Halofuginone with optical activity and synthesis method of intermediate of halofuginone

An optically active and chiral technology, applied in organic chemistry methods, organic chemistry, etc., can solve problems such as cumbersome synthetic routes, highly toxic use, and low yields

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

The methods involved in the asymmetric synthesis of optically active hemosanone or hemosanine have disadvantages such as cumbersome synthetic routes, harsh reaction conditions, low yield, complicated separation and purification, or the use of highly toxic and expensive reagents.

Method used

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  • Halofuginone with optical activity and synthesis method of intermediate of halofuginone
  • Halofuginone with optical activity and synthesis method of intermediate of halofuginone
  • Halofuginone with optical activity and synthesis method of intermediate of halofuginone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] The synthesis of embodiment 1 racemic hemosanone

[0183] Intermediate compound 4 (R 1 = Synthesis of Et)

[0184]

[0185] 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 crystalliz...

Embodiment 2

[0247] Synthesis of compounds of formula (+)-9 (dextrorotatory optically active [(+)-(2S,3S)-2-(2-chloropropenyl)-3-hydroxypiperidine])

[0248]

[0249]Step (1): At room temperature, add racemic compound of formula 9 (140 g, 0.797 mol, prepared according to the method of Example 1) and acetonitrile (1400 ml) into a 5 L three-neck flask, heat to 60 ° C and stir to dissolve. L-(-)-dibenzoyltartaric acid (300 g, 0.837 mol) of formula 15 was dissolved in acetonitrile (800 ml) and added dropwise to the reaction flask, and the drop was completed in about 10 minutes. After dropping, stir for 20-30 minutes, then move to room temperature and stir for 2 hours. Filter, rinse with acetonitrile (300ml), and drain to obtain the crude double salt. Add pure water-acetonitrile (1:4, 2000ml) to the crude product, stir, heat to 80°C to dissolve, filter while hot, and stir the filtrate at room temperature for 2 hours to crystallize. Filter, wash with acetonitrile, and dry to obtain the refi...

Embodiment 3

[0256] Synthesis of Compound of Formula (-)-9 (Levorotatory Optically Active [(-)-(2R,3R)-2-(2-Chloropropenyl)-3-Hydroxypiperidine])

[0257]

[0258] Step (1): At room temperature, add racemic compound of formula 9 (14 g, 79.7 mmol, prepared according to the method of Example 1) and acetonitrile (140 ml) into a 5 L three-neck flask, heat to 60° C. and stir to dissolve. L-(-)-dibenzoyltartaric acid (30g, 83.7mmol) of formula 16 was dissolved in acetonitrile (80ml) and added dropwise to the reaction flask, and the dropwise was completed in about 10 minutes. After dropping, stir for 20-30 minutes, then move to room temperature and stir for 2 hours. Filter, rinse with acetonitrile (30ml), and drain to obtain the crude double salt. Add pure water-acetonitrile (1:4, 200ml) to the crude product, stir, heat to 80°C to dissolve, then filter while hot, and stir the filtrate at room temperature for 2 hours to crystallize. Filter, wash with acetonitrile, and dry to obtain the refine...

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Abstract

The invention relates to a preparation method of cis-2-(2-chloropropene)-3-hydroxyl piperidine with optical activity and application of cis-2-(2-chloropropene)-3-hydroxyl piperidine in preparing halofuginone. The preparation method of cis-2-(2-chloropropene)-3-hydroxyl piperidine with optical activity comprises the following steps: (1) in a first organic solvent, performing a salt forming reactionon racemic cis-2-(2-chloropropene)-3-hydroxypiperidine and dibenzoyltartaric acid or a derivative thereof so as to generate precipitate, recrystallizing the precipitate so as to obtain a chiral composite salt; and (2) in a second organic solvent, neutralizing the chiral composite salt to alkaline by using an alkali water solution, so as to obtain the cis-2-(2-chloropropene)-3-hydroxyl piperidinewith optical activity. The method is cheap in raw material, easy in raw material obtaining, simple in preparation process, small in product impurity and free of column chromatography purification, andin addition, on-scale production preparation of halofuginone with a high optical purity can be achieved.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing optically active hematanone and its intermediates. Background technique [0002] The Changshan alkaloids isolated from the traditional Chinese medicine Changshan include Febrifugine, Isofebrifugine and its halogenated derivative Halofuginone, which have various pharmacological activities, especially in recent years. Studies have shown that, in addition to being used as the prevention and treatment of coccidiosis in animals, fushanone also has a variety of important pharmacological effects in human diseases. Changshanone specifically inhibits the synthesis of type I collagen fibers by fibroblasts to prevent liver fibrosis, pulmonary fibrosis, scleroderma and other diseases characterized by excessive synthesis of type I collagen. The inhibition of collagen synthesis leads to the reduction of cell activity, which is a key role in the growth of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/42C07D401/06
CPCC07B2200/07C07D211/42C07D401/06
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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