Preparation method and application of 2, 4-diamino-6-hydroxy-5-formamidopyrimidine

A technology of hydroxypyrimidine and diamino, which is applied in the field of preparation of intermediates of Lowe antiviral drugs, can solve the problems of high raw material cost, low safety, and large amount of "three wastes", and achieve high atom utilization, yield and The effect of high purity and low price

Active Publication Date: 2020-09-11
潍坊奥通药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Aiming at the problems of high cost of raw materials, low safety and large amount of "three wastes" existing in the traditional process, the present invention provides a very good preparation method with low "three wastes" production, high safety, high conversion rate of the target product, and high atom economy

Method used

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  • Preparation method and application of 2, 4-diamino-6-hydroxy-5-formamidopyrimidine
  • Preparation method and application of 2, 4-diamino-6-hydroxy-5-formamidopyrimidine
  • Preparation method and application of 2, 4-diamino-6-hydroxy-5-formamidopyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Dissolve 50g of nitrosopyrimidine (MW155.11, 0.32mol) and 5g of sodium metabisulfite (MW190.11, 0.03mol) in 50g of formamide (MW45.04, 1.11mol) and 50g of water (MW18.02, 2.78mol) In the process, slowly raise the temperature to 70-80°C, keep the temperature for 2 hours, then raise the temperature to 105-115°C, and keep the temperature for 3 hours.

[0061] At the same time, the ammonia and carbon dioxide generated during the reaction were passed into 100 g of ice water to prepare a 33% aqueous solution of ammonium carbonate (which can be used for the free purification of guanine).

[0062] After the reaction is complete, add 150g of water, stir to dissolve, cool down to 5-15°C, keep the crystal for 2 hours, filter, and dry to obtain 53.2g of off-white solid powder, which is the target product 2,4-diamino-6- Hydroxy-5-carboxamidopyrimidine, the molar yield is 97.0%, and the purity is 99.0%.

[0063] The structural analysis data of the 2,4-diamino 6-hydroxyl-5-carboxamid...

Embodiment 2

[0067] Dissolve 200g of nitrosopyrimidine (MW155.11, 1.29mol) and 30g of sodium metabisulfite (MW190.11, 0.16mol) in 180g of formamide (MW45.04, 4.00mol) and 250g of water (MW18.02, 13.87mol) In the process, slowly raise the temperature to 70-80°C, keep the temperature for 2 hours, then raise the temperature to 105-115°C, and keep the temperature for 3 hours.

[0068] At the same time, the ammonia and carbon dioxide generated during the reaction were introduced into 400 g of ice water to prepare a 33% ammonium carbonate aqueous solution (which can be used for the free purification of guanine).

[0069] After the reaction is complete, add 600g of water, stir to dissolve, cool down to 5-15°C, keep the crystal for 2 hours, filter, and dry to obtain 213.0g of off-white solid powder, which is the target product 2,4-diamino-6- Hydroxy-5-carboxamidopyrimidine, the molar yield is 97.0%, and the purity is 99.0%.

Embodiment 3

[0074] Dissolve 50g (MW169.14, 0.29mol) of 2,4-diamino-6-hydroxy-5-carboxamidopyrimidine in 150g of 85% formic acid (MW46.03, 2.77mol), heat up to 120-130°C and reflux React for 13 hours.

[0075] After the reaction is complete, formic acid is reclaimed by distillation (recovering formic acid can be applied mechanically), 100 g of water is added, and after being cooled to room temperature, it is stirred and beaten for 30 minutes, and filtered to obtain 85 g of crude guanine. Dissolve the crude guanine formate in 200g of water, raise the temperature to 70-80°C, add dropwise 33% ammonium carbonate aqueous solution, adjust the pH of the reaction system to 7.5-8.5, stir for 0.5 hours, filter and dry to obtain 42.5g off-white The solid powder is the finished product of guanine, with a molar yield of 95% and a purity of 99.0%.

[0076] Its structural analysis data of the guanine prepared in the present embodiment are as follows:

[0077] ESI-MS(M / Z): 151.0[M] or 153.0[M+2H] such a...

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Abstract

The invention discloses a preparation method of 2, 4-diamino-6-hydroxy-5-carboxamido pyrimidine. The preparation method comprises the following step: carrying out an acylation reaction on 2, 4-diamino-5-nitroso-6-hydroxypyrimidine in formamide and water under the catalytic action of a catalyst A to obtain the 2, 4-diamino-6-hydroxy-5-carboxamido pyrimidine. The invention also discloses a preparation method of guanine formate or guanine. The preparation method of guanine formate or guanine comprises the following step: reacting the 2, 4-diamino-6-hydroxy-5-formamidopyrimidine in formic acid toobtain guanine. According to the synthesis methods of the 2, 4-diamino-6-hydroxy-5-formamidopyrimidine and guanine, the production process is greatly shortened, the generation amount of three wastes is greatly reduced, the product quality of the guanine product meets related quality requirements, and the molar yield is higher than that of the guanine product prepared by the prior art. Therefore, the preparation methods disclosed by the invention are efficient, economic, green and environment-friendly preparation methods.

Description

technical field [0001] The invention belongs to the technical field of preparation of intermediates of antiviral drugs of the Lowe class, in particular to a preparation method of 2,4-diamino 6-hydroxyl-5-carboxamidopyrimidine and the use of 2,4-diamino 6-hydroxy -A new method for the preparation of guanine from 5-carboxamidopyrimidine. 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, such as erythema multiforme, herpes zoster, first and recurrent genital herpes, HSV encephalitis, chickenpox, herpes zoster and VZV encephalitis, AIDS, Pneumonia, enteritis and retinitis caused by severe CMV infection in organ transplantation and malignant tumor patients. [0003] The synthetic method of 2,4-diamino 6-hydroxy-5-carboxamidopyrimidine, there are not many published documents, and there are few exa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCC07D473/18
Inventor 晏金华张帅魏海鹏刘晓磊
Owner 潍坊奥通药业有限公司
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