DE915339C - Process for the preparation of substituted pteridines - Google Patents

Description

Process for the preparation of substituted pteridines The invention relates to substituted pteridines.

The group of compounds commonly known as pteridines has before recently acquired great importance, as some of its limbs are valuable therapeutic Possess properties. The most known and used compound of these Class is folinic acid, also known chemically as pteroylglutamic acid. It this compound has been found to be useful in the treatment of macrocytic anemia, Sprue and other related diseases of the circulatory system is valuable.

According to the invention, substituted pteridines are prepared by reacting the perbromide of 2-acylamino-6-oxy-8-methyl-pteridine with an aminobenzoic acid or an amide thereof. The conversion can be represented by the following equation In these formulas, R 'denotes an acyl radical, X denotes hydrogen or a hydroxyl group and R denotes a hydroxyl group, an amino or substituted amino radical.

The perbromides of 2-acylamino-6-oxy-8-methylpteridines used as starting materials are new connections. They are prepared in such a way that 2-amino-6-oxy-8-methylpteridine acylated and the reaction product in a solvent such as glacial acetic acid and bromine, heated. The product obtained does not constitute a compound in which one or several hydrogen atoms of the methyl group have been replaced by bromine, as to would have been expected, but a perbromide. That this actually happens is to recognize that the product obtained under these conditions is in the Color differentiates from 8-bromomethylpterines and that one induces the connections can release the loosely bound bromine, which is typical for perbromides. Preferred is the perbromide of 2-Acetvl-amino-6-oxy-8-methylpteridine, but can also other perbromides in which the acetyl group of the above-mentioned compound is through other acyl radicals, such as the propionyl, butyryl and nicotinyl radical, is used will.

The carbonyl radical with its substituent R can with respect to the Amino group occupy any position in the benzene ring, although it is preferred is in p-position. p-Aminobenzoic acid or one of its amides can be used in the inventive Procedures are used. There can also be a hydroxyl group on the benzene ring are located. The preferred amides are amino acid amides as the end products in this Traps possess the most valuable biological properties. The preferred amino acid amide is the amide of glutamic acid, although other amino acid amides, for example those of glycine, aspartic acid, leucine, alanine, isovaline and Cysteines with aminobenzoic acid can be used. The group R can also be a Represent amino radicals with one or more peptide bonds, for example the GlutamyIglutamine, diglutamylglutamine and glutamylglycerylglutamine residues. In which Processes according to the invention can also use the salts or esters of these amino acid amides Find use.

The reaction conditions can be varied widely, in particular in terms of hydrogen ion concentration. If the implementation at a pH 3 to 4 or up to about ir is carried out, the desired result is obtained Reaction product. The reaction temperature can be between about 0 and 10 °.

The reaction is preferably carried out in aqueous solution, however This solution can contain small amounts of other water-miscible solvents as well Contain buffer substances such as sodium hydroxide, potassium hydroxide and sodium acetate.

The reaction products obtained by the process of the present invention are 2-acylaminopteridines; the acyl radical can, however, by heating the 2-acylaminopteridines in 2 to 3 N hydrochloric acid on the steam bath or by letting it stand in o, i n sodium hydroxide solution, usually removed at room temperature.

In the present invention, a well-defined crystalline Intermediate used in the reaction, which is carried out in stages. The yields are very good. Furthermore, the process can be carried out in an aqueous medium what compared to the solvents required in the known processes is more economical. Finally, the aminobenzoyl compounds, which are rare Represent intermediate products, are stored. Example 10 g of 2-amino-6-oxy-8-methylpteridine is refluxed for about 41j2 hours in 1 1 acetic anhydride and then left to stand overnight at room temperature. A fine one separates out of the solution crystalline precipitate along with some brown insoluble material. That The whole mixture is therefore refluxed again to the boil, the crystalline material goes into solution; the brown insoluble material becomes from the hot solution filtered off. On cooling, fine orange colored particles separate from the solution Needles off. They are filtered off, washed twice with water, acetone and ether. The yield of 2-acetamino-6-oxy-8-methylpteridine is 6.3 g or 51 ° j. That The filtrate from this first fraction of acetylated product gives a on standing second fraction, the weight of which is 1.9 g. The first fraction of acetylated Material (6.3 g) is recrystallized five times from hot glacial acetic acid. With every recrystallization something becomes Color removed, so that after five recrystallization the 2-acetamino-6-oxy-8-methylpteridine almost white.

46 g of 2-acetamino-6-oxy-8-methylpteridine which has been recrystallized twice are dissolved in glacial acetic acid heated to 95 °. As soon as the pteridine has gone into solution, 11.5 cc of bromine are added all at once. The reaction is carried out with light and the temperature of the reaction mixture is kept at 84 °. After the whole thing has been stirred for 3 to 5 minutes, a dark red precipitate begins to separate out from the solution. The reaction mixture is stirred for about 11/2 hours under irradiation, after this time the dark red precipitate is filtered off, washed with acetic acid and ether and dried. The yield of 2-acetamino-6-oxy-8-methylpteridine-perbromide is 539 or 66.50%.

1 / 2g of the perbromide is mixed in small portions into a vigorously stirred, solution of 2.4 g of p-aminobenzoylglutamic acid maintained at a p11 value of ii added in 6o cc of water. The addition only takes 5 minutes. The reaction mixture is stirred for 1 hour at room temperature; during this time the pH will decrease if necessary kept at a value of io to ii by adding sodium hydroxide solution. To At the end of this time, the clear solution is brought to a pH of 3.5 with hydrochloric acid acidified, a yellow amorphous material separating out. The mix will then to 8o ° heated, strongly cooled and filtered. The yield of 2 acetylpteroylglutamic acid is 0.23 g; in the chemical experiment it showed gi, 2 "/" purity, in the biological experiment 7i, i "/" purity.

The above-described condensation of the perbromide of 2-acetamino-6-oxy-8-methylpteridine with p-aminobenzoylglutamic acid, in aqueous solution can also be used at a pH value from 3 to 4 can be performed. At this pH, either by using by sodium hydroxide or by the buffering action of acetic acid and sodium acetate is maintained, the purity of the reaction product is essentially 8o to 90 °, '"or more. Example 2 To 175 cc of glacial acetic acid at steam bath temperature 5.439 (0.025M01) 2-acetylamino-6-oxy-8-methylpteridine was added. At one temperature from about 87 ° the solution is complete. 1.28 cc (0.025 moles) of bromine become at once added with stirring. Exposure will increase the temperature within 18 Minutes gradually increased to 120 degrees. The reaction product is filtered with acetic acid and ether washed and dried. The 2-acetylamino-6-oxy-8-methylpteridine-perbromide has a weight of 4.35 g.

1/2 g of the perbromide is condensed with 2.4 g of p-aminobenzoylglutamic acid at a pH of z1. 0.25 g of 2-acetyipteroylglutamic acid of 70.5 ", I" purity is obtained. EXAMPLE 3 0.5 g of the perbromide of 2-acetylamino-6-oxy-8-methylpteridine was added all at once to a solution of 2.4 g of p-aminobenzoylglutamic acid in 60 ccm of water at room temperature with vigorous stirring, the pH being is kept at a value of 3.5 to 4. The red perbromide slowly goes into solution with a yellow color, and in 20 minutes the light yellow crystalline product begins to precipitate. The reaction mixture is stirred for 1 1/2 hours and left to stand in the cold room overnight. The product is filtered off, washed with alcohol and ether and dried. The 2-acetylpteroylglutamic acid has a weight of 0.15 g and a purity of 90.50. / 0. Example A series of reactions was carried out using a) i equivalent of p-aminobenzoylglutamic acid, weight 0.35 g, b) 2 equivalents of p-aminobenzoylglutamic acid, weight 0.70 g, c) 3 equivalents of p-aminobenzoylglutamic acid, weight 1.05 g , d) 4.75 equivalents of p-aminobenzoylglutamic acid, weight 1.67 g in 6o ccm of water with vigorous stirring at room temperature, the pH being kept at a value of 3 to .4 and the p-aminobenzoylglutamic acid in each case with 0 , 5 g of the perbromide of 2-acetylamino-6-oxy-8-methylpteridine was converted. The mixtures were each stirred for 11/2 hours and left to stand in the cold room overnight. The reaction products were filtered, washed with water, acetone and ether and dried. purity Weight of the product in the chemical test B 070 a) 0.1 797 b) 0.3 86, o c) 0.27 81.2 d) 0.22 76, o Example 5 Five reactions were carried out at pH 11 using varying amounts of p-aminobenzoylglutamic acid. To the solution of p-aminobenzoylglutamic acid in 60 cc of water at room temperature and with vigorous stirring, 0.5 g of the perbromide of 2-acetylamino-6-oxy-8-methylpteridine was added in small portions, the pH being kept at ii . After stirring for one hour at p $ ii, the solution was brought to a pH of 3.5, heated to 80 ° and cooled overnight. The product of each of these reactions was filtered, washed with acetone and ether, and dried. Equivalent weight of the p-amine p-amino weight purity im benzoyo benzoyl- des chemical Blutamin- Blutamin- product trial acid acid B g ° / o a) 1 0.35 0.25 62.2 b) 2 o, 70 0.2o 67, o c) 3 1.05 0.27 50.5 d) 4.75 1.67 0.21 51, o e) 6.82 2.4o 0.25 515 Example b 1543 g of 3-OXY-4-nitrobenzoic acid (Ber. Dtsch. Chem. Ges. 20, 405 A887;) are dissolved in 66o cc of thionyl chloride in the course of 70 minutes by refluxing. The excess thionyl chloride is removed in vacuo, leaving a solid residue of the acid chloride. The residue is added to 199o cc of an aqueous solution containing 252 g of glutaric acid and 627 g of sodium bicarbonate. The mixture is stirred overnight. After about constant stirring, the solution is clarified by filtration, the filtrate is heated to 70 °, acidified with 55o cc of concentrated hydrochloric acid, stirred for a few minutes and the heavy precipitate formed is filtered off. This residue is the recovered 3-oxy-4-nitrobenzoic acid. This last filtrate is cooled well and the 3-oxy-4-nitrobenzoylglutamic acid is filtered off. The product is dried at 60 ° and has a weight of 93 g. This product is reduced to the amine in 186o ccm of water with a pn value of 3 with 190 g of coupled zinc-copper. About 160 cc of concentrated hydrochloric acid is used to maintain a constant pH. During the reduction, the temperature rises to about 60 °. The excess zinc-copper is filtered off. The filtrate is immediately reacted with 65.3 g of the perbromide of α-acetylamino-6-oxy-8-methylpteridine in glacial acetic acid. During the reaction, the pR is kept constant at 3 ° with sodium hydroxide. The condensation mixture is stirred for about 16 hours, the product is filtered off and washed with a little water, ethanol and ether and dried at 60 °. The weight is 31.6 g.

The product obtained above is dissolved in 15 l 0.1 N sodium hydroxide. This solution is warmed to go ° on the steam bath for 1/2 hour in order to hydrolyze the acetyl groups. The reaction product is treated with 50% lime by adding 139 cc of a 30 ° calcium chloride solution. This precipitation was carried out at a temperature of 60 °. The calcium salt is filtered with diatomaceous earth and discarded. The zinc salt of the product is precipitated from this last filtrate by adding 50% zinc chloride solution up to a pn value of 6.8. This salt is filtered and sucked as dry as possible. The zinc cake is dissolved in concentrated hydrochloric acid and the solution is treated with activated charcoal at 60 °. The filtrate is diluted to such an extent that it is in, the purified product separating out. The mixture is cooled to 25 ° and filtered, washed and dried at 60 °. The weight of this N- [q '- (2-amino-6-oxy-8-methylpyrimidino-.4,5-pyrazyl) -amino-3'-oxybenzoyl-glutamic acid is 8 g. Example 7 To a solution of 7 g of tetraethyl-p-aminobenzoyla-glutamyl-a-glutamylglutamate in .40 cc of ethanol and 20 cc of water "earths with a px value of 8 to 9 o.5 g of the perbromide of 2-acetylamino -6-oxy-8-methylpteridine added in small portions, keeping the p $ at a value of 8 to 9. The product, tetraethyl-2-acetylpteroyl-a-glutamyl-a-glutamylglutamate, is isolated in a manner similar to that described for 2-acetylpteroyl-glutamic acid in Example i. EXAMPLE 8 50 g of the perbromide of 2-acetylamino-6-oxy-8-methylpteridine are added to a solution of 329 f-aminobenzamide in 600 cc of water, the px at a value of 3 to q. is held. After stirring for one hour «-erden iq. g of 2-acetylpteroic acid amide of 68.5 ° joiger purity.

Claims (3)

PATENT CLAIMS: i. Process for the preparation of substituted pteridines of the general formula in which R 'denotes an acyl radical, X denotes hydrogen or a hydroxyl group and R denotes a hydroxyl group, an amino or substituted amino radical, characterized in that a perbromide of a 2-acylamino-6-oxy-8-methylpteridine of the formula reacted with an aminobenzoic acid or an amide thereof and the acyl radical is optionally removed from the reaction products by hydrolysis under acidic or alkaline conditions. 2. The method according to claim i, characterized in that that the reaction is carried out in an aqueous medium at a pH between 3 and ii will. 3. The method according to claim i or 2, characterized in that the implementation is carried out at a temperature between 0 and 100 °. Referred publications: French patents nos. 956 652, 955 983, 92726o.