-yl] phenyl} -2-methylpropanoate is subjected to a hydrolysis reaction; obtained 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidin-1-yl] phenyl}-2-methyl propioric acid is subjected to a condensation reaction to obtain the Alectinib intermediate. According to the method, the operation is simplified, the cost is low, and the method is an environment-friendly technical method and 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 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 陈健张建国童明
Owner HUNAN BOAODE BIOPHARML TECH DEV
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