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Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine

A technology for hydroxypyrimidine and intermediates, which is applied in the field of synthesizing dipyridamole intermediates, can solve problems such as long production cycle, high reaction temperature, and difficult stirring, and achieve the effects of saving time and labor, mild reaction conditions, and shortened reaction time

Active Publication Date: 2010-12-01
ZHEJIANG HUABANG MEDICAL & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The task of separating the aminoorotic acid obtained by hydrogenation in the first step is heavy, requiring the use of a plate and frame filter press, which is inefficient
Lead to long production cycle and high labor cost
[0011] The second step reaction needs to be reacted under the condition of urea melting, and the stirring is difficult
Moreover, the required reaction temperature is as high as 190°C, and the heating time is as long as 10 hours. These shortcomings lead to high equipment requirements, fast depreciation, and high energy consumption per unit product.

Method used

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  • Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine
  • Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine
  • Method for synthesizing persantine intermediate 2,4,6,8-tetrahydroxy pyrimido[5,4-d] pyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The existing "urea method" process.

[0031] The synthetic route of urea method is illustrated as follows:

[0032]

[0033] Specific steps are as follows:

[0034] 1. Add 50g of nitroorotic acid into 500ml of aqueous solution of 15g of sodium hydroxide, and stir until completely dissolved. Transfer this solution to the hydrogenation kettle, add 10g Raney nickel, the average nickel contact area of ​​Raney nickel is 100m 2 / g, hydrogenation at 80°C and 0.8MPa for 8 hours, no hydrogen absorption. Cool to 35°C and filter off the catalyst. Slowly add 35g of industrial hydrochloric acid to the filtrate to obtain a thick slurry. The crude product of aminoorotic acid was obtained by filtering with a plate and frame filter press.

[0035] 2. Mix the obtained aminoorotic acid crude product, 20ml diethylene glycol, and 145g urea, heat to 120-140°C for 2 hours, evaporate a small amount of water, and continue to heat the obtained viscous product to 190°C for 10 hours.

[0...

Embodiment 2

[0044] A method for synthesizing dipyridamole intermediates—2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine,

[0045] The synthetic route is illustrated as follows:

[0046]

[0047] Specific steps are as follows:

[0048] 1. Dissolve 50g of nitroorotic acid in 500ml of aqueous solution of 35g of sodium hydroxide, transfer the resulting solution into a hydrogenation kettle, add 10g of Raney nickel, and the average nickel contact area of ​​Raney nickel is 100m 2 / g, hydrogenated at 80°C and 0.8MPa for 8 hours, no more hydrogen was absorbed.

[0049] Cool to 35°C and filter off the catalyst. The filtrate was directly used in the next reaction without separation.

[0050] 2. Add concentrated hydrochloric acid dropwise to the obtained filtrate to adjust the pH value to 3.

[0051] Raise the temperature to 70°C, add sodium cyanate in batches, and add 55g of 90% sodium cyanate in about 1 hour. Insulate at 70°C and continue to incubate for 1.0 hour.

[0052] Add sodium hydroxi...

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PUM

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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 [0001] The invention relates to a method for synthesizing a dipyridamole intermediate-2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine, which belongs to the field of organic chemistry. Background technique [0002] Dipyridamole, another name dipyridamole, dipyridamole is a non-nitrate coronary artery dilator, which can expand coronary blood vessels, promote the formation of collateral circulation and mild anticoagulation. Dipyridamole can be used for coronary heart disease, and as an anti-platelet aggregation drug to prevent thrombosis and disseminated intravascular coagulation. It can also be used in the treatment of nephropathy. It mainly plays the role of anti-blood viscosity and anti-thrombosis. 2,4,6,8-Tetrahydroxypyrimido[5,4-d]pyrimidine plays a very important role as an intermediate of dipyridamole. [0003] Related studies have been carried out abroad, such as Fisher, F.G.et al., Annalen, 1950,572,217, which reported a yield of 67%. The method used po...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 洪道送刘新科伍小唐
Owner ZHEJIANG HUABANG MEDICAL & CHEM
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