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Preparation method of isoxazoline insectifuge

A technology for isoxazolines and anthelmintics, applied in the field of chemical drug synthesis, can solve problems such as increased cost, complicated operation, etc., and achieves the effects of saving raw materials, cheap raw materials, and short time consumption

Inactive Publication Date: 2020-09-18
TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This technical scheme has many steps in the synthetic route, and the operation is complicated. Some intermediates can be carried out to the next step without separation, and the scale-up production will increase the cost.

Method used

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  • Preparation method of isoxazoline insectifuge
  • Preparation method of isoxazoline insectifuge
  • Preparation method of isoxazoline insectifuge

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The first step: amidation condensation reaction

[0034]

[0035] Add 200ml of DMF to a 500ml four-neck flask, stir, then add 20g (0.11mol) of intermediate I, control the temperature at 20-30°C, add 18.0g (0.13mol) of HOBt, 25.6g (0.13mol) of EDC to the reaction solution Hydrochloride and 30g (0.16mol) intermediate II, then add 25.9g (0.26mol) Et 3 N, keep the reaction for 2 hours, use PE:EA=1:1 (volume ratio) developer to perform TLC detection, until the reaction of intermediate I is complete.

[0036] Step 2: Substitution Reaction

[0037]

[0038] Then 19.4g (0.15mol) NCS was slowly added in batches to the above reaction solution, and after the addition was completed, the reaction was incubated at 20-30°C for 2 hours. TLC (PE:EA=1:1) detected that the reaction of product 1 was complete.

[0039] The third step: ring closing reaction

[0040]

[0041] 32.2 g (0.13 mol) of intermediate III was added to the reaction solution obtained in the second step, and ...

Embodiment 2

[0050] Add 200ml of DMSO to a 500ml four-neck flask, stir, then add 20g (0.11mol) of intermediate I, control the temperature at 20-30°C, add 18.0g (0.13mol) of HOBt, 25.6g (0.13mol) of EDC salt into the reaction solution salt and 30g (0.16mol) of intermediate II, then add 25.9g (0.26mol) of Et 3 N, keep the reaction for 2 hours, TLC detection (PE:EA=1:1) until the reaction of intermediate I is complete. Then slowly add 19.4 g (0.15 mol) NCS to the reaction liquid in batches, keep the reaction at 20-30° C. for 2 hours after the addition, and detect by TLC (PE:EA=1:1). Add 32.3g (0.13mol) of intermediate III to the reaction liquid, keep the reaction for 3 hours, and detect by TLC (PE:EA=1:1).

[0051] The reaction solution was slowly added to 2.8 L of purified water, stirred while adding, stirred for 1 hour after the addition, and filtered. The solid was recrystallized from petroleum ether and ethyl acetate, filtered, and air-dried to obtain 44 g, with a molar yield of 79.1%, ...

Embodiment 3

[0053] Add 200ml of DMF to a 500ml four-neck flask, stir, then add 20g (0.11mol) of intermediate I, and control the temperature at 20-30°C, add 37.8g (0.28mol) of HOBt, 53.48g (0.28mol) of EDC salt into the reaction solution salt and 32.6g (0.17mol) of intermediate II, then add 39.59g (0.39mol) of Et 3 N, keep the reaction for 2 hours, TLC detection (PE:EA=1:1) until the reaction of intermediate I is complete. Then slowly add 22.4g (0.17mol) NCS to the reaction liquid in batches, keep the reaction at 20-30°C for 2 hours after the addition, and detect by TLC (PE:EA=1:1). Add 40.5 g (0.17 mol) of intermediate III to the reaction liquid, keep the reaction for 3 hours, and detect by TLC (PE:EA=1:1).

[0054] The reaction solution was slowly added to 2.8 L of purified water, stirred while adding, stirred for 1 hour after the addition, and filtered. The solid was recrystallized from toluene and ethyl acetate, filtered, and air-dried to obtain 42.6 g, with a molar yield of 76.5%, a...

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Abstract

The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of an isoxazoline insectifuge. The preparation method is characterized in thatthe isoxazoline insectifuge is fluralaner; an intermediate I is sequentially subjected to an amidation condensation reaction, a substitution reaction and a ring closing reaction in the same reactioncontainer; and after the reactions are finished, a reaction product is poured into water, stirring and filtering are conducted to obtain a solid, and the obtained solid is recrystallized to obtain theisoxazoline insectifuge. The method has the beneficial effects that the method uses a solvent and one-pot method to synthesize fluralaner, technological operation of a synthesis process is reduced, treatment time and reaction time are shortened, product yield is improved, and the method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and in particular relates to a preparation method of isoxazoline anthelmintics. Background technique [0002] Fluralaner (Fluralaner), has been sold in European and American markets as an insecticidal veterinary drug (trade name Bravecto) in 2014. It is mainly used for killing insects in and out of animals. The drug composition on the market is a mixture of R and S configurations. CAS number: 864731-61-3; chemical formula: C 22 h 17 Cl 2 f 6 N 3 o 3 , the 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]benzamide is a class of very effective insecticidal active compounds; Fluralaner is the earliest and the only one that can quickly and effectively kill insecticides. A veterinary medical product for killing lice and fleas, a new type of isoxazoline animal insecticide that is safe f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/04A01N43/80A01P17/00
CPCC07D261/04A01N43/80
Inventor 张永赞崔志刚任连泉程雪娇姜艳华刘紫薇张磊陈明霞
Owner TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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