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Preparation method and application of tubulin inhibitor plinabulin isomer impurity

A technology of Plinabulin and isomers, applied in the field of medicinal chemistry, can solve problems affecting product purity, etc., and achieve the effects of avoiding solvent loss, high yield, and simple operation of the method

Pending Publication Date: 2022-04-15
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the original research patent WO2005 / 07790, the synthesis process of Plinabulin is described, in the last step of condensation reaction, the double bond isomer of the benzene ring position will be produced, and the isomer impurity will affect the purity of the product

Method used

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  • Preparation method and application of tubulin inhibitor plinabulin isomer impurity
  • Preparation method and application of tubulin inhibitor plinabulin isomer impurity
  • Preparation method and application of tubulin inhibitor plinabulin isomer impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of (3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazinedione

[0029]

[0030] Under nitrogen protection, add 5.0g (32.85mmol) 5-(tert-butyl)-1H-imidazole-4-carbaldehyde and 35mL DMF into the reaction flask, then add 13.02g (65.7mmol) N,N-diacetylpiperazine -2,5-diketone and 16.05g (49.28mmol) cesium carbonate were stirred and reacted at room temperature for 20h in the dark. The reaction solution was poured into (500 mL) ice water, and the suction filter cake was washed with water (100 mL*2) and petroleum ether / ethyl acetate 8 / 1 (400 mL) successively. The filter cake was dispersed ultrasonically with ethanol and dichloromethane, and filtered off. The insoluble matter was concentrated under reduced pressure, and anhydrous ethanol was added with water. Ethyl acetate (200mL) was beaten to give a brownish yellow solid (Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2, 4.16 g of 5-diketone, yield 43.62%. ...

Embodiment 2

[0044] Preparation of (3Z,6E)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazinedione

[0045]

[0046] In a 500mL glass reaction bottle, add (3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(phenylene Methyl)-2,5-piperazinedione 1.0g and 100mL tetrahydrofuran, stirring and dissolving at room temperature, stirring for 72 hours under the irradiation of 365nm ultraviolet lamp (300W), sampling HPLC monitoring during the reaction, until (3Z,6Z) -3-[(5-tert-butyl-1H-imidazol-4-yl) methylene]-6-(benzylidene)-2,5-piperazinedione remaining 45% when the reaction reached equilibrium, the The reaction solution was concentrated to dryness under reduced pressure to obtain 1.03 g of a yellow solid. Crystallization was attempted with various solvents on the solid. Some solvents are not easy to crystallize because of their better solubility, such as DMF, DMA, DMSO, etc.; some solvents are not conducive to crystallization because of their poor solubility, su...

Embodiment 3

[0051] Preparation of (3Z,6E)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazinedione

[0052] Weigh the purity of 99.74% (3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazine Add 300mg of diketone into a 100mL glass reaction bottle, add 50mL of acetonitrile, stir and dissolve at room temperature, and stir for 72 hours under the irradiation of a 365nm ultraviolet lamp (300W) in a black airtight environment, and take samples to monitor the reaction by HPLC, (3Z, 6Z) -3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazinedione remaining 43%, depressurize the reaction solution Concentrate to dryness to obtain a yellow solid, dissolve the yellow solid in 100mL of acetonitrile under reflux, add 50mL of purified water dropwise at the temperature, keep for 10min after the dropwise addition, naturally cool down to room temperature, stir and crystallize for 3 hours, a light yellow solid precipitates, filter and...

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Abstract

The invention discloses a preparation method and application of a tubulin inhibitor plinabulin isomer impurity, and belongs to the technical field of medicinal chemistry. (3Z, 6Z)-3-[(5-tert-butyl-1H-imidazole-4-yl) methylene]-6-(benzylidene)-2, 5-piperazinedione is subjected to illumination, and after the reaction reaches equilibrium, a mixed solvent is recrystallized and purified to obtain the impurity with the 6Z-to-6E configuration. The impurity is very key in quality research on preparation of a medicine plinabulin for treating and resisting tumor diseases and neutropenia, and can be used as an impurity reference substance based on related characteristics of the impurity.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a tubulin inhibitor plinabulin isomer impurity (3Z,6E)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene] The preparation method and application of -6-(benzylidene)-2,5-piperazinedione. Background technique [0002] Plinabulin is a diketopiperazine-like tubulin inhibitor synthesized on the basis of the structure of Phenylahistin, a natural product isolated from Aspergillus pyogenes, through structure-activity relationship research. Plinabulin is a microtubule inhibitor that acts at a site between the α and β microtubule subunits, close to the site of action of colchicine, but not in the groove of the colchicine binding site. The Phase I clinical study found that Plinabulin has good pharmacodynamics, pharmacokinetics and safety properties. The combination of Plinabulin and Docetaxel can significantly improve the bioavailability of Plinabulin without interfering with each other...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06
Inventor 王世潇唐宇刘晓坤田帅方诗源张俊逸
Owner OCEAN UNIV OF CHINA
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