The preparation method of ponatinib

A technology of ponatinib and imidazolium, applied in the field of preparation of ponatinib, can solve the problems of high preparation cost, unfavorable industrialization, long reaction time and the like, and achieve the effects of promoting development, easy availability of raw materials, and simple process

Active Publication Date: 2015-08-05
中铁装配式建筑科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the reaction process, triphenylphosphine palladium, cuprous iodide catalyst and organic base ligand are used repeatedly, the preparation cost is high, the reaction time is long, and the yield is also low, which is not conducive to industrialization

Method used

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  • The preparation method of ponatinib
  • The preparation method of ponatinib
  • The preparation method of ponatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add 4-methylbenzoic acid (III) (13.6 g, 0.1 mol) and 200 mL of 1,2-dichloroethane into a dry three-necked reaction flask, add aluminum trichloride (26.6 g, 0.2 mol), and imidazo[1,2-b]pyridazine-3-carbonyl chloride (II) (20.1 g, 0.11 mol) in 100 mL of 1,2-dichloroethane was added dropwise. The temperature was raised to 50-60° C. for 5 hours, and TLC detected that the reaction was complete. Cool down to room temperature, add 1M dilute hydrochloric acid to quench the reaction, filter, and wash the filtrate with saturated sodium bicarbonate solution, saturated brine and pure water successively, and dry over anhydrous magnesium sulfate. Filtration, the filtrate was concentrated, and the resulting crude product was recrystallized from toluene and n-hexane (2:1) to obtain an off-white solid 3-(imidazo[1,2-b]pyridazin-3-yl)-(4-methylbenzoic acid -3-yl)methanone (IV) 22.1g, yield 78.1%.

Embodiment 2

[0033] Add 3-(imidazo[1,2-b]pyridazin-3-yl)-(4-methylbenzoic acid-3-yl)methanone (IV) (2.83g, 10mol ) and 50 mL of tetrahydrofuran, cooled to -78°C with acetone on dry ice. Under the protection of nitrogen, add lithium hexamethyldisilazide (2.0 g, 12 mmol) and diethyl dichloromethylphosphonate (2.4 g, 11 mmol) in 25 mL of tetrahydrofuran dropwise, and keep the reaction at -78 ° C After 30 minutes, the temperature was slowly raised to 0°C, and the reaction was continued for 1 hour. Cool down to -78°C again, add n-butyllithium (14mL, 22mmol) dropwise under stirring, raise the temperature to 0°C within 30 minutes, continue to stir and react for 40 minutes, and detect the reaction by TLC. Add 20 mL of water to quench the reaction. It was extracted three times with ether, and the organic phases were combined, washed with water, dilute hydrochloric acid and water successively, and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, add deionized water to t...

Embodiment 3

[0035] Add 3-(imidazo[1,2-b]pyridazin-3-yl)-(4-methylbenzoic acid-3-yl)methanone (IV) (2.83g, 10mol ) and 50 mL of toluene, cooled to -78°C with acetone on dry ice. Under the protection of nitrogen, add lithium hexamethyldisilazide (2.0 g, 12 mmol) and diethyl dichloromethylphosphonate (2.4 g, 11 mmol) in 25 mL of tetrahydrofuran dropwise, and keep the reaction at -78 ° C After 30 minutes, the temperature was slowly raised to 0°C, and the reaction was continued for 1 hour. Add 0.25 g of polyethylene glycol (PEG-400) and potassium hydroxide (1.23 g, 22 mmol), react at room temperature for 12 hours, and detect the reaction by TLC. Add 20 mL of water to quench the reaction. It was extracted three times with ether, and the organic phases were combined, washed with water, dilute hydrochloric acid and water successively, and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, add deionized water to the residue, stir and crystallize at room temperature. Af...

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Abstract

The invention discloses a preparation method for Ponatinib (I). The preparation method comprises the following steps: imidazo [1, 2-b] pyridazine-3-formyl chloride (II) is used as a raw material and subjected to the Friedel-Crafts acylation reaction with 4-methyl benzoic acid (III) to generate an intermediate (IV) being 3-(imidazo[1, 2-b] pyridazine-3-yl)-(4-methyl benzoic acid-3-yl) ketone, the intermediate (IV) is subjected to the Omair-Amos reaction with a Wittig reagent under alkaline condition to obtain an intermediate (V) being 3-(imidazo[1, 2-b] pyridazine-3-ethynyl)-4-methyl benzoic acid, the intermediate (V) is subjected to the amidation reaction with side chain (VI) being 4-((4-methyl piperazine-1-yl)-methyl)-3-(trifluoromethyl) aniline to obtain the Ponatinib (I). According to the preparation method provided by the invention, the raw materials are easy to obtain, the process is concise, and the method is economical and environment-friendly and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of ponatinib. Background technique [0002] Ponatinib is a third-generation tyrosine kinase inhibitor developed by Ariad Pharmaceuticals in the United States. Because the compound does not yet have a standard Chinese translation, the applicant hereby transliterates it as "Ponatinib". In December 2012, the drug was approved by the U.S. Food and Drug Administration (FDA), with the trade name Iclusig. For the treatment of adult patients with two rare leukemias, chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). [0003] The chemical name of Ponatinib is: 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[(4-(4-methyl Piperazin-1-yl)-methyl)-3-(trifluoromethyl)phenyl]benzamide, its structural formula is: [0004] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 许学农
Owner 中铁装配式建筑科技有限公司
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