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Synthetic method of isoxazoline anthelmintic

A technology of isoxazolines and synthetic methods, which is applied in the field of chemical drug synthesis, can solve problems such as complicated operations and increased costs, and achieve the effects of cheap raw materials, saving raw materials, and improving yields

Pending Publication Date: 2020-09-22
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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  • Synthetic method of isoxazoline anthelmintic
  • Synthetic method of isoxazoline anthelmintic
  • Synthetic method of isoxazoline anthelmintic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Step 1: Substitution Reaction

[0034]

[0035] Add 160ml of DMF to a 500ml four-neck flask, stir, and add 20g (0.112mol) of intermediate I at room temperature. Slowly add 19.37g (0.145mol) NCS in batches, keep warm for 2 hours after adding, use PE:EA=5:1 developer for TLC detection, and proceed to the next step after the reaction of raw material intermediate I.

[0036] The second step: addition and ring closure reaction

[0037]

[0038] Then add 32.27g (0.134mol) intermediate II to the reaction solution of the first step, slowly add 25.97g (0.257mol) Et 3 The DMF (60ml) solution of N was incubated for 3 hours, and the TLC detection was carried out using the developer of PE:EA=5:1 (volume ratio), and the next step was carried out after the product 1 was reacted.

[0039] The third step: amidation condensation reaction

[0040]

[0041] Add 18.08g (0.134mol) HOBt, 25.58g (0.134mol) EDC hydrochloride and 30g (0.156mol) intermediate III to the reaction soluti...

Embodiment 2

[0050] Add 160ml DMSO to a 500ml four-necked flask, stir at room temperature, and then add 20g (0.112mol) of Intermediate I. Slowly add 19.37g (0.145mol) NCS in batches, add heat preservation reaction for 2 hours, use PE:EA=5:1 (volume ratio) developer to carry out TLC detection, after the raw material intermediate I has reacted, add to the reaction solution Add 32.27g (0.134mol) of intermediate II to , slowly drop 25.97g (0.257mol) of Et at room temperature 3 A solution of N in DMSO (60ml) was incubated for 3 hours. After the reaction was detected by TLC (PE:EA=5:1), the temperature was controlled to normal temperature and 18.08g (0.134mol) of HOBt, 25.58g (0.134mol) of EDC hydrochloride and 30g (0.156mol) of intermediate Body III, incubated for 2 hours, and detected by TLC until the reaction was complete (PE:EA=5:1).

[0051] The reaction solution was slowly added to 2.2 L of purified water, stirred while adding, and stirred for 1 hour after the addition. Filtration, the ...

Embodiment approach 3

[0053] Add 200ml of DMF to a 500ml four-neck flask, stir at room temperature, and then add 20g (0.112mol) of intermediate I. Slowly add 22.43g (0.168mol) NCS in batches, and keep warm for 2 hours after the addition is completed. After the reaction of raw material intermediate I is detected by TLC (PE:EA=5:1), add 40.49g (0.168mol) to the reaction solution Intermediate II, control the temperature to normal temperature and slowly add 39.59g (0.392mol) Et 3 A solution of N in DMF (80ml) was incubated for 3 hours. After the reaction was detected by TLC (PE:EA=5:1), the temperature was controlled to normal temperature and 37.8g (0.28mol) of HOBt, 53.48g (0.28mol) of EDC hydrochloride and 32.26g (0.168mol) of EDC hydrochloride were added to the reaction solution. Intermediate III was incubated for 2 hours, and TLC detected that the reaction of the raw materials was complete (PE:EA=5:1).

[0054] The reaction solution was slowly added to 2.8 L of purified water, stirred while addin...

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Abstract

The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a synthesis method of an isoxazoline anthelmintic. The method is characterized in that the isoxazoline anthelmintic is fluralaner, and the method includes the steps of: carrying out substitution reaction, addition cyclization reaction and amidation condensation reaction on an intermediate I in a same reaction container sequentially; and after the reaction is finished, adding water and performing filtering, recrystallizing the obtained solid, and conducting filtering and airing to obtain the product. The method has the beneficial effects that: the method uses a solvent one-pot process to synthesize fluralaner, the technological operation of the synthesis process is reduced, the treatment time and the reaction time are shortened, meanwhile, the 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 medicine synthesis, and in particular relates to a synthesis method of isoxazoline anthelmintics. Background technique [0002] Frelaner is an isoxazoline organic compound, which can be used as a broad-spectrum insecticide, and has good insecticidal activity against pests such as ticks, fleas, lice, hemiptera and diptera , and its toxicity is higher than or equivalent to commonly used insecticides. Not only does Freilaner have no significant cross-resistance with existing insecticides, it even has good insecticidal activity against partially resistant pests. As an API, Frellana has a large demand in the market, but the price is relatively expensive, and the process needs to be simplified. [0003] A kind of synthetic technique of Fluralaner is provided in the prior art (Hubei University of Technology, Huang Daoyou, the synthetic technique research of novel veterinary drug Fluralaner, 2017), car...

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 崔志刚张永赞程雪娇余贵菊姜淋洁韩怡杨雪王猛甄盼盼罗潇
Owner TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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