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The preparation method of sunitinib malate

A technology of sunitinib malate and malic acid, applied in carboxylate preparation, organic chemistry, etc., can solve the problems of difficult scale-up production, large equipment damage, and affecting product quality, and achieve the goal of reducing impurities and improving purity Effect

Active Publication Date: 2019-05-28
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thionyl chloride is a strong corrosive reagent, which will cause great damage to equipment and is not easy to scale up production
The reactivity of compound 11 is low, especially in large-scale preparation, the reaction of compound 11 may be incomplete, which will affect the quality of the product

Method used

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  • The preparation method of sunitinib malate
  • The preparation method of sunitinib malate
  • The preparation method of sunitinib malate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: (Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene Preparation of base)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole malate

[0035] 2,4-Dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (200g, 1.2mol, 1eq), carbonyldiimidazole (260g, 1.6mol, 1.3eq) and tetrahydrofuran (4L) were added sequentially In a 10L reaction bottle, control the internal temperature to 35-45°C, and stir for 4 hours. Put the reaction bottle at room temperature, add 1-hydroxybenzotriazole (40g, 0.30mol, 0.25eq), and stir for 1 hour. Cool the reaction to an internal temperature of 10-15°C, slowly add N,N-diethylethylenediamine (460g, 4.0mol, 3.3eq) dropwise to the reaction liquid, control the internal temperature at 10-25°C, and stir for 13 hours . Concentrate the reaction solution to dryness under reduced pressure, add 4 L of ethyl acetate and stir to dissolve, wash four times with 1.5 L of 20% potassium carbonate solution, wash twice with 1.5 L of saturated so...

Embodiment 2

[0041] Example 2: (Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene Preparation of base)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole malate

[0042] 2,4-Dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (200g, 1.2mol, 1eq), carbonyldiimidazole (260g, 1.6mol, 1.3eq) and toluene (6L) were added sequentially In a 10L reaction bottle, control the internal temperature to 50-60°C, and stir for 3 hours. Put the reaction bottle at room temperature, add 2-hydroxypyridine (14g, 0.15mol, 0.13eq), and stir for 1 hour. Cool the reaction to an internal temperature of 10-15°C, slowly add N,N-diethylethylenediamine (460g, 4.0mol, 3.3eq) dropwise to the reaction liquid, control the internal temperature at 10-25°C, and stir for 15 hours . Then the reaction solution was washed four times with 1.5 L of 20% potassium carbonate solution, washed twice with 1.5 L of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to ...

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Abstract

The present invention relates to a sunitinib malate preparation method, wherein particularly 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid is adopted as a starting raw material, carboxyl activation with carbonyl diimidazole is performed, the obtained material and N, N-diethylethylenediamine are subjected to condensation under catalysis of 1-hydroxybenzotriazole to obtain an intermediate 1, the intermediate 1 and 5-fluoro-2-oxindole react to obtain sunitinib, and the sunitinib and malic acid are directly subjected to salifying without separation so as to obtain the target product. The method of the present invention has characteristics of easy operation, high yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of sunitinib malate. Background technique [0002] Sunitinib malate, chemical name: (Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H- Indole-3-ylidene)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole malate, CAS: 341031-54-7, structure: [0003] [0004] Sunitinib malate is a tyrosine kinase inhibitor with the potential to inhibit angiogenesis and antitumor effects. The FDA-approved indications are: 1) gastrointestinal stromal tumor (GIST) that fails or cannot be tolerated with imatinib mesylate; 2) advanced renal cell carcinoma (RCC); 3) unresectable locally advanced Progressive, well-differentiated pancreatic neuroendocrine neoplasm (pNET) in patients with metastatic disease. Developed and listed by Pfizer. [0005] At present, the preparation methods of Sunitinib and Sunitinib Malate disclosed in the literature include the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06C07C59/245C07C51/41
CPCC07D403/06
Inventor 吕爱锋赵明礼陈明余俊杨宝海
Owner JIANGSU HANSOH PHARMA CO LTD
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