A kind of 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

Active Publication Date: 2019-08-02
湖南润星制药有限公司
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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 intermediate
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  • A kind of preparation method of alectinib intermediate

Examples

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Embodiment 1

[0041] A) Preparation of 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate:

[0042] 2-(4-ethyl-3-hydroxyphenyl) ethyl acetate (10.0g, 48.0mmol) was dissolved in triethylamine (9.7g, 95.9mmol), and trifluoromethanesulfonic anhydride (18.3g, 64.9mmol), stirred and reacted at 20°C for 2 hours. After post-treatment and purification, 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate was obtained as a light yellow solid (15.8g ), the yield is 97%.

[0043] B) Preparation of ethyl 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}ethyl acetate:

[0044] 5-[(Ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate (15.0g, 44.1mmol) was dissolved in N,N-dimethylformamide (250mL), and 4- (4-piperidinyl)morpholine (16.9g, 99.3mmol), sodium methoxide (6.0g, 111.1mmol), the reaction mixture was stirred and reacted at 100°C for 12 hours, the reaction solution was cooled to room temperature, water (180mL) was added and cooled to Crystallize at 0°C for...

Embodiment 2

[0052] A) Preparation of 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate:

[0053] Ethyl 2-(4-ethyl-3-hydroxyphenyl)acetate (12.0g, 57.6mmol) was dissolved in N,N-diisopropylethylamine (18.6g, 143.9mmol), and trifluoromethyl was slowly added dropwise Sulfonic acid anhydride (24.4g, 86.5mmol), stirred and reacted at 25°C for 1 hour, after post-treatment and purification, 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate was obtained , Light yellow solid (18.6g), yield 95%.

[0054] B) Preparation of ethyl 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}ethyl acetate:

[0055] 5-[(Ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate (18.0g, 52.9mmol) was dissolved in N,N-dimethylformamide (350mL), and 4- (4-piperidinyl)morpholine (24.3g, 142.7mmol), sodium ethoxide (10.8g, 158.7mmol), the reaction mixture was stirred at 110°C for 6 hours, the reaction solution was cooled to room temperature, water (200mL) was added and cooled to Cr...

Embodiment 3

[0063] A) Preparation of 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate:

[0064] 2-(4-Ethyl-3-hydroxyphenyl) ethyl acetate (2.0g, 9.6mmol) was dissolved in pyridine (1.2g, 15.2mmol), and trifluoromethanesulfonic anhydride (3.3g, 11.7mmol) was slowly added dropwise ), the reaction was stirred at 0°C for 4 hours, after post-treatment and purification, 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate was obtained as a pale yellow solid (2.6g), The yield is 80%.

[0065] B) Preparation of ethyl 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}ethyl acetate:

[0066] 5-[(Ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate (2.5g, 7.3mmol) was dissolved in 1,4-dioxane (40mL), and 4-( 4-piperidinyl)morpholine (2.3g, 13.5mmol), sodium isopropoxide (1.2g, 14.6mmol), the reaction mixture was stirred at 90°C for 18 hours, the reaction solution was cooled to room temperature, water (30mL) was added and cooled Crystallize at 0°C for 3 hours...

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Abstract

The invention discloses a preparation method of an alectinib intermediate, tert-butyl 4-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}-4-methyl-3-oxovalerate. The preparation method comprises: subjecting ethyl 2-(4-ethyl-3-hydroxyphenyl)acetate and triflic anhydride to triflic acid esterification; subjecting the obtained 5-[(ethoxycarbonyl)methyl]-2-ethylphenyltriflate and 4-(4-piperidyl)morpholine to substitution reaction; subjecting the obtained ethyl 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}acetate and methyl iodide to bis-methylation reaction; hydrolyzing the obtained ethyl 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}-2-methylpropanoate; subjecting the obtained 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}-2-methylpropanoic acid and mono-tert-butyl malonate to condensation reaction to obtain the alectinib intermediate. The preparation method is simple to perform and low in cost, is a green technique and is applicable to industrial production.

Description

Technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of alectinib intermediate. Background technique [0002] The chemical name of the new anaplastic lymphoma kinase (ALK) inhibitor Alectinib 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 therapy drug by the US FDA and has accelerated approval as a new oral anti-lung cancer drug for the treatment of advanced (metastatic) ALK gene mutations. Treatment of non-small cell lung cancer (NSCLC) or patients who are resistant to crizotinib. [0005] Patent US20130143877 and WO2012023597A1 disclose a synthetic route for preparing alectinib: starting with 7-methoxy-3,4-dihydro-2-naph...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 陈健李涛钟云健
Owner 湖南润星制药有限公司
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