A kind of method of synthesizing neratinib intermediate

A technology of neratinib and its synthetic method, which is applied in the field of preparation of raw material drug intermediates, and can solve problems such as unsuitability for industrial production, increased processing costs, and large raw material costs

Active Publication Date: 2022-04-12
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It not only consumes a lot of raw material costs, but also produces a lot of waste solids and wastewater containing heavy metal chromium, which increases the treatment cost
Moreover, there are few suppliers of raw material aminoacrylonitrile, and the source is inconvenient, so it is not suitable for industrialized production.

Method used

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  • A kind of method of synthesizing neratinib intermediate
  • A kind of method of synthesizing neratinib intermediate
  • A kind of method of synthesizing neratinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Preparation of 2-bromo-4-ethoxy-5-nitrobenzoic acid (Formula II, X=Br)

[0031]

[0032] Add 2-bromo-4-fluoro-5-nitrobenzoic acid (10g, 37.9mmol, 1eq) and ethanol (20g) into a 250mL reaction flask, stir to dissolve, and cool down to 0-10°C in an ice bath. Sodium ethoxide (5.7g, 83.3mmol, 2.2eq) was dissolved in ethanol (40g), and added dropwise to the reaction solution under ice cooling, and the temperature was controlled at 0-10°C. After the dropwise addition, the reaction solution was raised to 60° C. and stirred for about 5 h. After the reaction was completed, the system was concentrated under reduced pressure to remove the solvent and cooled to room temperature. Add purified water (150g) to the concentrate, stir and dissolve, adjust the pH to 2-3 with hydrochloric acid, filter, and obtain the compound of formula II (X=Br, 10.59g, 96.4%) after drying in a solid oven at 60°C. for the next reaction.

Embodiment 2

[0033] Example 2: Preparation of 2-(2-bromo-4-ethoxy-5-nitrobenzoyl)-3-(dimethylamino)acrylonitrile (formula III, X=Br)

[0034]

[0035] Add 2-bromo-4-ethoxyl-5-nitrobenzoic acid (5g, 17.2mmol, 1eq), dichloromethane (25g) and catalytic amount of DMF in the 100mL reaction flask, add dropwise in the reaction solution under ice bath Oxalyl chloride (3.50g, 27.6mmol, 1.6eq), temperature controlled 0-10°C. After the dropwise addition, the temperature of the reaction solution was raised to 30° C. and stirred for about 1 h. After the reaction was completed, the system was concentrated under reduced pressure to remove the solvent, and dichloromethane (2×15 mL) was added twice under reduced pressure to remove incompletely reacted oxalyl chloride. The concentrate was dissolved by adding toluene (25g) and then used. Add 3-dimethylaminoacrylonitrile (1.74g, 18.1mmol, 1.05eq), triethylamine (2.09g, 20.7mmol, 1.2eq), DMAP (0.42g, 3.4mmol, 0.2eq) and toluene in 100mL reaction flask (2...

Embodiment 3

[0036] Example 3: Preparation of 3-amino-2-(2-bromo-4-ethoxy-5-nitrobenzoyl)acrylonitrile (formula IV, X=Br)

[0037]

[0038] The reaction solution prepared in Example 3 was added to a 100 mL reaction flask, 24% ammonia water (3.02 g, 20.7 mmol, 1.2 eq) was added, and stirred at 25° C. for about 1 h. After the reaction was completed, the reaction solution was washed with purified water and separated. After the organic phase was concentrated under reduced pressure to remove the solvent, the compound of formula IV (X=Br, 4.25 g, 72.6%) was obtained.

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Abstract

The present invention is to provide a new route for preparing neratinib key intermediate 3-cyano-4-oxo-6-nitro-7-ethoxyl-1,4-dihydroquinoline, which uses 2 ‑Halo‑4‑fluoro‑5‑nitrobenzoic acid is used as the starting material, and the synthesis of the target intermediate is conveniently achieved through 4 steps of reaction.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of raw material drug intermediates, in particular to the preparation of neratinib intermediate 3-cyano-4-oxo-6-nitro-7-ethoxy-1,4-dihydroquinoline preparation. Background technique [0002] Neratinib is an oral, irreversible pan-human epidermal growth factor receptor (EGFR) inhibitor that inhibits HER1, HER2, and HER4 receptors and associated tyrosine kinases. It is used for adjuvant treatment of adult breast cancer patients with early HER2 overexpression and amplification, and plays an anti-cancer role by preventing the transduction of HER1, HER2 and HER4 signaling pathways. The FDA approved it as an intensive adjuvant therapy for breast cancer patients who have completed trastuzumab for injection, whose disease has not improved and who still have high-risk factors. It can prolong the disease progression-free survival of patients with HER2+ breast cancer and reduce the risk of cance...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/56
CPCC07D215/56
Inventor 许志伟胡林邹平吴伟左昂禾邱小龙左智伟刘文博储玲玲王平张大永
Owner WISDOM PHARM CO LTD
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