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Preparation method of sulfadoxine midbody 4,6-dichloro-5-methoxypyrimidine

A methoxy pyrimidine and methoxy pyrimidine technology is applied in the field of preparation of 4,6-dichloro-5-methoxy pyrimidine as a periodic sulfonamide intermediate, which can solve the problems of low production efficiency, unfavorable continuous production, Problems such as many purification steps, to achieve the effect of improving yield, improving industrial production efficiency, and reducing purification steps

Active Publication Date: 2018-10-16
舞阳威森生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, this method has many purification steps, which is not conducive to continuous industrial production, and the production efficiency is low.

Method used

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  • Preparation method of sulfadoxine midbody 4,6-dichloro-5-methoxypyrimidine
  • Preparation method of sulfadoxine midbody 4,6-dichloro-5-methoxypyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] A preparation method of sulfonamide intermediate 4,6-dichloro-5-methoxypyrimidine, the steps are as follows:

[0047] 1) Preparation of 2-chloro-dimethyl malonate

[0048] Add 800L of dichloromethane into the No. 1 reaction kettle with a diaphragm pump, start stirring, add 400kg of dimethyl malonate, continue stirring and control the temperature at 8°C, open the tail gas absorption device, and start to introduce chlorine gas, and the chlorine gas and propane The molar ratio of dimethyl malonate is 1:0.812, and the passage of dimethyl malonate is completed in 3 hours; after the addition of chlorine gas, the temperature is raised to 25° C., and the reaction is carried out for 4 hours; sampling, detection by high-efficiency gas chromatography, the remaining dimethyl malonate does not exceed 1%, depending on For the completion of the chlorination reaction; concentrate under reduced pressure to remove dichloromethane, and take away excess chlorine gas; directly add 200L of m...

Embodiment 2

[0056] A kind of preparation method of sulfonamide intermediate 4,6-dichloro-5-methoxypyrimidine,

[0057] It differs from Example 1 in that:

[0058] 1) Preparation of 2-chloro-di-tert-butyl malonate

[0059] Add 800 L of dichloroethane into the No. 1 reactor with a diaphragm pump, start stirring, add 654.8 kg of di-tert-butyl malonate, continue stirring and control the temperature at 8°C, start the tail gas absorption device, and start to introduce chlorine gas, and The molar ratio of chlorine gas to di-tert-butyl malonate is 1:0.812, and the passage is completed in 3 hours; after the addition of chlorine gas, the temperature is raised to 25° C., and the reaction is carried out for 4 hours; sampling is carried out and detected by high performance gas chromatography, and there is no remaining di-tert-butyl malonate If it exceeds 1%, it is considered that the chlorination reaction is complete; the dichloroethane is removed by concentration under reduced pressure, and the exce...

Embodiment 3

[0065] A kind of preparation method of sulfonamide intermediate 4,6-dichloro-5-methoxypyrimidine,

[0066] It differs from Example 1 in that:

[0067] 1) Preparation of 2-chloro-dimethyl malonate

[0068] Add 800L of dichloromethane into the No. 1 reaction kettle with a diaphragm pump, start stirring, add 400kg of dimethyl malonate, continue stirring and control the temperature at 8°C, open the tail gas absorption device, and start to introduce chlorine gas, and the chlorine gas and propane The molar ratio of dimethyl malonate is 1:0.812, and the passage is completed in 3 hours; after the addition of chlorine gas, start to heat up to 25° C., and react for 8 hours; sampling, high performance gas chromatography detection, dimethyl malonate remains no more than 1%, depending on In order to complete the chlorination reaction; concentrate under reduced pressure to remove dichloromethane, and take away excess chlorine gas; directly add 200L of methanol to the remaining liquid to di...

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Abstract

The invention belongs to the technical field of the preparation of a sulfadoxine midbody, and particularly relates to a preparation method of the sulfadoxine midbody 4,6-dichloro-5-methoxypyrimidine.The method comprises the following steps: (1) adopting malonic acid diester as a raw material, and successively performing the chlorination to prepare 2-chloro-malonic acid diester; (2) performing themethoxidation reaction, and obtaining 2-methoxyl-malonic acid diester; (3) performing the cyclization reaction, and obtaining 4,6-dihydroxyl-5-methoxypyrimidine disodium salt; and (4) performing thesecondary chlorination, and obtaining 4,6-dichloro-5-methoxypyridine. By adopting the preparation method, the purification steps can be reduced, the continuous flow and no material discharge of the production process can be realized, and the continuous flow process is environment-friendly and safe; and moreover, at least two hours can be saved, the time cost can be reduced, and the industrial production efficiency can be improved.

Description

technical field [0001] The invention belongs to the technical field of preparation of sulfonamide intermediates, and in particular relates to a preparation method of sulfonamide intermediates—4,6-dichloro-5-methoxypyrimidine. Background technique [0002] 4,6-dichloro-5-methoxypyrimidine is an important organic intermediate and the main raw material for the synthesis of broad-spectrum antibacterial drug sulfadoxine. It is also widely used in the field of pesticides and is one of the important intermediates for the synthesis of salicylic acid pyrimidine herbicides. [0003] For the preparation method of 4,6-dichloro-5-methoxypyrimidine, studies have shown that there are many methods, such as using 2-methoxy-dimethyl malonate as the starting material, and thiourea through condensation to synthesize The mercaptopyrimidine ring is demercaptolated using Raney nickel to obtain an aqueous solution of 4,6-dihydroxy-5-methoxypyrimidine, which is then chlorinated with phosphorus oxyc...

Claims

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Application Information

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IPC IPC(8): C07D239/34
CPCC07D239/34
Inventor 彭学东张梅赵金召闫勇义
Owner 舞阳威森生物医药有限公司
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