A kind of preparation method of pazopanib related substance

A compound and organic solvent technology, applied in the field of preparation of pazopanib-related substances, can solve problems such as difficult synthesis of impurities, synthesis methods of unreported impurities, etc., and achieve high purity and high synthesis yield

Active Publication Date: 2022-03-08
NANJING CHIA TAI TIANQING PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the research paper (J.Pharm.Biomed.Anal., 2010,52,493-507) published by GlaxoSmithKline, it was reported that there is a key impurity (compound shown in the following formula VII) in Pazopanib hydrochloride API, but it was not reported Synthesis method of the impurity
The synthesis of this impurity is very difficult, and the complete synthesis method has not been reported in literature or patents. In order to ensure the smooth progress of drug quality research, this impurity needs to be synthesized

Method used

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  • A kind of preparation method of pazopanib related substance
  • A kind of preparation method of pazopanib related substance
  • A kind of preparation method of pazopanib related substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Compound III(X 1 for the preparation of bromine):

[0063]

[0064] Under the protection of nitrogen, cool 23.8ml of isopropylmagnesium chloride-lithium chloride (1.3M / tetrahydrofuran solution) to -20°C ~ 0°C, add 8.4g of compound I, keep the reaction for 2 hours, dissolve 5.6g of compound II in 10ml of tetrahydrofuran Add it dropwise to the above system, stir and react at -20°C to 0°C for 3 hours, warm up to room temperature, add 100ml of saturated ammonium chloride aqueous solution, 100ml of ethyl acetate, stir and stand for liquid separation, and wash the organic phase with saturated brine Evaporate under reduced pressure to obtain a light yellow solid, add 100ml of petroleum ether, beat at room temperature for 2 hours, then filter, and dry the filter cake under reduced pressure to obtain 9.7g of off-white solid, namely compound III. Yield 92.6%, 1 H-NMR (400M, DMSO-d6) δ: 2.16(s, 6H), 5.89~5.90(d, J=4.0Hz, 1H), 5.93~5.95(d, J=8.0Hz, 1H), 7.15~7.17 (d, J=8.0Hz,...

Embodiment 2

[0080] Compound III(X 1 for the preparation of bromine):

[0081] Under the protection of nitrogen, cool 11.6ml of butyl lithium (1.6M / n-hexane solution) to -80°C ~ -60°C, dissolve 5.0g of compound I in 10ml of tetrahydrofuran, drop it into the above system, and keep it warm for 2 hours. 3.4 g of compound II was dissolved in 10 ml of tetrahydrofuran, added dropwise to the above system, kept stirring for 3 hours, heated to -20°C to 0°C for 2 hours, then warmed up to room temperature, added 100 ml of saturated ammonium chloride aqueous solution, ethyl acetate 100ml, stirred and left to separate liquids, the organic phase was washed with saturated brine, and then evaporated to dryness under reduced pressure to obtain a light yellow solid. Compound III. The yield is 94.8%.

[0082] Compound IV(X 1 for the preparation of bromine, hydrochloride):

[0083] 5.0 g of compound III and 2.5 g of aniline were mixed, and the temperature was raised to 100°C. Dissolve 1.8g of zinc chlor...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of related substances of pazopanib. Using the compound shown in formula I as a raw material, reacting with the compound of formula II to prepare the compound shown in formula III, and then reacting with aniline to prepare the compound shown in formula IV or its acid addition salt, the compound shown in formula IV and benzophenone imine reaction, and then react with the compound shown in formula VIII to prepare the compound shown in formula V, and then prepare the compound shown in formula VII, the related substance of pazopanib, through nitro reduction and condensation reaction.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of related substances of pazopanib. Background technique [0002] Pazopanib hydrochloride, the chemical name is 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]pyrimidin-2-yl]amino]-2-methyl Benzenesulfonamide monohydrochloride is a vascular endothelial growth factor receptor (VEGFR) inhibitor. It inhibits tumors by inhibiting neovascularization that supplies blood to tumors, and is suitable for the first-line treatment of patients with advanced renal cell carcinoma and the treatment of patients with advanced renal cell carcinoma who have previously received cytokine therapy. Researched and developed by GlaxoSmithKline, it was launched in the United States, the European Union, Japan and China in October 2009, June 2010, September 2012 and February 2017. The trade name is Votrient. [0003] The synthesis and control of impurities is very important through...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 赵明礼舒伟王喆方从坤章建明王峰峰柴雨柱徐丹
Owner NANJING CHIA TAI TIANQING PHARMA
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