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A kind of synthetic method of pazopanib hydrochloride crude drug trimer impurity

A technology for the synthesis of pazopanib hydrochloride and its synthesis method, which is applied in the field of synthesis of trimer impurities of pazopanib hydrochloride raw material drug, which can solve the problems of low drug impurity content, small amount of impurities, and difficulty in large-scale production, and achieve an improvement Quality standard, high yield effect

Active Publication Date: 2020-11-10
博泽格霖(山东)药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low content of the drug impurity itself, it is difficult to extract and synthesize, and there are great difficulties in separation and structure identification
In addition, the amount of impurities is small, it is not easy to produce on a large scale, and the benefits generated are small, so a lot of manpower and material resources are needed for research and development
[0006] Pazopanib hydrochloride trimer impurity is an important related substance in the raw material of pazopanib hydrochloride. At present, there is no synthesis method for this impurity. In order to ensure the comparison of subsequent substances, it is necessary to study a reasonable method to prepare this impurity. The standard product of impurities, and the successful synthesis of the impurities can also play a great role in improving the quality of pazopanib hydrochloride raw materials

Method used

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  • A kind of synthetic method of pazopanib hydrochloride crude drug trimer impurity
  • A kind of synthetic method of pazopanib hydrochloride crude drug trimer impurity
  • A kind of synthetic method of pazopanib hydrochloride crude drug trimer impurity

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preparation example Construction

[0023] The present invention provides a kind of synthetic method of pazopanib hydrochloride crude drug trimer impurity, the structural formula of described pazopanib hydrochloride crude drug trimer impurity is following formula (V):

[0024]

[0025] figure 1 A synthetic flow diagram according to an embodiment of the invention is shown. Such as figure 1 Shown, the synthetic method of described pazopanib hydrochloride crude drug trimer impurity formula (V) comprises:

[0026] Step 1: take compound I, make it condense with 2-methyl-5-nitrobenzenesulfonyl chloride to obtain compound II;

[0027] Specifically, the solvent for the condensation reaction includes one or more of acetone, tetrahydrofuran, and dioxane. Preferably, the solvent for the condensation reaction is tetrahydrofuran, and the acid-binding agent for the condensation reaction includes triethylamine, One or more of pyridine, sodium hydroxide, potassium hydroxide and potassium carbonate, preferably, the acid-bi...

Embodiment example 1

[0036] Embodiment case one, the synthetic method of compound II is:

[0037] Take a 100mL two-necked reaction flask, add 4.05g of compound I, 40ml of tetrahydrofuran and 5mL of pyridine respectively, and add 2-methyl-5-nitrobenzenesulfonyl chloride (2.95g, 12.51mmol, 1.1eq), and then at room temperature Then, add ethyl acetate and water to the reaction solution, extract and separate the liquid, wash the organic phase obtained after the liquid separation with saturated brine, dry over anhydrous sodium sulfate, filter, and rotary evaporate to dryness ; The obtained crude product was purified by silica gel column to obtain 3.85g yellow solid; yield: 61%.

[0038] The above reaction formula is:

[0039]

Embodiment example 2

[0040] Embodiment two, the synthetic method of compound III is:

[0041] Take a 100mL two-necked reaction flask, under nitrogen protection, add 3.85g of compound II, 50ml of tetrahydrofuran, 0.1g of triphenylphosphine palladium, 2.50g of potassium carbonate and an appropriate amount of tert-butyl carbamate, and heat up to 70°C After the reaction, the solvent was removed by rotary evaporation, and then ethyl acetate and water were added for extraction and liquid separation. After the liquid separation, the organic phase obtained was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness. The obtained crude product was purified by silica gel column to obtain 5.07 g of yellow solid; yield: 98%.

[0042] The above reaction formula is:

[0043]

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Abstract

The invention provides a synthesis method of a trimer impurity of a pazopanib hydrochloride bulk drug. The synthesis method comprises following steps: taking a compound (I) as the raw material, carrying out condensation reactions between the compound (I) and 2-methyl-5-nitrobenzene sulfonyl chloride to obtain a compound (II); reacting the compound (II) with tert-butyl carbamate to generate a compound (III); reacting the compound (III) with hydrochloric acid to obtain a compound (IV); and finally carrying out condensation reactions between the compound (IV) and N-(2-chloropyrimidine-4-yl)-N-methyl-2,3-dimethyl-2H-indazole-6-amine to obtain the trimer impurity (V). The yield of the synthesis method is high; and the prepared impurity can be used as a reference substance in quality analysis ofpazopanib hydrochloride.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for synthesizing the trimer impurity of pazopanib hydrochloride crude drug. Background technique [0002] Pazopanib hydrochloride, the chemical name is 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)- 2-Methylbenzenesulfonamide hydrochloride, the molecular formula is C 21 h 23 N 2 o 2 S HCl, the molecular weight is 473.98, its structural formula is as follows: [0003] [0004] Pazopanib hydrochloride is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) developed by GlaxoSmithKline, UK, through selective inhibition of VEGFR-1, VEGFR-2, VEGFR-3 and ATP Competitively binds to extracellular ligand binding sites, blocks the self-sulfation of tyrosine, inhibits VEGFR activation, thereby accelerating cell apoptosis, inhibiting angiogenesis, and inhibiting tumor invasion and metastasis. Studies have found that...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14
CPCC07D403/14Y02P20/55
Inventor 孙文东张旭李久青李昊蔡保理尹鲲
Owner 博泽格霖(山东)药业有限公司
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