Polymorphism of deuterium-substituted plinabulin compound and preparation method and application of polymorphism

A technology of deuterated methylene and crystal form, applied in the field of medicinal chemistry

Active Publication Date: 2018-03-09
SHENZHEN HUAHONG MARINE BIOMEDICINE CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, there is no information about (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-di Report on the crystal form of ketone and its preparation method

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  • Polymorphism of deuterium-substituted plinabulin compound and preparation method and application of polymorphism
  • Polymorphism of deuterium-substituted plinabulin compound and preparation method and application of polymorphism
  • Polymorphism of deuterium-substituted plinabulin compound and preparation method and application of polymorphism

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Experimental program
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Effect test

Embodiment 1

[0052] Preparation of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione

[0053] Its specific preparation process comprises the following steps:

[0054] 1) Preparation of ethyl 5-(tert-butyl)oxazole-4-carboxylate

[0055] 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 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 pressure. After passing through a silica gel (200...

Embodiment 2

[0073] (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuterated methylene)piperazine-2,5-dione purification process and Preparation of α crystal form

[0074] 6.66 g of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5 - Place the crude diketone in a brown bottle, add 400mL of isopropanol under heating conditions until it is completely dissolved, then add 160mL of water without crystallization, place at room temperature, stir and cool to crystallize, filter with suction, isopropanol: water = Wash the filter cake at a ratio of 1:1, beat the filter cake with 100 mL of ethyl acetate for 10 h, filter, wash the filter cake with ethyl acetate, and dry to obtain 5.323 g of a yellow powdery solid. The obtained solid crystal form is α crystal form, and the yield is 80.0%. . The main characteristic peaks of the X-ray powder 2θ angle diffraction peaks of the α crystal form are shown in Table 1, and the specific diffraction patterns are sh...

Embodiment 3

[0080] (3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione β crystal form preparation

[0081] The specific preparation process includes the following steps: Weigh (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl) deuterated 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 0.5mm, and place it in the dark at 25°C for evaporation. After 72 hours, β-crystal crystals are precipitated, filtered, and dried to obtain 142 mg of a cubic solid with a yield of 71%. The obtained β-crystal The melting point of the type is 263.6-264.4°C. The obtained β crystal form is tested by X-ray powder diffraction, and the characteristic peaks of 2θ diffract...

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Abstract

The invention provides polymorphism of a deuterium-substituted plinabulin compound and a preparation method and application of the polymorphism, specifically polymorphism of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) deuterium-substituted methylene)piperazidine-2,5-diketone and preparation method and application of the polymorphism. Based on (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) deuterium-substituted methylene)piperazidine-2,5-diketone, the polymorphism of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) deuterium-substituted methylene)piperazidine-2,5-diketone is researched, and alpha, beta, gamma, delta, and epsilon crystal forms are found. The polymorphism and preparation method and application are of great significance on research of pharmaceutical polymorphism and screening of a crystal form with excellent pharmaceutical effect, and alpha, beta, gamma, delta, and epsilon crystal forms are fully developed and applied with respect to curative effect and dosage form selection of antitumor drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to polymorphs of deuterated dehydrophenylahistin compounds and a preparation method and application thereof. Background technique [0002] (3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione belongs to deuterated The polymorphic form of hydrophenyl ahistine compound, its structural formula is: [0003] [0004] (3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione is derived from marine The fungal cyclic dipeptide Phenylahistin derivative dehydrophenylahistin (Plinabulin, in the third phase of clinical trials) is the lead compound, a new type of tubulin binding agent obtained through structural modification, which has good anti-tumor activity, And it can overcome the drug resistance of paclitaxel, it selectively acts near the colchicine binding site of endothelial tubulin, inhibits tubul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07B59/00A61K31/496A61P35/00
CPCC07B59/002C07D403/06C07B2200/05C07B2200/13
Inventor 李文保王世潇丁忠鹏侯英伟管华诗
Owner SHENZHEN HUAHONG MARINE BIOMEDICINE CO LTD
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