Preparation method of isoxazoline anthelmintic fluralaner

A technology of isoxazolines and flurelana, applied in the field of chemistry or medicinal chemistry, can solve the problems of harsh conditions, high experimental operation requirements, high price, etc., and achieves mild reaction conditions, short synthetic routes, and easy operation. Effect

Active Publication Date: 2022-01-07
CHANGZHOU YABANG QH PHARMACHEM +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Among the above three routes, although the route (l) has fewer steps, the price of 4-acetyl-2-methylbenzoic acid and 2-amino-N-(2,2,2-trifluoroethyl)acetamide is relatively high. Expensive, high production cost; in route (2), 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene is expensive and the key step is l,3-dipolar addition ring closure The yield of the reaction is extremely low; in the route (3), gas CO participates in the reaction, and the reaction conditions need to be reacted at a pressure of 5 atmospheres, the conditions are relatively harsh, and the experimental operation requirements are relatively high
The above routes have certain limitations and are not suitable for mass production

Method used

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  • Preparation method of isoxazoline anthelmintic fluralaner
  • Preparation method of isoxazoline anthelmintic fluralaner
  • Preparation method of isoxazoline anthelmintic fluralaner

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) Ring: 4- [3- (3,5-dichlorophenyl) -4,4,4-trifluorobutyl-2-enyloyl] -2-methyl-benzene in the 1L reaction bottle Ethyl formate was ethyl formate 43.1 g (0.1 mol) and hydroxylamine hydroxylamine (0.2 mol) of isoamate, acetate is 10.2 g (0.03 mol), and lithium hydroxide 6.0 g of hydroxide is added in batches under stirring (0.25) Mol) / water 30g, add 5 hours after 25-30 ° C, the reaction is completed, stationary, the upper organic layer is concentrated under reduced pressure, the temperature is 60 ° C, the degree of vacuum is -0.09 MPa, resulting in a condensate 46.5 g. HPLC detection was 98.1%.

[0037] [M] = 446.0 (see figure 1 )

[0038] (2) Hydrolysis: The above condensate 46.5 g (0.1 mol) and 320 g of methanol, 20.2 g (0.25 mol) of ammonia were 80-65 ° C for 6 hours, and the temperature was 10-15 ° C. PH = 2-3 by phosphoric acid. Pumped filtration, water rinsing to neutral. It was dried at 50 ° C for 16 hours to give 39.5 g of hydrolyzate. Ring and hydrolysis two-step...

Embodiment 2

[0047] (1) Ring: 4- [3- (3,5-dichlorophenyl) -4,4,4-trifluorobutyl-2-enyloyl] -2-methyl-benzene in the 1L reaction bottle Ethyl formate was ethyl formate and 7.6 g (0.11 mol) of hydroxylamine hydroxylamine, butyl acetate 250g, benzyl triethyl ammonium chloride 1.14 g (0.005 mol), and potassium hydroxide was added batch with stirring (EtOAc) 0.15 mol) / water 20g, the addition of 25-30 ° C for 2 hours, the reaction is completed, stationary, the upper organic layer is concentrated under reduced pressure, the temperature is 60 ° C, the vacuum is -0.1MPa, resulting in a condensate 46.8 g. HPLC detection was 98.0%.

[0048] (2) Hydrolysis: The above-mentioned condensate 46.8 g (0.1 mol) and isopropyl alcohol 320g, 10.1 g (0.18 mol) / water 25g, temperature rise to 40-45 ° C for 4 hours, cool down 10 -15 ° C. PH = 1-2 was adjusted with 30% hydrochloride. Pumped filtration, water rinsing to neutral. 60 ° C is dried for 15 hours to give hydrolyzate 39.7 g. Ring and hydrolysis of two-step ...

Embodiment 3

[0051] (1) Ring: 4- [3- (3,5-dichlorophenyl) -4,4,4-trifluorobutyl-2-enyloyl] -2-methyl-benzene in the 1L reaction bottle Ethyl formate 43.1 g (0.1 mol) and hydroxylamine hydroxylamine (0.16 mol), methyl tert-butyl ether 280g, triethylmomethyl ammonium chloride 4.04 g (0.01 mol), stirred with batch of sodium carbonate under stirring 15.9 G (0.15 mol) / water 60g, the addition is completed at 25-30 ° C for 2 hours, the reaction is completed, stationary, the upper organic layer is concentrated under reduced pressure, the temperature is 40 ° C, the vacuum is -0.08MPa, resulting in a condensate 46.3 g. HPLC detection was 98.2%.

[0052] (2) Hydrolysis: The above-mentioned condensate 46.8 g (0.1 mol) and 460 g of methanol, 26.5 g (0.25 mol) / water 100g, temperature rise to 75-80 ° C for 4 hours, cooling 10-15 ° C . PH = 1-2 with formic acid. Pumped filtration, water rinsing to neutral. The heating was dried at 90 ° C for 10 hours to give 30 hydrolyzate 39.3 g. The ring combination and...

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Abstract

The invention discloses a preparation method of an isoxazoline anthelmintic fluralaner. The preparation method comprises the following steps: by taking ethyl 4-[3-(3,5-dichlorophenyl)-4,4,4-trifluorobutyl-2-enoyl]-2-methyl-benzoate and hydroxylamine hydrochloride as initial raw materials, carrying out cyclization reaction under the catalysis of a phase transfer catalyst and an acid-binding agent, then carrying out alkaline hydrolysis reaction, and finally carrying out condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to obtain the fluralaner. The synthetic route is short, the reaction condition is mild, the operation is simple and convenient, the conversion rate is high, the method is suitable for industrial production, the purity can reach 99.5% or above, and the single impurity content is less than 0.1%.

Description

Technical field [0001] The present invention belongs to the field of chemical or pharmaceutical chemistry, and more particularly to the preparation method of florconaner. Background technique [0002] Japan's Nissan Chemical Industrial Co., Ltd. (Nissanchemic Industries) successfully developed the use of the iszazoline-based brewormic agent Fluores (English name: Fluralalancr), and obtained the authorization of international patents in 2005. This compound is a patented expiration time of 2025. The chemical structure is as follows: [0003] [0004] Fluores is the active substance of the latest listing veterinary drug Bravecto (chewable tablets), a new inner capabilities and acaricides, suitable for treating scorpions and fleas in dogs. Listed in April 2014 in Germany, Spain, Italy, France, the Netherlands and the UK, mainly used for inner and outer insecticides in animals, the listing of drug components of the R and S configurations. This chewable tablet is the earliest and is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/04
CPCC07D261/04
Inventor 朱建民张继瑜王学成金叶峰苏文杰杨枭荣李冰高新宇蒋泽龙
Owner CHANGZHOU YABANG QH PHARMACHEM
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