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Synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine

A technology of ethynylimidazole and ponatinib, which is applied in the direction of organic chemistry, can solve the problems of great harm to the human body, unsuitable for large-scale production and use of enterprises, and achieve high product yield, simple operation steps, and cheap and easy-to-obtain raw materials Effect

Active Publication Date: 2020-04-14
SHANDONG BOYUAN PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the Heck reaction process of the above two synthetic methods, precious metal palladium catalyst and expensive reagent trimethylsilylacetylene are used, which are not suitable for large-scale production of enterprises.
Simultaneously, the synthesis of its starting material imidazo[1,2-b]pyridazine is made by using 3-pyridone and 2-chloroacetaldehyde in the traditional method, and 2-chloroacetaldehyde is a toxic substance, which is harmful to the human body. more damage

Method used

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  • Synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine
  • Synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine
  • Synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine

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Experimental program
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Embodiment 1

[0035] 1) Put 936g of 3-pyridanone and 900g of chloroform in a 2L reaction flask, add 122g of 2-chloroethylamine hydrochloride, 222g of triethylamine, add 10g of anhydrous sodium sulfate, and stir for 1 hour at 20-25°C Afterwards, the temperature was raised to 60°C for reflux reaction for 4 hours, and TLC (EA:PE=1:3) detected that all 3-pyridine ketones had reacted, and the temperature was lowered to 20-25°C, and 200 g of water was added and stirred for 1 hour. layer, and the chloroform layer was dried with 20 g of anhydrous magnesium sulfate for 3 hours, filtered by suction, and the mother liquor directly entered the next step of reaction.

[0036] 2) Add 2g of azobisisobutyronitrile to the reaction solution in the previous step, and add 187g of NBS in batches, pay attention to the reaction in the dark, after the addition, control the temperature at 40-45°C and stir for 5-6 hours, a large amount of solids are precipitated, and the configuration The good 10% sodium bisulfite s...

Embodiment 2

[0040] Put 100g of compound III into the autoclave, put in 600g of DMF, add 71g of potassium carbonate, after nitrogen replacement, pass in acetylene gas to raise the pressure to 0.4Mpa, react at room temperature 20-25°C until the pressure of the pressure gauge does not drop anymore, and maintain the reaction for 3 hour, after the replacement with nitrogen gas should be completed, after the material is taken out, unreacted potassium carbonate is removed by suction filtration, DMF is recovered to about 80%, and the residue is added to 1000ml of water to stir for half an hour, and dried by suction filtration to obtain 41.0g of the product. rate of 82%.

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Abstract

The invention discloses a synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine. The synthesis method comprises the following steps: synthesizing a compound I from 3-pyridazinone and 2-chloroethylamine acid salt under an alkaline condition; reacting a compound I with NBS to generate a compound II, reacting the compound II with sodium p-toluenesulfonate to generate an active ester III, and finally introducing acetylene gas into the compound III in an aprotic solvent to react to obtain the 3-acetenylimidazo [1, 2-b] pyridazine. The method has the advantages of simple operation steps, cheap and easily available raw materials, and suitableness for large-scale production of generative enterprises.

Description

technical field [0001] The invention relates to a synthesis method of a ponatinib intermediate 3-ethynyl imidazo[1,2-b]pyridazine, which belongs to the technical field of organic synthesis. Background technique [0002] Ponatinib (ponatinib) is an oral multi-target tyrosine kinase inhibitor developed by Ariad Company of the United States, which can effectively inhibit the activities of Bcr-Ab1 (including T315I mutation), Flt-3 and Scr kinases. It is mainly used for the treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). The structural formula of ponatinib is shown below. [0003] [0004] 3-Ethynylimidazo[1,2-b]pyridazine is a key intermediate in the synthesis of ponatinib. Tian Kun etc. disclose the synthetic method of above-mentioned intermediate (Tian Kun, Yue Hongliang, Zhou Changling, et al. Synthesis of Ponatinib [J]. Guangdong Chemical Industry, 2013, 12 (40), 24-25), the synthetic method Us...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 朱义胜吕红超李斌张吉哲张杰
Owner SHANDONG BOYUAN PHARM CO LTD
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