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A method for synthesizing neratinib intermediate 3-cyano-4-chloro-6-amino-7-ethoxyquinoline

An ethoxyquinoline and neratinib technology, applied in the direction of organic chemistry and the like, can solve the problems of unobtainable raw materials, poor process safety, complicated operation, etc., and achieves low-cost reagents, high total yield, and simple operation. Effect

Active Publication Date: 2019-04-23
山东金吉利新材料有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is to overcome the difficulty of obtaining raw materials, expensive, high production cost in the technology reported in the existing preparation formula (I) compound 3-cyano-4-chloro-6-amino-7-ethoxyquinoline , low yield, complex operation, poor process safety and other defects that are not conducive to industrial production, provide an effective method for preparing 3-cyano-4-chloro-6-amino-7-ethoxyquinoline, the method Less steps, mild reaction conditions, lower production cost, suitable for industrial production

Method used

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  • A method for synthesizing neratinib intermediate 3-cyano-4-chloro-6-amino-7-ethoxyquinoline
  • A method for synthesizing neratinib intermediate 3-cyano-4-chloro-6-amino-7-ethoxyquinoline
  • A method for synthesizing neratinib intermediate 3-cyano-4-chloro-6-amino-7-ethoxyquinoline

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Embodiment 1

[0025] Embodiment 1 The preparation of formula (III) compound 2-(4-ethoxy-2-chloro-5-nitrobenzoyl)-3-aminoacrylonitrile

[0026] With 50mmol 3-aminoacrylonitrile, 50mmol solid base catalyst ZrO 2 -Cr 2 o 3 and 50mL tetrahydrofuran were added to the reaction flask, stirred at room temperature, and then the mixture of 55mmol 4-ethoxy-2-chloro-5-nitrobenzoic acid methyl ester and 15mL tetrahydrofuran was dropped into the above reaction flask. Stir and react for 2 hours, then reflux for 2 hours, filter the catalyst after cooling, and re-use the catalyst after drying. The solvent was evaporated under reduced pressure, 400 mL of dichloromethane was added to the residue, washed three times with 50 mL of distilled water, the organic layers were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the compound of formula (III) with a yield of 87 %.

Embodiment 2

[0027] Embodiment 2 The preparation of formula (IV) compound 3-cyano-4-oxo-6-nitro-7-ethoxy-1,4-dihydroquinoline

[0028] Add 40mmol of the compound of formula (III), 40mmol of anhydrous potassium carbonate and 40mL of DMF into the reaction flask, stir the reaction at 50-60°C for 4h, cool to room temperature, add 60mL of water, stir for 0.5h, filter the precipitated solid, and dilute the crude The solid was recrystallized from ethanol and dried under reduced pressure to obtain the compound of formula (IV) with a yield of 90%.

Embodiment 3

[0029] The preparation of embodiment 3 formula (V) compound 3-cyano-4-chloro-6-nitro-7-ethoxyquinoline

[0030] Add 40mmol of the compound of formula (IV) and 180mL of phosphorus oxychloride into the reaction flask, heat and stir to reflux for 3h. Cool the reaction bottle to about 0°C, and slowly pour 1500mL 2mol / L sodium carbonate solution into the reaction bottle at this temperature, stir for 0.5h, filter with suction, wash the filter cake with warm water, and dry under reduced pressure to obtain the formula (V ) compound with a yield of 88%.

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Abstract

A method of synthesizing a neratinib intermediate that is 3-cyano-4-chloro-6-amino-7-ethoxyquinoline is disclosed. The method includes (1) subjecting methyl 4-ethoxy-2-chloro-5-nitrobenzoate and 3-amino acrylonitrile to a condensation reaction under the action of a catalyst 1 to obtain 2-(4-ethoxy-2-chloro-5-nitrobenzoyl)-3-amino acrylonitrile; (2) subjecting the 2-(4-ethoxy-2-chloro-5-nitrobenzoyl)-3-amino acrylonitrile to a cyclization reaction to obtain 3-cyano-4-oxo-6-nitro-7-ethoxy-1,4-dihydroquinoline; (3) subjecting the 3-cyano-4-oxo-6-nitro-7-ethoxy-1,4-dihydroquinoline and phosphorus oxychloride to a chlorination reaction to obtain 3-cyano-4-chloro-6-nitro-7-ethoxyquinoline; and (4) subjecting the 3-cyano-4-chloro-6-nitro-7-ethoxyquinoline and hydrazine hydrate to a reduction reaction under the action of a catalyst 2 to obtain a target product. According to the method, synthetic steps are few, reaction conditions are mild, agents are cheap and easily available, operation is simple and the total yield is high. The method provides a novel route for preparation of neratinib and the intermediate.

Description

technical field [0001] The invention belongs to the technical field of organic preparation, and in particular relates to a method for synthesizing neratinib intermediate 3-cyano-4-chloro-6-amino-7-ethoxyquinoline. Background technique [0002] Neratinib (formula A), chemical name (E)-N-{4-[3-chloro-4-(2-pyridylmethoxy)anilino]-3-cyano-7-ethoxy -6-quinoline}-4-dimethylamino-2-butenamide, jointly developed by Wyeth Company of the United States and Puma Biotechnology Company, is an irreversible pan-ErbB1 and ErbB2 receptor tyrosine kinase inhibitor , can selectively inhibit the activity of ErbB1 and ErbB2 tyrosine kinases, and has good efficacy and tolerance for HER-2-positive advanced breast cancer patients who have been or have not been treated with trastuzumab. In July 2016, PUMA Biotechnology Company announced the results of the fifth year of phase III clinical trials. Its metastatic recurrence rate for early HER-2 positive breast cancer was 90.4%, which was 26% lower than...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 程青芳张浩王启发徐鑫
Owner 山东金吉利新材料有限公司
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