DE870262C - Process for the preparation of 2-amino-6-oxy-substituted pteridines - Google Patents

Description

Process for the preparation of 2-amino-6-oxy-substituted pteridines It has been found that biologically and pharmaceutically valuable 2-amino-6-oxy-substituted pteridines can be obtained in a simple manner as intermediates or end products by using a 2, 6-diamino-pteridine of the general formula in which R denotes an alkyl or substituted alkyl radical, preferably heated in aqueous solution to a temperature of at least 95 ', preferably to about 95 to 105', while maintaining alkaline conditions.

The procedure can be expressed by the equation: Suitable? "6-Diaminopteridine which in 'the present invention can be used are those in.welchen R in the above general GleichuDg a substituted methyl group -CH2NHR', wherein R 'represents an aromatic group. As examples, the following compounds apply: N- [4 '- (2,6-diamino-8-methyl-pyrimidino-4,5-pyrazyl) aminobenzoyl] -glutamic acid, N- [4' - (2,6-diamino-8-methyl- pyrimidino-4,5-pyrazyl) -aminobenzoyl] -aspartic acid and N-4 '- (2,6-diamino-8-methyl-pyrimidino-4,5-pyrazyl) -arainobenzoic acid and its amino acid amides with one or more polypeptide-like chained amino acid residues Furthermore, 2,6-diamino-8- or -9-alkylpteridines, for example -, 6-diamino-8-methylpteridine and 2,6-diamino-g-methylpteridine, can be used as starting materials.

It is preferably used in aqueous solution while maintaining more alkaline Conditions worked. For this purpose one uses z. B. Alkali hydroxides, such as sodium and Potassium hydroxide, barium and calcium hydroxide, or ammonia and benzyltrimethylainmonium hydroxide. If necessary, water-miscible solvents can also be added.

The temperature required to carry out the reaction should be at least 95 ' and is preferably kept between about 95 and 10 5'.

It may be advisable to have the response in its absence to let the air go by, but this is not essential to their success necessary.

If one works under mild conditions, for example while maintaining an i ii-alkalinity, the reaction time should be at least 2 hours.

In the examples below, all parts are parts by weight unless otherwise specified. Example I 2.7 parts of 2, 4, 5, 6-Tetraaminopyrimidinsulfat and 2.4 parts of Ba C12 - H 2, 0 parts of water are with 6o: 'triturated [o minutes examples long 6o to a pulp. After cooling to 45 ', 1.33 parts of p-aminobenzoylglutamic acid are added and the pu is adjusted with alkali. The following solutions are then added simultaneously within 10 minutes: 2.2 parts of dibromopropionaldehyde, dissolved in acetic acid, 1.3 parts of iodine and 2.5 parts of potassium iodide in 8 parts of water and also alkali to keep the pil at 3 . This is done with stirring. Stirring is continued at the same temperature and the same pli for a further 30 minutes, after which the slurry is cooled, treated with a part of diatomaceous earth, filtered and washed with water and alcohol.

A sample of this crude product, which contains 2 parts of N- [4 '- (- 2, 6-diamino-8-methyl-pyrirnidino-4,5-pyrazyl) -aminobenzoyl] -glutamic acid, is mixed with 4 parts of lime and 2,000 parts of water Grind to a paste for 15 minutes at 6o to 70 ' , after which diatomaceous earth is added and filtered. The filtrate is treated with kieselguhr and a 20/0 zinc chloride solution is added until a pu of: ro.6 is reached. The slurry is then clarified by filtration and the filtrate heated to 80 '. Züikchloridlösung is now added up to a pji of 6.8 and the zinc salt is filtered with kieselguhr. The filter residue is ground to a pulp with 4 parts of lime and 1,000 parts of water and filtered again. The filtrate is adjusted to Pil 4 with dilute hydrochloric acid, cooled and filtered with kieselguhr. This filter residue is triturated with 4 parts of magnesium carbonate and 70o parts of water at 85 to go 'to a paste, stirred with 1.5 parts of active charcoal for 5 minutes and filtered again. The filtrate is adjusted to P # I 4, cooled and filtered again. The filter residue contains i, i parts and the analysis shows a degree of purity of 74.3 "/ o.

A solution of 0.5 parts of the purified product in sodium carbonate solution is heated to 100% in a nitrogen atmosphere for 6 hours. The solution is then cooled, made up to 100 parts with water and adjusted to 3 pil. The product contains 0.394 parts of a 70% pteroylglutamic acid. Analysis twice reveals a yield of 65.5 % pure product% t. Example 2 A slurry of 26 g of 2 "4, 5, 6-tetraaminopyrimidine sulfate dihydrate, 24 g of barium chloride dihydrate and 15 g of p-methylaminobenzoic acid in 700 cc of water is heated to 80 'for 5 minutes, adjusted to a Pff of 3 and with 59 g of 1 , 1,3-tribromoacetone. The mixture is heated to 8o 'for 1 hour, the pu being kept at 3 by the addition of 50% alkali solution. After cooling to 10 ', the crude N- (z, 6-diamino-8-methyl-pyrimidin0-4, 5-py-razyl) -N-methylaminobenzoic acid is filtered, washed and dried.

A slurry of 3o g of this crude material in 1 1 of water containing 6 grams of lime, 40 minutes, heated at 6o 'and filtered at this temperature. The filter residue is washed with water and hydrochloric acid is added to the filtrate to adjust it to a pii of 3.02. After cooling overnight, the precipitate is filtered off and triturated at 80 'in 750 cc of water, which has been adjusted to a p # I from ii to 11.6 with sodium hydroxide. When the solution is complete, the mixture is adjusted to a pI of 7 at 2.0 '. After filtering, the filtrate is brought to the pli of 4 to 5 with hydrochloric acid and the precipitate obtained is filtered off. This is rubbed into a paste with 500 ccm of water and treated with magnesium oxide at 8C in order to obtain a pI from 8.9 to 9.3 . Then 0.5 g of activated charcoal are added and the mixture is heated to 80 'for a further 15 minutes. After filtration, the filtrate is brought with dilute hydrochloric acid to 4 to 5 Pu several - stored e hours at io '. Filtration gives about 1 g of an orange-yellow crystalline substance.

A solution of 25 parts of the purified product obtained as above in 2500 parts of sodium hydroxide solution is heated to 100% in a nitrogen atmosphere for 6 hours. After dilution with water, the solution is adjusted to hydrochloric acid n-Pil 3 to 4 by 5. The precipitate obtained is centrifuged, washed and dried. The product contains a 85% N- (2-amino-6-oxy-8-methyl-1) yrimidino-4,5-pyrazyl) -N-nonlaminoboic acid.

EXAMPLE 3 To a solution of 27.9 2, 4, 5, 6-tetraaminopyrimidine sulfate in 2000 cem 4N hydrochloric acid, at 40 ° 25 cc of a 30% methylglyoxal solution is added, whereupon a deep gold-yellow color appears immediately. After about an hour, 1:30 g of 50% sodium hydroxide solution are added. Yellow crystals precipitate from the cooled solution and are filtered off, washed with water and dried. The yield of: z, 6-diamino-g-methylpteridine is ii g (620j,) t. 5 parts of 2,6-diamino-g-methylpteridine in 100 parts of iN sodium hydroxide solution are heated to 10%, with one a weak current of oxygen is passed through it. After 4 hours, the solution is then acidified and the precipitate that forms is collected on a centrifuge. It is redissolved in a very dilute sodium hydroxide solution with adjustment to a pH of * ii to 1: 2, treated with a little activated charcoal and then filtered. The filtrate is acidified with dilute hydrochloric acid and the precipitate is centrifuged, washed and dried. Yield 3.5 parts of 2-amino-6-o-xy-q-methyl-pteridip. with 950 /, purity. Identification was made by comparison with a purified product manufactured in another way. - In another experiment under the same conditions, except that a nitrogen stream in place of the oxygen stream was passed through the reaction mixture, were obtained in a yield of 3.9 parts of 2-amino-6-oxy-q-methylpteridine. Example 4 A mixture of 26 g of 2, 4, 5, 6-tetraaminopyrimidine sulfate dihydrate and 26 g of sodium sulfate in 1 o cc of water is heated to 60 'and then cooled to about 30'. A solution of 22ccm 3o0 /, methylglyoxal and 5g sodium bisulfite in water is added to this, which has been made up to 100cem beforehand. After 40 minutes the yellow precipitate is filtered off and washed with water. It is now rubbed again to a pulp with 500 ccm of water and filtered again. After repeating this process twice, the product weighs approximately 12 g after drying. This is now further purified by treating 5 g with 250 cc of 100% hydrochloric acid. The insolubles are eliminated, the clear filtrate is treated with active charcoal and neutralized to 6.4 with ammonia. The light yellow precipitate of 2, 6-Diamino-8-methyl-pteridine is filtered, first with water, then washed with acetone and - up to 3 hours in a vacuum at 1.3 mm Hg at ioo 'dried.

5 parts of 2,6-diamino-8-methyl-pteridine are heated in: 250 parts of sodium hydroxide solution in a nitrogen atmosphere to 100 'for 5 to 6 hours. The filtered solution is acidified to Pu 4. The filtered and washed precipitate is dissolved in 17 parts of very dilute sodium hydroxide solution again, whereupon the NaOH content increased to n. 5 The precipitated sodium salt is dissolved in water, cleaned with activated charcoal and neutralized with acetic acid. The dried product (4 parts) is identified as 2-amino-6-oxy-8-methyl-pteridine. EXAMPLE 5 Part 2, 6-diamino-g-methyl-pteridine in approximately 50 parts of 5N sodium hydroxide solution is heated to 100 to 10 5 for a few minutes until a clear solution is obtained. After cooling, the sodium salt of: z-amino-6-oxy-q-methyl-pteridine crystallizes out after several hours. It is obtained through a filter, dissolved in water, reprecipitated by acidification and identified by comparison with a sample of known material. Example 6 A mixture of 5 parts of 2,6-diamino-g-methylpteridine, 2,000 parts of water and 2oo parts of barium hydroxide is heated on a steam bath for 3 hours. The insolubles are removed by filtration and the clear solution is acidified to Pil 3 to 4. The precipitate is centrifuged, washed and dried. This gives 4.25 parts of --- amino-6-oxy-q-methylpteridine. Example 7 A mixture of 2 parts of 2,6-diamino-g-methylpteridine with 200 parts of ammonium hydroxide (-.8%) is heated on the steam bath in an open vessel until the boiling stops. Then another 200 parts of ammonium hydroxide are added and heating is continued until the boiling has ceased. After repeating the process three times, the clear solution is decolorized with a little activated charcoal and acidified to Ni 3.5 to 4. A precipitate of 0.2 part of 2-amino-6-oxy-q-methyl-pteridine crystallizes out and is isolated, washed and dried. EXAMPLE 8 20 parts of 2,6-diamino-g-methyl-pteridine are added to 100 parts of n-benzyltrimethylammonium hydroxide, and the mixture is heated to 95 to 105 ° for 4 to 5 hours on a reflux condenser. Then a small amount of activated charcoal is added, the solution filtered, the filtrate acidified with hydrochloric acid and the precipitate centrifuged, washed and dried to give 16.8 parts of L "-amino-6-oxy-q-methyl-pteridine.

In a similar experiment using ioco parts of i n-aminonium hydroxide 4 parts of 2-amino-6-o.xy-q-methyl-pteridine are used in place of the benzyltrimetylammonium hydroxide obtain.

Claims (2)

PATE N TAN S P RETURN: i. Process for the preparation of 2-amino-6-oxy-substituted pteridines, characterized in that a 2,6-diamino-pteridine of the general formula in which R denotes an alkyl or substituted alkyl radical, heated to a temperature of at least 95 ', preferably to about 95 to 10 5', while maintaining alkaline conditions, preferably in aqueous solution. 2. The method according to claim: [, characterized in that the reaction is carried out in i n-alkaline solution within a period of at least 2 hours. 3. The method according to claim i and 2, characterized in that it is carried out with the exclusion of air.