Plinabulin compound polycrystalline type and preparation method thereof

A technology of crystal form and β crystal form, which is applied in the field of polymorphic forms of dehydrophenylahistine compounds and their preparation, can solve problems such as restricting application, and achieves clear conformation, high purity and method reproducibility Good results

Inactive Publication Date: 2017-08-04
深圳华大海洋科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the only dosage forms declared for clinical use are concentrated solutions for injection with added solubilizers, which seriously restricts its application in clinical medicine.

Method used

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  • Plinabulin compound polycrystalline type and preparation method thereof
  • Plinabulin compound polycrystalline type and preparation method thereof
  • Plinabulin compound polycrystalline type and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione α crystal form

[0038] Its specific preparation process technology includes the following steps:

[0039] 1) Preparation of ethyl 5-(tert-butyl)oxazole-4-carboxylate

[0040] Add 90g (796mmol) ethyl isocyanoacetate to 1000mL tetrahydrofuran, slowly dropwise add 145g (955mmol) DBU, then dropwise add 178g (955mmol) trimethylacetic anhydride, and stir the reaction at room temperature for 48h after dropping. After the reaction was completed, it was concentrated under reduced pressure. For extraction, add an appropriate amount of 1500mL of dichloromethane, wash with 800mL of 10% sodium carbonate, 800mL of 10% citric acid, and 800mL of saturated brine, and back-extract the aqueous phase twice with 1000mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction after half an hour, and concentrated under reduced pressur...

Embodiment 2

[0055] Preparation of β Crystal Form of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione

[0056] The specific preparation process includes the following steps: Weigh the (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2 , 5-diketone (200mg, 0.59mmol), using a mixed solution of 20mL methanol and 0.1mL water as a solvent, dissolved at 70°C, filtered into a crystallization dish, covered the bottle mouth of the crystallization dish with plastic wrap, and placed on the plastic wrap Prick 16 holes with a capillary tube with an outer diameter of 0.5 mm, and place it in the dark for evaporation at room temperature. After 72 hours, crystals of the β crystal form precipitated, filtered, and dried to obtain 148 mg of a cubic solid, with a yield of 74%. The obtained β crystal form was tested by X-ray powder diffraction, and the characteristic absorption peaks of 2θ diffraction angles were 7.365°, 7.670°, 8.097°, 9.069°, 1...

Embodiment 3

[0062] Preparation of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione γ crystal form

[0063] The specific preparation process includes the following steps: Weigh the (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2 , 5-diketone (200mg, 0.59mmol), using a mixed solution of 20mL methanol and 0.8mL water as a solvent, dissolved at 68°C, filtered into a crystallization dish, added seed crystals, covered the mouth of the crystallization dish with plastic wrap, Prick 16 holes on the plastic wrap with a capillary tube with an outer diameter of 0.5 mm, and place it in the dark for evaporation at room temperature. After 72 hours, crystals of the γ crystal form precipitated, filtered, and dried to obtain 98 mg of needle-columnar solids with a yield of 49%. The obtained γ crystal form was tested by X-ray powder diffraction, and the characteristic absorption peaks of 2θ diffraction angles were 7.918°, 9.168°, 9.905°, 12...

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Abstract

The invention provides a plinabulin compound polycrystalline type and a preparation method thereof, and particularly relates to a polycrystalline type of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) methylene)piperazidine-2,5-diketone and a preparation method thereof. Three kinds of crystalline types beta, gamma and delta are developed on the basis of the crystalline type alpha of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) methylene)piperazidine-2,5-diketone, wherein the three kinds of crystalline types beta, gamma and delta can be prepared into monocrystallines; the three kinds of crystalline types have the advantages of clear conformation, high purity and high method repeatability; the important significance is realized on implementation of plinabulin biological effectiveness study and dosage form variety development.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a polymorphic form of a drug and a preparation method thereof, in particular to a polymorphic form of a dehydrophenylahistin compound and a preparation method thereof. Background technique [0002] (3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione belongs to dehydrophenyl Cistine compound, its structural formula is: [0003] [0004] The compound, also known as Plinabulin (KPU-2, NPI-2358), was developed by Nereus Pharmaceutical Company of the United States. It is a synthetic derivative of low-molecular-weight cyclic dipeptide phenylahistin or halimide derived from marine Aspergillus. It is a tubulin-binding agent. Plinabulin can bind to the vicinity of the colchicine-binding site of tubulin, act on cells, stop cells in early mitosis, and induce cell death. At the same time, it also inhibits microtubule formation, migration of ...

Claims

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Application Information

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IPC IPC(8): C07D403/06
CPCC07D403/06C07B2200/13
Inventor 李文保王世潇丁忠鹏侯英伟管华诗
Owner 深圳华大海洋科技有限公司
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