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

Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound

A synthetic method and compound technology, applied in the direction of organic chemistry, can solve the problems of good environmental protection and inability to take into account low cost, and achieve the effect of saving labor costs, taking into account costs, and reducing the risk factor

Active Publication Date: 2020-01-03
TIANJIN ASYMCHEM PHARMA
View PDF9 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The main purpose of the present invention is to provide a continuous synthesis method of 2-chloropyrimidine-4-carboxylic acid compounds, to solve the problem of low cost and high product quality when preparing 2-chloropyrimidine-4-carboxylic acid compounds in the prior art Yield, environmental protection and other aspects of the problem

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
  • Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound
  • Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound
  • Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0033] In formula I, R 1 and R 2 independently selected from hydrogen, alkoxy, aryl, benzyl or fluorine; the synthesis method comprises the following steps: S1, under the action of a non-noble metal catalyst, compound A and methyl Grignard reagent B are subjected to continuous methylation chemical reaction to obtain compound C; compound A is , compound C is , R 1 and R 2 With the same definition as above, the non-precious metal catalyst is one or more of iron salt, cobalt salt, nickel salt; S2, the compound C is subjected to continuous oxidation reaction under the action of oxygen to obtain 2-chloropyrimidine-4-carboxylic acids compound.

[0034]The present invention greatly improves the reaction efficiency and yield through the two-step continuous reaction, and the total yield of 2-chloropyrimidine-4-carboxylic acid compounds can also be increased to more than 70%, correspondingly greatly reducing the synthesis of the product cost. At the same time, the present inven...

Embodiment 1

[0052] Synthesized 2-chloropyrimidine-4-carboxylic acid in this embodiment, and concrete route is as follows:

[0053]

[0054] Step1 continuous methylation reaction:

[0055] 2,4-dichloropyrimidine 50g (compound A, 1.0equiv.), co-solvent N-methylpyrrolidone NMP 39.9g (1.2equiv.), catalyst FeCl 3 1.1 g (0.02 equiv.) was dissolved in 500 mL THF to obtain the first raw material solution. Then use the pump 1 to pump the first raw material solution into the coil of the coil reactor at a speed of 8.9g / min, and simultaneously use the pump 2 to pump 131g of methylmagnesium chloride Grignard reagent B into the coil with a speed of 2.2g / min In the tube, the coil is placed in an external bath at -55~-60°C for continuous methylation reaction. Wherein, the retention time of the first raw material liquid in the coil tube is 20min. The outlet of the coil is directly connected to a four-neck bottle with 200mL of ice water at 0~5°C. After feeding, the system is concentrated to remove T...

Embodiment 2

[0059] Compared with embodiment 1, be that the selected catalyst of step 1 is different

[0060] Step1 continuous methylation reaction:

[0061] 50g of 2,4-dichloropyrimidine (Compound A, 1.0equiv.), 39.9g (1.2equiv.) of N-methylpyrrolidone NMP as a cosolvent, and 0.93g (0.02equiv.) of catalyst NiCl2 were dissolved in 500mL THF to obtain the first raw material liquid. Then use the pump 1 to pump the first raw material solution into the coil of the coil reactor at a speed of 8.9g / min, and simultaneously use the pump 2 to pump 131g of methylmagnesium chloride Grignard reagent B into the coil with a speed of 2.2g / min In the tube, the coil is placed in an external bath at -55~-60°C for continuous methylation reaction. Wherein, the retention time of the first raw material liquid in the coil tube is 20min. The outlet of the coil is directly connected to a four-neck bottle with 200mL of ice water at 0~5°C. After the feeding is completed, the system is concentrated to remove THF, a...

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 provides a continuous synthesis method of a 2-chloropyrimidine-4-formic acid compound. The 2-chloropyrimidine-4-formic acid compound has a structure represented by a formula I, wherein in the formula I, R1 and R2 are respectively and independently selected from hydrogen, alkoxy, aryl, benzyl or fluorine. The synthesis method comprises the following steps: S1, under the action of a non-noble metal catalyst, carrying out continuous methylation reaction on a compound A and a methyl Grignard reagent B to obtain a compound C, wherein the compound A is a compound shown in the specification, the compound C is a compound shown in the specification, R1 and R2 are respectively and independently selected from hydrogen, alkoxy, aryl, benzyl or fluorine, and the non-noble metal catalyst is one or more of ferric salt, cobalt salt and nickel salt; and S2, carrying out continuous oxidation reaction on the compound C under the action of oxygen, an oxidation catalyst and an additive, and thus obtaining the 2-chloropyrimidine-4-formic acid compound. By adopting the process provided by the invention to synthesize the 2-chloropyrimidine-4-formic acid compound, the aspects of cost, yield,environmental friendliness and the like can be considered.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a continuous synthesis method of 2-chloropyrimidine-4-carboxylic acid compounds. Background technique [0002] 2-Chloropyrimidine-4-carboxylic acid is a key intermediate in the synthesis of benzenesulfonamide pyrazole kinase inhibitors for the treatment of hyperphosphatemia, which is expensive. Regarding the preparation of 2-chloropyrimidine-4-carboxylic acid, there are few effective synthesis methods reported at present. There are reports in the literature that 2-chloropyrimidine-4-formyl chloride is prepared by dissociation of ammonia water (US5591853, 1997, A), and there are also 2- Chloro-4-methylpyrimidine hydrochloride as raw material, after POCl 3 High-temperature dissociation, followed by oxidation of potassium permanganate or selenium dioxide, the post-reaction treatment is cumbersome, the three wastes are huge, and highly toxic substances are used, making it ...

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): C07D239/30
CPCC07D239/30
Inventor 洪浩卢江平张恩选魏福亮杨思航
Owner TIANJIN ASYMCHEM PHARMA
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