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Novel technology with introduced catalyst to optimize synthesis of dipyridamole

A dipyridamole and new process technology, applied in the field of pharmaceutical intermediates, can solve the problems of serious environmental pollution, easy oxidative decomposition, difficult post-processing, etc., achieve simple post-processing, easy operation, and improve environmental pollution and operational danger. effect of the problem

Active Publication Date: 2017-07-14
大连万福制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] But there are some problems in this method, the yield of oxidation and nitration steps is low, the process of reducing nitro to amino requires the use of sodium hydrosulfite, which has strong reducibility, but pollutants such as sodium sulfite and sodium sulfate will be produced in the reaction, and insurance The powder is easily hydrolyzed in water to produce hydrogen gas, and it is easy to oxidize and decompose when it encounters moisture and acid, which has the potential danger of burning and explosion; phosphorus oxychloride and phosphorus pentachloride are used in the chlorination process, these two substances are extremely corrosive, and the environment Severe pollution and difficult post-processing; preparation of 2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimido[5,4-d]pyrimidine from perchloropyrimido[5,4-d]pyrimidine In the process, the selectivity of the reaction is poor, the yield is low, and the post-processing is very difficult.

Method used

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  • Novel technology with introduced catalyst to optimize synthesis of dipyridamole
  • Novel technology with introduced catalyst to optimize synthesis of dipyridamole
  • Novel technology with introduced catalyst to optimize synthesis of dipyridamole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Synthesis of 5-nitro-2,6-dioxo-1,3-dihydropyrimidine-4-carboxylic acid

[0024]

[0025] (a) In a 500ml three-necked flask, sequentially add 6-methylpyrimidine-2,4(1H,3H)-dione (10.0g, 79.4mmol), AIBN (azobisisobutyronitrile, 0.26g, 1.6mmol ), cobalt acetate (0.28g, 1.6mmol), glacial acetic acid 250ml, and oxygen (flow rate is 6-10m / s, diameter area is 9×10 -6 m 2 ), heated to 80°C for 15 hours, after the reaction, poured into saturated brine, filtered under reduced pressure, dried, recrystallized (good solvent chloroform, poor solvent methanol) to obtain 11.4g of white solid, the yield was 92.0 %. MS(EI):m / z:156.0169([M] + ).

[0026] (b) In a 500ml three-necked flask, add 2,6-dioxo-1,3,5-trihydropyrimidine-4-carboxylic acid (11.4g, 73.1mmol), 125ml of NaOH aqueous solution (500g sodium hydroxide +1500g purified water), stirred for 3h;

[0027] (c) Add nitric acid into a 500ml three-necked flask, cool it at minus 25°C with liquid nitrogen, then slow...

Embodiment 2

[0028] Example 2: Synthesis of pyrimido[5,4-d]pyrimidine-2,4,6,8-tetraol

[0029]

[0030] d) Substrate 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (13.0g, 64.7mmol), activated copper powder (8.28g , 129.4mmol), was added to a 500ml dry two-necked flask, and 200ml of dilute hydrochloric acid (volume ratio of concentrated hydrochloric acid: water = 1:10) was added as a reaction solvent. The reaction solution was extracted with methyl chloride, and after the solvent was evaporated by rotary evaporation, it was directly put into the next step of reaction;

[0031] e) Put 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid and urea (7.7g, 128.0mmol) into a two-necked flask, and add 125ml of NaOH solution dropwise (500g sodium hydroxide + 1500g purified water), after the dropwise addition, the temperature was rapidly raised to 100°C, and kept for one hour; continued to stir for 3h, cooled to room temperature (25°C), filtered to obtain a solid, ...

Embodiment 3

[0033]

[0034](f) Add pyrimido[5,4-d]pyrimidine-2,4,6,8-tetraol (10.9g, 55.2mmol), SOCl2 (8.1ml, 110.0mmol, ρ=1.638g) into a 500 three-necked flask / ml), dioxane 200ml was used as the reaction solvent to react for 1 hour, and DMF (4.2ml, 55.2mmolρ=0.95g / ml) was added to react in dark for 1.5 hours. After the reaction, the solvent was removed under reduced pressure, the solid was extracted with hot toluene solution, and the crude product was subjected to column chromatography with PE:DCM=2:1 to obtain 13.1 g of white solid with a yield of 88.59%. MS(EI):m / z:267.8872([M] + ).

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Abstract

The invention discloses a novel technology with an introduced catalyst to optimize the synthesis of dipyridamole, and belongs to the technical field of medical intermediates. According to the technology, in the step of oxidizing a methyl group of 6-methyl uracil into formic acid, a Co(OAc)2 / HOAc / AIBN / O2 catalytic system is introduced, and the reaction yield is increased to 90 to 95%. In the step of reducing a nitro group of nitro-orotic acid into an amino group, activated copper powder is taken as the catalyst, the yield is more than 85%; and moreover, the environmental pollution and danger caused by sodium hydrosulfite are avoided. In the step of converting substituted hydroxyl group into substituted chlorine, SOCl12 and N,N-dimethyl formamide are introduced into the reaction system so as to reduce the environment pollution and the difficulty of post treatment. In the reactions of preparing 2,6-dichloro-4,8-bis(piperidine-1-yl)pyrimido[5,4-d]pyrimidine from perchloro pyrimido[5,4-d]pyrimidine, a CuI / PhNO2 catalytic system is introduced into the reaction system, the reaction yield reaches 95%, moreover, the operation is easy, and the treatment is simple. The provided technology increases the yield, reduces the cost, guarantees the safety, saves the energy, and meets the requirements of green reactions and modern chemical production.

Description

technical field [0001] The invention relates to a new process for optimizing the synthesis of dipyridamole by introducing a catalyst, which belongs to the technical field of pharmaceutical intermediates. Background technique [0002] Dipyridamole has been extensively studied and applied as a cardiovascular disease drug. Studies have shown that dipyridamole dilates blood vessels, inhibits platelet aggregation and adhesion, and has antithrombotic effects. In addition, it can be used to prevent thrombosis after artificial heart valve or artificial blood vessel transplantation, secondary prevention after myocardial infarction, ischemic cerebrovascular disease and other diseases, and the market demand is very large. The traditional process includes a series of processes such as nitrification, reduction, condensation, chlorination, connection with piperidine, synthesis of final product, salt formation, desalination, decolorization and pressure filtration. [0003] But there are ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 孙庆发
Owner 大连万福制药有限公司
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