Method for preparing alectinib intermediate

A technology of intermediates and tinib, which is applied in the field of medicine, can solve the problems of difficult acquisition of reaction raw materials, many side reactions, and difficult purification, and achieve the effects of low cost, high total yield, and short synthesis steps

Inactive Publication Date: 2018-07-24
董丹丹
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Most of the existing methods for synthesizing eritinib are synthesized by preparing intermediates. Analyzing the above synthetic routes, the core of preparing intermediates (11) and intermediates (12) is the step of indole ring formation, but the reaction process is secondary There are many reactions, purification is difficult, and the reaction raw materials involved are difficult to obtain. Therefore, in view of the defects in the existing technology, it is necessary to develop a high yield and few side reactants. The improvement of economic and social benefits of intermediates has important practical significance

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  • Method for preparing alectinib intermediate
  • Method for preparing alectinib intermediate

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Embodiment 1

[0051] A preparation method of alritinib intermediate, comprising the following processing steps:

[0052] A. Cyclization reaction

[0053] Dissolve 90% hydrochloric acid (30ml) in water (60ml) to prepare a hydrochloric acid solution, add 3-cyanophenylhydrazine ① (22g, 2.4mol) and 6-nitro-4,4-dibromo-1-hydroxy- 1,2,3,4-tetrahydronaphthalene-3 ketone ② (25g, 2.78mol) mixture, after stirring, add reaction accelerator boron trifluoride (5.4g, 1.7mol) and organic solvent 1,2-dichloro Ethane (40ml), N, N-dimethylformamide (DMF) (40ml), heated in a water bath to 20°C, after 3 hours of reaction, continue to dropwise add hydrochloric acid solution (30ml) and oxidative dehydrogenation agent to the reaction solution Chlorobenzoquinone (3.9g, 1.5mol), fully stirred, heated to 60°C for ring closure reaction, cooled to 2°C in an ice-water bath after the reaction, removed the organic solvent, and recrystallized to obtain 6,6-dibromo- 8-nitro-11-hydroxy-6,11-dihydro-5H-benzo[b]carbazole-3-...

Embodiment 2

[0065] A preparation method of alritinib intermediate, comprising the following processing steps:

[0066] A. Cyclization reaction

[0067] Dissolve 90% hydrochloric acid (60ml) in water (120ml) to prepare a hydrochloric acid solution, add 3-cyanophenylhydrazine ① (60g, 5.8mol) and 6-nitro-4,4-dibromo-1-hydroxyl- 1,2,3,4-tetrahydronaphthalene-3 ketone ② (57g, 4.6mol) mixture, after stirring, add reaction accelerator boron trifluoride (11.5g, 2.6mol) and organic solvent 1,2-dichloro Ethane (80ml), N,N-dimethylformamide (DMF) (80ml), heated to 25°C in a water bath, after 4.5 hours of reaction, continue to dropwise add hydrochloric acid solution (100ml) and oxidative dehydrogenation agent to the reaction solution Chlorobenzoquinone (5.9g, 2.7mol), fully stirred, heated to 64°C for ring closure reaction, cooled to 5°C in an ice-water bath after the reaction, removed the organic solvent, and recrystallized to obtain 6,6-dibromo- 8-nitro-11-hydroxy-6,11-dihydro-5H-benzo[b]carbazol...

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Abstract

The invention discloses a method for preparing an alectinib intermediate. The alectinib intermediate has a chemical name of 9-ethyl-6,6-dimethyl-8-(4-chloro-piperidine-1-yl)-11-oxa-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile. The structural formula is shown in the description. The preparation method disclosed by the invention comprises the following steps: taking 3-nitrile phenylhydrazine and6-nitro-4,4-dibromo-1-hydroxy-1,2,3,4-tetrahydronaphthalene-3-one as raw materials, and carrying out a ring-closure reaction, a Wurtz-Fittig reaction, an oxidizing reaction, a reduction reaction, a hydrolysis reaction and a condensation reaction, thereby completing preparation. The method is mild in reaction conditions, low in cost, short in steps of synthesis, less in by-products and high in total yield and is suitable for industrial production.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of an alritinib intermediate. Background technique [0002] Alectinib is a new anaplastic lymphoma kinase (ALK) inhibitor developed by Chugai Pharmaceutical, a subsidiary of Roche, for the treatment of non- For patients with small cell lung cancer, since the drug does not yet have a standard Chinese translation, the applicant hereby transliterates it as "Eritinib". [0003] The PCT patents WO2010143664 and WO2012023597 of the original research company, "Bioorganic & Medicinal Chemistry" 2012, Volume 20, pages 1271-1280 and "J.Med.Chem.", 2011, Volume 54, pages 6286-6294, etc., have reported the synthesis of Eritinib The method is to prepare the intermediate (11) by condensation of 3-iodo-4-ethyl tert-butylbenzene (9) and mono-tert-butyl malonate (10), which is condensed with 3-nitrobenzonitrile Obtain 3-carboxyindole derivatives (12), intermediate (12) obt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 董丹丹
Owner 董丹丹
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