CN108558776A - The preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines and guanine - Google Patents
The preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines and guanine Download PDFInfo
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- CN108558776A CN108558776A CN201810426489.7A CN201810426489A CN108558776A CN 108558776 A CN108558776 A CN 108558776A CN 201810426489 A CN201810426489 A CN 201810426489A CN 108558776 A CN108558776 A CN 108558776A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
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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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Abstract
The invention discloses a kind of preparation methods of 5 nitroso of 2,4 diamino, 6 hydroxy pyrimidine, including：(1) in methanol solution of sodium methylate, malonic methyl ester nitrile carries out ring-closure reaction with guanidine salt；(2) recycling absolute methanol dilution is added, by-product sodium nitrate is recovered by filtration；(3) filtrate is concentrated, the absolute methanol of recycling；(4) the excessive sodium methoxide of water destruct, concentration and recovery aqueous methanol is added；(5) in dilute formic acid solution, obtained concentrate and sodium nitrite, nitrosation mother liquor are subjected to nitrosation reaction；(6) after the reaction was complete, cooling crystallization, filtering, for filtrate as nitrosation mother liquid recycle, obtained filter cake dries to obtain 2,4 diamino, 5 nitroso, 6 hydroxy pyrimidine.The present invention realize nitrosation mother liquor apply mechanically and the recycling of sodium nitrate and methanol, while using dilute formic acid solution instead of the existing concentrated sulfuric acid carry out nitrosation reaction, facilitate the recycling of solvent and reagent, reduce wastewater displacement.
Description
Technical field
The invention belongs to the key intermediate preparing technical fields of Lip river Wei class antiviral agent and folic acid, are specifically related to one kind
The type preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines and guanine.
Background technology
Lip river Wei class drug includes mainly acyclovir, Ganciclovir, Valaciclovir and famciclovir etc., is the anti-of wide spectrum
Viral medicine.It is used clinically for treatment herpe simplex and infects relevant disease with HSV.
Folic acid (folic acid) be also Vitamin B9, is a kind of vitamin of water-soluble anti-anemia action.Folic acid helps albumen
The metabolism of matter, and generation and the maturation of red blood cell are collectively promoted with vitamin B12, it is the manufacture indispensable substance of red blood cell,
The synthesis of merisis and nucleic acid, amino acid, protein to cell plays an important role.
2,4,5-triamino-6-hydroxypyrimidine sulfate is the important intermediate of synthesis folic acid and Luo Wei class drugs, and sub-
Nitre pyrimidine is the important intermediate for synthesizing 2,4,5-triamino-6-hydroxypyrimidine sulfate and guanine, paper document (Guangdong
Work, the 24th phases of volume 39 in 2011, P59~60), patent document (CN1966504A, CN10247866A, CN105541729,
CN106478630A and CN102399194) etc., all use the synthetic method for the nitrous pyrimidine being shown below：
Synthesis technology disclosed in these documents, all employs a large amount of excessive sulfuric acid and sodium nitrite progress nitrosation is anti-
It answers, produces a large amount of with high salt, acid waste water.Again because the sulfuric acid concentration in mother liquor is too low, the excessive concentration of sodium sulphate, and can not
It realizes mother liquid recycle, causes the waste of excessive nitrite sodium and sulfuric acid, increase the processing cost of waste water.
The nitrous pyrimidine being prepared obtains 2,4,5- triamido -6- hydroxy pyrimidines, 2,4,5- tri- ammonia by hydrogenating reduction
After base -6- hydroxy pyrimidines and sulfuric acid are at salt, then with formic acid and sodium formate ring-closure reaction is carried out, finally obtains guanine
(CN1966504A, CN106478630A, CN1247866A etc.).In the ring-closure reaction for preparing guanine：
On the one hand the recycling dilute formic acid solution of a large amount of (account for recovery total 1/3~1/2) is will produce, this part dilute formic acid is molten
The mass percent concentration of formic acid is generally 65% hereinafter, since the formic acid concn that the step ring-closure reaction needs needs in liquid
70% or more, thus the obtained dilute formic acid solution of recycling cannot direct recovery in this step, need to be further processed, this
Manufacturing cost will certainly be greatly increased.
On the other hand, it needs to use a large amount of sodium formate (about the 3 of 2,4,5- triamido -6- hydroxy pyrimidines in the step
~4 times of equivalents), this also further increases the manufacturing cost of guanine.
Invention content
The present invention provides the preparation method of one kind 2,4- diamino -5- nitroso -6- hydroxy pyrimidines, the preparation method,
The method achieve the recycling of the recovery of nitrosation mother liquor, methanol and byproduct sodium formate and sodium nitrate, while utilizing dilute
Formic acid solution carries out nitrosation reaction instead of the existing concentrated sulfuric acid, facilitates the recycling of solvent and reagent, reduces waste water row
Biodegradability in amount and its processing procedure.
The present invention also provides a kind of preparation method of guanine, realize nitrosation mother liquor apply mechanically and sodium nitrate and
While the recycling of methanol, the recycling of dilute formic acid solution is realized, while using dilute formic acid solution instead of the existing concentrated sulfuric acid
Nitrosation reaction is carried out, the recycling of solvent and reagent is facilitated, reduces wastewater displacement.
The preparation method of one kind 2,4- diamino -5- nitroso -6- hydroxy pyrimidines, including：
(1) in methanol solution of sodium methylate, malonic methyl ester nitrile carries out ring-closure reaction with guanidine salt；
(2) step (1) is added recycling absolute methanol dilution, by-product sodium nitrate is recovered by filtration after the reaction was complete；
(3) filtrate that step (2) obtains is concentrated, and the absolute methanol of recycling is applied to step (2)；
(4) into the residue of step (3), the excessive sodium methoxide of water destruct, concentration and recovery aqueous methanol is added；
(5) in dilute formic acid solution, concentrate and sodium nitrite, nitrosation mother liquor that step (4) is obtained carry out nitrosation
Reaction；
(6) step (5) is after the reaction was complete, cooling crystallization, filtering, and filtrate is as nitrosation mother liquid recycle, obtained filter cake
After drying be 2,4- diamino -5- nitroso -6- hydroxy pyrimidines (hereinafter referred to as：Nitrous yl pyrimidines), structural formula is as follows：
A kind of preparation method of guanine, including：
(1) in methanol solution of sodium methylate, malonic methyl ester nitrile carries out ring-closure reaction with guanidine salt；
(2) step (1) is added recycling absolute methanol dilution, by-product sodium nitrate is recovered by filtration after the reaction was complete；
(3) filtrate that step (2) obtains is concentrated, and the absolute methanol of recycling is applied to step (2)；
(4) into the residue of step (3), the excessive sodium methoxide of water destruct, concentration and recovery aqueous methanol is added；
(5) in dilute formic acid solution, concentrate that step (4) is obtained (be 2,4- diamino -6- hydroxy pyrimidines (with
Lower abbreviation：Di-amino-pyrimidine)) and sodium nitrite, nitrosation mother liquor progress nitrosation reaction；
(6) step (5) is after the reaction was complete, cooling crystallization, filtering, and filtrate is as nitrosation mother liquid recycle, obtained filter cake
It is 2,4- diamino -5- nitroso -6- hydroxy pyrimidines after drying；
(7) 2, the 4- diamino -5- nitroso -6- hydroxy pyrimidines that step (6) is prepared pass through hydrogenating reduction, obtain 2,
4,5- triamido -6- hydroxy pyrimidines, 2,4,5- triamido -6- hydroxy pyrimidines obtain 2,4,5- triamido -6- again with sulfuric acid at salt
Hydroxy pyrimidine sulfate, 2,4,5-triamino-6-hydroxypyrimidine sulfate carry out ring-closure reaction, closed loop with formic acid and sodium formate again
After reaction, recycling obtains filtrate or/and cleaning solution through distillation：The one kind of mass percent concentration more than or equal to 70% is mixed
It closes object to use as the formic acid raw material of step (7), the one kind of mass percent concentration less than 70% or mixture are as described
The dilute formic acid solution of step (5) is applied mechanically.
The reaction process of the preparation method of the 2,4- diamino -5- nitroso -6- hydroxy pyrimidines of the present invention is shown below：
The preparation method technique of the guanine of the present invention is as follows：
In step (1), ring-closure reaction carries out under reflux conditions.
In step (1), the guanidine salt is any one of guanidine nitrate, guanidine sulfate, guanidine hydrochloride, phosphoguanidine.It is further excellent
It is selected as guanidine nitrate.
Preferably, in step (2), the volume mass ratio of the recycling absolute methanol and methyl cyanoacetate is：(5~
10)：1(L/Kg).Further preferably (6~8)：1(L/Kg).The present invention recycles absolute methanol by addition, simple to realize
Recycling to by-product sodium nitrate；By the control to recycling absolute methanol and the addition of methyl cyanoacetate, ensure as far as possible
More sodium nitrate are recovered, and further improve the yield of by-product.By the method obtained by-product sodium nitrate of the present invention
Quality has reached the pure index of chemistry of market sale, can direct list marketing.
Preferably, being specifically included in step (5)：
In the concentrate that (5-1) is obtained to step (4), the part nitrous reaction mother liquor and nitrous acid of batch recycling in addition
Sodium is configured to cyclization feed liquid, spare；In this step, the addition of the part nitrous reaction mother liquor of recycling does not limit strictly, energy
Enough for the purpose of dissolving concentrate.
(5-2) is into dilute formic acid solution, while the remaining nitrous that the cyclization feed liquid of a dropping step (5-1) is recycled with upper batch
Change mother liquor, control ph 1~4 carries out nitrosation reaction.
Preferably, the mass percent concentration of the dilute formic acid solution is 35-65%.The 2,4- that the present invention is prepared
Diamino -5- nitroso -6- hydroxy pyrimidines can be used the further hydrogenating reduction of existing technique, obtain bird at salt and ring-closure reaction
Purine.After ring-closure reaction, the largely filtrate containing formic acid can be obtained, the content of formic acid is generally in 50- in these filtrates
70%, after distillation, there is the concentration of 1/3~1/2 distillate between 35~65%, since concentration is relatively low, is no longer suitable for
Directly set is in the ring-closure reaction.But this partially recycled dilute formic acid solution can be in direct reuse to step (5).It is logical
Cross the present invention, the thorough recycling for realizing the dilute formic acid solution obtained to ring-closure reaction.
In addition, in step (5), after nitrosation reaction, the filtrate being obtained by filtration can be applied to down directly as reaction mother liquor
In batch of reaction.Obtained cleaning solution collects concentration and recovery sodium formate, the sodium formate which obtains, can direct reuse extremely
In above-mentioned ring-closure reaction.
In step (5), the nitrosation reaction temperature is preferably 30~80 DEG C, further preferably 55~65 DEG C.
In step (5), preferably, the molar ratio of sodium nitrite and methyl cyanoacetate is preferably (1.05~2)：1, into one
Step is preferably (1.05~1.2)：1.
Preferably, the molar ratio (1.1~3) of formic acid and methyl cyanoacetate：1, further preferred (2~2.5)：1.
The content of formic acid can be measured by existing method wherein in dilute formic acid solution.
In step (6), the cleaning solution of filter process is collected, recycles the sodium formate being recycled, the sodium formate set of the recycling
With in step (7).When practical operation, the cleaning solution of collection is through a small amount of piece alkali neutralization, MVR concentrations, crystallization, you can recycling formic acid
Sodium.
In step (7), 2,4,5-triamino-6-hydroxypyrimidine sulfate is again 1 with the molar ratio of formic acid and sodium formate：(3
~4)：(9~10).
The technique of the present invention, the shortcomings that just overcoming prior art, realize what environmentally friendly, energy saving, by-product comprehensively utilized
Purpose is embodied in：
1, the quality of method through the invention, obtained by-product sodium nitrate has reached the pure finger of chemistry of market sale
Mark, can list marketing；
2, the byproduct sodium formate that the present invention obtains, the production that can be used for guanine feed intake, realize to the reasonable of sodium formate
It utilizes；
3, in the present invention, the recycled of nitrous mother liquor takes full advantage of excessive formic acid and sodium nitrite.
The present invention realize nitrosation mother liquor apply mechanically and the recycling of sodium nitrate and methanol, while utilize dilute formic acid solution
Nitrosation reaction is carried out instead of the existing concentrated sulfuric acid, the recycling of solvent and reagent is facilitated, reduces wastewater displacement.
The present invention realizes the reasonable utilization of the dilute formic acid solution of recycling simultaneously, greatly reduces guanine and 2,4- diaminos
The manufacturing cost of base -5- nitroso -6- hydroxy pyrimidines, realizes recycling for waste water and waste liquid.The entire technique of the present invention,
Using recovery process, no waste water and waste liquid discharge, no environmental protection pressure is suitble to large-scale production.
Specific implementation mode
In order to keep technical scheme of the present invention and advantage clearer, the preferred embodiment of the present invention is made into one below
The detailed description of step, the present invention include but not limited to following embodiment and its technological parameter shown.
Embodiment 1：
950Kg methanol solution of sodium methylate is put into 3KL enamel reaction stills, stirring is opened under nitrogen protection, is then put into
325Kg guanidine nitrates.It feeds intake complete, is warming up to back flow reaction 90 minutes.
Then, start that 253Kg methyl cyanoacetates are added dropwise.Drop finishes, and continues reflux ring-closure reaction 4 hours, and reaction was completed.
After reaction, turn material in 5KL enamel salt crystallization kettles, be added on 2000L batch absolute methanol being distilled to recover, after
Continuous back flow reaction 30min.Then, 50 DEG C are cooled to, insulated and stirred 60min.It is steamed with nitrogen press filtration, to dry, then on 150L batches
The absolute methanol washing filter cake of recycling, merging filtrate and cleaning solution are evaporated, is transferred in 5KL enamel concentration kettles；Filter cake is by-product nitre
Sour sodium obtains 220Kg white granular solids, content >=99.0%, the rate of recovery 97.2% after drying.
Filtrate first carries out air-distillation concentration, recycling methanol with cleaning solution.When there is powdered granule, then it is concentrated under reduced pressure
It is extremely dry.Obtain 850Kg recycling absolute methanols, the rate of recovery 86.2%.Then, 300Kg is added into concentrated residues object under stirring
Tap water is stirred to white turbid, then is concentrated to dryness.Obtain 250Kg recycling aqueous methanols, content 75%, pure recycling
Rate is 85.4%.
After above-mentioned 2 times are concentrated under reduced pressure, 500Kg drinking water is added, stirs 15 minutes, adds 200Kg sodium nitrites
The nitrosation mother liquor recycled is criticized on solid and 1100L, continues stirring clarification, obtains " cyclization feed liquid ".
By the dilute formic acid water of the nitrosation mother liquor for criticizing recycling on 900L and the recycling obtained after 200L guanine preparation units
In solution (mass percent of formic acid is 55%) input 5KL enamel nitrating pots, stirring, 40~50 DEG C of temperature control start in dropwise addition
" cyclization feed liquid " made from face, control system pH value are 1~2.
After drop finishes, in 60 DEG C of insulation reactions 2 hours.Filtering while hot is extremely done, and 3050L filtrates are obtained, and as nitrosation is female
Liquid can directly cover and use lower batch and feed intake.Filter cake is washed with 2000L hot water, is filtered dry；Cleaning solution is gone " recycling sodium formate ".
Filter cake obtained 390Kg light brown red pulverulent solids, as target product in 75~85 DEG C of forced air dryings 7 hours
" nitrous pyrimidine ", yield 98.5%；Moisture 0.51%, cyclocomplex residual 0.35%, ash content 0.44%, content 97.2%.
Embodiment 2：
950Kg methanol solution of sodium methylate is put into 3KL enamel reaction stills, stirring is opened under nitrogen protection, is then put into
325Kg guanidine nitrates.It feeds intake complete, is warming up to back flow reaction 30 minutes.
Then, start that 253Kg methyl cyanoacetates are added dropwise.Drop finishes, and continues reflux ring-closure reaction 2 hours, and reaction was completed.
After reaction, turn material in 5KL enamel salt crystallization kettles, be added on 2000L batch absolute methanol being distilled to recover, after
Continuous back flow reaction 60min.Then, 60 DEG C are cooled to, insulated and stirred 30min.It is steamed with nitrogen press filtration, to dry, then on 150Kg batches
The absolute methanol washing filter cake of recycling, merging filtrate and cleaning solution are evaporated, is transferred in 5KL enamel concentration kettles；Filter cake is by-product nitre
Sour sodium obtains 215Kg white granular solids, content >=99.0%, the rate of recovery 95.0% after drying.
Filtrate and cleaning solution first carry out air-distillation concentration, recycling methanol.When there is powdered granule, then depressurized with dense
It is reduced to dry.Obtain 890Kg recycling absolute methanols, the rate of recovery 90.3%.Then, it is added into concentrated residues object under stirring
300Kg tap water is stirred to white turbid, then is concentrated to dryness.200Kg recycling aqueous methanols are obtained, content 78% is pure
The rate of recovery is 86.9%.
After above-mentioned 2 times are concentrated under reduced pressure, 500Kg drinking water is added, stirs 15 minutes, adds 190Kg sodium nitrites
The nitrosation mother liquor recycled is criticized on solid and 1200L, continues stirring clarification, obtains " cyclization feed liquid ".
The dilute formic acid solution for nitrosation mother liquor and 200L guanine the preparation units recycling that on 850L batches is recycled be (formic acid
Between mass percent concentration is 50%) it puts into 5KL enamel nitrating pots, stirring, 30~40 DEG C of temperature control, start to be added dropwise system above
" the cyclization feed liquid " obtained, control pH value of reaction system are 2~3.
Drop finished, in 50 DEG C of insulation reactions 3 hours.Filtering while hot, to dry, obtain 2970L filtrates, as nitrosation mother liquor,
It can directly cover and use lower batch and feed intake.Filter cake is washed with 2000L hot water, is filtered dry；Cleaning solution removes " recycling sodium formate " operating unit.
Filter cake obtained 383Kg light brown red pulverulent solids, as target product in 75~85 DEG C of forced air dryings 6 hours
" nitrous pyrimidine ", yield 96.7%；Moisture 0.45%, cyclocomplex residual 0.25%, ash content 0.36%, content >=98.8%.
2,4- diamino -5- nitroso -6- hydroxy pyrimidines13C-NMR spectrums are as follows：
13C-NMR (100MHz, DMSO, ppm)：δ 161.1 (C-2), δ 151.5 (C-4), δ 130.0 (C-5), 165.6 (C- of δ
6)。
2,4- diamino -5- nitroso -6- hydroxy pyrimidines1H-NMR spectrums are as follows：
1H-NMR (300MHz, DMSO, ppm)：δ 6.99 (s, 2H, NH2), δ 8.49 (s, 2H, NH2), δ 11.53 (s, H,
OH)。
In embodiment, for the formic acid used subsequently to prepare the aqueous formic acid of the recycling obtained after guanine, wherein bird is fast
The preparation route of purine is as follows：
The prior art can be used in above-mentioned preparation method, such as：By the nitrous pyrimidine (2,4- diamino -5- of 1 times of equivalent
Nitroso -6- hydroxy pyrimidines) it is mixed with the sig water (sodium hydrate aqueous solution) of 0.8 times of equivalent, catalytic hydrogenation is carried out, is obtained
The alkaline aqueous solution of the Triaminopyrimidine arrived directly carries out salt-forming reaction with the concentrated sulfuric acid of 1.5~2.0 times of equivalents, press filtration, washing,
Drying, obtains Triaminopyrimidine sulfate.
Finally, by the sodium formate of " the triamido sulfuric acid pyrimidine " of 1 times of equivalent and 3.5 times of equivalents, the formic acid of 9~10 times of equivalents
(content is in 70% or more, generally 80% or more) mixing, back flow reaction, then after crystallisation by cooling, press filtration, washing, obtain bird
The thick wet product of purine, the mass percent concentration of formic acid is about 50-70% in filtrate, is mixed with cleaning solution, after distillation, recycling
Dense formic acid can directly apply mechanically recycling in this step, the formic acid concn of the distillate of residue 1/3~1/2 35~65% it
Between, the dilute formic acid solution that this part may be used as the recycling of the embodiment of the present invention 1~2 uses.
Claims (10)
1. one kind 2, the preparation method of 4- diamino -5- nitroso -6- hydroxy pyrimidines, which is characterized in that including：
(1) in methanol solution of sodium methylate, malonic methyl ester nitrile carries out ring-closure reaction with guanidine salt；
(2) step (1) is added recycling absolute methanol dilution, by-product sodium nitrate is recovered by filtration after the reaction was complete；
(3) filtrate that step (2) obtains is concentrated, and the absolute methanol of recycling is applied to step (2)；
(4) into the residue of step (3), the excessive sodium methoxide of water destruct, concentration and recovery aqueous methanol is added；
(5) in dilute formic acid solution, the concentrate and sodium nitrite, the progress nitrosation of nitrosation mother liquor that step (4) is obtained are anti-
It answers；
(6) step (5) is after the reaction was complete, cooling crystallization, filtering, and filtrate as nitrosation mother liquid recycle, dry by obtained filter cake
It is 2,4- diamino -5- nitroso -6- hydroxy pyrimidines afterwards.
2. the preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines according to claim 1, which is characterized in that
Step specifically includes in (5)：
In the concentrate that (5-1) is obtained to step (4), the part nitrous reaction mother liquor and sodium nitrite of batch recycling, match in addition
Cyclization feed liquid is made, it is spare；
(5-2) is into dilute formic acid solution, while the remaining nitrosation that the cyclization feed liquid of a dropping step (5-1) is recycled with upper batch is female
Liquid, control ph 1~4 carry out nitrosation reaction.
3. the preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines according to claim 1 or 2, feature exist
In the mass percent concentration of the dilute formic acid solution is 35-65%.
4. the preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines according to claim 1 or 2, feature exist
In in step (2), the volume mass ratio of the recycling absolute methanol and methyl cyanoacetate is：(5~10)/1 (L/Kg).
5. the preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines according to claim 1 or 2, feature exist
In in step (1), the guanidine salt is any one of guanidine nitrate, guanidine sulfate, guanidine hydrochloride, phosphoguanidine.
6. the preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines according to claim 1 or 2, feature exist
In in step (5), the nitrosation reaction temperature is 30~80 DEG C.
7. the preparation method of 2,4- diamino -5- nitroso -6- hydroxy pyrimidines according to claim 1 or 2, feature exist
In in step (5), the molar ratio of the sodium nitrite, formic acid and methyl cyanoacetate is：(1.05~2)：(1.1~3)：1.
8. a kind of preparation method of guanine, which is characterized in that including：Claim 1~6 any one of them step (1)~
(6)；
(7) 2, the 4- diamino -5- nitroso -6- hydroxy pyrimidines that step (6) is prepared pass through hydrogenating reduction, obtain 2,4,5-
Triamido -6- hydroxy pyrimidines, 2,4,5- triamido -6- hydroxy pyrimidines obtain 2,4,5- triamido -6- hydroxyls again with sulfuric acid at salt
Pyrimidine sulfate, 2,4,5-triamino-6-hydroxypyrimidine sulfate carry out ring-closure reaction, ring-closure reaction with formic acid and sodium formate again
After, recycling obtains filtrate or/and cleaning solution through distillation：The one kind or mixture of mass percent concentration more than or equal to 70%
Formic acid raw material as step (7) uses, and the one kind of mass percent concentration less than 70% or mixture are as the step
(5) dilute formic acid solution is applied mechanically.
9. the preparation method of guanine according to claim 8, which is characterized in that in step (6), collect filter process
Cleaning solution, recycles the sodium formate being recycled, and the sodium formate of the recycling is applied in step (7).
10. the preparation method of guanine according to claim 8, which is characterized in that in step (6), in step (7), 2,
4,5- triamido -6- hydroxy pyrimidines sulfate is again 1 with the molar ratio of formic acid and sodium formate：(3~4)：(9~10).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114380832A (en) * | 2022-01-24 | 2022-04-22 | 湖北李泽园医药科技有限公司 | One-step synthetic method of guanine |
| CN114524771A (en) * | 2020-11-23 | 2022-05-24 | 江苏八巨药业有限公司 | Preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate |
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| CA765399A (en) * | 1967-08-15 | Fujimoto Yasuo | Method for preparing guanine and its derivatives | |
| CN1247866A (en) * | 1998-08-27 | 2000-03-22 | 克里安诺瓦特殊化学股份有限公司 | Process for preparation of guanine |
| CN1966504A (en) * | 2005-11-18 | 2007-05-23 | 上海医药工业研究院 | Guanine one-pot synthesis method |
| CN105541729A (en) * | 2015-12-31 | 2016-05-04 | 南昌大学 | Method for separating and purifying salt in 2,4,5-triamino-6-hydroxy pyrimidine sulfate production process |
| CN107602487A (en) * | 2017-10-09 | 2018-01-19 | 潍坊奥通药业有限公司 | The hydroxy pyrimidine formates of 2,4,5 triamido 6, preparation method and application |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114524771A (en) * | 2020-11-23 | 2022-05-24 | 江苏八巨药业有限公司 | Preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate |
| CN114380832A (en) * | 2022-01-24 | 2022-04-22 | 湖北李泽园医药科技有限公司 | One-step synthetic method of guanine |
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| CN108558776B (en) | 2020-08-11 |
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