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A method of synthesizing a neratinib intermediate, 3-cyano-4-chloro-6-amino-7-ethoxyquinoline

A technology of ethoxyquinoline and neratinib, which is applied in the direction of organic chemistry, can solve the problems of complex operation, poor process safety, and difficult availability of raw materials, and achieve simple operation, high total yield, and cheap reagents Effect

Active Publication Date: 2017-06-30
山东金吉利新材料有限公司
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  • Summary
  • 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 of synthesizing a neratinib intermediate, 3-cyano-4-chloro-6-amino-7-ethoxyquinoline
  • A method of synthesizing a neratinib intermediate, 3-cyano-4-chloro-6-amino-7-ethoxyquinoline
  • A method of synthesizing a neratinib intermediate, 3-cyano-4-chloro-6-amino-7-ethoxyquinoline

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Example 1 Preparation of compound of formula (III) 2-(4-ethoxy-2-chloro-5-nitrobenzoyl)-3-aminoacrylonitrile

[0026] Add 50mmol 3-aminoacrylonitrile, 50mmol solid base catalyst ZrO 2 -Cr 2 O 3 Add 50mL of tetrahydrofuran and 50mL of tetrahydrofuran to the reaction flask, stir evenly at room temperature, and then drop a mixture of 55mmol of methyl 4-ethoxy-2-chloro-5-nitrobenzoate and 15mL of tetrahydrofuran into the above reaction flask. The reaction was stirred for 2 hours, and then refluxed for 2 hours. After cooling, the catalyst was filtered, and the catalyst could be reused after drying. The solvent was evaporated under reduced pressure, 400 mL of dichloromethane was added to the residue, washed with 50 mL of distilled water for three times, the organic layers were combined, dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the compound of formula (III) with a yield of 87 %.

Embodiment 2

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

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

Embodiment 3

[0029] Example 3 Preparation of compound 3-cyano-4-chloro-6-nitro-7-ethoxyquinoline of formula (V)

[0030] Add 40 mmol of the compound of formula (IV) and 180 mL of phosphorus oxychloride to the reaction flask, and heat and stir to reflux for 3 hours. Cool the reaction flask to about 0°C, and slowly pour 1500mL 2mol / L sodium carbonate solution into the reaction flask 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, the yield is 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 specifically relates to a method for synthesizing 3-cyano-4-chloro-6-amino-7-ethoxyquinoline, an intermediate of lenatinib. Background technique [0002] Lenatinib (formula A), chemical name (E)-N-{4-[3-chloro-4-(2-pyridinemethoxy)anilino]-3-cyano-7-ethoxy -6-quinoline}-4-dimethylamino-2-butenamide, jointly developed by Wyeth and Puma Biotechnology, is an irreversible pan-ErbB1 and ErbB2 receptor tyrosine kinase inhibitor It is an inhibitor that can selectively inhibit ErbB1 and ErbB2 tyrosine kinase activity, and has good efficacy and tolerability for advanced HER-2 positive breast cancer patients who have been treated with or without trastuzumab. In July 2016, PUMA Biotechnology announced the results of the fifth-year phase III clinical trial. Its non-metastatic recurrence rate for early HER-2 positive breast cancer was 90.4%, which was 26% lower than the relative risk of the placeb...

Claims

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Application Information

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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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