Preparation method of neratinib

A technology of neratinib and tinib hydrochloride, which is applied in the field of preparation of neratinib, can solve the problems of large amount of dimethylaminocroton hydrochloride, unfavorable industrial production, lengthy reaction steps, etc.

Inactive Publication Date: 2019-10-22
JIANGSU CHUANGUO PHARMA CO LTD +2
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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

Method used

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  • Preparation method of neratinib
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  • Preparation method of neratinib

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preparation example Construction

[0057] The preparation method of Neratinib of the present invention may comprise the following steps:

[0058]

[0059] (1) Dissolve trans-4-dimethylaminocrotonyl chloride hydrochloride in organic solvent 1, and then react with a chlorination reagent to obtain trans-4-dimethylaminocrotonyl chloride salt solution;

[0060] (2) Dissolve 6-amino-4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline in In the organic solvent 2, then dropwise added to the solution obtained in step (1) to react, thereby obtaining neratinib hydrochloride;

[0061] (3) Dissolving neratinib hydrochloride obtained in step (2) in water and an organic solvent 3, adjusting the pH value to 7-10, and reacting to obtain neratinib.

[0062] In the step (1), the chlorination reagent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride or combinations thereof, preferably thionyl chloride.

[0063] In the step (1), the molar ratio of the ...

Embodiment 1

[0081] The preparation of neratinib described in embodiment 1 present invention

[0082] (1) Add 10g of trans-4-dimethylaminocroton hydrochloride and 60ml of dimethyl sulfoxide to a 250ml three-neck flask, stir at room temperature, add 10.8g of thionyl chloride dropwise into a constant pressure dropping funnel, for 1h After the dropwise addition, the reaction temperature was controlled at -25 to -20°C. During the reaction, the solution gradually changed from white to light brown, monitored by HPLC, and the reaction was stopped after 2 hours, and the obtained reaction solution was used for later use;

[0083] (2) Add 18 g of 6-amino-4-[[3-chloro-4-[(pyridine-2- Base) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinoline (also known as aminoquinoline) 70ml N-methylpyrrolidone solution, 1h dropwise, the reaction temperature is controlled at -25~-20 ℃, insulation reaction 4h, HPLC detects (at this moment, the content of aminoquinoline in the reaction solution is 0.08%, and its reten...

Embodiment 2

[0085] Embodiment 2 The preparation of Neratinib according to the present invention

[0086] (1) Add 10g of trans-4-dimethylamino croton hydrochloride and 80ml of N,N-dimethylacetamide to a 250ml three-necked flask, stir at room temperature, add 10.8g of chlorine The addition of sulfoxide was completed in 1 hour, and the reaction temperature was controlled at -15 to -10°C. During the reaction, the solution gradually changed from white to light brown, monitored by HPLC, and the reaction was stopped after 2 hours, and the obtained reaction solution was used for later use;

[0087] (2) Add 18 g of 6-amino-4-[[3-chloro-4-[(pyridine-2- base) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinoline in 70ml of N-methylpyrrolidone solution, after 1h dropwise addition, the reaction temperature was controlled at -15~-10°C and kept warm After reacting for 2 hours, stop the reaction, add 10ml of methanol dropwise, filter with suction, rinse twice with 10ml of dichloromethane, and obtain nerati...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 周吴戴光福胡猛
Owner JIANGSU CHUANGUO PHARMA CO LTD
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