Preparation method of neratinib

Abstract

The invention relates to a preparation method of neratinib. The preparation method specifically comprises the steps: (1) in an organic solvent 1, trans-4-dimethylaminocrotonic acid hydrochloride and achloride agent react, and thus a solution containing (e)-4-(dimethylamino)but-2-enoyl chloride (hydrochloride) is obtained; (2) a solution of an organic solvent 2 containing 6-amino-4-[[3-chloro-4-[(pyridine-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline is added into the solution obtained in the step (1) to react, and then neratinib hydrochloride is obtained; and (3) the neratinib hydrochloride obtained in the step (2) is mixed with water and an organic solvent 3, a reaction is carried out after the pH value is regulated to be 7-10, and then the neratinib is obtained. The synthesis method has the advantages that the yield is high, the product purity is high, the production cost is low, operation is safe, easy and convenient, and large-scale industrial production is easy.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and drug synthesis, and in particular relates to a preparation method of neratinib. Background technique [0002] Neratinib was developed by Wyeth Pharmaceutical Company of the United States, and in July 2009, a global phase III clinical trial of breast cancer was launched in patients who had previously received trastuzumab-based treatment. In October 2011, Wyeth Pharmaceutical Company licensed Puma Biomedical Company of the United States to develop neratinib, and then Puma started the research on neratinib in the third-line treatment of recurrent and metastatic breast cancer. In April 2014, it announced the development of neratinib. Positive data from a Phase II clinical study of Neratinib showed that Neratinib was superior to Roche Herceptin in the treatment of HER-2 positive breast cancer; on July 23, 2014, Puma announced the experimental anti- Positive top-line data from the phase III clini...

AI Technical Summary

Problems solved by technology

[0007] The route is chlorinated with trans-4-dimethylamino croton hydrochloride and oxalyl chloride, and then reacted with 6-amino-4-[[3-chloro-4-[(pyridin-2-yl) Condensation reaction of methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline to obtain neratinib, the disadvantage is trans-4-dimethylaminocroton hydrochloride The dosage is too large, up to 2.3-2.5eq; and the unconverted 6-amino-4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano Base-7-ethoxyquinoline (referred to as aminoquinoline) is about 2.98%, and 6-amino-4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl] Amino]-3-cyano-7-ethoxyquinoline has similar physical and chemical properties to neratinib, and requires multiple recrystallizations to obtain a product suitable for pharmaceutical use

[0010] This route uses methyl 3-amino-4-ethoxybenzoate as a raw material to prepare Neratinib through reactions such as condensation, nitration, reduction, cyclization, bromination, alkylation, chlorination, and coupling. The difference is that the reaction steps are lengthy and the total yield is lower than 10%, which is unfavorable for industrialized production

[0019] This route also adjusts the order of the reactive groups, and then reduces and condenses after substitution with a nitro intermediate. Due to the use of the reduction reaction in this route, the production cost is relatively high

[0020] The existing preparation method has complicated operation, long reaction cycle, low yield and high cost, which is not conducive to industrial production

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