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Preparation method of neratinib

A technology of neratinib and preparation steps, applied in the field of neratinib preparation, can solve the problems of high temperature and long-term reflux, restricting the industrialization prospects of the process route, etc., and achieves the effects of promoting development, easy availability of raw materials, and simple process

Inactive Publication Date: 2013-08-28
SUZHOU MIRACPHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route has a classic reaction and a stable process, but the cyclization reaction requires high temperature and long-term reflux, especially the chlorination reaction requires the use of highly toxic substances such as phosphorus oxychloride that have an impact on the environment, thus limiting the industrialization prospects of this process route

Method used

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  • Preparation method of neratinib
  • Preparation method of neratinib
  • Preparation method of neratinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-amino-3-quinolinecarbonitrile (II) into the three-neck reaction flask (3.4g, 10mmol), triethylamine (1.5g, 15mmol) and methanol 25mL, warm up to 50-55°C, stir until the system is uniformly dissolved. A methanol solution of 3-chloro-4-[(pyridin-2-yl)methoxy]benzaldehyde (III) (3.0 g, 12 mmol) was slowly added dropwise to the reaction liquid, and the drop was completed in about 1 hour. Keep this temperature and continue to react for 3 hours, and TLC detects that the reaction is complete. The temperature was lowered to 0-5°C, and sodium borohydride (1.9 g, 50 mmol) was added in portions, and the addition was completed in about 1 hour. Keep the room temperature to continue the reaction for 2 hours, and TLC detects that the reaction is complete. The reaction was quenched by adding dilute hydrochloric acid. Concentrate under reduced pressure to one-third of the total volume, cool down and crystallize, and recrystallize ...

Embodiment 2

[0030] Add 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-amino-3-quinolinecarbonitrile (II) into the three-neck reaction flask (3.4g, 10mmol), triethylamine (1.5g, 15mmol) and methanol 25mL, warm up to 50-55°C, and stir until the system is uniformly dissolved. A methanol solution of 3-chloro-4-[(pyridin-2-yl)methoxy]benzaldehyde (III) (1.9 g, 12 mmol) was slowly added dropwise to the reaction liquid, and the drop was completed in about 1 hour. Keep this temperature and continue to react for 3 hours, and TLC detects that the reaction is complete. Cool down to room temperature, add 0.3 g of palladium / calcium carbonate and 3 mL of acetic acid, inject hydrogen gas under normal pressure, keep the room temperature and continue the reaction for 5 hours, and TLC detects that the reaction is complete. The catalyst was recovered by filtration. Concentrate under reduced pressure to one-third of the total volume, cool down and crystallize, and recrystallize the crude product with ab...

Embodiment 3

[0032] Under dryness and a nitrogen atmosphere, 3-ethoxy-4-[(E)-4-(dimethylamino)-2-butenamido]aniline (IIa) (2.6g, 10mmol), triethyl orthoformate (IIb) (1.63g, 11mmol) and malononitrile (IIc) (0.80g, 12mmol) and absolute ethanol 25mL, heated to reflux for 3 hours. After cooling and crystallization, the crude product was dissolved in 25 mL of N,N-dimethylformamide, then aluminum trichloride (5.32 g, 40 mmol) was added, heated to 140° C., and kept for 2 hours for reaction. After cooling, the reaction system was poured into ice water, and a solid precipitated out. Filtration, the filtrate was extracted with dichloromethane, concentrated, and the crude product was recrystallized from ethanol to obtain a white solid 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4 -Amino-3-quinolinecarbonitrile (II) 2.9g, yield 85.5%.

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Abstract

The invention discloses a preparation method of neratinib (I). The preparation method comprises the step that 6-[(E)-4-(dimethylamino)-2-butenamide]-7-ethoxy-4-amino-3-quinolinecarbonitrile (II) and 3-chloro-4-[(pyridine-2-yl)methoxy]-benzaldehyde (III) carry out condensation and reduction reactions to obtain neratinib (I). The preparation method is easy in obtainment of raw materials, concise in process, economical and environment-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of neratinib. Background technique [0002] Neratinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor developed by Wyeth Pharmaceuticals, a subsidiary of Pfizer in the United States, which can effectively inhibit the activity of ErbB1 and ErbB2 tyrosine kinases , is an anti-breast cancer drug that has been in clinical research but has not been marketed. An open clinical phase II study was used to evaluate the efficacy of neratinib + trastuzumab in patients with ErbB-2 positive progressive breast cancer, and the results showed that oral neratinib showed a good clinical effect . And for patients with ErbB-2-positive advanced breast cancer, trastuzumab can be well tolerated regardless of whether they have used trastuzumab before. The drug is currently in Phase...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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