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Preparation methods of lenvatinib mesylate drug impurities

A technology of lenvatinib mesylate and a compound, which is applied in the field of drug synthesis and can solve problems such as no report on process impurities

Inactive Publication Date: 2017-10-20
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route is a synthetic route with industrial production value, and there is no report about the process impurities of this production route

Method used

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  • Preparation methods of lenvatinib mesylate drug impurities
  • Preparation methods of lenvatinib mesylate drug impurities
  • Preparation methods of lenvatinib mesylate drug impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Synthesis of impurity A

[0035] Impurity A, 4,4'-(((Carbonylbis(ureadiyl))bis(3-chloro-4,1-phenyl))bis(oxy))bis(7-methoxyquinoline-6 -Formamide) synthesis

[0036] Add 20ml of N-methylpyrrolidone to a 100ml three-necked flask, add 1.00g LVTN-1, 0.92g pyridine, nitrogen protection, and cool to 0~10°C under stirring. Start adding 1.46g phenyl chloroformate dropwise. , Continue to stir for 20-30 minutes, increase the temperature to 60°C, and stir overnight; take a sample of TLC to detect (methanol:dichloromethane=1:10) that the raw material disappears. Add 20ml of water, a large amount of solids will precipitate out, continue stirring for 30 minutes. Filter, drain, and blast dry at 40°C for 30 minutes to obtain a crude solid product. The crude product is purified by column chromatography. The elution ratio is: methanol:dichloromethane=1:50. Collect the eluate in a total of 160mL, and control the temperature. 30~40℃, vacuum degree: -0.08MPa, vacuum distillation, e...

Embodiment 2

[0044] Example 2: Synthesis of impurity B

[0045] Impurity B, the synthesis of 4-(3-chloro-4-(3,3-dimethylureido)phenoxy)-7-methoxyquinoline-6-carboxylic acid amide.

[0046] To a 50ml three-necked flask were added 463.87mg of levatinib mesylate intermediate LVTN-2 and 9mL of N-methylpyrrolidone. The reaction temperature was controlled at 0-10°C, 99.18 mg dimethylamine was added to the reaction system, and stirring was continued for 30 minutes, monitored by TLC (dichloromethane:methanol=10:1), and the reaction was completed. 18 mL of 80% acetone / water (V / V) mixed solvent was added to the reaction system, and a large amount of solids were precipitated. After stirring for 30 minutes, it was filtered and air-dried at 60° C. to obtain crude impurity B. The crude product was purified by column chromatography. The developing solvent and the ratio were: methanol:dichloromethane=1:20 (V / V), and a total of 150 mL of eluent was collected. The temperature was controlled at 30-40°C, and the ...

Embodiment 3

[0047] Example 3: Synthesis of impurity C

[0048] Impurity C, the synthesis of 4-ethoxy-7-methoxyquinoline-6-carboxamide

[0049] Add 2.00 g of lenvatinib mesylate and 50 mL of ethanol to a 100 ml three-necked flask. Stir under reflux for 72 hours, monitored by TLC (methanol:dichloromethane=1:10, new spots are generated). The solvent was evaporated under reduced pressure, and the crude product obtained was purified by column chromatography. The elution ratio was: methanol:dichloromethane=1:20, and a total of 60 mL of eluate was collected. The temperature was controlled at 30-40°C, and the vacuum degree: -0.08MPa Under reduced pressure distillation, the solvent was distilled off until no distillate was evaporated to obtain 122 mg of pale pink solid, yield: 6.10%, namely impurity C: 4-ethoxy-7-methoxyquinoline-6-carboxamide.

[0050]

[0051] Impurity C

[0052] The structure confirmation of impurity C is shown in the following table:

[0053] Table 2 Impurity C 1 H-NMR and 13 C-NMR t...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and relates to impurities in a raw medical material production process and preparation methods of the impurities, in particular to preparation methods of process impurities A, B and C of lenvatinib mesylate, namely, 4-[3-chloro-4-(N'-cyclopropylureido) phenoxy]-7-methoxyquinoline-6-carboxamide mesylate), as a drug for treating radioiodine-refractory thyroid cancer and an application of the impurities to quality research of lenvatinib mesylate. With adoption of the methods, the process impurities A, B and C are obtained through chemical synthesis for the first time, and the target compounds shown in the description can be obtained through efficient and rapid separation.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and relates to process impurities in the production process of the raw material drug levatinib mesylate and its preparation. In particular, it relates to process impurities of lenvatinib mesylate and a preparation method thereof. Background technique [0002] Lenvatinib was developed and developed by Eisai, and there is no standard Chinese translation of its name. Therefore, the applicant hereby transliterates it as "Levatinib". The drug was approved by the US FDA in February 2015 for the treatment of patients with locally recurring or metastatic, progressive, and radioiodine refractory differentiated thyroid cancer. The trade name is LENVIMA. In March 2015, levatinib mesylate was approved for marketing by the Ministry of Health and Welfare of Japan, becoming the first molecular targeted therapy for the treatment of unresectable thyroid cancer (including differentiated thyroid cancer, medullary thyroid ...

Claims

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Application Information

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IPC IPC(8): C07D215/48G01N30/04G01N30/06
CPCC07D215/48G01N30/04G01N30/06G01N2030/042G01N2030/067
Inventor 贾慧娟陈岩张帆何学敏
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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