DE2146440A1 - 4,8-dihydroxy-2,6-dimercaptopyrimido (5,4-d)-pyrimidine prepn - start from s-alkylisothiourea and oxalacetic ester - Google Patents

Abstract

5,4-d pyrimidine (I) is prepd. by reacting R2OCC.COM:CH.COOR1 (where R1 and R2 are lower alkyl and M is alkali metal) with H2N.C(NH)SR3 (where R3 is lower alkyl) in the presence of NH3; halogenating the 2-alkylthio orotic acid amide obtd. and reacting the product with NH3; and reacting the 5-amino-2-alkylthio orotic acid amide obtd. with alkali metal hydrosulphide and X.C(S)SH (where X is H, free or substd. OH, NH2 or SH) in any order. Cpd. (I) is an inter. for the vasodilator 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido 5,4-d -pyrimidine.

Description

Description of the patent application Process for the production of 4,8-dihydroxy-2,6-dimercaptopyrimido [5,4-d] pyrimidine The invention relates to a storage for the production of 4,8-dihydroxy-2,6-dimercaptopyrimido [5, 4-d] pyrimidine of the formula This process uses an oxaloacetic acid ester of the formula in which R1 and R2 each represent a lower alkyl group and M an alkali atom with a lower S-alkylisothiourea of the formula in which R3 is a lower alkyl group, reacted in the presence of ammonia, where a lower 2-alkylthioorotsaureamid of the formula in which R3 has the meaning given above, arises. This lower 2-alkylthiooroteamide is halogenated in a known manner and the product is reacted with ammonia to give a lower 5-amino-2-alkylthioorotamide of the formula in which R3 has the meaning given above, arises.

This amide is combined with an alkali metal hydrosulfide and with a dithio (or irithioJ compound of the general formula in which X is a hydrogen atom, a free or substituted hydroxyl group, an amino group or a mercapto group. The order of the last two stages is arbitrary.

The product produced by the process of the invention is an important intermediate for the production of 2,6-bis (diethanolamino) -4,8-dipiperidinopyrimidog5,4-d7pyrimidine ("Dipyridamole"), used as a vasodilator (vasodilator) for the coronary arteries suitable is.

For the production of 4,8-dihydroxy-2,6-dimethylmercaptopyrimido / 5, 4-7pyrimidine of the formula I, which is produced by the process according to the invention is to be, a process is known in which 2,5-dichloro-4,8-d-hydroxypyrimidot5,4-d7pyrimidine is reacted with an alkali hydrosulfide (FR-PS 1 184 519). With this one The desired product can be obtained from the starting substances in a fairly process high yield (e.g. 86%) can be obtained, but the starting material is commercially available not available and must be made from other compounds. E.g. can the starting material 2,6-dichloro-4,8-dihydroxypyrimido [5,4-d] pyrimidine is convenient according to a known method, starting from 4-Bydroxy-2-mercapto-6-methylpyrimidine, can be produced by reacting acetoacetate and thiourea and via 5-nitroorotic acid, 5-aminoorotic acid, 2,4,6,8-tetrahydroypyrimido [5,4-d] pyrimidine and 2,4,6,8-tetrachloropyrimido-5,4-d] pyrimidine. If such a known method for the production of the starting material 2,6-dichloro-4,8-dihydroxypyrimido / S, 4-d7pyrimidine is applied, however seven steps are required to get the desired Product of formula 1 from the commercially available acetic acid according to the process specified in the French patent. The desired Product obtained in an overall yield of only 15 ffi. Hence it possesses in this one The patent specification only has a low technical value, although the the starting material required for this is easily accessible.

Another process is known for producing the desired product, the pyrimidopyrimidine ring by reacting a pyrimidinecarboxylic acid derivative of the general formula in which R1 is a mercapto, lower alkylthio, lower alkyl or aryl group, R2 is an amino group or a halogen atom and R3 is a hydrogen atom or a hydroxyl group or a functional derivative thereof is obtained with thiourea, urea or a rhodanide with heating (DU- PS 1 093 801). In this patent, however, no process for the preparation of the product to be prepared according to the invention is disclosed and in the attempt to produce this product by reacting a 5-amino-2- (lower) alkylthioorotic acid, 5-amino-2-mercaptoorotic acid or an amide of these compounds with thiourea or To prepare ammonium rhodanide according to the teaching of the German patent, the reaction proceeded only very slowly at temperatures below 100 ° C. and at temperatures above 100 ° C. many by-products were formed and hydrogen sulfide was evolved. The yield of the desired product and the purity of this product were very low. The process according to this patent specification is therefore also unsuitable for technical purposes (see Tables I to III). In addition, in this process the starting material is not commercially available and must be prepared from other commercially available compounds. For example, the starting material used according to the German patent can be prepared by reacting an oxaloacetic acid ester, which is also used as starting material for the process according to the invention, and a lower 5-alkylisothiourea, a lower 2-alkylthioorotic acid being formed which is halogenated according to a known method. The product is reacted with ammonia, whereby a 5-amino-2- (lower) alkylthioorotic acid is formed, which, if necessary, is treated with an alkyl hydrosulfide.

When the desired product of formula I is obtained by the method of the above specified German patent is produced, it is according to the state of Technique considered favorable, the starting material after the above-mentioned process to manufacture. The overall yield of the desired product from the oxaloacetic ester however, it is very small.

The process specified in DT-PS 1 093 801 when reworking results obtained are shown below.

Preparation of 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido5,4-d7pyrimidine monohydrate: 1. Conversion of 5-amino-2-methylthioorotic acid (1 g) and ammonium rhodanide (3.8 g) in an amount of 10 moles based on 1 mole of 5-amino-2-methylthioorotic acid.

Table I Readtions Reaction Yield Sulfur Content Comments temperature time (h) (mg) (%) in the end product (° C) (%) (calculated: 24.64) 100 1.25 680 52 16.78 almost no conversion 6.5 520 40 20.64 a lot of unreacted starting material 0.25 605 47 19.49 n 130 0.5 485 37 21.67 ft 1 555 43 20.60 "2 591 45 19.51 almost complete reaction 6.5 605 47 18.69 "150 0.25 560 43 19.78 remaining starting material Note: The sulfur content in the product was the value that was obtained by analyzing the solid product in which the unreacted ammonium thiocyanate was removed by treating the liquid reaction product with water.

When the reaction temperature was higher than 1750C, the decomposition proceeded quickly and the sulfur content in the product was less than 15% or the product was impure.

2. In this case, experiment I was carried out in a solution that was saturated with hydrogen sulfide, carried out in a sealed tube (with 1/5 of the starting material and the reagent).

Table II Reaction-Reaction Yield Sulfur Content Comments temperature time (h) (mg) (%) in the end product (° C) (calculated: 24.64) 0.5 100 38 20.96 remaining original 130 material 1 130 50 20.06 2 125 48 20.22 n 3. In this case were 1.0 mg of 5-amino-2-methylthioorotic acid amide and 380 mg of ammonium rhodanide or 380 g of thiourea implemented in the 10 molar amount of the amide.

Table III Reaction temperature (° C) 130 not all converted 150 n 170 partially reacts 190 reacts, but the sulfur content of the product was up very low 17.15 - 17.87% (calculated: 24.64) Now it has to Extended studies showed that very pure 4,8-dihydroxy-2,6-dimercaptopyrimidog5,4-d7 pyrimidine from an oxaloacetic acid ester with an overall yield of about 30 can be produced by the above-mentioned method.

The process according to the invention and the above-mentioned known processes are shown in the following reaction scheme.

where R1, R2 and R3 each represent a lower alkyl group uX X is a halogen atom means.

Method according to the invention where R1 ', R2 and R3 are each a lower alk group and X is a halogen atom.

It is known that a lower 2-Alkylthioorotsaure by reaction of the oxalesaetic acid ester of the formula II with the lower S-alkylisothiourea of formula III is obtained. However, it is unexpected that 2-thiooroacetic acid of formula IV directly in the presence of ammonia as in the first stage of the invention Procedure can be obtained.

DT-PS 1 093 801 also specifies the pyrimido / 5,4-d7pyrimidine ring by reacting 5-amino-2-mercapto-, a lower alkylthio-orotic acid or a functional derivative thereof with a mopothio compound such as an ammonium rhodanide or to produce thi charnstoff, In such a process, however, a large amount of by-products is formed and it is impossible to get the desired product in high yield and with high purity under mild reaction conditions to obtain (see Tables I to III).

It is also unexpected that on such an industrial scale the pyrimido [5,4-d] pyrimidine ring by reaction of a lower 5-amino-2-alkylthioorotic acid amide and a dithio (or trithio) compound of the formula IV under proportional mild conditions, i.e. in an organic solvent according to the fourth Stage of the process according to the invention, can be prepared without any by-products are formed.

Thus, according to the process according to the invention, 4,8-dihydroxy-2,6-dimetcaptopyrimido [5,4-d] pyrimidine of the formula I from the oxaloacetic ester of the formula II by combining these unexpected process steps can be obtained in good yield, i.e. in an overall yield across all procedural stages approx.

30 fi, making the inventive method for industrial purposes becomes very economical.

It has been a process for producing dipyridamole in high yield from the product according to the invention 4,8-dihydroxy-2,6-dimercaptopyrimidog5,4-d7pyrimidine of the above formula I, which can be obtained in high yield (DT-OS 2 003 043). This process developed some time ago is excellent, has the disadvantage, however, that the starting material, namely that of the invention product to be manufactured is not available cheaply in the industry. By the inventive method these difficulties are overcome and it this makes it possible to manufacture dipyridamole at a low cost.

The invention is described below in relation to the individual process steps explained in more detail.

1st stage: The first stage of the process according to the invention is carried out by adding the compound of formula II and an equimolar amount or an excess of the lower S-alkylisothiourea of the formula III at room temperature or below Cooling, preferably at temperatures below 50C in the presence of ammonia, e.g. in 5 to 28 percent, preferably 10 to 15 percent aqueous ammonia, implements.

The compound of formula IV thus formed is readily crystalline Condition obtained in / in which only the pH value of the liquid contained in the product can be determined adjusts to an acidic area. The crystals thus formed can be collected and can be used directly for the second stage. S kCinne; i odoch, if necessary, e.g. by recrystallizing or the like to be further cleaned.

2nd stage: The halogenation of the compound of formula IV is carried out well known way. For example, the halogenation is carried out by the compound of formula IV suspended in glacial acetic acid and in the suspension a introduces equimolar amount of bromine or chlorine and the mixture to preferably 50 to Heated to 1000C.

By simply cooling the liquid containing the reaction product, the compound of formula IV 'thus formed crystallizes. The crystals thus formed can be filtered off and used directly for the third process stage.

However, if necessary, they can be isolated or by recrystallization or the like can be further cleaned.

3rd stage: the amination of the compound of formula IV 'by Ammonaik can be carried out in a known manner. E.g. the amination of the compound of the formula IVt carried out by adding a compound of this formula in excess Ammonia, usually in an aqueous ammonia solution, in the presence of copper powder by heating to preferably 90 to 100 ° C.

The compound of formula V is crystallized by, for example, the The reaction mixture is cooled and the crystals thus formed are filtered off, in aqueous ammonia dissolves and the pH of the solution thus obtained to an acidic range, preferably to about 6, sets. The precipitate obtained by simply filtering off can be used directly for the next fourth level. l @@@ product can be if necessary, isolated or further purified by recrystallization or the like will.

4th stage: By reacting the compound of the formula V and the compound of formula VI in an amount greater than the equimolar or 10-facie Amount of the compound of the formula V in an organic solvent such as pyr @ idin, Dimethylformamide or an alcohol under reflux conditions within 10 to The pyrimidopyrimidine ring is formed in 20 h.

The compound of the formula V thus formed is separated off by a customary procedure, e.g. such concentration, extraction, recrystallization or ihuliches carried out, examples of Verbin aungen of the formula VI, according to the invention can be used are xanthogenic acids, e.g.

Methyl xanthate and ethyl xanthate, etc., free or substituted Dithocarbamic acids, e.g. N, N-diethylcarbamic acid etc., trithiocarboxylic acid derivatives, e.g. trithiocarboxylic acid esters, etc. and dithioformic acid. In addition, according to the invention functional derivatives of dithio compounds that have the same effect, be used. For the reaction it is preferable to use the dithio (or trithio) compounds, harvested as above, in the form of an inorganic salt or an organic salt such as an alkali metal salt, an alkaline earth salt or an organic amine salt, e.g. in the form of sodium, potassium or amine salts etc. to be used. In addition to the According to the invention, the above-mentioned di- or trithio-compounds can also be a substance which forms such a compound during the reaction. Examples for such substances include a mixture of carbon disulfide and potassium hydroxide, which easily forms a xanthate if a lower alcohol is used as the reaction solvent is used or a mixture of carbon disulfide and ammonia (or a Amine), which is easily a substituted or unsubstituted dithiocarbamic acid forms in a solvent.

5th stage: This stage is carried out by making the connection of the formula V 'with an excess of an alkali hydrogen sulfide such as sodium hydrogen sulfide in an organic solvent such as ethylene glycol with heating to preferably 1800C implements.

The compound of formula I, which is prepared in this way, can be separated off in the usual way, e.g. by concentration, extraction and recrystallization will.

In addition, the treatment with an alkali hydrogen sulfide in the 5th stage (separation of the lower alkyl group) before treatment with the dithio (or Trithio3 compound 4th stage (formation of the pyrimidopyrimidine ring) carried out will.

The invention is explained in more detail with the aid of the following examples.

Example 1 To 50 ml of a 14 percent aqueous, ice-cooled Ammonia solution was 5.0 g of the sodium salt of ethyl methyl oxaloacetate added and the mixture stirred for 1 h while cooling with ice. To the one so produced 3.8 g of S-methylisothiourea sulfate were added to the solution and the mixture was further added Stirred for 3 h while cooling with ice. After the completion of the reaction, the pH of the System adjusted to 4 to 5 by adding glacial acetic acid and the mixture for a time left to stand for a long time, resulting in a white crystalline powder of 2-methylthioorotic acid amide parted, which was filtered off and washed with a small amount of water. the The amount of the product obtained was 2.9 g (yield 61%), the melting point was 270 to 2720C.

The product recrystallized from ethanol had a melting point from 2760C.

Elemental analysis C6H7N302S: N () S () calculated 22.69 17.31 found 22.82 17.10 Example 2 To 50 ml of 7 percent aqueous, at a temperature below from 50C cooled ammonia, 5.0 g of the sodium salt of oxaloacetic acid ethyl methyl ester was added and the mixture was 2 h at the same temperature touched. Then 3.8 g of S-methylisothiourea sulfate were added to the solution thus prepared added and the mixture stirred at this temperature for a further 3 h.

After the reaction was over, the pH became that of the reaction product The liquid contained is adjusted to 4 to 5 by adding glacial acetic acid and the Liquid left to stand for a while, during which time a white crystalline precipitate forms of 2-methylthioorotic acid amide, which was filtered off and mixed with a small amount Water was washed. The amount of the product obtained was 5.2 g (68%) and the melting point was 275 to 2760C.

Example 3 To 50 ml of 28 percent aqueous ammonia, the Temperature of below 5 "C had cooled, were 5.0 g of the sodium salt of ethyl methyl oxaloacetate added and the mixture stirred for 30 min at this temperature. Then became the Solution 3.8 g of S-methylisothiourea sulfate were added and the mixture on the same Temperature stirred for a further 3 h.

After the reaction was over, it became the reaction product containing liquid treated as in Example 1.

2.6 g (55%) of a white crystalline powder of 2-methylthicrotic acid amide were obtained with a melting point of 272 to 273 ° C.

Example 4 To 50 ml of 14 percent aqueous ammonia, the Temperature of below 5 ° C had cooled, 5.0 g of the sodium salt of methyl oxaloacetate were added and the mixture stirred for 1 hour at this temperature. Then were to 5.3 g of S-methylisothiourea sulfate were added to the solution and the mixture at the Stirred at the same temperature for a further 3 h. After the reaction was complete, the liquid containing the reaction product was treated further as in Example 1. 3.7 g (79%) of a white crystalline powder of 2-methylthioorotic acid amide were obtained with a melting point of 270 to 27,100.

Example 5 5.9 g of dimethyl oxalate and 2.7 g of sodium methylate were added to 100 ml of toluene and 4.4 g of ethyl acetate were added and the mixture was stirred at 60 ° C. for 3 h. Then became the solution cooled to below 50C and 90 ml of 7 percent aqueous ammonia, which had cooled to below 50 ° C. was added to the solution prepared in this way. That The resulting mixture was stirred at a temperature below 50 ° C. for 2 h.

Then 7.0 g of S-methyl isothiourea sulfate was added to the like solution prepared above was added and the mixture for 3 h at temperatures below stirred from 5 ° C. The resulting aqueous layer was from the reaction mixture severed.

Then the pH of the aqueous layer was adjusted by adding glacial acetic acid adjusted to 4 to 5 and allowed to stand for a while. It was part 2-methylthioorotic acid emerges as a white crystalline precipitate, which can be filtered off recovered and washed with a small amount of water.

The amount of the product obtained was 5.4 g (overall yield Steps 58%) and the melting point was 2760C.

Example 6 50 g of 2-methylthioorotic acid amide were added to 400 ml of glacial acetic acid suspended and 49.3 g of bromine were added dropwise to the suspension with stirring. then the suspension was heated to 50 ° C. and after stirring for 1 hour it became up Heated at 1000C and stirred for another hour. The suspension was allowed to dissolve Cool to room temperature and the crystals which precipitated out were filtered off and washed with a small amount of glacial acetic acid. The crystals were then in 125 ml of benzene suspended and the suspension heated to boiling for 30 min. After cooling down the crystals were filtered off and washed with a small amount of methanol. 53.7 g (yield 74.9) of 5-bromo-2-methylthioorotic acid amide were obtained.

The product possessed after recrystallization from a dimethylformamide-methanol mixture a melting point of 244 to 2450C.

Elemental analysis: N (ffi) S (ffi) Br (%) calculated 15.96 12.14 30.25 found 15.97 11.94 29.65 Example ~ 7 To 180 ml of 28 percent aqueous ammonia, 50 g of 5-bromo-2-methylthioorotic acid amide were added and after after adding 0.5 g of copper powder to the solution, the mixture was reduced to 90% for 3 hours Heated at 1000C in a sealed tube. After completion of the reaction, the the liquid containing the reaction product is cooled, the precipitating yellow Crystals filtered off and dissolved in 800 ml of 2 percent aqueous ammonia by heating solved. Then, after adding activated carbon to the solution and filtering the mixture the filtrate is cooled and the pH of the solution is increased by adding acetic acid 6 set, with a yellow crystalline precipitate formed. The so educated Crystals were filtered off, washed with water and then with methanol and dried.

29.2 g (yield 77) of 5-amino-2-methylthioorotic acid amide were obtained with a melting point of 2800C.

In addition to the first separation of the yellow crystalline precipitate The resulting filtrate was added to activated charcoal and the mixture was filtered. The pH the filtrate was adjusted to 6 by the addition of acetic acid, whereby again a yellow crystalline precipitate formed. The crystals were filtered off, washed with water and dissolved in 400 ml of 2 percent aqueous ammonia with heating solved.

Activated charcoal was then added again to the solution and the Solution filtered. The filtrate was then cooled and the pH of the solution below Addition of acetic acid adjusted to 6, with yellow crystals separating out. The crystals were filtered off, washed with a small amount of water and methanol and dried. 4.05 g (10.7) of 5-amino-2-methylthioorotic acid amide were obtained a melting point of 2800C. The overall yield of the product was 33.25 g (87.7 %).

Elemental analysis: c (%) H (%) N () S (%) calculated 35.99 4.03 27.98 16.01 found 35.41 4.10 27.19 15.63 Example 8 To a mixture of 10 ml of pyridine and 6 ml of ethanol were 100 mg of 5-amino-2-methylthioorotic acid amide and 1.6 g of potassium ethyl xanthate added and the mixture refluxed overnight. The solvent was distilled off and 3 ml of water were added to the yellow crystalline residue and the pH is adjusted to 4 to 5 with acetic acid. The crystals were filtered off and washed twice with 0.5 ml of water each time. The crystals thus obtained were t 10 ml of 3N aqueous ammonia dissolved. Activated charcoal was added to the solution and the mixture is filtered. The pH of the filtrate was adjusted by adding acetic acid adjusted to 4 to 5 and the precipitating cream-colored crystals were filtered off, washed twice with 1 m water and dried.

96 g (74%) of 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido5,4-d7pyrimidine were obtained with a melting point of over 2800C.

Elemental analysis for C7H6N4S202.H20: C (%) H (%) N (%) S (%) calculated 32.23 3.21 21.48 24.66 found 32.30 3.10 21.52 24.64 Example 9 In 10 ml of i'yrZidine 100 mg of 5-amino-2-methylthioorotsaureamid and 2.2 g of N, N-diethyldithiocarbamic acid diethylamine were added dissolved and the solution heated to reflux overnight.

The liquid containing the reaction product was concentrated and 3 ml of water became the black-brown thus formed Residue admitted. After the pH of the mixture by adding acetic acid to 4 to 5, 10 ml of ether was added to the mixture and shaken well. The mixture was allowed to stand for about 1 hour at room temperature and the precipitated Crystals were filtered off and washed twice with 0.5 ml of water each time. The so obtained crystals were dissolved in 10 ml of 3N aqueous ammonia. To the mixture activated charcoal was added and the charcoal and dissolved constituents were filtered off. The filtrate was weakly acidified with acetic acid and the precipitated light yellow crystalline precipitate was filtered off and washed twice with 1 ml of water each time and dried. 80 mg (61.5) of the desired compound were obtained. The infrared absorption spectrum the compound was completely the same as that obtained in Example 8 Link.

Elemental analysis for C7H6N4S202.H2 a (%) H (%) N (ffi) 5 (%) calculated 32.98 2.83 21.48 25.07 found 32.30 Dfi10 21.52 24.64 B e i s p i e l 10 to a A solution of 0.28 g of potassium hydroxide in 3 ml of ethanol became 0.38 g of carbon disulfide and then 50 mg of 5-amino-2-methylthioorotic acid amide and 5 ml of pyridine were added.

After refluxing the mixture for 23 hours, became the liquid containing the reaction product is treated further as in Example 8. 30.5 g of the cream-colored crystals of the desired product were obtained in one 47% yield. The infrared absorption spectrum of the compound was complete the same as that of the product prepared in Example 8.

Elemental analysis for C7H6N4S22 .H20: c (ffi) H (%) N (%) S (%) calculated 32.18 2.94 21.41 24.39 found 32.30 3.10 21.52 24.64 B e i 8 p i e l 11 to one sodium alcoholate solution obtained by adding 0.115 g of metallic sodium to 3 ml of ethanol 0.38 g of carbon disulfide was added. The yellow solution thus obtained was 50 mg of 5-amino-2-methylthioorotic acid amide and 5 ml of pyrimidine were added and the mixture Heated under reflux for 18 h. Then the solution was cooled to room temperature and the precipitated crystals are filtered off. 1 ml of water was added to the crystals added and the pH of the mixture by adding acetic acid to approx 4 set.

The light yellow crystals thus obtained were filtered off, twice washed with 0.5 ml of water and dried. 53.4 mg of the desired were obtained troductes in a yield of 82.2. The IR spectrum of the product was completely correct with that of the product obtained according to Example 8.

Elemental analysis: calculated s 24.64% found s 24.32% B e i s p i e l 12 50 mg of 5-amino-2-methylthioorotic acid amide were added to 5 ml of dimethylformamide and 0.8 g of potassium ethyl xanthate added and the solution at 110 to 1150 ° C. for 19 h heated. After the completion of the reaction, the yellow crystals thus formed were filtered off. The dark green filtrate was concentrated under reduced pressure and that formed Residue mixed with the crystals obtained above. To the mixture were 3 ml of water are added and the pH of the mixture is adjusted to approximately with acetic acid 4 set. The crystals formed were filtered off and washed twice with 0.5 ml of water each time.

The crystals thus obtained were dissolved in 7 ml of 3N aqueous ammonia dissolved and after treating the solution with activated charcoal it was filtered off, the pH of the filtrate is adjusted to about 4 with acetic acid. The unusual Crystals were filtered off, washed twice with 0.5 ml of water each time and dried. 49 mg (75.4) of yellow crystals of the desired product were obtained. The IR spectrum this product completely agreed with that obtained according to example 8 Product.

Elemental analysis: calculated S 24.64% found s 24.93% B e i s p i e 1 13 50 mg of 5-amino-2-methylthiQorotic acid amide were added to a mixture of 5 ml of pyridine and 3 ml of ethanol and 1 g of potassium dithioformate were added and the mixture was refluxed for 22 h.

The reaction mixture was concentrated and the black-brown residue treated as in Example 8. 38 mg of yellow crystals of 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido were obtained g5,4-d7pyrimidine in a yield of 58.5%. The IR spectrum of the product was correct completely identical to that of the product obtained according to Example 8.

Elemental analysis: calculated S 24.64%, found S 24.48% B e i s t i e 1 14 In a solution of 2.5 g of anhydrous sodium hydrogen sulfide in 25 ml Ethylene glycol was 2.42 g of 4,8-dihydroxy-6-mercapto-2-methylthiopyrimidog5,4-d7pyrimidine suspended and the mixture stirred for 1 h at room temperature, wherein a light green-yellow slurry was formed. This slurry was at 155 for 3 hours stirred up to 1600C.

The liquid containing the reaction product was cooled and after adding 15 ml of methanol, the mixture was thoroughly stirred. The resulting one Precipitate was filtered off and washed with 10 ml of methanol, a crude Product emerged. This crude product was dissolved in 50 ml of water with heating and after adding activated charcoal and filtering off the charcoal, the pH became of the filtrate adjusted to 3 to 4 by adding acetic acid, whereby a Precipitate formed which was filtered off and washed with water and methanol. 1.83 g (yield 80.2%) of the fine yellow powder of 4,8-dihydroxy-2,6-dimercaptopyrimido were obtained 5, 4-d7 pyrimidine.

B e i 5 n i e 1 15 To a mixture of 5 ml of pyridine and 3 ml of ethanol 50 ml of 5-Amino-2-mercaptoorotsaureamid, which was obtained by treating 5-Amino-2-methylthioorotsäureamid was obtained with sodium hydrogen sulfide and 0.8 g of potassium ethyl xanthate, was added and the mixture was refluxed for 20 hours. The the reaction product containing liquid was concentrated and 1 ml of water became the resultant added crystalline solid and the pH of the aqueous mixture by adding adjusted to about 4 by acetic acid. The crystals thus formed were filtered off and washed with 0.5 ml of water.

The total amount of the crystals was dissolved in 5 ml of 3N aqueous ammonia dissolved and after the addition of activated charcoal this was together with non-dissolved constituents filtered off. The pH of the filtrate was adjusted to approximately 4 with acetic acid and the crystalline precipitate was filtered off, twice with each 1 ml of water washed and dried. Mar received 50 mg (82%) of the light yellow crystalline Product 4,8-dihydroxy-2,6-dimetcaptopyrimido [5,4-d] pyrimidine.

Elemental analysis: calculated s 28.10% found s 27.80% B e i 5 p i e 1 16 50 mg of 5-amino-2-mercaptoorotic acid amide were added to 5 ml of pyridine Treatment of 5-amino-2-methylthioorotic acid amide with sodium hydrogen sulfide and 1.11 g of N, N-diethyldithiocarbamic acid diethylamine were added and that The mixture was refluxed for 15 h. The reaction mixture was concentrated and the The residue was treated further as in Example 15, the desired product being obtained. The infrared absorption spectrum of the product completely corresponded to that of the product obtained in Example 15. The yield was 40 mg (66.7%).

Elemental analysis: calculated s 28.10 ffi found s 27.55% patent claims

Claims (3)

Patent claims 1. A process for the preparation of 4,8-dihydroxy-2,6-dimercaptopyrimido [5,4-d] pyrimidine of the formula characterized in that the oxaloacetic acid ester of the general formula in which R1 and R2 each represent a lower alkyl group and M an alkali atom and a lower S-alkylisothiourea of the general formula in which R3 is a lower alkyl group, reacts in the presence of ammonia, the resulting lower 2-alkylthioorotauramide of the formula in which R3 has the meaning given above, halogenated in a known manner, the product is reacted with ammonia and the resulting lower 5-amino-2-alkylthioorotic acid amide of the formula in which R3 has the meaning given above, in any order with an alkali metal hydrogen sulfide and a dithio compound of the general formula in which 1 denotes a hydrogen atom, a free or substituted hydroxyl group, an amino group or a mercapto group. 2. The method according to claim 1, thereby g e k e n n -æ e i c h n e t that the lower 5-amino-2-alkylthioorotsäureamid first with the dithio compound and then treated with the alkali hydrogen sulfide 3. Process for the preparation of a 4,8-dihydroxy-6-mercaptopyrixid og, 4-d] pyrimdin derivative of the formula in which R4 denotes a hydrogen atom or a lower alkyl group, thereby denoting that the 5-aminoorotic acid amide derivative of the formula in which R4 has the meaning given above, with an ithiot compound of the formula in which X is a hydrogen atom, a free or substituted hydroxyl group, an amino or a mercapto group, treated.