Synthesis method of Alectinib

A synthesis method and dihydrogen technology, applied in the direction of organic chemistry, etc., can solve the problems of short process flow, difficult to obtain, use a large amount of solvents, etc., and achieve the effects of reasonable technical solution, simplified operation and less impurities

Active Publication Date: 2016-07-20
湖南欧亚药业有限公司
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  • Claims
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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 require

Method used

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  • Synthesis method of Alectinib
  • Synthesis method of Alectinib
  • Synthesis method of Alectinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] A) Preparation of 6-ethyl-3,4-dihydro-2-naphthone:

[0037] 6-Bromo-3,4-dihydro-2-naphthalenone (22.5g, 0.10mol) was dissolved in N,N-dimethylformamide (100mL), cooled to -78°C, and n-butyllithium was slowly added dropwise (0.12mol), the reaction mixture was stirred and reacted at -78°C for 2 hours, slowly added pinacol diboronate (38.1g, 0.15mol), the reaction mixture was stirred and reacted at -78°C for 1 hour, then naturally rose to 20°C and stirred for 10 hours, Slowly add methanol (40mL), and concentrate to dryness by rotary evaporation to obtain 3,4-dihydro-2-naphthone-6-boronic acid, add bromoethane (9.8g, 0.09mol), tetrakis(triphenylphosphine)palladium (5.8g, 5mmol), potassium carbonate (20.0g, 0.145mol), N,N-dimethylformamide (100mL) and water (60mL), the reaction mixture was heated to 95 ° C for 14 hours, TLC spot plate to determine the reaction After completion, the reaction solution was lowered to room temperature, concentrated to dryness by rotary evaporat...

Embodiment 2

[0055] A) Preparation of 6-ethyl-3,4-dihydro-2-naphthone:

[0056] 6-Bromo-3,4-dihydro-2-naphthalenone (22.5g, 0.10mol) was dissolved in N,N-dimethylacetamide (150mL), cooled to -78°C, and n-butyllithium was slowly added dropwise (0.115mol), the reaction mixture was stirred at -78°C for 2 hours, slowly added trimethyl borate (14.5g, 0.14mol), the reaction mixture was stirred at -78°C for 1.5 hours, naturally raised to 22°C and stirred for 10 hours, slowly added Methanol (40mL), concentrated to dryness by rotary evaporation to obtain 3,4-dihydro-2-naphthone-6-boronic acid, added bromoethane (10.4g, 0.095mol), [1,1'-bis(diphenyl Phosphino) ferrocene] palladium dichloride (4.8g, 6.5mmol), sodium carbonate (17.0g, 0.16mol), N,N-dimethylacetamide (150mL) and water (70mL), the reaction mixture Heat to 100°C and react for 14 hours, TLC spot plate confirms that the reaction is complete, the reaction solution is cooled to room temperature, concentrated to dryness by rotary evaporation...

Embodiment 3

[0068] A) Preparation of 6-ethyl-3,4-dihydro-2-naphthone:

[0069] 6-Bromo-3,4-dihydro-2-naphthone (22.5g, 0.10mol) was dissolved in tetrahydrofuran (120mL), cooled to -78°C, and n-butyllithium (0.115mol) was slowly added dropwise, the reaction mixture- Stir the reaction at 78°C for 2 hours, slowly add triethyl borate (23.4g, 0.16mol), stir the reaction mixture at -78°C for 2 hours, naturally rise to 25°C and stir for 10 hours, slowly add methanol (40mL), and concentrate by rotary evaporation To dryness, 3,4-dihydro-2-naphthone-6-boronic acid was obtained, bromoethane (10.9g, 0.10mol), bis(triphenylphosphine)palladium dichloride (4.2g, 6mmol), Potassium phosphate (38.2g, 0.18mol), tetrahydrofuran (120mL) and water (70mL), the reaction mixture was heated to 90 ° C for 17 hours, TLC spot plate confirmed the completion of the reaction, the reaction solution was cooled to room temperature, concentrated to dryness by rotary evaporation, added Extracted with ethyl acetate, washed w...

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Abstract

The invention discloses a synthesis method of Alectinib. The method comprises the following steps: carrying out a borating reaction between 6-bromo-3,4-dihydro-2-naphthalenone and n-butyl lithium and then an organic boron reagent; carrying out a catalytic coupling reaction between the obtained 3,4,-dihydro-2-naphthalenone-6-boric acid and bromoethane; carrying out a dimethylation reaction between the obtained 6-ethyl-3,4-dihydro-2-naphthalenone and iodomethane; carrying out a bromination reaction between the obtained 1,1-dimethyl-6-ethyl-3,4-dihydro-2-naphthalenone and a bromination reagent; carrying out a substitution reaction between the obtained 1,1-dimethyl-6-ethyl-7-bromo-3,4-dihydro-2-naphthalenone and 4-(4-piperidyl)morpholine; carrying out a cyclization reaction between the obtained 1,1-dimethyl-6-ethyl-7-[4-(morpholine-4-yl)piperidine-1-yl]-3,4-dihydro-2-naphthalenone and 3-cyanophenylhydrazine; and carrying out an oxidation reaction between the obtained 9-ethyl-6,6-dimethyl-8-[4-(morpholine-4-yl)piperidine-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile and dichlorodicyanobenzoquinone to obtain a finished product of Alectinib. The synthesis method has the advantages of relatively short route, simplified operation and relatively low cost and is a green and environment-friendly method 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 synthesis 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 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 preparation of Alectinib: s...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 刘叶熊远强
Owner 湖南欧亚药业有限公司
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