CN101899046A - Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine - Google Patents
Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine Download PDFInfo
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- CN101899046A CN101899046A CN2009100519991A CN200910051999A CN101899046A CN 101899046 A CN101899046 A CN 101899046A CN 2009100519991 A CN2009100519991 A CN 2009100519991A CN 200910051999 A CN200910051999 A CN 200910051999A CN 101899046 A CN101899046 A CN 101899046A
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Abstract
The invention relates to a method for synthesizing a persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine, comprising the following steps of: (1) adding nitro orotic acid in an alkali liquid, then hydrogenating with Ni/H2, and filtering to obtain an amino orotic acid solution which is directly used for next reaction without separation; (2) adjusting pH of the amino orotic acid solution with concentrated hydrochloric acid to 3, adding sodium cyanate for temperature control reaction to obtain the urea derivatives of the amino orotic acid; then dropping a 30% sodium hydroxide solution to adjust pH to 13, heating for cyclization, dropping a 50-60% sulfuric acid solution to adjust pH to 3; (3) cooling to room temperature, filtering, washing to neutrality and drying to obtain the product. The intermediate of step (1) is not needed to separate, thereby saving a lot of time and labor, reducing about 50% of total reaction time with mild reaction condition and maximum reaction temperature reduced to 95 DEG C so that the device is less required and more durable.
Description
Technical field
The present invention relates to a kind of synthetic dipyridamole intermediate---2,4,6, the method for 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine belongs to organic chemistry filed.
Background technology
Dipyridamole another name Dipyridamole, dipyridamole is non-nitrate esters coronary artery dilator, has the expansion coronary vasodilator, promotes side Zhi Xunhuan to form and slight anticoagulation.Dipyridamole can be used for coronary heart disease, and as the anti-platelet aggregation medicine, control thrombosis and disseminated intravascular coagulation.Also can be used in the treatment of kidney disease, mainly play anti-hyperlipidemia effect, preventing thrombosis forms.2,4,6,8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine has a very important role as the dipyridamole intermediate.
Carried out relevant research abroad, as Fisher, F.G.et al., Annalen, 1950,572,217, this article report yield 67%, described method has been used potassium cyanate, but has also used ammonium chloride.Reaction conditions and Wyler's process are basic identical in the literary composition, and temperature is up to 210 ℃.
It is as follows that urea participates in reaction:
Classical
Synthesis method
Northen, Julian S.et al., Journal of the Chemical Society, Perkin Transactions1,108-115; 2002, this article is reported yield 73%, has continued the method for top first piece of document substantially, and temperature of reaction is similarly 210 ℃.
Domestic have a kind of " Wyler's process ", and Wyler's process synthetic route diagram is as follows:
The amino vitamin B13 separation task that the first step hydrogenation obtains is heavy, needs to use plate and frame(type)filter press, and efficient is low.Cause the production cycle long, the cost of labor height.
The second step reaction needed is reacted under the urea melting condition, stirs difficulty.And desired reaction temperature reaches 10 hours heat-up time up to 190 ℃, and these shortcomings cause the equipment requirements height, and depreciation is fast, and energy consumption of unit product is big.
Summary of the invention
Existing 2,4,6,8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine production process temperatures is up to 210 ℃; " Wyler's process " need react under the urea melting condition, stirs difficulty, and desired reaction temperature is up to 190 ℃, and heat-up time is long, causes energy consumption height, equipment requirements height and production capacity low, and needs the amino vitamin B13 of separation of intermediates, causes the separation task heavy.Technical problem to be solved by this invention is to provide a kind of synthetic dipyridamole intermediate---and 2,4,6, the method for 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine is to solve the many weak points of existing in prior technology.This invention is applicable to 2,4,6, the large-scale production of 8-tetrahydroxy pyrimidine.
The technical problem that will solve required for the present invention can be achieved through the following technical solutions:
A kind of synthetic dipyridamole intermediate---2,4,6, the method for 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine may further comprise the steps:
(1) with nitroorotic acid in alkali lye, use Ni/H again
2Hydrogenation is filtered and is obtained amino vitamin B13 solution, without separation, is directly used in next step reaction;
(2) with amino vitamin B13 solution concentrated hydrochloric acid pH regulator to 3, add Zassol, temperature control reacts, and obtains the urea derivatives of amino vitamin B13; Drip content 30% sodium hydroxide solution again with pH regulator to 13, the heating cyclization drips content 50%-60% sulphuric acid soln and transfers pH to 3;
(3) be cooled to room temperature, filter, be washed to neutrality, dry product.
The described alkali of step (1) is sodium hydroxide; Described nickel is Raney's nickel.
The described acid of step (2) is sulfuric acid, and described alkali is sodium hydroxide.
(ratio of quality and the number of copies) of each component of described step (1) is 50 parts of nitroorotic acids, 35 parts in sodium hydroxide, 10 parts of Raney's nickels, H
20.52 part, filter and obtain amino vitamin B13 solution.
55 parts of 90% Zassols of interpolation (ratio of quality and the number of copies) of described amino vitamin B13 solution.
Maximum temperature is 95 ℃.
Beneficial effect of the present invention:
1, the first step intermediate does not need to separate, and can be directly used in next step reaction, saves loaded down with trivial details filtration step.Saved the plenty of time and artificial.
2, total reaction time shortens approximately 50%, and the production cycle foreshortened to about 16 hours from original about 32 hours, and production capacity is greatly improved.
3, reaction conditions gentleness makes equipment requirements reduce, and equipment is more durable.Maximum temperature is reduced to 95 ℃ from original 190 ℃.
Embodiment
In order to make technique means of the present invention, creation characteristic, to reach purpose and effect is easy to understand,, further set forth the present invention below in conjunction with specific embodiment.
Embodiment 1
Existing " Wyler's process " technology.
Wyler's process synthetic route diagram is as follows:
Concrete steps are as follows:
1, the 50g nitroorotic acid is added in the 500ml aqueous solution of 15g sodium hydroxide, be stirred to whole dissolvings.This solution is transferred in the hydrogenation still, adds the 10g Raney's nickel, the average nickel contact area of Raney's nickel is 100m
2/ g in 80 ℃, following hydrogenation 8 hours that are incubated of 0.8MPa, no longer absorbs hydrogen.Be cooled to 35 ℃, filtration catalizer.Slowly add the 35g technical hydrochloric acid to filtrate, obtain the heavy-gravity soup compound.Plate and frame(type)filter press filters and obtains amino vitamin B13 crude product.
2, the amino vitamin B13 crude product of gained, 20ml Diethylene Glycol, 145g urea are mixed, be heated to 120～140 ℃ of insulations 2 hours, steam and remove less water, the gained dope was continued to be heated to 190 ℃ of insulation reaction 10 hours.
Be cooled to 85 ℃, add 1000ml water, stir 30min and obtain filbert suspension.90 ℃ of insulated and stirred 1 hour.
3, be cooled to room temperature, filter, washing dry product.
2,4,6, the total recovery 62%～65% of 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine.
The shortcoming of existing " Wyler's process " is:
The amino vitamin B13 separation task that the first step hydrogenation obtains is heavy, needs to use plate and frame(type)filter press, and efficient is low.Cause the production cycle long, the cost of labor height.
The second step reaction needed is reacted under the urea melting condition, stirs difficulty.And desired reaction temperature reaches 10 hours heat-up time up to 190 ℃, and these shortcomings cause the equipment requirements height, and depreciation is fast, and energy consumption of unit product is big.
The technology of product refers to table: referring to table 1.
Embodiment 2
A kind of synthetic dipyridamole intermediate---2,4,6, the method for 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine,
The synthetic route diagram is as follows:
Concrete steps are as follows:
1, the 50g nitroorotic acid is dissolved in the 500ml aqueous solution of 35g sodium hydroxide, gained solution is transferred in the hydrogenation still, add the 10g Raney's nickel, the average nickel contact area of Raney's nickel is 100m
2/ g in 80 ℃, 0.8MPa hydrogenation 8 hours, no longer absorbs hydrogen.
Be cooled to 35 ℃, filtration catalizer.Without separation, filtrate is directly used in next step reaction.
2, drip concentrated hydrochloric acid to gained filtrate, regulate pH value to 3.
Be warming up to 70 ℃, add Zassol in batches, adding in about 1 hour finishes, and adds 90% Zassol 55g altogether.Be incubated 70 ℃ and continued insulation reaction 1.0 hours.
The sodium hydroxide solution that in batches adds content 30% is regulated pH to 13, and interior temperature rise is incubated about 95 ℃ reactions 1.5 hours to about 95 ℃.
Be chilled to 70 ℃ slightly, the sulphuric acid soln of content 50%-60% is regulated pH to 3, insulated and stirred 1 hour.
3, be chilled to 20 ℃ of filtrations, be washed to neutrality, dry product.
2,4,6, the total recovery 70～75% of 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine.
Experimental principle of the present invention:
With the Zassol is raw material, produces the isocyanic acid of lower concentration under solutions of weak acidity.As carbamylation reagent, generate urea derivatives with the isocyanic acid of this lower concentration with amino vitamin B13 reaction.The gained urea derivatives heats cyclization under strong alkaline condition, obtain dipyridamole intermediate 2,4,6,8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine.
Compare with existing synthetic method:
1. the amino vitamin B13 of the first step product is directly used in next step reaction without separation, has saved loaded down with trivial details filtration.
2. being raw material with the Zassol under the solutions of weak acidity, producing the isocyanic acid of lower concentration, is carbamylation reagent with the isocyanic acid of this lower concentration, with amino vitamin B13 reaction, obtains urea derivatives.
3. this urea derivatives obtains the dipyridamole intermediate in strong alkaline condition heating cyclization down---and 2,4,6,8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine.
4.2,4,6, the total recovery of 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine brings up to 70～75% from 62%～65%.The content of product also is significantly improved.
Above method does not have reported in literature, belongs to initiative both at home and abroad.
The technical indicator of product: referring to table 1.
The technical indicator of table 1 product (according to weight percent)
| Embodiment 1 | Embodiment 2 | |
| The content of product | ＞85.0％ | ＞90.0％ |
| Moisture | ＜1.0％ | ＜1.0％ |
| Weight loss on drying | ＜1.5％ | ＜1.5％ |
| Ignition residue | ＜0.3％ | ＜0.3％ |
The technical indicator of product of the present invention (embodiment 2) all meets or exceeds the product index of existing " Wyler's process " (embodiment 1).
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. synthetic dipyridamole intermediate---2,4,6, the method for 8-tetrahydroxy Mi Dingbing [5,4-d] pyrimidine may further comprise the steps:
(1) with nitroorotic acid in alkali lye, use Ni/H again
2Hydrogenation is filtered and is obtained amino vitamin B13 solution, without separation, is directly used in next step reaction;
(2) with amino vitamin B13 solution concentrated hydrochloric acid pH regulator to 3, add Zassol, temperature control reacts, and obtains the urea derivatives of amino vitamin B13; Drip content 30% sodium hydroxide solution again with pH regulator to 13, the heating cyclization drips content 50%-60% sulphuric acid soln and transfers pH to 3;
(3) be cooled to room temperature, filter, be washed to neutrality, dry product.
2. method according to claim 1 is characterized in that: the described alkali of step (1) is sodium hydroxide.
3. method according to claim 1 is characterized in that: the described nickel of step (1) is Raney's nickel.
4. method according to claim 1 is characterized in that: the described acid of step (2) is sulfuric acid, and described alkali is sodium hydroxide.
5. according to claim 1,2 or 3 described methods, it is characterized in that: (ratio of quality and the number of copies) of each component of described step (1) is 50 parts of nitroorotic acids, 35 parts in sodium hydroxide, 10 parts of Raney's nickels, H
20.52 part, filter and obtain amino vitamin B13 solution.
6. method according to claim 5 is characterized in that: 55 parts of 90% Zassols of interpolation (ratio of quality and the number of copies) of described amino vitamin B13 solution.
7. method according to claim 1 is characterized in that: maximum temperature is 95 ℃.
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| CN2009100519991A CN101899046B (en) | 2009-05-26 | 2009-05-26 | Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine |
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| CN2009100519991A CN101899046B (en) | 2009-05-26 | 2009-05-26 | Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine |
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| CN101899046B CN101899046B (en) | 2012-07-04 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153170A (en) * | 2015-11-03 | 2015-12-16 | 芮城县虹桥药用中间体有限公司 | Refining method for 2,6-dichloro-4,8-dipiperidinopyrimidino[5,4-d]pyrimidine serving as dipyridamole intermediate |
| CN106946887A (en) * | 2017-03-24 | 2017-07-14 | 大连万福制药有限公司 | It is a kind of to introduce the new technology that catalyst optimization synthesizes Dipyridamole |
| CN115677707A (en) * | 2022-10-18 | 2023-02-03 | 启东东岳药业有限公司 | Method for preparing 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine by using diaminomaleonitrile method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR065996A1 (en) * | 2007-04-13 | 2009-07-15 | Schering Corp | DERIVATIVES OF PYRIMIDINDIONA, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USES IN THE TREATMENT AND / OR PREVENTION OF OBESITY, DIABETES, DYSLIPIDEMIA BETWEEN OTHER PATHOLOGIES. |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153170A (en) * | 2015-11-03 | 2015-12-16 | 芮城县虹桥药用中间体有限公司 | Refining method for 2,6-dichloro-4,8-dipiperidinopyrimidino[5,4-d]pyrimidine serving as dipyridamole intermediate |
| CN106946887A (en) * | 2017-03-24 | 2017-07-14 | 大连万福制药有限公司 | It is a kind of to introduce the new technology that catalyst optimization synthesizes Dipyridamole |
| CN106946887B (en) * | 2017-03-24 | 2019-05-28 | 大连万福制药有限公司 | A kind of preparation method introducing catalyst optimization synthesis Dipyridamole |
| CN115677707A (en) * | 2022-10-18 | 2023-02-03 | 启东东岳药业有限公司 | Method for preparing 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine by using diaminomaleonitrile method |
| CN115677707B (en) * | 2022-10-18 | 2023-12-22 | 启东东岳药业有限公司 | Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method |
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Effective date of registration: 20170920 Address after: Taizhou City, Zhejiang province 317016 coastal city waterfront Toumen Port District Du Sichuan Road No. 32 Patentee after: Zhejiang state rich Biotechnology Co., Ltd. Address before: 318000 No. 56 Binhai Road, rock head industrial zone, Jiaojiang District, Zhejiang, Taizhou Patentee before: Taizhou City Hwasun Pharmacuetical and Chemical Co., Ltd. |