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Synthetic method of triamterene intermediate

A technology of triamterene and a synthesis method, applied in the field of medicine, can solve the problems of high cost of triaminopyrimidine, low equipment return, high environmental pressure and the like

Inactive Publication Date: 2021-07-27
河北利德检测技术有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The production process of 5-nitroso-2,4,6-triaminopyrimidine, an important intermediate used in the synthesis of triamterene, is faced with problems: 5-nitroso-2,4,-triaminopyrimidine is produced from guanidine nitrate[ 1] or 2,4,6-triaminopyrimidine[2], guanidine nitrate belongs to explosive hazardous chemicals, and 2,4,6-triaminopyrimidine is expensive
[0006] The existing triamterene refining process will produce 80 to 100 times more waste water [3], which puts too much pressure on the environment, and the cost of post-processing three wastes is high, and the return on equipment is low

Method used

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  • Synthetic method of triamterene intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation of embodiment 1 triamterene intermediate

[0025] 1. Add 340.2g of pure water and 134.5g of propanedinitrile to the reaction kettle in sequence. After stirring for 25 minutes to dissolve, turn on the nitrogen protection, add 485.7 aqueous solution containing 162.1g of sodium nitrite at 15°C, and add 8% HCl dropwise to adjust the pH3 ~4. After the sodium nitrite aqueous solution is added dropwise, 70.4g of dilute hydrochloric acid is consumed, and kept at 18°C ​​for 2.5h;

[0026] 2. Add 226.3g of guanidine hydrochloride solid to 1, stir for 30min; add 17.6g of NaCO3 solid to adjust the pH to 9-10;

[0027] 3. Add 1340ml of a mixed solvent of dimethyl sulfoxide and xylene, heat up to reflux with water, keep warm at 140°C for 2 hours, and prepare for filtration; the composition of the mixed solvent: dimethyl sulfoxide: xylene is 5:1;

[0028] 4. After the reaction system is cooled to below 50°C, add 1460g of pure water and continue to stir. After the temp...

Embodiment 2

[0035] The preparation of embodiment 2 triamterene intermediate

[0036] 1. Add 420.7g of pure water and 201.4g of propanedinitrile to the reaction kettle in sequence. After stirring for 35 minutes to dissolve, turn on nitrogen protection, add 517.6g of aqueous solution containing 221.6g of sodium nitrite at 15°C, and add 8% HCl dropwise to adjust pH3~4, after the sodium nitrite aqueous solution is added dropwise, dilute hydrochloric acid consumes 90.2g, and keep warm at 15~20°C for 2h;

[0037] 2. Add 307.1g guanidine hydrochloride solid to 1, add 32.7g NaCO3 solid to adjust pH=10;

[0038] 3. Add 2000ml of a mixed solvent of dimethyl sulfoxide and xylene, heat up to reflux with water, keep warm at 140°C for 3 hours, and prepare for filtration; the composition of the mixed solvent: dimethyl sulfoxide: xylene is 5:1;

[0039] 4. After the reaction system is cooled to room temperature, add 2000g of pure water, continue to stir, and filter; the filter cake is rinsed with deioni...

Embodiment 3

[0046] The preparation of embodiment 3 triamterene intermediate

[0047] 1. Add 597.8g of pure water and 303.9g of propanedinitrile to the reaction kettle in turn. After stirring for 34min to dissolve, turn on the nitrogen protection, add 773.9 aqueous solution containing 335.1g of sodium nitrite at 15°C, and add 8% HCl dropwise to adjust the pH3 ~4. After the sodium nitrite aqueous solution is added dropwise, 147.6g of dilute hydrochloric acid is consumed, and kept at 18°C ​​for 2.5h;

[0048] 2. Add 464.7g guanidine hydrochloride solid to 1, stir for 30min; add 50.7g NaCO3 solid to adjust pH=10;

[0049] 3. Add 2400ml of a mixed solvent of dimethyl sulfoxide and xylene, heat up to reflux with water, keep warm at 140°C for 4 hours, and prepare for filtration; the composition of the mixed solvent: dimethyl sulfoxide: xylene is 5:1;

[0050] 4. When the reaction system is cooled below 50°C, add 5000g of pure water and continue to stir. After the temperature cools down to 30°C,...

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Abstract

The invention improves a synthesis method of triamterene from an intermediate to a triamterene finished product. The method adopts guanidine hydrochloride as a starting material to prepare 5-nitroso-2, 4, 6-triaminopyrimidine, and comprises the following steps: (1) sequentially adding water and malononitrile into a reaction kettle, stirring for 25 minutes for dissolving, starting nitrogen protection, adding a sodium nitrite saturated solution at 20 DEG C, dropwise adding 8% HCl at the same time for adjusting the pH value to 3-4, after the sodium nitrite aqueous solution is dropwise added, keeping the temperature for 2.5 hours at 18 DEG C, wherein the dosage weight ratio of the water to the sodium nitrite to the malononitrile to the 8% hydrochloric acid is as follows: the use mass ratio of the sodium nitrite to the malononitrile to the 8% hydrochloric acid is 2.5:1.15:1:0.35; and (2) adding guanidine hydrochloride solid into the solution obtained in the step (1), and stirring for 30 minutes, and adding NaCO3 solid to adjust the pH value to 9-10, wherein the weight ratio of guanidine hydrochloride to sodium carbonate to malononitrile in (1) is as follows: guanidine hydrochloride to malononitrile to sodium carbonate is 1.60:1:(0.10-0.12). According to the method, the synthesis risk of the triamterene intermediate is reduced, wastewater generated in the refining process is reduced, and safe production, energy conservation and emission reduction are facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a triamterene intermediate and a synthesis method thereof. Background technique [0002] Triamterene: Chemical name: 2,4,7-triamino-6-phenylpteridine, a potassium-sparing diuretic. It is used to treat various types of edema, such as edema and ascites caused by heart failure, liver cirrhosis and chronic nephritis, as well as water and sodium retention during glucocorticoid therapy. Often used in combination with potassium-sparing diuretics. It is also used in cases where hydrochlorothiazide or spironolactone is ineffective. [0003] Hypertension is a common disease worldwide, and the prevalence rate in the world is as high as 10% to 20%. Antihypertensive drugs with triamterene as the main component have been widely used clinically in my country's hypertensive population, with outstanding curative effects And the price is low. [0004] Triamterene faces some problems in productio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/46C07D475/08
CPCC07D239/46C07D475/08
Inventor 常云飞薛晨光刘晗
Owner 河北利德检测技术有限公司
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