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The continuous synthesis method of 2-chloropyrimidine-4-carboxylic acid compounds

A synthesis method and compound technology, applied in organic chemistry and other fields, 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 making the synthesis process green

Active Publication Date: 2020-05-26
TIANJIN ASYMCHEM PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

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  • The continuous synthesis method of 2-chloropyrimidine-4-carboxylic acid compounds
  • The continuous synthesis method of 2-chloropyrimidine-4-carboxylic acid compounds
  • The continuous synthesis method of 2-chloropyrimidine-4-carboxylic acid compounds

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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...

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Abstract

The invention provides a continuous synthesis method of 2-chloropyrimidine-4-formic acid compounds. 2-chloropyrimidine-4-formic acid compound has the structure shown in formula I: in formula I 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 continuously methylated Reaction, obtain compound C; Compound A is, compound C is, R 1 and R 2 Have the same definition as above, the non-precious metal catalyst is one or more in iron salt, cobalt salt, nickel salt; S2, compound C is carried out continuous oxidation reaction under the effect of oxygen, oxidation catalyst and additive, obtains 2-chloro Pyrimidine‑4‑carboxylic acid compounds. Synthesizing 2-chloropyrimidine-4-carboxylic acid compounds by adopting the process provided by the invention can take into account aspects such as cost, yield, and environmental protection.

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

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Application Information

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Patent Type & Authority Patents(China)
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
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