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Preparation method of impurities in synthesis of cabozantinib malate

A technology for cabozantinib malate and impurities is applied in the field of preparation of impurities in the synthesis of cabozantinib malate to achieve the effect of high impurity purity

Inactive Publication Date: 2019-11-08
新乡双鹭药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] For the above-mentioned impurity, there is no defect in the synthesis method reported in the literature at present, and the object of the present invention is to provide a kind of preparation method of cabozantinib malate impurity

Method used

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  • Preparation method of impurities in synthesis of cabozantinib malate
  • Preparation method of impurities in synthesis of cabozantinib malate
  • Preparation method of impurities in synthesis of cabozantinib malate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The impurity evolution process of cabozantinib malate:

[0074] KB-2-A impurities: impurities introduced in step (2) nucleophilic substitution reaction.

[0075] In this step reaction, KB-1 and p-fluoroaniline release a nucleophilic substitution reaction under alkaline conditions. When they are different bases or different solvents, two products KB-2 and KB-2-A will be generated. , see the following reaction:

[0076]

[0077] The control method of this impurity is as follows: can control the generation of KB-2-A by controlling reaction conditions, under this reaction conditions (potassium tert-butoxide / dimethyl subalkali), the generation amount of this byproduct is very little, after passing through Disposal can be removed.

[0078] During the establishment of the analytical method and quality control of intermediate KB-2, the existence of impurity KB-2-A was considered. The level of this impurity can be controlled by available analytical methods. Since the impu...

Embodiment 2

[0091] The preparation method of said KB-2-A comprises the steps of:

[0092] Step a, add KB-1, KBTN-SM-2, and isopropanol to reaction vessel A in sequence, heat to reflux for 5 hours, lower to room temperature, and stir for 14 hours;

[0093] Step b, suction filtration, 80ml of isopropanol rinses the filter cake;

[0094] Step c, add 180ml of diethyl ether to reaction vessel B, filter cake, stir at room temperature for 1 hour, filter with suction, and blow dry at 45°C for 2.5 hours to obtain a yellow solid which is KB-2-A impurity.

[0095] In this example, 13 g of yellow solid was obtained, the product purity was 97%, and the yield was 49.0%.

Embodiment 3

[0097] The preparation method of said KB-2-A comprises the steps of:

[0098] Step a, add KB-1, KBTN-SM-2, and isopropanol to reaction vessel A in sequence, heat and reflux for 5-7 hours, lower to room temperature, and stir for 14-18 hours;

[0099] Step b, suction filtration, 80-120ml of isopropanol rinses the filter cake;

[0100] Step c, add 180-220ml ether to reaction vessel B, filter the cake, stir at room temperature for 1-3 hours, filter with suction, and air-dry at 45-55°C for 1.5-2.5 hours to obtain a yellow solid which is KB-2-A Impurities (KB-2-A4-[(6,7-Dimethoxy-4-quinolyl)amino]phenol CAS: 748707-58-6 Molecular weight: 296.32); KB-1, KBTN-SM-2 and The feeding ratio of isopropanol is 20g: 12g: 200ml.

[0101] In this example, 12 g of yellow solid was obtained, the product purity was 96%, and the yield was 45.2%.

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Abstract

Belonging to the field of chemical pharmacy, the invention discloses a preparation method of impurities in synthesis of cabozantinib malate. The impurities include KB-2-A, KB-A and SM-3-B. The invention also provides a preparation method of impurity KB-2-A, a preparation method of impurity KB-A, and a preparation method of impurity SM-3-B. The impurity SM-3-B in the starting material, the impurities KB-2-A and KB-A in intermediate products are prepared to control the quality of cabozantinib malate and control the impurities in the preparation process of cabozantinib malate. The prepared impurities have high purity, and can be used as reference substances to contrast the intermediates and starting material of cabozantinib malate and perform qualitative and quantitative analysis on the intermediates and starting material of cabozantinib malate.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a method for preparing impurities in the synthesis of cabozantinib malate. Background technique [0002] Cabozantinib is a new molecular targeted drug developed by Exelixis Biopharmaceutical Company of the United States. On November 29, 2012, the US Food and Drug Administration (FDA) approved cabozantinib for the treatment of unresectable malignant locally advanced or metastatic medullary thyroid carcinoma. The main target: C-met, VEGFR, also effective Acts on Ret, Kit, FLT1, FLT3, FLT4, Tie2 and AXL, weakly inhibits RON and PDGFR-β. In vitro biochemical and (or) cytological analysis showed that cabozantinib inhibited RET, hepatocyte growth factor receptor (human hepatocyte growth factor receptor, MET), vascular endothelial growth factor receptor 1 (Vascular endothelial growth factor receptor 1, VEGFR- 1), VEGFR-2, VEGFR-3, stem cell factor receptor (stemc...

Claims

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Application Information

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IPC IPC(8): C07D215/44C07D215/22C07C231/02C07C235/82
CPCC07D215/44C07D215/22C07C231/02
Inventor 郭本泉李璞葛永彪
Owner 新乡双鹭药业有限公司
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