Unlock instant, AI-driven research and patent intelligence for your innovation.

Synthesis of fluralaner

A technology of flurelana and trifluorobutane, applied in the field of chemical synthesis, can solve the problems of side reactions, product purification and industrial production bottlenecks, impurities in the preparation process, etc., and achieve the effect of less side reactions

Pending Publication Date: 2021-10-19
江苏君若药业有限公司
View PDF10 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Based on the current preparation methods of Frellaner, it is not difficult to find that the methods all involve the step of ring-closing to prepare 4,5-dihydroisoxazole intermediates, and the current ring-closing precursors all contain multiple active groups, such as ester group, amido group, carboxyl group, etc., and the ring-closing reagent is hydroxylamine hydrochloride. These active groups are very easy to have side reactions with hydroxylamine hydrochloride, which will lead to impurities in the entire preparation process. bring bottleneck

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis of fluralaner
  • Synthesis of fluralaner
  • Synthesis of fluralaner

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzonitrile

[0028]Under nitrogen protection, 4-acetyl-2-methylbenzonitrile (40g, 251.3mmol), 1-(3,5-dichlorophenyl)-2,2,2-trifluoro Ethan-1-one (81.8 g, 336.6 mmol), triethylamine (56.8 g, 561.3 mmol) and anhydrous toluene (300 mL). After the addition, the system was stirred at room temperature for 10 minutes until the system was dissolved. Then, the reaction system was slowly heated to reflux until the reaction was tracked by TLC until the reaction of 4-acetyl-2-methylbenzonitrile was substantially complete. The system was naturally cooled to room temperature, then kept stirring for 2 hours; the system was added with H 2 O (300mL), the system uses 2M hydrochloric acid to adjust the pH value to weak acidity, separate the organic phase, and extract the aqueous phase with toluene (200mL) once; combine the organic phase, dry over anhydrous sodium sulfate, filter, and add to...

Embodiment 2

[0029] Embodiment two: (Z)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enone base)-2-methyl-benzonitrile preparation

[0030]

[0031] Under nitrogen protection, 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzonitrile (48.0 g, 119.3 mmol), DMAP (1.1 g, 9.0 mmol), acetic anhydride (19.0 g, 186.1 mmol) and xylene (150 mL). After the addition, the system was stirred at room temperature for 10 minutes, and then the system was slowly heated to 80° C. for 6 hours. The temperature of the system was lowered to 50°C, and a dilute aqueous solution of sodium bicarbonate (with gas evolution) was slowly added while maintaining the temperature to adjust the pH value to neutral. Then the system was layered at 50°C, the organic phase was collected, the temperature of the organic phase was cooled to room temperature, and the silica gel Pad was passed through the obtained organic phase to remove the solvent under high vacuum and reduced pressure to obtain (Z)-4-...

Embodiment 3

[0032] Example 3: 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-benzene Preparation of forminonitrile

[0033]

[0034] Under nitrogen protection, sodium hydroxide (13.1g, 327.5mmol), H 2 O (150mL), hydroxylamine hydrochloride (22.7g, 326.7mmol), THF (120mL), after the addition, the system was stirred for 20 minutes, and the system was cooled to 5°C; then (Z)-4-(3-( 3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enonyl)-2-methyl-benzonitrile (43.7g, the product of Example 2) in THF (160mL) After the dropwise addition, the system was slowly warmed up to room temperature and stirred for 6 hours. Then the system was removed under high vacuum and reduced pressure to remove the solvent, the residue was added ethyl acetate (300mL) and water (300mL), stirred thoroughly and left to stand for layering, the aqueous phase was extracted once with ethyl acetate (100mL), and the organic phases were combined. Remove the solvent from the organic phase under ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to synthesis of fluralaner, and the key step of synthesis relates to preparation of the fluralaner through reaction of 4-(5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4, 5-dihydroisoxazole-3-yl)-2-methyl-benzonitrile and 2-amino-N-(2, 2, 2-trifluoroethyl) acetamide under the action of Zn(OTf)2 / hydroxylamine hydrochloride.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to the synthesis of Freilaner. Background technique [0002] Fluralaner (English translation name: Fluralaner), has been used as an insecticidal veterinary drug (trade name Bravecto) in 2014 TM ) is marketed in Germany, Spain, Italy, France, the Netherlands and the United Kingdom, and is mainly used to kill insects in and out of animals; in July 2016, the US FDA approved the application of Merck. (Frellaner Topical Solution) is used to treat fleas and ticks in cats and dogs and is effective for up to 12 weeks at a single dose. Studies have shown that Freilaner is a class of very effective insecticidal active compounds, which interfere with the gamma-aminobutyric acid (GABA) gate channel and lead to overexcitability of the nervous system and death. As a new type of high-efficiency GABA-controlling chloride ion channel disruptor, compared with phenylpyrazoles, cyclopentadienes and...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/04
CPCC07D261/04
Inventor 朱灿杨晓瑜
Owner 江苏君若药业有限公司