CN115677707B - Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method - Google Patents
Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method Download PDFInfo
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- CN115677707B CN115677707B CN202211277467.1A CN202211277467A CN115677707B CN 115677707 B CN115677707 B CN 115677707B CN 202211277467 A CN202211277467 A CN 202211277467A CN 115677707 B CN115677707 B CN 115677707B
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- 238000000034 method Methods 0.000 title claims abstract description 23
- ZEKJTVBUDUYZOU-UHFFFAOYSA-N 1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8-tetrone Chemical compound O=C1NC(=O)NC2=C1NC(=O)NC2=O ZEKJTVBUDUYZOU-UHFFFAOYSA-N 0.000 title claims abstract description 11
- DPZSNGJNFHWQDC-ARJAWSKDSA-N (z)-2,3-diaminobut-2-enedinitrile Chemical compound N#CC(/N)=C(/N)C#N DPZSNGJNFHWQDC-ARJAWSKDSA-N 0.000 title claims abstract description 7
- 230000002146 bilateral effect Effects 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 8
- VLJQDHDVZJXNQL-UHFFFAOYSA-N 4-methyl-n-(oxomethylidene)benzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N=C=O)C=C1 VLJQDHDVZJXNQL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 230000008034 disappearance Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 238000004458 analytical method Methods 0.000 abstract description 6
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 abstract description 5
- 229960002768 dipyridamole Drugs 0.000 abstract description 5
- 239000007791 liquid phase Substances 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 description 11
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HWCXJKLFOSBVLH-UHFFFAOYSA-N 5-amino-2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound NC1=C(C(O)=O)NC(=O)NC1=O HWCXJKLFOSBVLH-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 229960005010 orotic acid Drugs 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- WJFDCFHWFHCLIW-UHFFFAOYSA-N 2-(bromomethyl)-6-methylpyridine Chemical compound CC1=CC=CC(CBr)=N1 WJFDCFHWFHCLIW-UHFFFAOYSA-N 0.000 description 1
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical compound CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- HWGBHCRJGXAGEU-UHFFFAOYSA-N Methylthiouracil Chemical compound CC1=CC(=O)NC(=S)N1 HWGBHCRJGXAGEU-UHFFFAOYSA-N 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001546 nitrifying effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for preparing 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine by using diaminomaleonitrile as a raw material, carrying out condensation reaction with p-toluenesulfonyl isocyanate to obtain a bilateral substituent, then rearranging and hydrolyzing under alkaline conditions to obtain dipyridamole intermediate 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine, wherein the yield of liquid phase analysis products reaches 78%, and the purity is more than 98%. The process has the advantages of short route, simple operation and the like.
Description
Technical Field
The present invention relates to a process for the preparation of 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine.
Background
2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine (tetrahydroxy intermediate, I) is a key intermediate in the synthesis of dipyridamole. Dipyridamole is used in various fields due to its strong antithrombotic and broad antiviral effects, and has the advantages of low cost and high efficiency as a basic drug. However, the existing dipyridamole production process involves a step of preparing 5-amino orotic acid by nitro oxidation, which has great safety risk, and is unfavorable for industrial mass production due to large amount of three wastes. Therefore, it is urgent to design a new safe and environment-friendly dipyridamole synthesis process.
At present, two main methods for synthesizing and preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine are available:
1) Taking ethyl acetoacetate and thiourea as initial products, and condensing under alkaline conditions to prepare 6-methyl thiouracil; then nitrifying and oxidizing by mixed acid to obtain 5-nitro orotic acid; reducing the mixture by sodium dithionite to obtain 5-amino orotic acid; and then cyclizing with urea to obtain the tetrahydroxy compound. The process has the problems of complex operation steps, high production safety hidden trouble, low raw material utilization rate, difficult removal of impurities, long synthesis route and the like, wherein the biggest problems are safety risk of the nitrooxidation step and pollution of three wastes, and the production scale is limited.
2) The above process is also improved by separating high-risk oxidation and nitrification, i.e. using 6-methyluracil as raw material and Co (OAc) 2 /HOAc/AIBN/O 2 The catalytic system is oxidized to prepare the orotic acid, and then the orotic acid is nitrified by mixed acid, so that the yield can reach 90% -95%; the route greatly reduces the safety risk, but the problems of long route and more three wastes are also existed.
Disclosure of Invention
The invention aims to provide a method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by using a diaminomaleonitrile method, which has high safety coefficient, less three wastes and convenient operation.
The technical scheme of the invention is as follows:
a method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by a diaminomaleonitrile method is characterized in that: the method comprises the following specific steps:
(1) Dissolving diamino Ma Laiqing (II) in a solvent A, adding p-toluenesulfonyl isocyanate (III), stirring at room temperature, stopping the reaction after TLC monitoring the disappearance of the raw materials, and carrying out post-treatment and drying to obtain a bilateral substituent (IV);
(2) And (3) rearranging and hydrolyzing the bilateral substituent (IV) obtained in the step (1) in the solvent B, cooling to room temperature after the reaction is completed, filtering to obtain the tetrahydroxy sodium salt, adding hydrochloric acid into the tetrahydroxy sodium salt to adjust to be weak acid, stirring, filtering and washing to obtain a tetrahydroxy crude product (I).
The synthetic route is as follows:
in the step (1), the solvent A is tetrahydrofuran, acetonitrile or dimethyl sulfoxide; solvent B in step (2) is 4% wt sodium hydroxide, 8% wt sodium hydroxide, 12% wt sodium hydroxide or 16% wt sodium hydroxide.
The proportion of the bilateral substituent (IV) to the solvent B in the step (2) is 1:5-1:30 (g/ml).
The method has mild reaction conditions and simple and convenient operation, and is suitable for industrial production. The high-risk process is not involved, and the production management is convenient; short route, simple and convenient operation and less pollution of three wastes; the byproducts can be recycled. The yield of the liquid phase analysis product reaches 78 percent, and the purity is more than 98 percent.
The invention is further described below with reference to the drawings and examples.
Drawings
FIG. 1 is a diagram of liquid phase analysis of a product;
fig. 2 is a high resolution mass spectrum of the product.
Detailed Description
Example 1
And dissolving diamino Ma Laiqing (II) in tetrahydrofuran solvent, adding p-toluenesulfonyl isocyanate (III), stirring at room temperature, stopping the reaction after TLC monitoring the disappearance of the raw materials, and carrying out post-treatment and drying to obtain the bilateral substituent (IV).
The bilateral substituent (IV, 2.5g,5 mmol) was dissolved in 60ml of 4% NaOH solution, heated to 75 ℃ for 7 days, cooled to room temperature, filtered, the filter cake was transferred to water, 1M hydrochloric acid was added to adjust pH=6, stirred for 30min, filtered and washed to obtain 0.89g of crude product, and the content of tetrahydroxy was 78% as a result of liquid chromatography analysis, and the cyclic yield was 70%.
Example 2
And dissolving diamino Ma Laiqing (II) in acetonitrile, adding p-toluenesulfonyl isocyanate (III), stirring at room temperature, stopping the reaction after TLC monitoring the disappearance of the raw materials, and carrying out post-treatment and drying to obtain the bilateral substituent (IV).
The bilateral substituent (IV, 2.5g,5 mmol) was dissolved in 30ml of 8% NaOH solution, heated to 75 ℃ for 7 days, cooled to room temperature, filtered, the filter cake was transferred to water, 1M hydrochloric acid was added to adjust to pH=6, stirred for 30min, filtered and washed to obtain 0.77g of product with a tetrahydroxy content of 98% and a cyclization yield of 78%.
Example 3
And dissolving diamino Ma Laiqing (II) in dimethyl sulfoxide solvent, adding p-toluenesulfonyl isocyanate (III), stirring at room temperature, stopping the reaction after TLC monitors the disappearance of the raw materials, and carrying out post-treatment and drying to obtain the bilateral substituent (IV).
The bilateral substituent (IV, 2.5g,5 mmol) was dissolved in 20ml of 12% NaOH solution, heated to 75 ℃ for 7 days, cooled to room temperature, filtered, the filter cake was transferred to water, 1M hydrochloric acid was added to adjust to ph=6, stirred for 30min, filtered and washed to give 0.76g of a crude tetrahydroxy product, and the content of tetrahydroxy was 94% as a result of liquid chromatography analysis, and the cyclic yield was 73%.
1. Characterization of intermediate (V) in the cyclization process
Dissolving bilateral substituent (IV, 2.5g,5 mmol) in 30ml of 8% NaOH solution, heating to 75 ℃, and reacting for 0-5min, wherein bilateral substituent IV is completely dissolved in alkaline water; the orange solid gradually appears in the reaction liquid and is continuously increased in the following 5-30 min; 24 After h the orange solid gradually faded to a yellow solid. After cooling, filtration, the filter cake was washed three times with 5ml of water, and the remaining solid was transferred to water and ph=6 was adjusted with 1M hydrochloric acid to give a yellow solid. The following structure V is confirmed by nuclear magnetism, mass spectrum and element analysis characterization.
1 H NMR(400MHz，DMSO-d 6 )：δ11.88(s,1H)，11.75(s,1H)， 10.72(s,1H)，10.58(s,1H)，7.93(d,2H,J＝8.1Hz)，7.42(d,2H,J＝8.1Hz)， 2.39(s,3H)；C 13 H 11 N 5 O 5 S，ESI-MS[M-H] - = 348.0404; elemental analysis test value (%): c,43.16h,3.28; n,19.30; s,8.89; theoretical value (%): c,44.70H, 3.17; n,20.05; s,9.18.
2. Characterization of hydrolysis by-product (VI)
The bilateral substitution (2.5 g,5 mmol) was dissolved in 30ml of 8% NaOH solution and reacted at 75℃for 7 days. Cooling to room temperature, filtering, adding 1M hydrochloric acid into the filtrate to adjust the pH to be=5, precipitating white solid, and filtering to obtain white solid. The nuclear magnetism and mass spectrum characterization prove that the p-toluenesulfonamide VI is the p-toluenesulfonamide VI.
1 H NMR(400MHz，DMSO-d 6 )：δ7.69(d,2H,J＝8.1Hz)，7.37(d, 2H,J＝8.1Hz)，7.28(s,2H)，2.37(s,3H)；C 7 H 9 NO 2 S，EI-MS m/z＝171.0353。
Claims (2)
1. A method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by a diaminomaleonitrile method is characterized in that: the method comprises the following specific steps:
(1) Dissolving diamino Ma Laijing in a solvent, adding p-toluenesulfonyl isocyanate, stirring at room temperature, stopping the reaction after TLC monitoring the disappearance of the raw materials, and carrying out post-treatment and drying to obtain a bilateral substituent (IV); the chemical structural formula of the bilateral substituent (IV) is as follows:
(2) Rearranging and hydrolyzing the bilateral substituent (IV) obtained in the step (1) in a solvent B, cooling to room temperature after the reaction is completed, filtering to obtain a tetrahydroxy sodium salt, adding hydrochloric acid into the tetrahydroxy sodium salt to adjust to weak acidity, stirring, filtering and washing to obtain a tetrahydroxy crude product (I), wherein the chemical structural formula of the tetrahydroxy crude product (I) is as follows:
the tetrahydroxy sodium salt is the salt formed by a crude tetrahydroxy product and sodium;
solvent B in step (2) is 4% wt sodium hydroxide, 8% wt sodium hydroxide, 12% wt sodium hydroxide or 16% wt sodium hydroxide;
in the step (2), the g/ml ratio of the bilateral substituent (IV) to the solvent B is 1:5-1:30.
2. The process for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by the diaminomaleonitrile process as claimed in claim 1, wherein: the solvent in the step (1) is tetrahydrofuran, acetonitrile or dimethyl sulfoxide.
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| CN202211277467.1A CN115677707B (en) | 2022-10-18 | 2022-10-18 | Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method |
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| CN202211277467.1A CN115677707B (en) | 2022-10-18 | 2022-10-18 | Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method |
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| CN115677707B true CN115677707B (en) | 2023-12-22 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4110607C1 (en) * | 1991-04-02 | 1992-11-26 | Arzneimittelwerk Dresden Gmbh, O-8122 Radebeul, De | Treatment of highly viscous mixt. from dipyridamole prodn. - involves heating and mixing with methyl urea, adding hydrochloric acid, further heating etc. to recover valuable intermediates |
| CN101899046A (en) * | 2009-05-26 | 2010-12-01 | 台州市华南医化有限公司 | Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine |
| 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 |
-
2022
- 2022-10-18 CN CN202211277467.1A patent/CN115677707B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4110607C1 (en) * | 1991-04-02 | 1992-11-26 | Arzneimittelwerk Dresden Gmbh, O-8122 Radebeul, De | Treatment of highly viscous mixt. from dipyridamole prodn. - involves heating and mixing with methyl urea, adding hydrochloric acid, further heating etc. to recover valuable intermediates |
| CN101899046A (en) * | 2009-05-26 | 2010-12-01 | 台州市华南医化有限公司 | Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine |
| 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 |
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