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Preparation method and intermediate of Pazopanib

A system and compound technology, applied in the field of medicine and chemical industry, can solve the problems of harsh reaction conditions, high industrialization cost, complicated purification operation, etc., achieve the effect of mild reaction conditions, reduce the generation of by-products, and simplify the purification operation

Active Publication Date: 2018-02-23
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this synthetic method, there are the following problems: 1) the compound of formula I and the compound of formula II need higher temperature when preparing the compound of formula III, the impurities generated are more, and the yield is low; 2) the highly toxic substance methyl iodide is used or dimethyl sulfate; 3) the reaction conditions of the IV compound and the formula V compound are harsh, the by-products are more, the purification operation is complicated, and the industrialization cost is high

Method used

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  • Preparation method and intermediate of Pazopanib
  • Preparation method and intermediate of Pazopanib
  • Preparation method and intermediate of Pazopanib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the synthesis of formula 2 compound

[0037]

[0038] The compound of formula 7, triphenylphosphine, dichloromethane and dichlorodicyanobenzoquinone are added to the reaction flask, and methanol is added dropwise to the reaction solution. After the reaction is completed, an aqueous solution of sodium thiosulfate is added, and the layers are separated and organic The phase was washed with saturated brine, then methanol was added, the temperature was lowered to 0°C, and after stirring for 1-2 hours, the precipitated solid was the compound of formula 2 with a yield of 94%. 1H NMR (300MHz, d 6 DMSO) δ=8.53(s,1H),7.87(d,J=9.1Hz,1H),7.70(d,J=8.9,1H),4.26(s,3H),3.73(s,3H),2.61( s, 3H); MS (m / z) [M+H]+calcd for C10H14N3 176.1, found 176.3; white solid.

Embodiment 2

[0039] Embodiment 2: the synthesis of formula 3 compound

[0040]

[0041] Add 5.0 g of 2,4-dichloro-5-nitropyrimidine, compound of formula 2 (0.95 eq), diisopropylethylamine and 100 mL of toluene into the reaction flask at room temperature, heat, and react 4- 6 hours, controlled by TLC, after the reaction was completed, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, cooled to 0-5°C, added methyl tert-butyl ether under stirring, there was Solids were precipitated, and the stirring was continued at this temperature for 30 minutes, filtered, and dried to obtain the compound of formula 3 with a yield of 92%. 1H NMR (300MHz, d 6 DMSO) δ=10.2(s,1H),7.32(d,J=9.0Hz,1H),6.36(d,J=8.8,1H),6.29(s,1H),3.76(s,3H),3.57( s,3H), 2.39(s,3H); MS (m / z) [M+H]+calcd for C14H14ClN6O2 333.1, found 333.3.

Embodiment 3

[0042] Embodiment 3: the synthesis of formula 5 compounds

[0043]

[0044] Add the compound of formula 3, the compound of formula 4, diisopropylethylamine and 100mL of methanol into the reaction flask at room temperature, heat up to 60°C, and react at this temperature for 4-8 hours, control in TLC, after the reaction is completed , concentrated under reduced pressure, washed with saturated brine, dried with anhydrous sodium sulfate, cooled to 0-5 °C, added methyl tert-butyl ether under stirring, solids were precipitated, and continued to stir at this temperature for 30 minutes, filtered and dried to obtain compound 5 with a yield of 87%. 1H NMR (300MHz, d 6 DMSO)δ=10.1(s,1H),7.81(d,J=6.2Hz,1H),7.67-7.71(m,2H),7.36(s,1H),7.32-7.26(m,2H),6.36( d,J=8.8,1H),6.29(s,1H),4.07(s,3H),3.76(s,3H),3.57(s,3H),2.39(s,3H);[M+H]+ calcd for C21H23N8O4S, 483.1, found 483.3.

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Abstract

The invention discloses a preparation method and an intermediate of Pazopanib. The preparation method comprises the steps of carrying out two-step condensation reaction on 2,4-dichloro-5-nitropyrimidine so as to obtain a compound of a formula 5 (shown in the description), and carrying out reduction on the compound of the formula 5, so as to obtain Pazopanib. The preparation method has the beneficial effects that the yield of Pazopanib is increased, reaction conditions are mild, column chromatography purification is not required, and the preparation method is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of pazopanib and an intermediate thereof. Background technique [0002] Pazopanib (Pazopanib) is a new oral angiogenesis inhibitor developed by GlaxoSmithKline that can interfere with the formation of new blood vessels required for the survival and growth of stubborn tumors, targeting the vascular endothelial growth factor receptor ( VEGFR), which acts by inhibiting the formation of new blood vessels to the tumor blood supply. In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-receptors, and in vivo, pazopanib inhibited VEGF-induced phosphorylation of VEGFR-2 in mouse lung, Angiogenesis in a mouse model, and xenograft growth of several human tumors in mice. It is indicated for the treatment of advanced renal cell carcinoma (a type of kidney cancer in which cancer cells are found in the kidney...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D231/56
CPCC07D231/56C07D403/12
Inventor 刘海东吉民宗玺王冬冬杨苏万广朋于文渊胡海燕张影
Owner 苏州东南药业股份有限公司
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