DE889298C - Process for the production of pteridines - Google Patents

Description

Process for the preparation of pteridines The therapeutic effectiveness of pteroylglutamic acid or folinic acid, the N-rL4 '- (: z-Amino-6 - oxy - 8 - methyl - pyrimidino - 4, 5 - pyrazole) - aminobenzoyl] glutamic acid, in the treatment mal, rocytic anemia, sprue and related blood diseases are known. Their preparation by synthesis and the related pteridines with biological activity is described in "Science", Vol. 103, May 1946, pp. 667 to 669 .

. It has now been found that the same valuable pteridines are obtained if 2, 4, 5-triamino-6-oxy-pyrimidine is used with I, I, 3-trihaloacetone and a p-aminobenzoic acid of the general formula where R is OR 'or NR'-R "and R' and R" are hydrogen or aromatic or aliphatic radicals, preferably at a p i value between i and 7, for example between i and 5, at suitable temperatures, preferably at such temperatures up to about ioo '.

As a starting material of the method according to the invention is used 2, 4, 5-triamino-6-oxy-pyrimidine or its tautomers, e.g. B. 2, 4, 5-triamino-pyrimidon-6, which are available in a known manner. The connection is usually in the form of theirs Sulphate or hydrochloride applied, but you can optionally also use the free Use base.

According to the invention, as a second participant in the implementation are known Way manufactured I, I, 3-trihaloacetones, their halogen atoms, such as chlorine, bromine and iodine, of the same type or different from one another, as further reactants serve according to the invention p-aminobenzoic acids of the above specified type. In addition to the free p-aminobenzoic acid, its salts, esters or amides can be used. The latter are preferred according to the invention, above all that of amino acids, of which glutamic acid is particularly preferred. Other usable amino acid amides of p-aminobenzoic acid are, for. B. that of the glycocolla, of aspartic acid, leucine, alanine, isovaline, cysteine and the like as the amino acid you can also polypeptide-like composed amino acids, z. B. Glutamylglutainic acid, Use glutamylglutamylglutamic acid, glutamylglycylglutamic acid and the like. Finally you can also use salts and esters of these amino acid amides, e.g. B. p-Aminobenzoylglutamic acid diethyl ester use.

According to the invention, these starting materials are reacted with one another according to the following general equation: In this equation, X denotes halogen, R has the meaning given at the beginning.

The method is preferably carried out in acidic solution with pli values between i and 7, the best results with pli values. between i and 5 can be achieved. The temperatures to be used are preferably between 0 and 100 °.

The conversion of the starting materials mentioned or their addition to the reaction mixture can take place in any order. For example, you can add them all at the same time, or you can first react the 2,4,5-triamino-6-oxy-pyrimidine with the I, I, 3-trihaloacetone and then the reaction product with the p-aminobenzoic acid. The latter can also be reacted first with the trihaloacetone and then the reaction product with the pyrimidine derivative. - Compared with the known synthesis using Dihalogenpropionaldehyden the inventive method offers the advantage that no addition of an oxidizing agent is required, and no polymerization of Trihalogenacetons is to be feared.

In the examples below, all parts are parts by weight unless otherwise specified. EXAMPLE 1 9.9 parts of 2, 4, 5- triamino -6- oxy - pyrimidine sulfate were added to a solution of 12.2 parts of barium chloride dihydrate in 350 parts of water of 60 '. After stirring at 60 'for 10 minutes, the mixture was cooled to 40' and 13.3 parts of p-aminobenzoylglutamic acid were added. The pI value of the solution was immediately adjusted to approximately 3 to 3.5 by adding 20% NaOH solution.

Then, while stirring, a solution of 10.3 parts of i, i-dichloro-3-bromoacetone in 15 parts of glacial acetic acid was slowly added over the course of 50 minutes, a temperature of 40 'being maintained and the p # I value of the solution by further addition of 7.00 /, iger NaOH solution was kept at 3 to 3.5 . The mixture was then stirred for 15 minutes at 40 'and then cooled to 15' by adding ice and filtered. After washing the filter residue with water and alcohol, it was -> 3.5 parts of a brown product consisting of barium sulfate and the reaction product.

This product contained approximately 10.8% pteroylglutamic acid and can be readily used as an animal feed additive. It can be purified by a number of methods, the preferred method being as follows: The crude product is dissolved in hot lime water at a concentration of approximately one part of pure pteroylglutamic acid dissolved to 1000 parts of solution, the temperature preferably being about 70 ' and the pH being about II, o After filtering the hot solution, it is cooled and adjusted to a value between 3 and 4. The pteroylglutamic acid which precipitates is through For further purification the is treated with concentrated hydrochloric acid in an amount of about 100 parts hydrochloric acid per 5 parts of pure pteroylglutamic acid, most of which dissolves to a clear brown solution. After addition of 25 parts of activated charcoal, it is filtered after 20 minutes The filter cake is now washed with about 30 parts of concentrated hydrochloric acid, whereupon d The filtrate combined with the washing liquid is diluted with 100 parts of water and cooled to about 5 '. It is then filtered after 1 hour and the precipitate is washed with water and acetone and dried. The product obtained in this way contains over 80 % pure substance and is suitable for most types of therapeutic use. The method can also be used for the purification of the products obtained according to the following examples. EXAMPLE 2 12.9 parts of 2,4,5-triamino-6-oxy-pyrimidine were added to a solution of 12.2 parts of barium chloride dihydrate in 35o parts of water of 60 '. After io minutes of stirring at 6o 'was at 40' cooled, whereupon the mixture was added 13.3 parts of p-aminobenzoylglutamic acid and the pH of the solution at the same time by the addition of 2o0 / strength Na 0 H solution to 3 to 3, 5 has been discontinued.

10.3 parts of 1,3-dichlorobromoacetone, dissolved in 15 parts of glacial acetic acid, were then added dropwise over the course of 50 minutes, with stirring , the pi value of the solution being increased to 3 by further addition of 1/3-inch NaOH solution until 3.5 was held. The mixture was then stirred for a further 15 minutes at 40 'and finally cooled to 15' by adding ice and filtered. After washing with water and alcohol, 20 parts of a brown substance were obtained which consisted of barium sulfate and the reaction product containing pteroylglutamic acid. 1.5 parts of a purer product were obtained from the mother liquor. Example 3 A solution of 13.3 parts of p-aminobenzoylglutamic acid in 175 parts of water, which had been brought to a pH value of approximately 10 by addition of NaOH, was admixed with 10.3 parts of i, i-dichloro-3-bromoacetone in 15 Parts of acetic acid were added with stirring over the course of 20 minutes, the temperature being kept at 4 to 10 'by adding ice. NaOH solution was added to maintain the pII value. Thereafter, stirring was continued and the temperature of the mixture was allowed to rise to room temperature. The solution was then neutralized by adding dilute hydrochloric acid.

This solution was then within 15 to 2o minutes with stirring at 40 'slowly added 175 parts of an aqueous solution of 7, o5 parts 2, 4, 5-triamino-6-oxy-pyrimidine, wherein the prz value always to approximately 3 , 5 to 4 was held. The mixture was then stirred at 40 'for 15 minutes and finally, after cooling by the addition of ice, for 1 hour at 20'. It was then filtered and washed with water and alcohol. 8.1 parts of a dark substance containing pteroylglutamic acid were obtained. Example 4 10.3 parts of i, i-dichloro-3-bromoacetone were added to a solution of 13.3 parts of p-aminobenzoylglutamic acid in 100 parts of alcohol. After standing overnight at room temperature, 15 parts of glacial acetic acid were added to the dark orange mixture.

A solution of 12.9 9 2,4,5-triamino-6-oxy-pyrimidine sulfate was then prepared together with 12.2 parts of barium chloride dihydrate in 375 ccm of water at 60 'and this with 10 parts of acetic acid and sufficient 200% NaOH Solution to achieve a pI value of about 4. The above-mentioned alcoholic solution was then added slowly with stirring at 40 'over 30 minutes, wherein the pH value of the solution H solution was kept approximately constant by the addition of dilute Na 0th The mixture was then stirred for 15 minutes at 40 'and then cooled to 15' by adding ice. It was then filtered and the filter residue was washed with water and alcohol. This gave 24.5 parts of a brown solid substance composed of barium sulfate and the reaction product, the biological examination of which showed a content of 75% pteroylglutamic acid. Example 5 To a solution of 12.2 parts of barium chloride dihydrate in 35o parts of water at 6o ', 5-triamino-6-oxy-pyrimidinsulfat added 12.9 parts of 2, 4,. After io minutes of stirring at 6o 'and cooling the mixture to 40' were added 13.3 parts of p-aminobenzoylglutamic acid and the solution made strongly acidic by the addition of 5 parts 3o N hydrochloric acid. Then 10.3 parts of 1,3-dichloro-i-bromoacetone, dissolved in 15 parts of glacial acetic acid, were added dropwise with stirring over the course of 40 minutes, a temperature of 40 'being maintained without further additives. The lemon-yellow solution was then cooled to 20 'by adding ice and its pI value was adjusted to approximately 3.5 to 4 by adding 200% NaOH solution, whereupon a brown precipitate began to separate out. After stirring for one hour at 2o to 25 ' , the mixture was filtered. A small amount of the product was obtained from the mother liquor after standing overnight. After washing the entire product, its weight was: 1.6 parts, it consisted of barium sulfate and the reaction product containing pteroylglutamic acid. Example 6 To a solution of 1? "2 parts barium chloride 'were 12.9 parts of 2,4,5-triamino-6-oxy-pyrimidinsulfatzugesetzt. After io minutes stirring at 6o' in 35o parts of water at 6o the mixture was au '40 It was cooled and 13.3 parts of p-aminobenzoylglutamic acid were added, and the pli value of the solution was then immediately adjusted to 3 to 3.5 using a 20% strength NaOH solution.

An i,: r, 3-tribromoacetone mixture which contained io.3 parts of I, I, 3-tribromoacetone was then added dropwise to the solution with stirring over the course of 25 minutes, maintaining a temperature of 40 'and the pli value by addition of 200 /, iger NaOH solution apf 3 to 4 was kept. The mixture was then stirred for 15 minutes at 40 'and cooled to 15' by adding ice and filtered. After washing the filter residue with water and alcohol, 23.0 parts of a brown substance were obtained which contained barium sulfate and the reaction product containing pteroylglutamic acid. EXAMPLE 7 9 parts of 2,4,5-triamino-6-oxy-pyrimidinesulphate were added to a solution of 12.2 parts of barium chloride dihydrate in 250 parts of water of 60 '. After stirring for 10 minutes at 60 ', the barium sulfate was filtered off, 100 parts of acetic acid were added to the filtrate and the pH was adjusted to approximately 4 at 40 to 45' with stirring. Then, within 35 minutes, 10.3 parts of i :, i-dichloro-3-bromoacetone, dissolved in 15 parts of acetic acid, were added and the mixture was additionally stirred for 40 minutes at 40 minutes. The temperature was then reduced to 15 'by adding ice and filtered. After washing with water and alcohol, it resulted in 5 parts of a dark substance.

The finely powdered substance was then suspended in 200 parts of water, whereupon dilute hydrochloric acid was added up to a pil value of about 1. Then was '5 parts of p-Aniinobenzoylglutamin-'säure stirred, after which the mixture by 2o0 /) sodium Na made 0 H solution alkaline (pji 8) and i hour at 4o' were stirred at 35 to 40. The mixture was then cooled to 15 'by adding ice and, after addition of dilute hydrochloric acid, stirred at this temperature to a pjl value of 4 for 15 minutes. 2 parts of diatomaceous earth were then added, followed by filtering and washing the residue with water and alcohol. 7.5 parts of a solid substance consisting of 2 parts of diatomaceous earth and the reaction product containing pteroylglutamic acid were obtained. Example 8 12.9 parts of 2,4,5-trian-iino-6-oxy-pyrimidine sulfate were added to a solution of 12 parts of barium chloride dihydrate in 200 parts of water at 60 'and the mixture was stirred at this temperature for 10 minutes. After completion the solution cooled to 40 'acetic acid and iz parts 2o0 / strength Na 0 H solution were added with adjusting the pH to approximately 3.5 io parts.

Thereupon 13.3 parts of p-aminobenzoylglutamic acid were dissolved in 2oo parts of water and this solution 5 parts of 5 N hydrochloric acid and 5 parts of glacial acetic acid was added. The pli value was adjusted to 3 to 3.5 by adding 2o0 /, iger NaOH solution , whereupon 10.3 parts of i, i-dichloro-3-dichloro-3- at 40 'with the addition of a little ice within 20 minutes while stirring bromoacetone were entered. Stirring was then continued for 15 minutes at 40 'and the mixture was then allowed to cool to room temperature. After the addition of 15 parts of acetic acid, this solution was slowly added over 30 minutes at 40 'with stirring to the 2,4,5-triamino-6-oxy-pyhrnidine solution described above, the p11 value being increased by adding 2o0 /, iger NaOH solution was kept at about 3.5 . After stirring for a further 15 minutes at 40 ', the mixture was cooled by adding ice and stirred for 15 minutes at 15'. It was then filtered and the filter residue was washed with water and alcohol. Were obtained 24.4 parts of a light brown solid which 11.9 0 / consisted of barium sulfate and about Pteroylglutanünsäure. Example 9 To a solution of ig, 7, parts Bariumehloriddihydrat in 35o parts "n water from 6o 'were added 12.9 parts of 2,4, 5-triamino-6-oxypyrimidinsulfat. After io minutes of stirring at 6o' the mixture was heated to 40 'and mixed with 13.3 parts of p-aminobenzoylglutamic acid, whose pu value was adjusted to 3 to 3.5 by adding 20% NaOH solution.

A solution of 7.3 parts (0.05 mol) of I, I, 3-trichloroacetone in 15 parts of acetic acid was then added dropwise at 40 'over the course of 1 hour, with stirring, the pH being reduced by the addition of? O0 /,) iger NaOH solution was kept at 3 to 3.5 . The mixture was then stirred for a further 15 minutes at 40 'and then cooled to 15' by adding ice. After stirring for a further 10 minutes, filtering and washing the residue on the filter with water and alcohol gave?, O, o parts of a solid brown substance consisting of barium sulfate and crude folinic acid. EXAMPLE 10 To 400 parts of water were added 2o, 6 parts of 2,4,5-triamino-6-oxy-pyrimidine sulfate and 21 parts of barium chloride dihydrate, and the mixture was heated to 6o 'for 20 minutes. Their were then 21.1 parts of p-aminobenzoyl-y - glutamyl-y-glutamyl - glutamic acid dissolved in 44o parts water was added and the pH value by means of 2o0 / acetic NA0 set H solution to 3 to 3.5. After reaching a temperature of 75 to 8o 'were within 5 minutes together with 2o0 /, Na added strength H 0 solution 4o Parts I, I, 3-Tribiomaceton, the pil value was maintained at 3 to 3.5. The mixture was then heated to 75 to 80 'for 1 hour, the pI value being maintained by adding 20 "/, NaOH solution. After cooling to 10", the dark red-brown solution was filtered and the residue was mixed with a small amount of ice water The wet filter cake contained 8 parts of pteroyl-γ-glutamyl-γ-glutamyl-glutamic acid, that is 30, 60/0 of theory, based on the applied p-aminobenzoyl-γ-glutamyl-γ-glutamyl-glutan-licic acid.

For purification, an amount of the product which contained 10.6 parts of pteroyl-γ-glutamyl-, γ-glutamyl-glutamic acid was suspended in 10,600 parts of an γ-n sodium hydroxide solution. The temperature was now increased to 60 'and the volume of the solution to 10,700 parts, whereupon 26o parts of a 300% calcium chloride solution and 100 parts of diatomaceous earth were added at 50 to 55'. After filtration, a filtrate of 11,350 parts by volume of the 5.99 parts pteroyl, y-glutamyl, y-glutainyl-glutamic acid contained greater purity was obtained. The product was further purified by the formation of the zinc salt at a pR of 10 to 10.8, removal of the insoluble substances and adjustment to pil 6.7 to 6.9 and precipitation.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of pteridines, characterized in that 2, 4, 5-triamino-6-oxy-pyrimidine with I, I, 3-trihaloacetone and a p-aminobenzoic acid of the general formula where R is OR'or NR'R "and wound R" is hydrogen or aromatic or aliphatic radicals, preferably at a pH between i and 7, for example between i and 5, at suitable temperatures, preferably at temperatures up to approximately ioo implements. 2. The method according to claim i, characterized in that p-aminobenzoylglutamic acid, p-aminobenzoylglutamylglutamic acid or p-aminobenzoylglutamylglutamylglutamic acid is used as p-aminobenzoic acid. 3. The method according to claims i and 2, characterized in that the three reactants are brought to implementation in any order.