RU2047616C1 - Method of synthesis of 2,4,6-triamino-6-phenylpteridine - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 2,4,6-triamino-6-phenylpteridine (1) is a drug triamteren. Synthesis is carried out by heating benzyl cyanide (2), 2,4,6-triamino-5-nitrosopyrimidine (3) and sodium hydroxide (4) at molar ratio 1:0.95:(0.25-0.5) in 8-10 m. d. butanol (5) per 1 m. d. (2) at 110-115 C for 8-12 hr followed by isolation and purification of (1). Reaction mass prepared by heating isonitrosomalononitrile guanidinium salt (6) and (4) at molar ratio (1.0-1.05):(0.25-0.5) per 1 mole (2) in 8-10 m. d. (5) at 105-115 C for 0.5-1.0 hr can be used instead components (3-5). Component (2) is added to the hot reaction mass followed by process at 110-115 C for 8-12 hr. The yield of (1) per (2) is 68-70% m. d. Content of basic substance is 99.5-100% In the case of (6) use the yield of (1) per (2) is 68-69% m. d content of basic substance is 99.3-100.1% Synthesized compounds were used in medicine. EFFECT: improved method of synthesis. 2 cl, 2 tbl

Description

 The invention relates to chemistry and technology for the preparation of a heterocyclic compound 2,4,7-triamino-6-phenylpteridine, which is used as a Triamteren potassium-sparing diuretic or as a component of the Triampur diuretic medication.

+ C₆H₅CH₂CN

Недостатками процесса по способу (1) являются невысокий выход триамтерена и использование дорогостоящих и дефицитных компонентов метилата натрия и этилцеллозольва.Triamteren was first obtained by condensation of 2,4,6-triamino-5-nitrosopyrimidine (TANP) with benzyl cyanide (CB) in ethyl cellosolve in the presence of sodium methylate base (1. Spickett RG, W. Timis GMJ Chem. So. 1954, N 8, p. 2887) with a yield of 55%

+ C ₆ H ₅ CH ₂ CN

The disadvantages of the process according to the method (1) are the low yield of triamteren and the use of expensive and scarce components of sodium methylate and ethyl cellosolve.

Возможно получение триамтерена из тетрааминопиримидина и бензоилцианида в кипящем ДМСО в присутствии щелочного агента (3. Пат. Японии 25914/67):

+ C₆H

CN ___→

Выходы в способах (2,3) около 60% общими их недостатками являются малая доступность используемых вместо ЦБ реагентов.There is also known a method for producing triamteren, in which instead of CB is used the salt of phenylbenzylpyridinium ketone in the presence of alkali metal cyanide (2. Pat. Germany 1 274585):

It is possible to obtain triamteren from tetraaminopyrimidine and benzoyl cyanide in boiling DMSO in the presence of an alkaline agent (3. Pat. Japan 25914/67):

+ C ₆ H

CN ___ →

The outputs in methods (2,3) of about 60%, their common disadvantages are the low availability of reagents used instead of CB.

The prototype of the proposed technical solution is taken from the most acceptable from our point of view method implemented in the pilot production of VNIHFI (4. Experimental-industrial regulation for the production of triamtrene. M. VNIHFI, 1989). It consists in heating CB, TANP and potassium carbonate in a molar ratio of 1: 0.77: 0.83 in DMF (16.8 ppm per 1 ppm CB) at 145-150 ^о С for 7 hours followed by purification of the formed triamteren through acetate by crystallization from 35% acetic acid (26 rd per 1 ppm triamteren) and regeneration of the triamteren by treatment with aqueous ammonia (0.78 rd per 1 ppm triamteren )

+ C₆H₅CH₂CN

Выход технического триамтерена составляет 78,3 фармакопейного триамтерена 68,8% на ТАНП, или 53,0% на ЦБ.Reaction scheme

+ C ₆ H ₅ CH ₂ CN

The yield of technical triamteren is 78.3 pharmacopoeial triamteren 68.8% on TANP, or 53.0% on the Central Bank.

The disadvantages of the process according to the method (4) are:
stringent requirements for raw materials in terms of moisture content (not more than 0.1% in DMF, 0.3% in potassium carbonate and TANP);
the complexity of its technological design associated with the high temperature of the process (either high-pressure steam or a circuit with a high-temperature coolant is needed to ensure it);
the difficulty of regenerating DMF;
high consumption of raw materials.

When the moisture content in the feed more than the specified temperature and below 145 ^{° C,} increasing process time and reduced yield triamterene (4).

 The aim of the proposed method is to simplify the process for obtaining triamteren, reducing the consumption of raw materials and expanding the raw material base.

 The goal is achieved by using in the process components and conditions different from that of the prototype.

The essence of the proposed method consists in heating CB, TANP and sodium hydroxide in a molar ratio of 1: 0.95: (0.25-0.5) in 8-10 ppm. 1 ppm butanol CB at 110-115 ^C for 8-12 hours followed by isolation and purification triamterene.

Instead of TANP, sodium hydroxide, and butanol, it is also proposed to use a reaction mass obtained by heating the guanidinium salt of isonitrosomalononitrile (HS) and sodium hydroxide in a molar ratio of (1.0-1.05): (0.25-0.5) per 1 mol of CB in 8-10 ppm 1 ppm butanol CB at 110-155 ^C for 0.5-1.0 hours followed by adding to the hot reaction mass CB and further continuation of the process at 110-115 ^{° C} for 8-12 hours. The isolation and purification of triamterene.

_____→

3CH₃COOH
П р и м е р 1. Получение триамтерена из 2,4,6-триамино-5-нитрозопиримидина.The process diagram of the proposed method
(NC) ₂ C = NOH · (H ₂ N) ₂ C = NH

_____ →

3CH ₃ COOH
PRI me R 1. Obtaining triamterene from 2,4,6-triamino-5-nitrosopyrimidine.

117 g (1 mol) of CB are added with stirring to the mixture of 146.3 g (0.95 mol) of TANP, 16 g (0.4 mol) of sodium hydroxide in 1170 (10 ppm per 1 ppm of CB) butanol. The mixture is heated at a temperature of 110-115 ^about With for 10 hours

(The end of exposure is controlled by TLC until the disappearance of TANP R _f 0.4, eluent EA: MeOH: CH ₃ COOH8: 1: 1). The reaction mass is cooled to 20 ^about C, the precipitate is filtered off, washed with water to pH 7, dried at 60-70 ^about C.

 The yield of technical triamterene is 203.9 g (80.6% on the Central Bank).

 Cleaning triamteren is carried out according to the method of the prototype (4).

To 5300 ml (26 rpm per 1 ppm of technical triamteren) of 35% acetic acid, 203.9 g of technical triamteren are sprinkled. The reaction mass is heated to 100-105 ^about C and give exposure at this temperature for 10-15 minutes until the triamterene is completely dissolved. The solution is cooled to 80-90 ^about C, sprinkled with 1.3 g (0.07 ppm) of activated carbon. The reaction mass is heated to 100-105 ^about C, give a 10-minute exposure, the charcoal is filtered through a heated funnel. The filtrate was cooled ^to 20 ° C for 2-3 hours. The precipitate was filtered off triamterene acetate.

To 2915 ml (14.3 vd) of water, 163 ml (0.8 vd) of 25% ammonia are added, and triamterene acetate is added. The suspension is stirred for 1 hour at a temperature of 20-25 ^{° C} (pH not less than 10).

The precipitate of pharmacopoeial triamteren is filtered off, washed with water, dried at 60-70 ^about C.

 173.3 g are obtained (68.5% on CB, 72.1% on TANP).

 Mass fraction of the main substance 100.0 The product meets all the requirements of the Interim Pharmacopoeia Article.

 PRI me R 2. Obtaining triamterene from the HS.

154 g (1 mol) of HS and 16 g (0.4 mol) of sodium hydroxide in the form of powder or fine granules in 1170 g (10 ppm per 1 ppm of CB) of butanol are heated with stirring at 110-115 ^о C for 1 h. During heating, a precipitate of TANP precipitates. The hot reaction mixture is poured 117 g (1 mol) and CB give holding at 110-115 ^{° C} for 10 hours. The reaction mixture was cooled ^to 20 ° C, the precipitate was filtered off, washed with water to pH 7, dried at 60-70 ^{° C} ,
The yield of technical triamterene is 203 g (80.2% on the Central Bank).

 Cleaning is carried out as described in example 1.

The yield of pharmacopeia triamterene 172.5 g (68.2%) on the Central Bank. Mass fraction of the main substance 99.8%
PRI me R s 3-10 performed according to the description given in example 1, with a different ratio of components, temperature and time of the process. The experimental results are shown in table 1.

 PRI me R s 11-18 performed according to the description given in example 2, with a variation in the ratio of components and the conditions of the process of obtaining triamteren. The results are shown in table.2.

 Analysis of the proposed method (examples 1-18) and the prototype method allows us to draw the following conclusions.

 Common features of the methods are to use the cyclization reaction of CB and TANP to obtain triamteren in the presence of a base in an organic solvent medium.

Distinctive features of the methods are that:
in the cyclization reaction of CB and TANP, sodium hydroxide was used as a base, butanol as a solvent in ratios, temperature and time different from the prototype;
in the cyclization reaction of CB and TANP, to obtain triamteren instead of TANP, sodium hydroxide and butanol, the reaction mass obtained by heating the HS and sodium hydroxide in butanol medium in the claimed proportions, temperature and time of the process is used.

 In justification of the selected process conditions for the proposed method, we note the following.

 The molar ratio of CB to TANP was chosen 1: 0.95 (Table 1), since the equimolar ratio does not ensure the completeness of TANP conversion (example 3). This can be explained by the partial decomposition of CB in an alkaline medium. In example 3, the mass fraction of the basic substance is more than 100% due to the admixture of TANP.

 The molar ratio of CB to sodium hydroxide was selected within the range of 1: (0.25-0.5), since when using less than 0.25 moles of sodium hydroxide (Example 6), despite a significant increase in the process time, it is not possible to ensure the complete conversion of TANP to triamterene . The triamteren obtained under such conditions cannot be purified from the TANP impurity. The use of more than 0.5 moles of sodium hydroxide in the process is impractical, since this only slightly decreases only the process time without changing the yield of triamterene.

Process temperature and cyclization CB TANP chosen in the range ^of 110-115 C, since provide greater temperature under atmospheric pressure, is impossible, and at a lower temperature increases the process time (Example 10).

Process time cyclization at 110-155 ^{° C} is taken in the range of 8-12 hours, because during this time ensures completeness of reaction that is easily controlled visually by TLC and the transition crimson coloration in yellow TANP triamterene.

 The amount of butanol is taken in the range of 8-10 ppm. at 1 ppm Central Bank based solely on ensuring acceptable fluidity of the reaction mass, since when the amount of butanol is less than 8 ppm mix the reaction mass and drain it from the reactor after the completion of the process is almost impossible. Within the specified limits, the yield and quality of triamteren change little.

 The use of the reaction mixture obtained by heating HS and sodium hydroxide in butanol and containing the same reaction components in the cyclization reaction with CB instead of the initial components of TANP, sodium hydroxide and butanol allows one to significantly expand the raw material base of the triamteren production process, since TANP is obtained from HS (5. French Patent. 1.364.734, 1964). When TANP is separated from the reaction mass, the process of obtaining triamterene is significantly complicated and the yield of triamterene is reduced due to the loss of TANP with spent solvent.

The ratio of the components upon preliminary preparation of the TANP from the HS (Table 2) was selected taking into account the conditions found in the examples of Table 1 for the further conversion of the TANP into a triamteren after adding CB to the reaction mass. 1.00-1.05 moles of HS are taken per 1 mol of CB, since this ensures the maximum yield of triamteren and its high quality. With a larger number of HS (example 15), triamterene does not meet the requirements of the VFS in terms of the mass fraction of the main substance, since in this case more TANP is formed than is necessary for the reaction with the CB. Therefore, the molar ratio of HS and sodium hydroxide is selected in the range (1.00-1.05) :( 0.25-0.50) per 1 mol of CB and the amount of butanol is 8-10 ppm per 1 ppm. Central Bank The temperature range for the conversion of HS to TANP was taken to be 110-115 ^о С, since this interval is used in the further process and in this interval the reaction of conversion of HS completes in 0.5-1.0 hours.

The novelty of the invention consists in the fact that
in the cyclization reaction of the Central Bank and TANP, a different base and solvent and process conditions are used in comparison with the prototype, which together provide a decrease in the process temperature;
The possibility of using TANP, which is formed in the reaction mass after heating the HS in butanol in the presence of sodium hydroxide instead of purified TANP, is shown to produce triamterene.

From a comparison of the proposed and prototype methods, the following conclusions can be drawn:
the process according to the proposed method is simpler than the prototype, since the temperature of the process 110-115 ^about With can be achieved by steam heating, in the prototype a special coolant.

 Butanol recovery is also technologically simpler. So, 80% of the taken butanol is regenerated by distillation from the mother liquor.

 The raw material base for the synthesis of triamterene is expanding, since HS, butanol and sodium hydroxide are used instead of TANP, DMF and potassium carbonate.

 Given that there is no industrial production of TANP, the advantages of the proposed method become obvious.

 The consumption of raw materials for obtaining 1 kg of triamterene is reduced (see additional materials).

 Thus, the set goal can be considered achieved.

Claims (2)

1. METHOD FOR PRODUCING 2,4,7-TRIAMINO-6-Phenylperidine including condensation of benzyl cyanide and 2, 4, 6-triamino-5-nitrosopyrimidine in the presence of a base in an organic solvent medium by heating, isolation and purification of the target product, characterized in that, sodium hydroxide is used as the base, butanol is used as the organic solvent at a molar ratio of benzyl cyanide, 2, 4, 6-triamino-5-nitrosopyrimidine and sodium hydroxide, 1 0.95 0.25 0.5 in 8 10 m .d. (1 ppm benzyl cyanide) butanol at 110 115 ^o C for 8 12 hours 2. The method according to p. 1, characterized in that benzyl cyanide is added to the hot reaction mass at 110 115 ^o C containing 2, 4, 6-triamino-5-nitrosopyrimidine, sodium hydroxide and butanol obtained by heating the guanidinium salt of isonitrosomalononitrile and hydroxide sodium in a molar ratio of 1.0 1.05 0.25 0.5 per 1 mol of benzyl cyanide in 8 10 ppm benzyl cyanide at 110-115 ^{° C.} for 0.5-1.0 hours, and cyclization is carried out.

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