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Preparation method of Crizotinib or deuterated Crizotinib

A technology of deuterium and compound, which is applied in the field of preparation of crizotinib or deuterated crizotinib, can solve the problems of large residual amount of organic solvent and large dosage, and achieve reduction of residual amount and use of organic solvent The effect of reducing the amount and increasing the yield

Active Publication Date: 2017-03-15
BEIJING KYNING BIOSCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The patent (CN104402868A) discloses deuterated crizotinib crystal form and preparation method thereof, but the organic solvent used in it is acetonitrile with high toxicity, and the amount of organic solvent and water is relatively large, so that the prepared deuterated crizotinib There is a large amount of organic solvent residue in rizotinib

Method used

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  • Preparation method of Crizotinib or deuterated Crizotinib
  • Preparation method of Crizotinib or deuterated Crizotinib
  • Preparation method of Crizotinib or deuterated Crizotinib

Examples

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Embodiment 1

[0050] The synthetic route of crizotinib in the present embodiment is as follows:

[0051]

[0052] In this example, the synthesis of the compound of formula VII and compound of formula II refers to the published patent (publication number: CN104327053A), and the synthesis of the compound of formula VI refers to the patent (WO2012116050A2).

[0053] The synthesis steps of crizotinib in this example are as follows:

[0054] Preparation of formula I compound: compound VII (50g, 238mmol) was added into a 5L three-neck flask containing 1800mL toluene (dried through molecular sieves), N 2 protection, cooling to -5°C; adding PPh 3 (1.1equiv, 262mmol, 68.6g); add compound VI (1.1equiv, 262mmol, 57g) toluene solution 400mL (molecular sieve drying); dropwise add diisopropyl azodicarboxylate (DIAD) (1.1equiv, 262mmol, 52mL ), keep the temperature 1 HNMR (400MHz, CDCl 3 ): 8.09-8.08 (d, J=1.8Hz, 1H), 7.41-7.40 (d, J=1.7Hz, 1H), 7.36-7.32 (dd, J=4.8Hz, 8.9Hz, 1H), 7.14-7.10 (dd, J=...

Embodiment 2

[0060] The synthetic route of deuterated crizotinib in this embodiment is as follows:

[0061]

[0062] In this example, the synthesis of the compound of formula VII and compound of formula II refers to the published patent (publication number: CN104327053A), and the synthesis of the compound of formula VI refers to the patent (WO2012116050A2).

[0063] The synthesis steps of deuterated crizotinib in this example are as follows:

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Abstract

Belonging to the field of pharmaceutical compounds, the invention relates to a preparation method of Crizotinib or deuterated Crizotinib. The preparation method of Crizotinib or deuterated Crizotinib includes: 1) preparation of a formula III compound; 2) preparation of a formula IV compound; and 3) preparation of a formula V compound. The method provided by the invention employs a formula I compound having nitro as the substrate to carry out palladium-catalyzed coupling reaction, nitro does not have lone pair electrons, and nitro and a palladium catalyst have weak complexation, thus reducing the dosage of palladium catalyst and the difficulty of removing palladium catalyst from the product. In addition, the method employs a mixed solvent of low toxicity isopropyl alcohol and water to conduct recrystallization, reduces the solvent residual in bulk drugs, and significantly increases the purification yield.

Description

technical field [0001] The invention relates to a preparation method of crizotinib or deuterated crizotinib, which belongs to the technical field of medical compounds. Background technique [0002] Crizotinib, chemical name 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidine Base)-1H-pyrazol-4-yl]-2-aminopyridine, developed by Pfizer for the treatment of anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC) The small-molecule kinase inhibitor is currently the only drug for the treatment of this type of disease. It was approved by the FDA in August 2011 to be launched in the United States, and then launched in South Korea, Japan, and the European Union. In January 2013, it was approved by the SFDA to be launched in China. name (The Chinese product name is Serek). This product targets ALK, hepatocyte growth factor receptor (c-met, H GFR) and tyrosine kinase receptor (RON), and blocks tumor cell growth and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07B2200/05C07B2200/07C07D401/14
Inventor 吴豫生牛成山耿阳霍云峰梁阿鹏李敬亚郭瑞云邹大鹏
Owner BEIJING KYNING BIOSCI
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