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Moxidectin intermediate and preparation method thereof, and preparation method of moxidectin

A technology for moxidectin and intermediates, applied in the field of medicinal chemistry, can solve the problems of expensive protective reagents, low intermediate yields, and unsuitability for large-scale industrial production

Active Publication Date: 2022-06-07
河北美荷药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the protective reagents for hydroxyl are mainly chlorosilanes and aryl formyl chlorides, such as tert-butyldimethylsilyl chloride, p-nitrobenzoyl chloride, benzoyl chloride, 4-chlorophenoxyacetyl chloride, etc., but existing These protective reagents are not suitable for large-scale industrial production, because the intermediate yield obtained after the protection is low, and the price of the protective reagent is expensive, and even some protective reagents such as p-nitrobenzoyl chloride and benzoyl chloride are tubes. products, highly toxic

Method used

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  • Moxidectin intermediate and preparation method thereof, and preparation method of moxidectin
  • Moxidectin intermediate and preparation method thereof, and preparation method of moxidectin
  • Moxidectin intermediate and preparation method thereof, and preparation method of moxidectin

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Embodiment 1

[0065] The present embodiment provides a kind of preparation method of moxidectin, comprises the following steps:

[0066] Nucleophilic substitution reaction (protection on hydroxyl group): Synthesis of 5-oxo(β-phenylacryloyl)nemoctine (moxidectin intermediate) from nemoctine

[0067] At room temperature (20-25°C), in a 250mL three-necked flask equipped with a stirrer, add 25g (41.0mmol) nimoctine, 3.3g DMAP (4-dimethylaminopyridine) and 100mL dichloromethane, After stirring and dissolving completely, add triethylamine (17.5mL) and 6.83g β-phenylacryloyl chloride (41.0mmol) successively, stir at room temperature (20-25°C) for 2h until the reaction is complete, then transfer the reaction solution to a 250mL container In a 500mL beaker of sodium bicarbonate solution (5wt%), after stirring for 10min to uniformity, then stand for 20min to separate layers, move the lower organic phase to a 250mL Erlenmeyer flask, add 50g of anhydrous magnesium sulfate for drying, and place overnigh...

Embodiment 2

[0087] The present embodiment provides a kind of preparation method of moxidectin, comprises the following steps:

[0088] Nucleophilic substitution reaction (protection on hydroxyl group): Synthesis of 5-oxo(β-phenylacryloyl)nemoctine (moxidectin intermediate) from nemoctine

[0089] At room temperature (20-25°C), in a 250mL three-necked flask equipped with a stirrer, add 25g (41mmol) nimoctine, 3.5g DMAP (4-dimethylaminopyridine) and 100mL dichloromethane, stir After completely dissolving, add triethylamine (25mL) and 6.83g β-phenylacryloyl chloride (41mmol) successively, stir at room temperature (20-25°C) for 1.75h until the reaction is complete, then transfer the reaction liquid to 250mL bicarbonate In a 500mL beaker of sodium solution (5wt%), stir for 10min until uniform, then let stand for 20min to separate layers, move the lower organic phase to a 250mL Erlenmeyer flask, add 50g of anhydrous magnesium sulfate to dry, and place overnight. The dried liquid was filtered a...

Embodiment 3

[0097] The present embodiment provides a kind of preparation method of moxidectin, comprises the following steps:

[0098] Nucleophilic substitution reaction (protection on hydroxyl group): Synthesis of 5-oxo(β-phenylacryloyl)nemoctine (moxidectin intermediate) from nemoctine

[0099] At room temperature (25-30°C), in a 250mL three-neck flask equipped with a stirrer, add 25g (41mmol) nimoctine, 3.0g DMAP (4-dimethylaminopyridine) and 100mL dichloromethane, stir After complete dissolution, add triethylamine (34mL) and 6.83g β-phenylacryloyl chloride (41mmol) in sequence, stir at room temperature (25-30°C) for 1.5h until the reaction is complete, then transfer the reaction solution to 250mL bicarbonate In a 500mL beaker of sodium solution (5wt%), stir for 10min until uniform, then let stand for 20min to separate layers, move the lower organic phase to a 250mL Erlenmeyer flask, add 50g of anhydrous magnesium sulfate to dry, and place overnight. The dried liquid was filtered and ...

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Abstract

The invention discloses a moxidectin intermediate and a preparation method thereof, and a moxidectin preparation method. The preparation method of the moxidectin intermediate comprises the following steps: carrying out nucleophilic substitution reaction on nemadectin and beta-phenylacryloyl chloride, and after the reaction is finished, carrying out post-treatment to obtain the moxidectin intermediate. According to the preparation method of the moxidectin intermediate provided by the invention, beta-phenyl acryloyl chloride is adopted as a protective reagent of hydroxyl, after the reaction is finished, post-treatment (column chromatography) purification is performed, the purity of the obtained moxidectin intermediate reaches 98% or above, the yield reaches 92% or above, the cost is low, the reaction time is short, and the method is suitable for industrial production. The method is suitable for large-scale industrial safety production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a moxidectin intermediate and a preparation method thereof, and a preparation method of moxidectin. Background technique [0002] Moxidectin (MOD), also known as moxidectin or moxidectin, is a semi-synthetic single-component macrolide antibiotic produced by the fermentation of streptomycin. MOD belongs to the milbemyeins (milbemyeins) family, is a macrolide antibiotic with a single structure derived from nemadectin chemically modified or derived, and belongs to the third generation of avermectins (AVMs) drugs . MOD has good anthelmintic activity, as well as long-acting and safe characteristics. It is a broad-spectrum, efficient and safe new macrolide anthelmintic antibiotic widely used in veterinary clinics. [0003] Most of the existing moxidectin preparation methods use nimoctine as a raw material, and obtain it through four-step chemical modification of hydroxyl ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22
CPCC07D493/22Y02P20/55
Inventor 孟冽王卫华孟藏锐赵军华赵云飞王志强张乾梁妍王晓雷
Owner 河北美荷药业有限公司
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