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3-hydroxy-2-piperidineamide framework febrifugine (halofuginone) and preparation method thereof

A technology of piperidinamide and tembrolizine, which is applied in the fields of 3-hydroxy-2-piperidine amide skeleton kefir, 3-hydroxy 2-piperidine amide skeleton kefir compound and analogs thereof and the fields of preparation thereof, and can solve the complicated route , difficult to operate, expensive and other problems, to achieve the effect of simple reaction conditions, simple route and simple operation

Active Publication Date: 2019-06-04
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although halosine (ketone) and its analogues have shown a series of activities such as antimalarial, antitumor, anti-tissue fibrosis, and promotion of cartilage hyperplasia in preclinical and clinical experiments, there is only one French company in the market at present. Production and sales (racemic hemosanone, trade name Sudan), and expensive; however, domestic synthesis is mostly limited to the preparation process research of quinazolones fragments, and there are few reports about the preparation method of chiral fragments and The reactions involved are relatively difficult, the route is cumbersome, difficult to operate, and it is difficult to achieve a large amount of preparation, resulting in very limited technical routes for the marketable core chiral fragments of hirsepine (ketone) and its derivatives

Method used

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  • 3-hydroxy-2-piperidineamide framework febrifugine (halofuginone) and preparation method thereof
  • 3-hydroxy-2-piperidineamide framework febrifugine (halofuginone) and preparation method thereof
  • 3-hydroxy-2-piperidineamide framework febrifugine (halofuginone) and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0038] Synthesis of compound 3a

[0039] (5R,6S)-5-((tert-Butyldimethylsilyl)oxy)-6-(2-oxopropyl)piperidin-2-one(3a)

[0040] Lithium diisopropylamide (8.3mmol, 10eq) was newly prepared under nitrogen protection at room temperature, diluted with anhydrous tetrahydrofuran solution (5mL), injected into acetone reagent (8.3mmol, 10eq) and reacted at room temperature for 0.5 hours. The newly generated negative ion was reacted with compound 2 (300mg, 0.83mmol, 1.0eq) at a low temperature of -78°C for 2.5 hours, then quenched by adding saturated ammonium chloride, extracted, concentrated, and then added 5mL of hydrochloric acid / dioxane solution in After reacting at room temperature for 0.5 hours to detect the completion of the reaction, spin dry on a rotary evaporator. After spin-drying, add sodium hydroxide solution (4M, 5mL) directly to it without purification, react at room temperature for 5 minutes, extract with ethyl acetate, wash with saturated brine, dry with anhydrous magne...

Embodiment 2

[0090] Synthesis of compound 3a

[0091] (5R,6S)-5-((tert-Butyldimethylsilyl)oxy)-6-(2-oxopropyl)piperidin-2-one(3a)

[0092] Lithium diisopropylamide (8.3mmol, 10eq) was newly prepared under nitrogen protection at room temperature, diluted with anhydrous tetrahydrofuran solution (5mL), injected into acetone reagent (8.3mmol, 10eq) and reacted at room temperature for 0.5 hours. The newly generated negative ion was reacted with compound 2 (300mg, 0.83mmol, 1.0eq) at a low temperature of -78°C for 2.5 hours, then quenched by adding saturated ammonium chloride, extracted, concentrated, added anhydrous methanol (20mL) and passed through grass Acyl chloride (16.6mmol, 20eq) was quenched, and then reacted at room temperature for 0.5 hours to check that the reaction was complete, and then spin-dried on a rotary evaporator. After spin-drying, add sodium hydroxide solution (4M, 50mL) directly to it without purification, react at room temperature for 5 minutes, extract with ethyl aceta...

Embodiment 3

[0094] Synthesis of compound 3a

[0095] (5R,6S)-5-((tert-Butyldimethylsilyl)oxy)-6-(2-oxopropyl)piperidin-2-one(3a)

[0096]Lithium diisopropylamide (1.25mmol, 1.5eq) was newly prepared under nitrogen protection at room temperature, diluted with anhydrous tetrahydrofuran solution (2mL), injected with acetone reagent (0.83mmol, 1.0eq) and reacted at room temperature for 1 hour. The newly generated negative ion was reacted with compound 2 (300mg, 0.83mmol, 1.0eq) at a low temperature of -78°C for 2.5 hours, then anhydrous methanol (5mL) was added and quenched with oxalyl chloride (1.66mmol, 2.0eq), and then After reacting at room temperature for 0.5 hours to detect the completion of the reaction, spin dry on a rotary evaporator. After spin-drying, add sodium hydroxide solution (4M, 5mL) directly to it without purification, react at room temperature for 5 minutes, extract with ethyl acetate, wash with saturated brine, dry with anhydrous magnesium sulfate, filter with suction, c...

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Abstract

The invention belongs to the technical field of chemical synthesis, and relates to a 3-hydroxy-2-piperidineamide framework febrifugine (halofuginone) and a preparation method thereof. The compound hasa structure represented by formula (I) shown in the description. The preparation method of the invention has the advantages of simplicity in operation, simple route and high yield, and all reagents used in the invention are common reagents, so the method is suitable for large-scale preparation; and the obtained target product can be used for the diversity-oriented synthesis research of various natural products with important physiological activities.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a 3-hydroxy 2-piperidine amide skeleton halosine (ketone), in particular to a 3-hydroxy 2-piperidine amide skeleton halosine (ketone) compound and an analog thereof and a preparation method thereof. Background technique [0002] The World Health Organization pointed out in the "2016 World Malaria Report": Malaria is still one of the most serious tropical parasitic diseases in the world, and its death rate is second only to tuberculosis, threatening the lives of millions of people in the Americas, Asia and the Pacific. life. Although in the past five years, governments of various countries have worked together and adopted a series of strong measures, such as substantially increasing the proportion of children's diagnostic testing and preventive treatment for pregnant women in sub-Saharan Africa, and further expanding the use of insecticide-treated nets by risk groups. Ratio and vi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
Inventor 魏邦国汪晨司长梅周雯周祝孙逊林国强
Owner FUDAN UNIV
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