CN114380832A - One-step synthetic method of guanine - Google Patents
One-step synthetic method of guanine Download PDFInfo
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- CN114380832A CN114380832A CN202210082862.8A CN202210082862A CN114380832A CN 114380832 A CN114380832 A CN 114380832A CN 202210082862 A CN202210082862 A CN 202210082862A CN 114380832 A CN114380832 A CN 114380832A
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- guanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a one-step method for synthesizing guanine, belonging to the field of biology. The synthesis method comprises the steps of mixing 2, 4-diamino-5-nitroso-6-hydroxypyrimidine with a formamide solution, heating to 80-160 ℃ under the action of a catalyst to perform formylation, and then heating to 160-180 ℃ and preserving heat to perform dehydration. The method has simple process, does not need hydrogenation reduction, and eliminates potential safety hazard; the by-products can be recycled, and meanwhile, the use of rare metal catalysts, alkali, formic acid and other reagents is also saved, so that the method is more environment-friendly. Meanwhile, the yield of the guanine crude product obtained by the one-step reaction in the reaction is more than 97 percent, and a pure guanine finished product is obtained after refining, the yield can reach 90 percent, and the purity is more than or equal to 99.5 percent.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a one-step synthesis method of guanine.
Background
Guanine is the major base constituent of nucleic acids and has important physiological functions. Meanwhile, guanine also has a plurality of medicinal values, is a medical intermediate of traditional Chinese medicines, such as synthetic antiviral drugs acyclovir, ganciclovir and other lowry drugs, and has great industrial production value.
The traditional production process of guanine takes methyl cyanoacetate as a starting material, and the following steps of reaction are carried out in sequence:
(1) condensation reaction: cyclizing methyl cyanoacetate and guanidine nitrate (or guanidine hydrochloride) to obtain 2, 4-diamino-6-hydroxypyrimidine.
(2) Nitrosation reaction: nitrosation reaction is carried out on the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine and sodium nitrite.
(3) Hydrogenation reduction reaction: obtaining the 2, 4, 5-triamino-6-hydroxypyrimidine through hydrogenation or iron powder reduction.
(4) Salt forming reaction: reacting with sulfuric acid to obtain 2, 4, 5-triamino-6-hydroxypyrimidine sulfate.
(5) And (3) cyclization reaction: and refluxing with sodium formate or formamide in formic acid to obtain guanine formate.
And (3) decoloring and refining the guanine formate obtained by the cyclization reaction in dilute hydrochloric acid to obtain guanine hydrochloride, and then dissociating in dilute alkaline water to obtain a guanine finished product. The iron powder reduction reaction in the third step in the process is forbidden in the elimination process, and the safety threshold is higher due to hydrogen and pressure involved in hydrogenation reduction. And because liquid caustic soda, sulfuric acid and formic acid are used, the treatment difficulty of byproducts is high, and the environmental protection treatment cost is high.
Disclosure of Invention
Aiming at the defects of the existing preparation process, the invention provides a one-step synthesis method of guanine, which has simple process, does not need hydrogenation reduction and eliminates potential safety hazard; the by-products can be recycled, and meanwhile, the use of rare metal catalysts, alkali, formic acid and other reagents is also saved, so that the method is more environment-friendly.
The invention is realized by the following technical scheme:
a one-step synthesis method of guanine, comprising:
mixing 2, 4-diamino-5-nitroso-6-hydroxypyrimidine with a formamide solution, heating to 80-160 ℃ under a catalyst for formylation, and then heating to 160-180 ℃ for heat preservation for dehydration.
Further, in a preferred embodiment of the present invention, the temperature is slowly increased for 6-8 hours during the formylation reaction.
Further, in a preferred embodiment of the present invention, the mass concentration of formamide in the formamide solution is 20-80%.
Further, in a preferred embodiment of the invention, the molar ratio of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to the formamide is 1: 5-8.
Further, in a preferred embodiment of the present invention, the time of the dehydration reaction is 1 to 3 hours.
Further, in a preferred embodiment of the present invention, the catalyst is a sulfite compound;
further, in a preferred embodiment of the present invention, the catalyst is at least one of sodium sulfite, sodium dithionite and sodium pyrosulfite;
further, in a preferred embodiment of the present invention, the mass ratio of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to the catalyst is 1:0.05 to 0.25.
Further, in a preferred embodiment of the present invention, the method further comprises a step of refining a reaction product obtained by the dehydration reaction: refining the reaction product in dilute acid to obtain guanine salt.
Further, in a preferred embodiment of the present invention, the method further comprises absorbing ammonia gas and carbon dioxide, which are by-products generated during the formylation reaction, with water to obtain a mixed alkali solution of ammonium carbonate and ammonium bicarbonate, and then refining the guanine salt in the mixed alkali solution to obtain the guanine.
Compared with the prior art, the invention at least has the following technical effects:
the synthesis method provided by the invention adopts 2, 4-diamino-5-nitroso-6-hydroxypyrimidine as a raw material, and directly obtains guanine by dehydration in formamide under the condition of a catalyst. The process comprises the steps of carrying out formylation reaction on dilute formamide and nitroso in the presence of a sulfite catalyst to obtain formamido pyrimidine, and then continuously dehydrating and directly cyclizing under the action of the catalyst to obtain guanine. Because the triaminopyrimidine is prepared without hydrogenation reduction, the potential safety hazard is eliminated, and the use of rare metal catalysts and alkali is also saved. Because triaminopyrimidine sulfate is not prepared, sulfuric acid is omitted. Because the reflux cyclization in formic acid is not needed, the formic acid is saved, and the environmental protection treatment cost is greatly reduced. Therefore, the one-step synthesis process provided by the application is a green process which is practical for production. Meanwhile, the yield of the guanine crude product obtained by the one-step reaction in the reaction is more than 97 percent, and a pure guanine finished product is obtained after refining, the yield can reach 90 percent, and the purity is more than or equal to 99.5 percent.
Drawings
FIG. 1 is a mass spectrum of guanine synthesized in example 1.
Detailed Description
Embodiments of the present invention will be described in detail with reference to the following examples, but those skilled in the art will understand that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention, and that the specific conditions not specified in the examples are carried out according to conventional conditions or conditions suggested by the manufacturer, and that the reagents or equipment used are not specified by the manufacturer, and are all conventional products available through commercial purchase.
The technical scheme of the invention is as follows:
a one-step synthesis method of guanine, comprising:
mixing 2, 4-diamino-5-nitroso-6-hydroxypyrimidine with a formamide solution, heating to 80-160 ℃ under a catalyst for formylation, and then heating to 160-180 ℃ for heat preservation for dehydration.
The reaction process of the synthesis method is as follows:
by adopting the process, in the synthesis process, 2, 4-diamino-5-nitroso-6-hydroxypyrimidine is added into a water-containing formamide solution, the temperature is slowly increased under the condition of a catalyst, redundant water in the formamide solution is gradually evaporated (the formamide cannot be evaporated along with the water due to the fact that the boiling point of the formamide is 210 ℃), and meanwhile, formylation reaction is initiated to obtain the formylaminopyrimidine transition intermediate. The intermediate can exist stably, and pure intermediate monomer can be obtained by separation means. However, in the one-step reaction provided in this embodiment, the crude guanine product can be obtained by further raising the reaction temperature to 160-180 ℃ (preferably 165-170 ℃, more preferably 170 ℃) without separating and purifying the intermediate, and then performing reflux dehydration.
Furthermore, in the formylation reaction process, the slow temperature rise time is 6-8 h (preferably 7-8 h), and the temperature rise process can be constant temperature rise. Or the temperature is slowly increased, the temperature cannot be increased too fast, and a large amount of gas is generated too fast to cause flash.
Further, the mass concentration of formamide in the formamide solution is 20-80%, preferably 40-70%, and more preferably 50-60%. In carrying out the formylation reaction, water participates in the reaction, and therefore the solvent of the formamide solution is water. And the concentration of the formamide solution is kept within the range of 20-80%, and water is excessive, so that the forward progress of formylation reaction is promoted in the temperature rising and volatilization process, and the reaction efficiency is improved.
Further, the molar ratio of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to the formamide is 1: 5-8.
Furthermore, the time of the dehydration reaction is 1-3 h, preferably 2 h. The dehydration reaction time is too long, a large amount of byproducts are increased, the separation is not easy, and the yield and the quality are greatly influenced.
Further, the catalyst is a sulfite compound. The catalyst can lead formamide to have decomposition reaction with water, and three moles of formamide react with one mole of water to generate one mole of active formyl group, so that the formyl group reacts with nitroso to generate formamidopyrimidine intermediate. Preferably, the catalyst is at least one of sodium sulfite, sodium dithionite and sodium pyrosulfite; more preferably, the catalyst is sodium dithionite.
Further, the mass ratio of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to the catalyst is 1: 0.05-0.25. Namely, the adding amount of the catalyst is 5 to 25 percent of the amount of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine. The mass ratio of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to the catalyst is preferably 1: 0.1-0.15. In this reaction, when the amount of the catalyst exceeds this range, not only the formylation reaction is not accelerated, but also safety accidents such as flash due to an excessively large amount of gas generation occur.
Further, the method also comprises the step of refining a reaction product obtained by the dehydration reaction: refining the reaction product in dilute acid to obtain guanine salt.
Further, the method comprises the steps of absorbing ammonia gas and carbon dioxide which are by-products generated in the formylation reaction process by using water to obtain mixed alkali liquor of ammonium carbonate and ammonium bicarbonate, and then placing the guanine salt in the mixed alkali liquor to refine to obtain the guanine.
In the synthesis process, a large amount of ammonia gas and carbon dioxide gas can be generated in the formylation reaction process, and can be absorbed by water to obtain the mixed alkali liquor of ammonium carbonate and ammonium bicarbonate with equal content, and the mixed alkali liquor can be directly used for dissociating and refining to obtain guanine. Or introducing ammonia gas to obtain ammonium carbonate, or introducing carbon dioxide to obtain ammonium bicarbonate, and selling as a byproduct.
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
Example 1
This embodiment provides a one-step synthesis method of guanine, which includes:
31g (0.2mol) of 2, 4-diamino-5-nitroso-6-hydroxypyrimidine is taken and added into 120ml of 75 percent formamide, stirring is started, the temperature is slowly raised to 80 ℃, 2.5g (about 8 percent) of sodium hydrosulfite is added, the temperature is continuously raised to initiate formylation reaction, simultaneously, a large amount of ammonia gas and carbon dioxide gas overflow, and deionized water is used for circularly absorbing. Collecting the water continuously evaporated in the heating process, and heating to 160 ℃ within 7h to complete the formylation reaction. And continuing to heat up, stopping water discharging when the temperature is raised to 170 ℃, carrying out reflux heat preservation for 2 hours, cooling after the materials turn yellow, and filtering to obtain a guanine crude product with the yield of about 99%.
Adding the crude product into 10 times of 15% diluted hydrochloric acid, and performing reflux decoloration and refining to obtain the white-like guanine hydrochloride with the yield of about 90%. Then putting guanine hydrochloride into 10 times of 10 percent diluted ammonia water for dissociating to obtain a white guanine finished product, wherein the content is more than or equal to 99.5 percent, and the yield is about 90 percent.
As a result of high-resolution mass spectrometry of the obtained guanine sample, the m/z of guanine was 151.0 as shown in FIG. 1.
Example 2
This embodiment provides a one-step synthesis method of guanine, which includes:
60g of wet 2, 4-diamino-5-nitroso-6-hydroxypyrimidine and 31g (0.2mol) of the wet 2, 4-diamino-5-nitroso-6-hydroxypyrimidine are taken, added into 120ml of 80% formamide, stirred, slowly heated to 80 ℃, added with 2.0g (about 6.5%) of sodium hydrosulfite, continuously heated to initiate formylation reaction, simultaneously overflowing a large amount of ammonia gas and carbon dioxide gas, and circularly absorbed by deionized water. Collecting the water continuously evaporated in the temperature rise process, and raising the temperature to 160 ℃ within 6h to complete the formylation reaction. When the temperature rises to 160 ℃, stopping water discharging, refluxing and preserving heat for 3 hours, cooling after the materials turn yellow, and filtering to obtain a guanine crude product with the yield of about 98.6%.
Adding the crude product into 10 times of 15% diluted hydrochloric acid, and performing reflux decoloration and refining to obtain the white-like guanine hydrochloride with the yield of about 85%. Then putting guanine hydrochloride into 10 times of 10 percent diluted ammonia water for dissociating to obtain a white guanine finished product, wherein the content is more than or equal to 99.5 percent, and the yield is about 90 percent.
Example 3
The embodiment provides a one-step synthesis method of guanine, which comprises the following steps:
31g (0.2mol) of 2, 4-diamino-5-nitroso-6-hydroxypyrimidine is taken and added into 120ml of 60 percent formamide, stirring is started, the temperature is slowly raised to 80 ℃, 2.5g (about 8 percent) of sodium sulfite is added, the temperature is continuously raised to initiate formylation reaction, and simultaneously, a large amount of ammonia gas and carbon dioxide gas overflow and are circularly absorbed by deionized water. Collecting the water continuously evaporated in the heating process, and heating to 160 ℃ within 5h to complete the formylation reaction. And continuing to heat up, stopping discharging water when the temperature is increased to 165 ℃, performing reflux heat preservation for 2.5 hours, cooling after the materials turn yellow, and filtering to obtain a guanine crude product with the yield of about 95%.
And adding the crude product into 10 times of 20% diluted hydrochloric acid for reflux decoloration and refining to obtain the white-like guanine hydrochloride with the yield of about 87%. And then putting guanine hydrochloride into mixed alkali liquor of ammonium carbonate and ammonium bicarbonate obtained after circularly absorbing ammonia and carbon dioxide for dissociation to obtain a white guanine finished product, wherein the content is more than or equal to 99.2 percent, and the yield is about 90.8 percent.
Example 4
This embodiment provides a one-step synthesis method of guanine, which includes:
31g (0.2mol) of 2, 4-diamino-5-nitroso-6-hydroxypyrimidine is taken and added into 120ml of 75 percent formamide, stirring is started, the temperature is slowly raised to 80 ℃, 2.5g (about 8 percent) of sodium metabisulfite is added, the temperature is continuously raised to initiate formylation reaction, and simultaneously, a large amount of ammonia gas and carbon dioxide gas overflow and are circularly absorbed by deionized water. Collecting the water continuously evaporated in the heating process, and heating to 160 ℃ within 5h to complete the formylation reaction. And continuing to heat up, stopping water discharging when the temperature is raised to 175 ℃, carrying out reflux heat preservation for 2.0 hours, cooling after the materials turn yellow, and filtering to obtain a guanine crude product with the yield of about 98%.
Adding the crude product into 10 times of 10% diluted hydrochloric acid, and performing reflux decoloration and refining to obtain the white-like guanine hydrochloride with the yield of about 90%. And then putting guanine hydrochloride into the mixed alkali liquor of ammonium carbonate and ammonium bicarbonate obtained after circularly absorbing ammonia and carbon dioxide for dissociation, wherein the content is more than or equal to 99.4 percent, and the yield is about 90.2 percent.
In conclusion, the one-step synthesis method of guanine provided by the application can effectively overcome the defects of the existing process, does not need hydrogenation reduction, and eliminates potential safety hazards; the by-products can be recycled, and meanwhile, the use of rare metal catalysts, alkali, formic acid and other reagents is also saved, so that the method is more environment-friendly. Meanwhile, the reaction is only one step, the operability is strong, the reaction yield is high (more than 90 percent), the purity of the refined product is as high as 99 percent, and the large-scale industrial production can be carried out.
Finally, it should be noted that: the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A one-step synthesis method of guanine is characterized by comprising the following steps:
mixing 2, 4-diamino-5-nitroso-6-hydroxypyrimidine with a formamide solution, heating to 80-160 ℃ under a catalyst for formylation, and then heating to 160-180 ℃ for heat preservation for dehydration.
2. The one-step synthesis method of guanine according to claim 1, wherein the slow temperature rise time is 6-8 h during the formylation reaction.
3. The one-step guanine synthesis process according to claim 1, wherein the mass concentration of formamide in the formamide solution is 20-80%.
4. The one-step synthesis method of guanine according to claim 1, wherein the molar ratio of 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to formamide is 1: 5-8.
5. The one-step synthesis method of guanine according to claim 1, wherein the time for the dehydration reaction is 1 to 3 hours.
6. The one-step synthesis method of guanine according to claim 1, wherein the catalyst is a sulfite compound.
7. The method of claim 6, wherein the catalyst is at least one of sodium sulfite, sodium dithionite, and sodium metabisulfite.
8. The one-step guanine synthesis process according to claim 1, wherein the mass ratio of the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine to the catalyst is 1:0.05 to 0.25.
9. The method according to claim 1, further comprising a step of purifying a reaction product obtained by the dehydration reaction: refining the reaction product in dilute acid to obtain guanine salt.
10. The one-step synthesis method of guanine according to claim 9, further comprising absorbing ammonia and carbon dioxide, which are by-products generated during the formylation reaction, with water to obtain a mixed alkali solution of ammonium carbonate and ammonium bicarbonate, and refining the guanine salt in the mixed alkali solution to obtain the guanine.
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