HU195817B - Process for producing 2,4,7-thiamino-6-phenyl-pteridine - Google Patents

Abstract

Improved prepn. of 2,4,7-triamino- phenyl-pteridine (VII) consists of a two step reaction carried out in the same reaction mix at 50-130 deg.C in the presence of a base. Solvents used are of alcohol, alcohol-ether or amide type. The first step consists of heating iso-nitroso-malonic-dinitride (V) guanidine salt to form 2,4,6-triamino -5-nitroso-pyrimidine (IV). Benzylcyanide reacts with (IV) in the second step to obtain (VII).

Description

The present invention relates to a process for the preparation of 2,4,7-triamino-6-phenylpteridine of formula VII.

2,4,7-Trianino-6-phenyl-pleridine (international generic name: Triamterene) is a known diuretic. The preparation of the compound was described by RGW Spickett and GM Timmis (.1. Chem. Soc 1954, 2887), 2,4,6-triamino-5-nitrosopyrimidine and benzyl cyanide 2-etho. condensed in xi-ethanol in the presence of sodium (2-ethoxy) ethylate at reflux at 135 ° C for 2 hours. After distilling off the solvent, the crude product was dissolved in hot dilute hydrochloric acid, and after clarification, the solution was made alkaline and the product recrystallized several times from butanol. The desired 2,4,7-triamino-6-phenylpteridine was obtained in a yield of 5554. This method is not suitable for the industrial preparation of the target compound due to the low yield and laborious purification operations.

Since that publication, numerous patents have been filed (for example, U.S. Patent Nos. 3,081,230, United Kingdom Nos. 932,256 and 982,360, German Democratic Republics 50,835 and 51,640, Federal Republic of Germany and 1,217,388 and Japanese Patent Nos. 42,259,142, 42,193 and 44,22,816 disclose various variants of the above reaction. In these variants, various solvents, in particular dimethylformamide and 2-ethoxyethanol, as well as formamide, dimethylacetamide, a mixture of dimethylsulfoxide and methanol, butanol, ethylene glycol, diethylene glycol, triethylene glycol and ethylene glycol monoalkyl ethers are used as solvents for the condensation reaction and are generally carried out at a boiling point of the mixture in a volume of 12 to 50 times the weight of the compound of formula IV. This high amount of solvent is necessary because the compound of formula IV is poorly soluble in organic solvents, even when hot. Essentially, this high solvent requirement is one of the disadvantages of the above methods.

A variety of reagents are also mentioned in the above descriptions as basic catalysts, such as metal sodium or alkali metal hydroxides dissolved in alcohol and ether-alcohol type solvents, and alkali metal alcoholates, usually sodium methylate, especially for the reaction in dimethylformamide. Alkali metal carbonates, alkali metal amides and alkali metal cyanides are also mentioned. The amount of the base varies widely, from 0.05 molar equivalent to 2 molar equivalent of the starting material of formula IV. Most of the methods described on an industrial scale use sodium methylate as the base, which, however, is not an ideal industrial raw material because of its degradability, air and moisture sensitivity. By these methods, 2,4,7-triamino-6-phenylpteridine is obtained in a yield of 66-84%.

The above-mentioned drawbacks are partially overcome by the method described in Japanese Patent Application No. 40 12 916, which is reacted in 2-ethoxyethanol (7 times by weight) in the presence of 0.1 molar equivalents of potassium hydroxide for 2 hours. bertzil cyanide. Thus, after recrystallization from a mixture of water and ethylene glycol, the compound of formula VII is obtained in a yield of 8754. It should be noted, however, that according to our own studies, this recrystallization is not well reproducible in terms of product purity or recrystallization yield.

A common disadvantage of all the above methods is that the reaction is carried out at relatively high temperatures of 130-180 ° C. At such high temperatures, significant amounts of by-products are formed in addition to the target product. However, the by-product is very difficult to remove because Compound VII is very poorly soluble in the most commonly used solvents with relatively low boiling points (bp <100 ° C) and therefore cannot be crystallized from them.

According to the literature, the purification of the crude product is not satisfactorily solved.

German Federal Patent Specification No. 1,217,388 discloses a purification method by adding the crude product to hot aqueous acetic acid, decanting the resulting solution from the insolubles and filtering off the precipitate formed by aqueous dilution and cooling. This precipitate is made alkaline by the addition of an aqueous solution of ammonium hydroxide to give a pure product. Recovery yield: 7454 Gross yield of starting material of formula IV: 6854. The product obtained above (measured by L ^; V spectroscopy) is 99.454. However, the method is rather cumbersome and, in our experience, also not reproducible well.

German Patent No. 1,193,508 also discloses a purification method. According to this method, the crude product is crystallized from aqueous acetic acid. According to the description, the recovery yield is 7154. In our experience, this recrystallization can only be achieved with a recovery yield of 55-6554.

Finally, U.S. Patent No. 1,620,334 also discloses a purification process in which crude Triamterene is dissolved in about 180-fold aqueous sodium hydrogen sulfate solution, and the salt that crystallizes on cooling is filtered off, and then an aqueous suspension is obtained. produced. A major drawback of this method is the extremely high volume requirements.

It is known in the literature that the 2,4,6-triamino-5-nitrosopyrimidine IV used as starting material for the above reaction can be prepared from two malonic acid dinitriles of formula I using the reaction route. In one method, the malonic acid dinitrile is first reacted with a guanidine salt in the presence of sodium alcoholate and then the resulting 2,4,6-triaminopyrimidine III is nitrosated in aqueous acetic acid (U.S. Patent No. 817, 337, CA 88, 74403). x (1978); and M. F. Maliette et al., J. Am. Chem. Soc. 69, 1814 (1947) and H. Sato et al., J. Chem. Soc. Japan, Fure Chem. Sect. 72, 866 (1951)]. A variant of this method is known, in which these two reactions are carried out without isolation of the intermediate, using the .one pof method, to give the compound of formula IV in 93% yield. However, no qualitative characteristics are given to this product except that it can be used directly for chemical synthesis (German Patent No. 2,651,794).

Alternatively, the malonic acid dinitrile is first nitrosated and then the resulting isonitrogen malonic acid dinitrile of formula II is reacted with guanidine carbonate. At this lower temperature, about 50 ° C, a separate crystalline guanidine salt of formula V is formed which isonitrose-malonic acid dinitrile. The resultant salt of Formula V is boiled with sodium ethylate in ethanol at 46%, and boiled with 2-methyl-5-ethylpyridine in 68% tetralin, and 89% in yield of 2,4,6-triamino-5. to nitrosopyrimidine. In another embodiment of this method, the compound of formula IV can be prepared without isolation of the salt of formula V by boiling isonitrose-malonic acid dinitrile potassium salt and guanidine carbonate in dimethylformamide [E. C. Taylor et al., J. Am. Chem. Soc., 81, 2442 (1959). When the salt of Formula V prepared as described above is boiled in dimethylformamide in the presence of potassium carbonate as catalyst, the two compounds of Formula IV can be prepared in these two steps with a yield of 85% relative to the starting malonic acid dinitrile (French Patent No. 1,364,734). ).

The intermediates of formula IV thus prepared are generally isolated from the aqueous medium as a precipitate. This precipitate has a very fine distribution and is difficult to filter and wash. The product obtained is highly water-binding, dried at 40-50 ° C to a constant weight of 10-11%, and only dried at 110-120 ° C to obtain anhydrous product.

There is also known a process for preparing 2,4,7-triamino-6-phenylpteridine of Formula VII, starting from the alkali metal salt of isonitrose-malonic acid dinitrile of Formula II, first in 15 times dimethylformamide.

Boiling at 1.78 molar equivalents with guanidine carbonate for 1.5 hours, it is converted to the pyrimidine derivative of formula IV by isolation in the same reaction mixture in the presence of sodium triethylate and boiling with benzyl cyanide to give 2,4,7-triamino-6-phenylpteridine shape. The crude product obtained is recrystallized from aqueous acetic acid to give the product VII (621%), in the form of a 62% yield of isonitrose-malonic acid dinitrile potassium salt. Disadvantages of this method are low yields, relatively high solvent requirements, high excess of guanidine carbonate, and particularly high reaction temperature (150 ° C).

It is disadvantageous for the industrial embodiment to start from the dinitrile potassium salt of isonitrose-malonic acid in the above process. The preparation of this salt is a relatively volumetric process, which can be separated from the reaction mixture used for its preparation by distilling 10 times the weight of the above-mentioned organic solvent (methanol).

In addition, some further syntheses of 2,4,7-triamino-6-phenylpteridine of formula VII are known and are summarized below: in one method, the 2,4,6-triamino-5-nitroso pyrimidine is first reduced to the tetraamino derivative of formula VI [M. F. Mailette et al., J. Am. Chem. Soc. 69, 1814 (1974)] followed by benzaldehyde in the presence of an alkali metal cyanide (yield 34%, I. J. Pachter, J. Org. Chem. 28, 1187 (1963)] or with benzoyl cyanide (Japanese Patent No. 42-25914). In another method, 2,4,6-triamino-5-nitrosopyrimidine IV is reacted with ethyl alpha-bromophenylacetic acid in the presence of sodium cyanide (British Patent No. 1,009,477), but the yield of the process is not given.

There is also known a process in which the intermediate of formula IV is first megacetylated, then reacted with a more soluble acetyl derivative than the parent compound of the benzyl cyanide and finally deacetylated to give the N-oxide of compound VII. The gross yield of this method for the compound of formula IV is 65-75% (German Patent No. 1,193,959).

Surprisingly, it has been found that the 2,4,7-triamino-6-phenylpteridine of Formula VII, starting from the guanidine salt of Form I, isonitrose-malonic acid dinitrile, can be prepared in a single reaction, in good yield and in excellent quality. Alkali metal hydroxide and / or carbonate is used as the basic catalyst in addition to a solvent previously used for the preparation of the compound of formula II. Furthermore, it has been found that under mild conditions than those known in the art, the salt of formula V can be converted to the 2,4,6-triamino-5-nitrosopyrimidine of formula IV at 80 ° C to 120 ° C without isolation. , in the same reaction mixture, under mild conditions than those known in the art, can be reacted with benzyl cyanide at temperatures between 70 ° C and 110 ° C. Thus, 2,4,7-triamino-6-phenyl-pLeridine of Formula VII is obtained in very good yields, which, due to the mild reaction conditions used, are very low in impurities and can be purified easily. Surprisingly, the crude product thus obtained is substantially more pure than starting from isolated 2,4,6-triamino-5-nitrosopyrimidine IV and is reacted with benzyl cyanide under the gentle reaction conditions mentioned above.

SUMMARY OF THE INVENTION The present invention relates to a process for preparing 2,4,7-triamino-6-phenylpteridine VII of the guanidine salt of isonitrose-malonic acid dinitrile V in an organic solvent in the presence of an inorganic base such as potassium carbonate as a catalyst. and heating the resulting 2,4,6-triamino-5-nitrosopyrimidine of formula IV in an ether-alcohol, alcohol-type or amide-type solvent, in the presence of an inorganic base such as potassium hydroxide as catalyst. mole equivalents of benzyl cyanide, and isolating and optionally purifying the resulting compound of formula VII, which comprises carrying out the two reaction steps at a temperature between 70 ° C and 120 ° C in the same reaction mixture without isolating intermediate IV, and the catalyst is an alkali metal hydroxide and / or carbonate Azun.

In a preferred embodiment of the process according to the invention, the first reaction step is carried out at a temperature of 80-120 ° C, preferably 90-110 ° C, and the second reaction step is carried out at a temperature of 70-110 ° C.

Suitable solvents include an ether-alcohol type solvent such as an alkoxyalkanol such as 2-ethoxyethanol, 2-methoxyethanol or an alkoxyalkoxyalkanol such as 2- (2-ethoxyethoxy). ethanol, 2- (2-methoxyethoxy) ethanol, or tetrahydrofurfuryl alcohol, or ethers thereof, such as polyethylene glycol (e.g., glycofurol); and a mono- or polyhydric alcohol such as benzyl alcohol, ethylene glycol or 1,2-propylene glycol; or an amide type solvent such as 1-methyl-2-pyrrolidone or dimethylformamide. Preferably 2- (2-methoxyethoxy) ethanol or 2-ethoxyethanol or 1,2-propylene glycol is used in an amount of 5 to 12 times, preferably 7 to 10 times, based on the starting salt of formula V .

In the first step of the process according to the invention, an inorganic base catalyst is an alkali metal hydroxide or carbonate such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably potassium carbonate, starting from the formula In an amount of from 05 to 1.0 molar equivalent, preferably from 0.1 to 0.5 molar equivalent.

In the second reaction step of the process according to the invention, the same inorganic base as in the first reaction step may be used, or any of the above bases may be used. Sodium hydroxide or potassium carbonate is particularly preferred in this reaction step in an amount of 0.5 to 1.5 molar equivalents, preferably 1.0 to 1.5 molar equivalents, relative to the salt of formula V.

The benzyl cyanide is used in an amount of 1.0 to 2.0 molar equivalents, preferably 1.3 to 1.6 molar equivalents, relative to the starting salt of formula V.

The product of formula VII can be isolated from the reaction mixture by methods known per se. For example, the mixture may be cooled, diluted with water or other solvent, and the precipitated product filtered off. It is also possible, for example, to cool the mixture and filter the precipitated product. The very high quality crude product thus obtained is optionally washed at room temperature with a suitable solvent such as the reaction solvent or an alcohol such as acetonitrile or optionally ethyl acetate and, if necessary, mixed with water at 80-90 ° C. wash with water and dry.

The starting salt of Formula V is known (see E. C. Taylor et al., Cited above, J. Am. Chem. Soc., 81, 2442, 1959) and French Patent No. 1,364,734; said literature discloses that the salt of formula V can be safely produced in at least 85% yield].

The process according to the invention has the following advantages:

1. The mild reaction conditions employed in the process of the present invention and the fact that the target compound of formula V is prepared from the compound of formula V without isolation of the compound of formula IV, which is very difficult to purify and dehydrate, allow it to be highly pure without recrystallization. 99% pure - produce crude product with good yield. (The purity of the crude product is very important because, as mentioned above, the recrystallization of the contaminated compound of formula VII presents many difficulties.)

2. The process according to the invention is technologically easy to implement

19581 low energy, solvent and solvent requirements in a single device.

The invention is further illustrated by the following non-limiting examples.

sulfur was replaced with 2-ethoxyethanol instead of 2- (2-methoxyethoxy) ethanol and the second reaction step. and at 80 ° C for 1 hour. Weight: 21.0 g, 83%, m.p. 326-329 ° C.

Example 1

To a solution of isonitrose-malonic acid dinitrile guadinine salt (15.4 g, 0.1 mol) in 2- (2-methoxyethoxyethyl ethanol) (110 ml) was added potassium carbonate (3.87 g, 0.028 mol) and the mixture was stirred for 2 hours. After stirring at 110 DEG C., a violet precipitate formed which was cooled to 70-75 DEG C. and then 5.0 g (0.125 mol) of powdered sodium hydroxide was added thereto, followed by stirring at 80 DEG C. for about a quarter. A mixture of benzyl cyanide (17.3 mL, 17.6 g, 0.15 mol) and 2- (2-methoxyethoxy) -ethanol (15 mL) was added dropwise under stirring, and the reaction mixture was stirred for another half hour at 80 ° C. After cooling to room temperature, water (125 mL) was added, stirred in an ice bath for half an hour, and the solid was filtered, washed with isopropanol (2 x 40 mL) and water (2 x 40 mL). It was dried at C. This gave 22.1 g of yellow, 2,3,7-triamino-G-phenylpteridine, m.p. 329-331 ° C, based on the guanidine salt V of isonitrose-malonic acid dinitrile. : 87.5%. The purity of the product is XX. 99.1% (relative to standard) as determined by UV spectrophotometry as described in Pharmacopoeia (1980).

Example 2

All of the procedures described in Example 1 were followed except that no water was added to the reaction mixture after cooling. Weight: 21.7 g, mp 326-30 ° C, 86% yield.

Example 3

The procedure described in Example 1 was repeated except that 2- (2-methoxyethoxy) ethanol was used as a solvent instead of 2-ethoxyethanol and the second reaction step was carried out at 80 ° C for 1 hour. Weight: 21.45 g, m.p. 327-30 ° C, 85% yield.

Example 4

All of the procedures described in Example 2 were repeated except that the solvent was 6

Example 5

All the procedures described in Example 1 were repeated except that the first reaction step was carried out in the presence of 6.9 g (0.05 mol) of potassium carbonate at 90 ° C for 3 hours. Weight: 20.8 g, m.p. 329-331 ° C, 82% yield.

Example 6

The procedure of Example 1 was repeated except that the first reaction step was carried out in the presence of 2.0 g (0.05 mol) of sodium hydroxide instead of potassium carbonate at 110 ° C for 1 hour. Weight: 19.5 g, mp 329-331 ° C, 77% yield.

Example 7

The procedure of Example 1 was repeated except that the second reaction step was carried out in the presence of 13.8 g (0.1 mol) of potassium carbonate instead of sodium hydroxide at 110 ° C for 3 hours. Weight: 20.8 g, m.p.

Yield: 326-328 ° C (82%).

Example 8

All of the procedures described in Example 1 were followed except that the second reaction step was carried out in the presence of particulate sodium hydroxide rather than powdered. Weight: 20.2 g, m.p. 325330 ° C, 80% yield.

Example 9

The procedure of Example 1 was repeated except that the second reaction step was performed in the presence of potassium hydroxide (7.0 g, 0.125 mol) instead of sodium hydroxide. Weight: 20.2 g, mp 325-328 ° C, 80% yield.

Example 10

All of the procedures described in Example 1 were followed except that 1,2-propylene glycol was used as the solvent in place of 2- (2-methoxyethoxy) -ethanol and the first step 510 at 110 ° C. with stirring for 1 hour and the second reaction step with stirring at 80 ° C for 3 hours. Weight: 21.45 g, m.p. 330-332 ° C, 85% yield. 5

Example 11

In the same manner as in Example 1, except that benzyl alcohol was used as the solvent instead of 2- (2-methoxyethoxy) ethanol, the second reaction step was carried out at 80 ° C with stirring for 4 hours, and the reaction mixture was cooled. after dilution with 125 ml of isopropanol instead of water. Weight: 16.0 g, m.p. 330-332 ° C, yield 63%.

Example 12

All of the procedures described in Example 1 were repeated except that 1-methyl-2-pyrrolidone was used as the solvent in place of 2- (2-methoxyethoxy) -ethanol and the product was treated with isopropanol and twice with 100 ml of ca. Wash with water. Weight: 17.0 g, m.p. 330-333 ° C, 67% yield.

Example 13

All of the procedures described in Example 1 were repeated except that dimethylformamide was used as the solvent instead of 2- (2-methoxyethoxy) -ethanol, the first reaction step being stirred at 110 ° C for 2 hours and the second reaction step being 100 ° C. After stirring at C for 1.5 hours, the filtered crude product was washed with isopropanol and hot water as described in Example 11. Weight: 16.0 g, m.p. 328-45

330 ° C, yield 63%.

Example 14

All of the procedures described in Example 1 were repeated except that 2-methoxyethanol was used as solvent instead of 2- (2-methoxyethoxy) ethanol. Yield: 21.8 g, m.p. 319-324 ° C, yield: 86.1%. 55

Example 15

All of the procedures described in Example 14 were followed except that the second reaction step was replaced by sodium hydroxide.

Stirring was performed in the presence of 10.6 g (0.10 mol) of sodium carbonate at 110 ° C for 3 hours. Weight: 20 g, m.p.

327-329 ° C, lysam: 79%.

Example 16

The procedure of Example 1 was repeated except that the first reaction step was carried out in the presence of potassium hydroxide (2.8 g, 0.05 mol) at 110 ° C for one hour in place of potassium carbonate. Weight: 19.8 g, m.p.

328-330 ° C, yield 78%.

Claims (4)

PATENT CLAIMS A process for the preparation of 2,4,7-triamino-6-phenylpteridine VII of formula VII by heating the guanidine salt of isonitrose-malonic acid dinitrile V in an organic solvent in the presence of an inorganic base such as potassium carbonate as a catalyst. and the resulting 2,4,6-triamino-5-nitrosopyrimidine of formula IV in an ether-alcohol, alcohol-type or amide-type solvent in the presence of an inorganic base such as potassium hydroxide as catalyst, By reacting with 0 molar equivalents of benzyl cyanide and isolating and, if desired, purifying the resulting compound of formula VII, wherein the two reaction steps are carried out at a temperature of 70 ° C to 120 ° C in the same reaction mixture without isolation of intermediate IV; the catalyst used is an alkali metal hydroxide and / or carbonate. The process according to claim 1, wherein the solvent is 2-methoxyethanol, 2-ethoxyethanol, 2- (2-methoxyethoxy) ethanol, benzyl alcohol, 1,2-propylene glycol, 1-methyl-2-pyrrolidone or dimethylformamide is used. The process according to claim 1 or 2, characterized in that the first reaction step comprises 0.1-1.0 molar equivalents of sodium hydroxide, potassium hydroxide, sodium hydroxide, based on the guanidine salt V of the isonitrose-malonic acid dinitrile. in the presence of carbonate or potassium carbonate at a temperature of 80 ° C to 120 ° C. 4. Process according to any one of claims 1 to 3, characterized in that the second reaction step is in the presence of 0.5 to 1.5 molar equivalents of the salt of formula V in the presence of 70 ° C to 110 ° C in the presence of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. temperature.