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Preparation method of polysubstituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with protecting groups

An extraction and extraction device technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of inconvenient vibration operation of the extraction device, difficulty in the implementation of the extraction process, and small volume of the extraction device.

Active Publication Date: 2020-11-27
北京六合宁远医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The first object of the present invention is to solve two specific problems in the prior art, one is to set out from 2,3-difluoroaniline, how to obtain ((2-difluoromethoxy )-5-hydroxypyridin-3-yl)methyl)carbamic acid tert-butyl ester problem, the application scheme perfectly solves this problem, and the second is that it is difficult to implement the extraction link, and the volume of the extraction device that is too small is too small, And the problem of inconvenient operation of the vibration of the excessive extraction device, which has been solved in this application

Method used

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  • Preparation method of polysubstituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with protecting groups
  • Preparation method of polysubstituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with protecting groups
  • Preparation method of polysubstituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with protecting groups

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] An ultrasonic extraction device is characterized in that it includes an extraction part 1 , a shell part 2 , an ultrasonic part 3 , a bar part 4 , a left support part 5 , a right support part 6 , a glassware 7 and an emulsion breaking component 8 . The extraction device can be divided into multiple specifications, for example, the volume of the extraction part can be 1L, 2L, 3L, 4L, 5L to meet different needs.

[0058]The extraction part 1 includes a cylindrical part 11 , an upper opening 12 , an upper cover 13 , a cone part 14 , a stopper set 15 and a liquid outlet 16 . The main part of the extraction part 1 is spliced ​​from top to bottom by an upper opening 12, a cylindrical part 11, and a cone part 14. The cylindrical part 11 is a hollow cylinder, the upper opening 12 is large and the bottom is small, and the inner surface is a frosted part. 121, the outer edge of the upper cover 13 adapted to the frosted part 121 is a frosted surface, the upper center of the upper ...

Embodiment 2

[0067] A method for preparing a multi-substituted fluorine-containing nitrogen-containing heterocyclic methylamine with a protective group. Due to the large amount of extraction required, it is carried out using an ultrasonic extraction device as described above. It is characterized in that it includes the following step.

[0068] (1) Dissolve 9-11g of 2-hydroxy-5-bromopyridine-3-carboxylic acid in 105-115ml of methanol, stir until the system is colorless and transparent, heat up to 65°C and reflux, and start to dropwise add 13-14g of chlorinated Sulfoxide, 6-8min dropwise, the system gradually turns yellow and transparent, keep warm at 65°C until the reaction is monitored by HPLC, then lower the reaction mixture to room temperature, spin the reaction mixture to dryness and concentrate, add 50ml of ethyl acetate to dilute, and then Add 20ml of water to wash, and the solid precipitates out. The whole reaction mixture is suction-filtered, and the solid is beaten with 50ml of met...

Embodiment 3

[0079] A method for preparing a multi-substituted fluorine-containing nitrogen-containing heterocyclic methylamine with a protective group. Due to the large amount of extraction required, it is carried out using an ultrasonic extraction device as described above. It is characterized in that it includes the following step.

[0080] (1) Dissolve 11g of 2-hydroxy-5-bromopyridine-3-carboxylic acid in 115ml of methanol, stir until the system is colorless and transparent, heat up to 65°C and reflux, start to add 14g of thionyl chloride dropwise, and add dropwise for 8 minutes Complete, the system gradually becomes yellow and transparent, keep warm at 65°C until the reaction is monitored by HPLC, then the reaction mixture is lowered to room temperature, the reaction mixture is spin-dried and concentrated, diluted with 50ml of ethyl acetate, then washed with 20ml of water, and a solid is precipitated. The whole reaction mixture was filtered with suction, and the solid was beaten with ...

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Abstract

The invention relates to a preparation method of polysubstituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with protecting groups. The method is carried out by using an ultrasonic extraction device. The method is characterized by comprising the following steps of: heating 2-hydroxy-5-bromopyridine-3-formic acid to 65 DEG C in methanol, performing refluxing, dropwise adding thionyl chloride, and performing a reaction to obtain 2-hydroxy-5-bromopyridine-3-methyl formate; and preparing (2-(difluoromethoxy)-5-hydroxypyridine-3-yl) methyl) tert-butyl carbamate through nine steps, and namely, obtaining the final product. The extraction is implemented by an ultrasonic extraction device, and comprises a preparation step, a covering step, a vibration shaking step, a repeating step and a receiving step. The ultrasonic extraction device comprises an extraction part (1), a shell part (2), an ultrasonic part (3), a transverse rod part (4), a left supporting part(5), a right supporting part (6), a glass device (7) and a demulsification assembly (8).

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of multi-substituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamines with protective groups. Background technique [0002] 4-Hydroxybenzoic acid and its derivatives are an important class of compounds with strong biological activity and are widely used in medicine, pesticides and other fields. Therefore, the synthesis of 4-hydroxybenzoic acid derivatives has received extensive attention, especially in It is widely used in pharmaceutical intermediates. A kind of preparation method of 3-chloro-4-hydroxybenzoic acid is provided in CN110357773A, and a kind of synthetic method of 3,5-di-tert-butyl-4-hydroxybenzoic acid is provided in CN109096099A, and this is all 4- Examples of the application and synthesis of hydroxybenzoic acid derivatives, but ((2-difluoromethoxy)-5-hydroxypyridin-3-yl)methyl)t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/69B01D11/04
CPCC07D213/69B01D11/0423Y02P20/55
Inventor 王海涛张义勇裴星先
Owner 北京六合宁远医药科技股份有限公司
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