Preparation methods of 2,4-diamido-5-nitroso-6-hydroxypyridine and guanine

A technology of hydroxypyrimidine and nitroso, which is applied in the field of preparation of 2,4-diamino-5-nitroso-6-hydroxypyrimidine and guanine, which can solve the problem that dilute formic acid solution cannot be recycled and applied mechanically, which increases the cost of preparation , Increase the cost of guanine preparation, etc., to achieve the effect of being suitable for large-scale production, reducing biodegradability, and facilitating recycling

CN108558776AActive Publication Date: 2018-09-21潍坊奥通药业有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2018-09-21

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Abstract

The invention discloses a preparation method of 2,4-diamido-5-nitroso-6-hydroxypyridine. The preparation method comprises the following steps: (1) in a sodium methoxide methanol solution, carrying outa ring-closure reaction between methyl cyanoacetate and guanidine salt; (2) adding recycled absolute methanol to be diluted, filtering and recycling byproduct sodium nitrate; (3) concentrating a filter liquor, and recycling absolute methanol; (4) adding water to destroy excessive sodium methoxide, concentrating and recycling water-containing methyl alcohol; (5) in a diluted methane acid solution,carrying out a nitrosation reaction among an obtained concentrate, sodium nitrite and a nitrosation mother liquor; (6) after the reaction ends, carrying out cooling crystallization, filtering, takinga filter liquor as the nitrosation mother liquor to be used indiscriminately, and drying an obtained filter cake to obtain the 2,4-diamido-5-nitroso-6-hydroxypyridine. According to the preparation method, indiscriminate use of the nitrosation mother liquor and recycling of sodium nitrate and methyl alcohol are realized, and simultaneously the diluted methane acid solution is used for replacing concentrated sulfuric acid used, in the prior art, to carry out the nitrosation reaction, so that the recycling of a solvent and a reagent is facilitated, and the displacement of waste water is reduced.
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Description

technical field

[0001] The invention belongs to the technical field of preparation of key intermediates of lowe-type antiviral drugs and folic acid, and specifically relates to a preparation method of 2,4-diamino-5-nitroso-6-hydroxypyrimidine and guanine. Background technique

[0002] Clovir drugs, mainly including acyclovir, ganciclovir, valacyclovir and faciclovir, are broad-spectrum antiviral drugs. It is clinically used to treat herpes simplex and diseases related to HSV infection.

[0003] Folic acid, also called vitamin B9, is a water-soluble anti-anemia vitamin. Folic acid helps the metabolism of protein, and together with vitamin B12, promotes the production and maturation of red blood cells.

[0004] 2,4,5-triamino-6-hydroxypyrimidine sulfate is an important intermediate for the synthesis of folic acid and Lovers, and nitrospyrimidine is the synthesis of 2,4,5-triamino-6-hydroxypyrimidine sulfate and The important intermediate of guanine, paper literature (Guangd...

Examples

Embodiment 1

[0054] Put 950Kg of sodium methoxide methanol solution into a 3KL enamel reaction kettle, start stirring under nitrogen protection, and then put in 325Kg of guanidine nitrate. After feeding, the temperature was raised to reflux for 90 minutes.

[0055] Then, dropwise addition of 253 Kg of methyl cyanoacetate was started. After dripping, continue the reflux ring closure reaction for 4 hours to end the reaction.

[0056] After the reaction is over, transfer the material to a 5KL enamel salt crystallization kettle, add 2000L of anhydrous methanol recovered by distillation in the previous batch, and continue the reflux reaction for 30 minutes. Then, lower the temperature to 50°C, and keep stirring for 60 minutes. Pressure filter with nitrogen to dryness, then wash the filter cake with 150L of anhydrous methanol recovered from the previous batch of distillation, combine the filtrate and washing liquid, and transfer it to a 5KL enamel concentration kettle; the filter cake is the b...

Embodiment 2

[0063] Put 950Kg of sodium methoxide methanol solution into a 3KL enamel reaction kettle, start stirring under nitrogen protection, and then put in 325Kg of guanidine nitrate. After feeding, the temperature was raised to reflux for 30 minutes.

[0064] Then, dropwise addition of 253 Kg of methyl cyanoacetate was started. After dropping, continue the reflux ring closure reaction for 2 hours to end the reaction.

[0065] After the reaction is over, transfer the material to a 5KL enamel salt crystallization kettle, add 2000L of anhydrous methanol recovered by distillation in the previous batch, and continue the reflux reaction for 60 minutes. Then, the temperature was lowered to 60°C, and the mixture was kept stirring for 30 minutes. Pressure filter with nitrogen until dry, then wash the filter cake with 150Kg of anhydrous methanol recovered from the previous batch of distillation, combine the filtrate and washing liquid, and transfer it to a 5KL enamel concentration kettle; th...