Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthetic method of 4,6- dichloro-5-(2-methoxyphenoxy)-2,2í»-dipyridine

A technology of methoxyphenoxy and dipyrimidine, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of being unsuitable for industrial production, difficult to scale up production, and low in total yield, and achieves reduction of intermediate operation steps and operation costs. , The effect of improving yield and convenient operation

Inactive Publication Date: 2008-10-08
南京博鸿电子材料开发有限公司
View PDF1 Cites 6 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the above scheme, when preparing 2-pyrimidine formamidine benzenesulfonate, it needs to be reacted at 230-250°C, and the reaction is carried out under solvent-free conditions. After the reaction is cooled, it will form a whole piece of solid, which is difficult to operate. , it is difficult to scale up production, so it is not suitable for industrialized production; in addition, the total yield of the five-step reaction of this route is low, only 8%

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
  • Synthetic method of 4,6- dichloro-5-(2-methoxyphenoxy)-2,2í»-dipyridine
  • Synthetic method of 4,6- dichloro-5-(2-methoxyphenoxy)-2,2í»-dipyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Preparation of 2-halogenated diethyl malonate (a):

[0033] In a 100L reactor, add 64L of 1,2-dichloroethane, 6.4KG of diethyl malonate, 11KG of benzenesulfonic acid, and finally add 5.4KG of NCS. Raise the temperature to 60-80°C and react for 5-8 hours. Evaporate 1,2-dichloroethane under reduced pressure, then add 30L water, stir and separate the liquid, extract the water layer with 1,2-dichloroethane 20L×3, combine the organic layers, wash with 10L water, add 6KG to the organic layer Dry over anhydrous sodium sulfate, filter after 3 hours, and evaporate to dryness under reduced pressure to obtain 7.24KG of a light yellow liquid with a yield of 93%.

[0034] (2) Preparation of 2-(2-methoxyphenoxy) diethyl malonate (b):

[0035] In a 50L reactor, add 25L of acetonitrile, 3.5KG of sodium carbonate, dropwise add 2.73KG of guaiacol, and then add dropwise of 4.27KG of 2-halogenated diethyl malonate in 5L of acetonitrile solution. Control the temperature at 60-80°C an...

Embodiment 2

[0044] (1) Preparation of 2-halogenated diethyl malonate (a):

[0045] In a 100L reactor, add 64L of acetonitrile, 6.4KG of diethyl malonate, 13KG of p-toluenesulfonic acid, and finally add 7.2KG of NBS. Raise the temperature to 50-70°C and react for 4-6 hours. Acetonitrile was distilled off under reduced pressure, then added to 30L of water, stirred and separated, the water layer was extracted with 1,2-dichloroethane (20L×3), the organic layers were combined, washed with 10L of water, and the organic layer was dried by adding 6KG anhydrous sodium sulfate, 3 After one hour, it was filtered and evaporated to dryness under reduced pressure to obtain 7.75 KG of a light yellow liquid with a yield of 81%.

[0046] (2) Preparation of 2-(2-methoxyphenoxy) diethyl malonate (b):

[0047] In a 50L reaction kettle, add 25L acetone, 3.5KG sodium methoxide, dropwise add 2.73KG guaiacol, and then add dropwise 5L acetone solution of 4.27KG 2-halogenated diethyl malonate. Control the tempe...

Embodiment 3

[0056] (1) Preparation of 2-halogenated diethyl malonate (a):

[0057] In a 100L reactor, add 50L of carbon tetrachloride, 6.4KG of diethyl malonate, 8KG of methanesulfonic acid, and finally add 4.8KG of NCS. Raise the temperature to 70-80°C and react for 5-7 hours. Carbon tetrachloride was evaporated under reduced pressure, then added to 30L of water, stirred and separated, the water layer was extracted with dichloromethane 20L×3, the organic layers were combined, washed with 10L of water, the organic layer was dried by adding 6KG anhydrous sodium sulfate, and after 3 hours Filter and evaporate to dryness under reduced pressure to obtain 5.06KG of a light yellow liquid with a yield of 65%.

[0058] (2) Preparation of 2-(2-methoxyphenoxy) diethyl malonate (b):

[0059] In a 50L reaction kettle, add 40L ethanol, 2KG sodium methoxide, dropwise add guaiacol 2.7KG, then add dropwise 4.27KG 2-halogenated diethyl malonate in 5L ethanol solution, after dropping, reflux React overn...

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 discloses a method to prepare 4,6-dichloro-5-(2- anisyl-phenoxyl)2-2`-bipyrimidine, a key intermediate compound for Bosentan which is a first-line drug for curing pulmonary hypertension. So 4,6-dichloro-5-(2- anisyl-phenoxyl)2-2`-bipyrimidine is of great market value. The method adopts reasonable processing route and takes ethyl malonate as material to produce 4,6-dichloro-5-(2- anisyl-phenoxyl)2-2`-bipyrimidine through halogenation, etherification, cyclization and chloro-substitution. The method is reduced in procedures, simple in process, high in yield and low in cost, with little pollution to the environment; therefore the method is applicable in industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing a drug intermediate, in particular to a drug intermediate 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine synthetic method. Background technique [0002] The first-line drug bosentan for the treatment of pulmonary arterial hypertension, its synthetic route is as follows: [0003] [0004] As an intermediate for the synthesis of the drug, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine has a huge market value. [0005] 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine, the appearance is light brown solid, the English name is 4,6-dichloro-5-(2-methoxy-phenoxy )-2-2'-bipyrimidine, CAS No. 150728-13-5. The synthetic method of this compound mainly comprises following 5 steps at present: [0006] 1) Diethyl malonate was chlorinated to obtain 2-chlorodiethyl malonate with a yield of 64%. This reaction method has been disclosed in US Patent No. 5,292,740; [0007] 2) 2-(2-methoxyphenoxy) diet...

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
IPC IPC(8): C07D239/34C07D239/46
Inventor 魏新
Owner 南京博鸿电子材料开发有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com