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Synthetic method for halofuginone and intermediate of halofuginone

A synthesis method and a halofuginone technology are applied in the field of synthesis of halofuginone and its intermediates, and can solve the problems of expensive raw materials, inability to meet the market demand of halofuginone, harsh reaction conditions and the like

Active Publication Date: 2019-11-15
广州朗启生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Even with the synthetic route of A, C or other types of intermediates, there are many problems, such as low overall yield, harsh reaction conditions, expensive raw materials, and the need for column chromatography separation and purification, etc.
[0029] Therefore, it is difficult for the products prepared by the existing synthetic methods to meet the quality standards of hemosanone, nor can it meet the huge market demand of hemosanone, let alone meet the reporting requirements of ICH

Method used

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  • Synthetic method for halofuginone and intermediate of halofuginone
  • Synthetic method for halofuginone and intermediate of halofuginone
  • Synthetic method for halofuginone and intermediate of halofuginone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Intermediate compound 4 (R 1 = Synthesis of Et)

[0180]

[0181] Step (a): At room temperature, add diethyl acetamidomalonate (5.00kg, 23.02mol), anhydrous potassium carbonate (6.35kg, 46.04mol), potassium iodide (0.76kg, 4.6mol) into a 50L reactor , tetrabutylammonium bromide (0.37kg, 1.15mol) and acetonitrile (25L), after stirring for 20 minutes, 2,3-dichloropropene (3.07kg, 27.62mol) was added. The temperature was raised to 85-90°C for reaction, and the reaction was monitored by HPLC. After the reaction is finished, the temperature of the reaction liquid is lowered to within 25°C, and the diluted hydrochloric acid is slowly dropped into the reaction kettle to neutralize to pH 7-7.5. After standing still, the layers were separated, and the organic layer was concentrated under reduced pressure at 50°C. The concentrated residue was added with ethanol-water (1:10, 20 L) and stirred for 1 hour to crystallize. Filter under reduced pressure, rinse the filter cake wi...

Embodiment 2

[0243] Synthesis of intermediate compound 13

[0244]

[0245] Step (i): In the 50L reactor at room temperature, add compound 9 (0.7kg, 3.98mol), 1,4-dioxane (3.5L), water (3.5L), sodium carbonate (0.63kg, 5.98 mol), stirred and cooled to 5-10°C. 9-Fluorenylmethyl chloroformate (1.03kg, 3.98mol) was dissolved in 1,4-dioxane (1.4L) and added dropwise to the reaction kettle, and the temperature was controlled not to exceed 20°C. After dropping, the reaction was continued to stir at room temperature and monitored by TLC. After the reaction was completed, ethyl acetate (15 L) and water (15 L) were added and stirred for liquid separation. The organic layer was washed with saturated sodium chloride (3L×2), and the layers were separated. The aqueous layer was extracted once with ethyl acetate (8 L). Combine the organic layers, add activated carbon (300 g) and stir at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain ...

Embodiment 3

[0256] Intermediate compound 4 (R 1 = Synthesis of Et)

[0257]

[0258] Step (a): At room temperature, add diethyl acetamidomalonate (2.50kg, 11.51mol), anhydrous potassium carbonate (3.18kg, 23.02mol), potassium iodide (0.38kg, 2.3mol) into a 50L reactor , tetrabutylammonium bromide (0.19kg, 0.58mol) and acetonitrile (13L), after stirring for 20 minutes, 2,3-dichloropropene (1.53kg, 13.81mol) was added. The temperature was raised to 85-90°C for reaction, and the reaction was monitored by HPLC. After the reaction is finished, the temperature of the reaction liquid is lowered to within 25°C, and the diluted hydrochloric acid is slowly dropped into the reaction kettle to neutralize to pH 7-7.5. After standing still, the layers were separated, and the organic layer was concentrated under reduced pressure at 50°C. The concentrated residue was added with ethanol-water (1:10, 10 L) and stirred for 1 hour to crystallize. Filter under reduced pressure, rinse the filter cake wi...

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Abstract

The invention relates to a synthetic method for halofuginone and an intermediate of the halofuginone. The reaction formula is shown in the description, wherein R1 is one selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and t-butyl; R2 is one selected from the group consisting of methyl and ethyl; and R3 is one selected from the group consisting of methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl and benzyl. The synthetic method provided by the invention has the advantages of a simple process, low costs, few by-products in the synthetic process, a simple purification process, no need of column chromatography purification, a high product yield, less impurities, high purity, and controllable product quality, easily meets ICH declaration requirements and can be used for industrial production of the halofuginone.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a synthetic method of fushanone and its intermediate. Background technique [0002] Halofuginone (Halofuginone, Formula 1) is a halogenated derivative of the natural product Febrifugine, also known as bromochlorofuginone, chloroquinone, and halofuginone. Changshanone is a new type of broad-spectrum anticoccidial drug, which has a strong inhibitory effect on various chicken coccidiosis. After medication, it can obviously control the symptoms of coccidiosis and completely inhibit the discharge of oocysts (except for Eimeria spp. ), so that the environment is no longer polluted and the possibility of reinfection is reduced. It has obvious inhibitory effect on the three stages in the development cycle of coccidia, that is, sporozoites, first-generation schizonts and second-generation schizonts. Due to its unique chemical structure, Changshanone has no cross-resistance wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/42C07D401/06
CPCC07D211/42C07D401/06Y02P20/55
Inventor 金冶华邱发洋徐华尹文浩
Owner 广州朗启生物科技有限公司
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