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

Preparation method of fluralaner intermediate

A technology for the production of Frellaner and its intermediates, which is applied in the field of preparation of the key intermediates of Frellaner, which can solve the problems of long reaction time, dangerous operation, and difficulty in product separation and purification, and achieve the advantages of simplified preparation process and mild process conditions Effect

Pending Publication Date: 2021-03-26
ZHEJIANG MENOVO PHARMA +1
View PDF7 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, according to the method disclosed in the prior art, the preparation of 4-formyl-2-methylbenzoic acid is difficult, the carbon insertion reaction requires special equipment, the gas source is very inconvenient, and the operation is very dangerous during large-scale preparation, and it is prone to explosion. Leakage is prone to poisoning and serious pollution. In addition, the reaction time of the above method is long, usually several days, the reaction is not complete, and the separation and purification of the product is difficult and the yield is low.

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
  • Preparation method of fluralaner intermediate
  • Preparation method of fluralaner intermediate
  • Preparation method of fluralaner intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation method of Freilaner intermediate in the present embodiment comprises the following steps:

[0033] (1) In a 500mL four-neck flask equipped with a thermometer and mechanical stirring, add 0.1moL of compound 5 (methyl 4-cyano-2-methylbenzoate) and 150mL of methanol, then add 25mL of triethylamine and 10.5 g of hydroxylamine hydrochloride, reacted at 50-55°C for 3 hours, after TCL detected that the reaction was complete, it was cooled to room temperature, concentrated under reduced pressure to 50-75mL, stirred at room temperature for 2-3 hours, filtered, and vacuum-dried to obtain 20.1g of off-white solid , this kind of white solid is compound 4. The yield was 96%, as figure 1 As shown, ESI-MS (m / z): 209[M+H]+, the sample molecular weight 208 is consistent with the target object;

[0034] (2) Add 15.6g of compound 4 (methyl 4-carboxamide oxime-2-methylbenzoate) to a 500mL reaction flask, add 100mL of acetonitrile and stir to dissolve, add 7mL of 36% conc...

Embodiment 2

[0037] The preparation method of Freilaner intermediate in the present embodiment comprises the following steps:

[0038](1) In a 500mL four-necked flask equipped with a thermometer and mechanical stirring, add 0.2moL of compound 5 (methyl 4-cyano-2-methylbenzoate) and 400mL of ethanol, then add 50mL of N,N-di Isopropylethylamine and 28g of hydroxylamine hydrochloride were reacted at 60-65°C for 5 hours, TCL detected that the reaction was complete, then lowered to room temperature, concentrated under reduced pressure to 100-150mL, stirred at room temperature for 2-3 hours, filtered, and vacuum-dried , to obtain 40.6 g of off-white solid, which is compound 4, and the yield is 98%;

[0039] (2) Add 20.8g of compound 4 (methyl 4-carboxamide oxime-2-methylbenzoate) into a 500mL reaction flask, add 100mL of ethylene glycol dimethyl ether and stir to dissolve, add 10mL of 47 % hydrobromic acid, add 25g of 30% sodium nitrite solution at 0-5°C, and keep it warm for 1h; then add dropw...

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 a preparation method of a fluralaner intermediate, which comprises the following steps of: carrying out addition reaction on 4-cyano-2-methyl toluate serving as an initial reactant and hydroxylamine to obtain 4-formamide oxime-2-methyl toluate, carrying out diazotization and denitrification reaction in sequence to obtain a halogen oxime compound, and finally carrying out addition cyclization reaction on the halogen oxime compound and 1, 3-dichloro-5-(1-trifluoromethyl-vinyl) benzene to obtain a target product fluralaner intermediate. Amidoxime is prepared through an addition reaction, and then halogenated oxime is prepared through a diazotization reaction. Compared with reduction, oximation and chlorination reactions in the prior art, the preparation process is greatly simplified, the process conditions are mild, safe and environmentally friendly, the yield can reach 70% or above, and the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of a key intermediate of Frelaner, specifically 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole -3-yl]-2-trifluoromethylbenzoic acid methyl ester preparation method of the preparation method. Background technique [0002] Frellana (English name: Fluralaner ) chemical name is 4,5-[(3,5-dichlorophenyl)-4,5-dihydro-5-trifluoromethyl-3-isoxazolyl]-2-methyl-nitrogen-[2 -Oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-benzamide. In 2004, Japan's Nissan Chemical Industry Co., Ltd. successfully synthesized Frellana. In 2014, Frellana was approved by the U.S. Food and Drug Administration (trade name Bravecto) to be sold in the European and American markets, with quarterly sales of 100 million US dollars. [0003] Frelaner mainly works by interfering with GABA-gated chloride ion channels, which are similar to the targets of pesticides such as cyclopentadienes, phenylpyrazoles and macrolides. T...

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 刘雄阮张寅刘文金黄想亮周国斌曹雨倩曹倩
Owner ZHEJIANG MENOVO PHARMA