A kind of preparation method of neratinib impurity d

A neratinib and impurity technology, which is applied in the field of neratinib impurities, can solve the problems of low yield of target product, many reaction by-products, and the need for column separation of products, so as to achieve high yield of final product and high yield of by-products. The effect of less and simple preparation method

Active Publication Date: 2021-05-28
CHONGQING MEDICAL UNIVERSITY
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

WO2009052264A discloses neratinib impurity D, and the master's thesis published in 2015, "Synthetic Method of Impurity of Antineoplastic Drug Neratinib and Research on New Synthesis Process of Choleretic Drug Cholerecin", records that Neratinib and two Methylamine undergoes Michael addition reaction to prepare neratinib impurity D, but there are many by-products in the reaction, and the product needs to be separated by column, and the yield of the target product after separation and purification is low

Method used

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  • A kind of preparation method of neratinib impurity d
  • A kind of preparation method of neratinib impurity d
  • A kind of preparation method of neratinib impurity d

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Preparation of compound 5

[0025]

[0026] Add 3.3g (20mmol) of N,N-dimethylaminotrans-croton hydrochloride into a 250mL dry three-necked flask, add 50mL of anhydrous THF, 0.2mL of anhydrous DMF, and cool down to about 0°C in a low-temperature cooling tank , Measure 1.66 mL (20 mmol) of oxalyl chloride with a syringe, dilute it with 15 mL of anhydrous THF and slowly add it dropwise to the system. The addition is completed in 10 minutes, and the reaction is carried out at room temperature for 3 hours to obtain compound 4. Cool down to 0°C, add 2.5g (10mmol) of compound 2 in 50mL of N-methylpyrrolidone (NMP) solution dropwise, drop it over 20min, move to room temperature for reaction, monitor the reaction progress by TLC, and end the reaction after 4h. Add 1M potassium carbonate solution to adjust the pH to about 11, filter under reduced pressure, wash the filter cake with water, and then recrystallize and dry the filter cake with THF / water to obtain 2.76 g of solid (...

Embodiment 2

[0028] Preparation of compound 6

[0029]

[0030] Put 2.76 g of the above-mentioned product (compound 5) into the reaction kettle, add 20 mL (2mol / L, 20 mmol) dimethylamine tetrahydrofuran solution, 40 mL THF, seal the reaction in an oil bath at 100 ° C for 8 hours, and add additional dimethylamine tetrahydrofuran solution 10mL (2mol / L, 20mmol), continued to react for 8h, the raw material reaction was completed, the reaction was terminated, the solvent was concentrated under reduced pressure to remove the crude product, and then recrystallized and dried with THF / water to obtain 2.2g of solid (compound 6), the yield was 71%. ESI-MS(m / z):404[M+H] + .

Embodiment 3

[0032] Preparation of neratinib impurity D

[0033]

[0034] Add 1.17g (5mmol) of compound 1 and 2g (5mmol) of compound 6 into a dry 100mL reaction flask, add 50mL of acetonitrile, 0.15g (0.5mmol) of zinc nitrate, heat up to the reflux reaction of the system under mechanical stirring, and a large amount of A yellow solid was formed, and TLC detected (PE / EA=1 / 4) that the reaction of the raw material was basically complete, and the reaction was terminated. The temperature of the system was lowered to room temperature, filtered, and the filter cake was washed with acetonitrile and ethanol respectively, and the filter cake was added to 40 mL of potassium carbonate solution with a concentration of 1M. After stirring, it was suction-filtered under reduced pressure, and the filter cake was washed with 50 mL of water several times. The filter cake was recrystallized and dried with acetonitrile / THF to obtain 2.7 yellow solids (neratinib impurity D), with an HPLC purity of 99.4% and ...

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Abstract

The invention provides a preparation method of neratinib impurity D, which uses N,N-dimethylaminotrans-crotonic acid as a raw material, and obtains the target product neratinib impurity D through 4-step reaction. The present invention uses zinc nitrate as a specific catalyst and acetonitrile as a solvent to prepare neratinib impurity D at a temperature of 60-85°C, and the yield can reach more than 48%, and the product can be realized without column treatment. The purity of more than 99.0% also solves the problems of ‑CN hydrolysis in the quinoline ring and side chain amide hydrolysis during the reaction process, ensuring the quality of the final product.

Description

technical field [0001] The present invention relates to neratinib impurity, in particular to a preparation method of neratinib impurity D. Background technique [0002] In the process of drug research, the safety of drugs is an important basis for evaluating the quality of drugs. Because impurities may be potentially toxic to the human body, impurity research is an important part of drug research, and it is of great significance to accurately identify trace impurities. According to the requirements of ICH (International Council for Harmonization of Registration Technology for Human Drugs), unknown impurities with a content greater than 0.10% should undergo structural identification to confirm their structure; unknown impurities with a content greater than 0.15% should undergo impurity confirmation, that is, it is required for this type of impurity Conduct safety studies, including genotoxicity studies, routine toxicity studies and other specific toxicity endpoint studies. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李雁武袁建勇
Owner CHONGQING MEDICAL UNIVERSITY
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