NO141137B - DEVICE FOR READING A PLATE-SHAPED RECORD CARRIER - Google Patents

Description

Process for the production of therapeutically effective sulfonamides of the pyrimidine series.

The present invention relates to a process for the production of previously unknown sulfonamides with the general formula:

in which R 1 and R 2 mean lower alkyl or alkenyl residues, such as methyl, ethyl, n-propyl, isopropyl, butyl, hexyl and allyl, as well as salts of such sulfonamides. The method according to the invention is characterized by (a) condensing a pyrimidine with the general formula: in which R 1 has the same meaning as stated above, and R 3 and R 4 stand for a halogen atom, e.g. chlorine, bromine or iodine, or an R20 group, with an alkali salt of a benzenesulphonic acid amide, which has in the para-position a free or protected amino group, e.g. an acylamino or carbalkoxyamino group and replaces a halogen atom possibly occurring in the condensation product with an R2Q group as well as cleaving off a possibly present protecting group, or that one (b) condenses a pyrimidine with the general formula

in which R1 and R3 have the above meaning, with a benzenesulfonhalide, which has in the para-position a substituent convertible to the amino group and, after condensation, replaces any halogen atom present with an R20 group as well as converting the para-substituent into the amino group.

According to a preferred embodiment of the process variant (a), pyrimidine of the formula II is used as starting material, in which Ri means a lower alkyl residue, especially methyl, ethyl, n-propyl or isopropyl, and Rs and R4 a halogen atom, especially a chlorine atom. Such preferred starting pyrimidines are e.g. 4,6-dichloro-5-methoxy-pyrimidine, 4,6-dichloro-5-ethoxy-pyrimidine, 4,6-dichloro-5-n-propoxy-pyrimidine. These 4,6-dihalo-5-alkoxy-pyrimidines are advantageously condensed with an alkali salt of sulfanilamide or of N4-acylsulfanilamide, e.g. with sulfanilamide sodium. As a condensation product, the corresponding 4-sulfanilamido-5-alkoxy-6-halo-pyrimidines and their N4-acyl derivatives are obtained. The condensation reaction is conveniently carried out in the presence of a solvent or diluent, such as dimethylformamide, at temperatures between 80 and 120 °C, particularly at approx. 90-100°C.

In another step, the 6-halogen atom of the obtained condensation product is replaced with an R 20 residue, in particular with a methoxy, ethoxy, n-propoxy, isopropoxy or allyloxy group. For this purpose, the obtained condensation product is heated with an alkali alcoholate of the corresponding alcohol, e.g. with a methanolic solution of sodium methylate, to reflux. The reaction with the alkali alcoholate can also be carried out under pressure at higher temperatures, e.g. at approx. 120-130°C. An N4-acyl group possibly occurring in the condensation product can be easily split off before or after the alcoholysis operation by heating the N4-acyl compound with dilute acids or alkalis, e.g. with diluted caustic soda. If the alcoholysis reaction is carried out under pressure at higher temperatures, any N4 acyl group that may be present is usually split off at the same time.

The particularly preferred 4,6-dihalo-5-alkoxy-pyrimidines as starting materials for method variant (a) can e.g. is obtained as follows: An methoxyacetic acid methyl ester is transferred with dimethyl carbonate to the corresponding dimethyl methoxymalonic acid ester and this ester is converted with ammonia to the corresponding alkoxymalonic acid amide. This di-amide is cyclized with the aid of formamide in the presence of sodium ethylate to 4,6-dihydr-oxy-5-alkoxy-pyrimidine, from which by halogenation with a phosphoric acid halide, e.g. with phosphorus oxychloride, 4,6-dihalogeno-5-alkoxy-pyrimidine can be obtained.

The 4-halo-5,6-dimethoxy-pyrimidines and 4,5,6-trimethoxy-pyrimidines that can be used as starting materials for the method variant (a) can be obtained from the 4,6-dihalo-5-alkoxy-pyrimidines just mentioned by replacement of one or both halogen atoms with alkoxy. The substitution of the halogen atoms for alkoxy groups can be carried out by reacting the halogen pyrimidine with the corresponding alkali alcoholate, e.g. with sodium methylate, -ethylate, -n-propylate or -isopropylate, optionally using pressure.

If a 4-halo-5,6-dialkoxypyrimidine is used as starting material, it may be advantageous to transfer the 4-halo atom in advance before sulfanilamidolysis in a manner known per se to a quaternary tri-alkylammonium halide group, e.g. by reaction with trimethylamine.

According to a preferred embodiment of method variant (b), 4-amino-pyrimidines of the formula III are used as starting materials, in which Rt means a lower alkyl residue, especially methyl, ethyl. n-propyl or isopropyl and R 3 a lower alkoxy or alkenyloxy, such as an allyloxy group. Particularly preferred starting pyrimidines are e.g. 4-amino-5,6-dimethoxypyrimidine, 4-amino-5-methoxy-6-ethoxy-pyrimidine or 4-amino-5-ethoxy-6-methoxy-pyrimidine. These 4-aminopyrimidines are condensed in a first step with a benzenesulfohalide, which in the para position exhibits a substituent that can be converted to the amino group and transfers this substituent after condensation to the amino group. Examples

on such p-substituents are: acylamino-,

in particular the acetylamino, carbaloxyamino, such as carbethoxyamino, carbobenzyloxyamino and nitro groups. These p-substituents can, after condensation has been carried out in a manner known per se, by hydrolysis or reduction, be transferred into the free amino group.

For the condensation reaction, the usual condensation agents can be used, e.g.

e.g. anhydrous pyridine or a benzolic solution of trimethylamine.

Depending on the amount of benzosulfonyl halide used, condensation products with one or two benzenesulfonyl residues can be obtained. If you work with equimolar amounts of pyrimidine and sulfohalide components, you mainly get monobenzosulfonyl compounds; if the molar ratio is 1:2, the bis-benzenesulfonyl compounds predominate in the coupling product.

The condensation of the aminopyrimidine compound with the sulfohalide component, e.g. with p-acetaminobenzene sulpho-chloride, can be carried out both at low temperatures as well as at temperatures up to the boiling point of the reaction mixture. When using p-acetaminobenzenesulfochloride as the sulfohalide component and pyridine as the solvent, it has proven particularly advantageous to work at lower temperatures, suitably at temperatures below approx. 5°C.

The 4-amino-5,6-dialkoxy-pyrimidines which are particularly preferred as starting materials for method variant (b) can be easily recovered from the above-mentioned 4,6-dihalogen-5-alkoxy-pyrimidines by reaction with ammonia and then with a alkali- | alcoholate. The ammonia can then be used in the form of a solution in an organic solvent or suitably in undiluted, liquid form. Thus, one can e.g. lead into a solution of 4,6-dihalo-5-alkoxy-pyrimidine in dimethylformamide dry ammonia gas at a temperature of approx. 80°C. When using liquid ammonia, it is advantageous to work at approx. room temperature and carries out the reaction in a closed vessel, suitably in a shaking autoclave. The 4-amino-5-alkoxy-6-halo-pyrimidine thus obtained can easily be transferred to the corresponding 4-amino-5,6-dialkoxy-pyrimidine by reaction with an alkali alcoholate. This reaction is conveniently carried out at the boiling temperature of the reaction mixture. The reaction can also be carried out in a closed vessel at temperatures above 100°C, e.g. at approx. 110-140°C.

For separation of the pyrimidines of the formula I obtained as end products from aqueous-alkaline solutions, it has proved particularly appropriate to partially neutralize the alkaline solution first with concentrated mineral acid, e.g. with hydrochloric acid, and then in the still phenol-phthale-inalkaline solution introduce carbon dioxide to a pH of 6-7.

The sulfonamides of the formula I obtainable according to the method according to the invention can be transferred both with strong acids, such as hydrochloric or sulfuric acid, and with bases, such as alkali hydroxides, carbonates or bicarbonates, in salts.

The process products prove to be highly active against infections from the various pathogens, such as Staphylococci, Pneumococci, E. coli and Salmonella. They are distinguished by a long-lasting effect. A chemotherapeutically particularly effective compound of the compound group obtained according to the invention is 4-sulfanilamido-5,6-dimethoxy-pyrimidine. This is far superior to the known 4-sulfanilamido-2,6-dimethoxy-pyrimidine, as in Staphylococcal Nephritis in rats and in Pneumococcal Sepsis in mice it is approx. 2 times, in case of Coli-Sepsis on mice approx. 3 times and in the case of mouse typhus approx. 7 times more effective (assessed according to CDf)0 mg/kg, i.e. the curative dose, which suppresses the induced infection in half of the animals).

In Example 1.

a) 4- sulfanilamido- 5- methoxy- 6- chloro-pyrimidtn.

42.7 g of sodium sulfanilamide (0.22 mol) are introduced in small portions into 140 ml of absolute dimethylformamide. The resulting porridge is heated with stirring to 95°C. 19.7 g (0.11 mol) of 4,6-dichloro-5-methoxy-pyrimidine are then stirred in portionwise. The rapidly occurring reaction is exothermic. It is ensured that the temperature in the reaction mixture remains at 90-100°C. After the addition of the pyrimidine compound is finished, it is kept for a further 5 minutes with stirring at 90°C. 3 hours of heating on the boiling water bath while excluding moisture makes the turnover complete. After this time, the solvent distilled off as completely as possible in vacuum leaves a brownish, crystallized residue, which, when triturated with 60 ml of water, dissolves for the most part. The main quantity of the sulfanilamide added in excess separates after a short time and is sieved, washed with a little water and dried.

The brownish colored filtrate is acidified with glacial acetic acid to pH 6, whereupon the 4-sulfanilamido-5-methoxy-6-chloro-pyrimidine precipitates as tough honey. Decanting and shaking the precipitate with a little aqueous alcohol quickly leads to crystallization. Yield: 29.1 g (84 per cent of the theoretical); melting point: 189—198°C. For cleaning, dissolve 15 g of this product in 250 ml of glacial acetic acid/water (1:1) under heating, add 5 g of animal charcoal and leave for 10 minutes in a hot water bath. After rapid filtration, 4-sulfanilamido-5-methoxy-6-chloropyrimidine crystallizes out in completely colorless small leaves.

The material that crystallizes in leaves is a labile modification, which during partial melting at 190°C turns into prisms and needles. These melt at 198-202°C during decomposition. A sample (melting point: 200-202°C) recrystallized once again from ethanol/water (1:1) is analyzed after drying at 110°C 0.5 mm.

The completely white 4-sulfanilamido-5-methoxy-6-chloro-pyrimidine is slightly soluble in water and ether, somewhat soluble in hot water, but soluble in alcohol and acetone. In alkalis, as well as soda and bicarbonate solution, the compound is soluble during salt formation, the same applies in strong mineral acids.

The 4,6-dichloro-5-methoxy-pyrimidine used as starting material can be obtained in the following way: 16.1 g of formamidine hydrochloride (0.2 mol) are introduced into an ice-cooled solution of 13.8 g of sodium (0 .6 gram atom) in 200 ml of absolute methanol. After addition of 32.4 g of methoxymalonic acid dimethyl ester (0.2 mol), the mixture is left to itself under the exclusion of moisture for half an hour in an ice bath and a further 48 hours at room temperature, whereby abundant sodium salt of 4,6-dihydroxy-5- methoxy-pyrimidine separates as a white, coarse crystal. After this time, the mixture is filtered off, the filtrate is brought to dryness in a vacuum and the crystallisate and the evaporation residue are washed with ether and dried at 110°C.

The finely powdered material is introduced

under ice-cooling in small portions in 170 ml of phosphorus oxychloride, whereby a vigorous reaction takes place under strong heating of the mixture. After adding 15 ml of dimethylaniline, it is heated for 1 hour below

reflux, whereby the majority of the solid material dissolves. The main amount of the excess phosphorus oxychloride is then distilled off in a vacuum and the remainder is poured with stirring onto 200 g of ice. The 4,6-dichloro-5-methoxy-pyrimidine separates

after a short time in the form of small reddish colored needles and is sucked off from the strongly acidic, aqueous phase (pH=l) by shaking with ether. The combined organic phases are washed acid-free with bicarbonate, dried and concentrated at 40-50°C bath temperature. 28.9 g of 4,6-dichloro-5-methoxy-pyrimidine are thus obtained. This is sufficiently clean for further processing. Melting point 53-58° C, sublimation from 40° C, yield 81 per cent of the theoretical. Sublimation at 60-80°C air bath temperature/0.5 mm gives analytical purity. white material with melting point 57-58°C.

The compound is hardly soluble in

hot or cold water, however soluble in lower alcohols, vinegar, ether, benzol and petroleum ether. At room temperature, it is considerably volatile and produces a strong irritating effect upon prolonged contact with the skin and eyes. b) 4-sulfanilamido-5,6-dimethoxy-pyrimidine.

15.75 g of pure 4-sulfanilamido-5-methoxy-6-chloro-pyrimidine (0.05 mol) are introduced into a solution of 5.75 g of sodium (0.25 gram atoms) in 100 ml of absolute methanol and heated in a autoclave 4 hours at 125°C. After cooling, the solvent is sucked off under vacuum and the evaporation residue is taken up in 50 ml of water. After treatment with animal charcoal, a clear yellow filtrate is obtained, like wood

acidification with glacial acetic acid separates from amorphous 4-sulfanilamido - 5,6 - dimethoxy - pyrimidine. The latter quickly becomes crystalline when torn. After filtration and drying in vacuum, an almost colorless product is obtained. Melting point: 182-190°C.

For cleaning, this product is placed in a warm solution for approx. 150 ml glacial acetic acid/water, treated with animal charcoal, filtered quickly and the solution left for crystallization. 10.6 g of pure, white 4-sulfanilamido-5,6-dimethoxy-pyrimidine are obtained, melting point 190-194°C. (Yield: 78.2 per cent of the theoretical).

The pure white compound is slightly soluble in cold water and ether. It is somewhat soluble in alcohol, better in acetone. In alkalis, as well as in soda and bicarbonate solution, it dissolves during salt formation, likewise in stronger mineral acids.

Example 2.

a) 4-(N-acetylsulfanilamido)-5-methoxy-6-chloropyrimidine.

2.36 g of N4-acetylsulfanilamide sodium (0.01 mol) are stirred with 7 ml of absolute dimethylformamide to form a slurry. After heating to 95 °C, 0.895 g of 4,6-dichloro-5-methoxy-pyrimidine (0.005 mol) are introduced in portions while stirring and the temperature in the reaction mixture is kept between 90 and

100°C, 5 minutes after the end of the addition, the thin-flowing resulting mixture is heated to the exclusion of moisture for 1 hour on the boiling water bath, whereby the majority of the solid material dissolves. The solvent, which has been completely distilled off in vacuum after this time, leaves a syrupy brown residue; triturated with a little water, this residue separates most of the N4-acetyl-sulfanilamide added in excess as a colorless crystal. This is removed by filtration.

The filtrate is brought to pH 5 with 50% acetic acid, whereby 4-(N4-acetylsulfanyl-amido)-5-methoxy-6-chloro-pyrimidine separates as a tough, quickly crystallizing gummy substance on tearing. The de-nutsed, slightly yellowish product weighs after drying in vacuum 1.65 g (92.5 per cent of the theoretical). Recrystallization from methanol under addition of carbon leads to a pure white product, which melts at 210-212°C (189°C conversion).

The pure white, odorless compound is very slightly soluble in water and alcohol; soluble in alkalis and soda solution. b) 4-sulfanilamido-5,6-dimethoxy-pyrimidine.

0.35 g of sodium (approx. 0.015 gram atoms) is dissolved in 8 ml of absolute methanol and 1.07 g of crude 4-(N4-acetylsulfanilamido)-5-methoxy-6-chloro-pyrimidine (0.003 mol) is introduced. The addition is kept at 115-125°C for 3 hours in a glass autoclave and the evaporation residue obtained after this time by distilling off the solvent is taken up in 10 ml of water, which after treatment with animal charcoal in a boiling water bath is filtered and acidified with 50 per cent.' s acetic acid; whereby 4-sulfanilamido-5,6-dimethoxy-pyrimidine differs from in amorphous form. Decantation and digestion with a little aqueous alcohol quickly lead to crystallization. After an hour's rest in a refrigerator, the collected raw material, vacuum dried, weighs 760 mg (82.5 per cent of the theoretical). Melting point 172-187°C.

The compound soluble in mineral acids melts after 2 recrystallizations from methanol/water (4:1) with the addition of animal charcoal at 192-194°C (corr.).

Example 3.

4-sulfanthlamido-5-methoxy-6-allyloxy-pyrimidine.

31.4 g of 4-sulfanilamido-5-methoxy-6-chloro-pyrimidine are introduced into a solution of 5.75 g of sodium in 200 ml of allyl alcohol. After 3 hours of boiling, the allyl alcohol is distilled off, the residue is dissolved in 150 ml of water and concentrated hydrochloric acid is added while adding ice, until a practically clear solution* is obtained. After treatment with animal charcoal and filtration, the solution is slowly adjusted with ammonia to pH 6 and the crystal lysate is sieved, washed with water and dried. The 4-sulfanilamido-5-methoxy-6-allyloxy-pyrimidine obtained melts at 145° C. (from butyl acetate).

Example 4.

a) 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine. 1 1030 g of dimethylformamide are introduced into 320 g of dry sulfanilamide sodium over the course of a short hour. The mixture is stirred intensively for one hour at 100°C. 160 g of 4,6-dichloro-5-ethoxy-pyrimidine are then introduced so that the temperature is maintained at 100 °C. The reaction mixture is stirred for a further 3 hours at 100°C and freed as completely as possible at 65°C bath temperature from di methylformamide in vacuo. The residue is dissolved in 600 ml of water at 40 °C and the solution is adjusted to pH 7.1 with approx. 45 ml 1 N hydrochloric acid. After standing for 2 hours at 0-5° C, the excess of sulfanilamide crystallizes out. This is filtered off, the light yellow filtrate is added to 300 ml of ethyl alcohol and adjusted to pH=5 with glacial acetic acid. This gives 217 g of 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine with a melting point of 215-216° C (from dimethylformamide/water). b). 4- sulfanilamido- 5- ethoxy- 6- methoxy-pyrimidine. 40 g of 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine are introduced into a solution of 6.9 g of sodium in 300 ml of methanol. The reaction mixture is boiled for 3 hours under reflux. Then 250 ml of methanol is distilled from. The remaining solution is boiled for a further 18 hours under reflux. After evaporation, the residue is dissolved in 200 ml of water and 130 ml of concentrated hydrochloric acid, filtered with animal charcoal and adjusted to pH=5-6 with ammonia. This gives 26 g of 4-sulfanilamido-5-ethoxy-6-methoxy-pyrimidine with a melting point of 224-227°C. After recrystallization from acetonitrile, the melting point is 228-229°C.

Example 5.

4- sulfanilamido- 5, 6- diethoxy- pyrimidine. 40 g of 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine is reacted, as described above, with 6.9 g of sodium in 300 ml of absolute ethanol to form 4-sulfanilamido-5,6-diethoxy-pyrimidine. Melting point: 173-174°C (from dimethylformamide/water).

Example 6.

4- sulfanilamido- 5- ethoxy- 6- allyloxy-pyrimidine.

40 g of 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine is boiled with a solution of 6.9 g of sodium in 300 ml of allyl alcohol for 4 hours. After 200 ml of allyl alcohol has been distilled off, the remaining reaction mixture is boiled for a further 5 hours, then the allyl alcohol is distilled off and the residue is dissolved in 190 ml of water and 130 ml of concentrated hydrochloric acid. The acidic solution is treated with animal charcoal, filtered, the filtrate is adjusted to pH 5 with 160 ml of concentrated caustic soda under distillation and extracted with acetic acid ethyl ester. The acetate solution is dried, evaporated in vacuo and the residue is suspended in 300 ml of water. After adding approx. 60 ml of 3 N caustic soda, the solution is treated with animal charcoal, filtered and neutralized with C02 gas. The crystalline precipitate 4-sulfanilamido-5-ethoxy-6-allyloxypyrimidine melts at 151-152°C. After redissolution from butyl acetate, the melting point is 152°C. Yield 24 g.

Example 7.

4- sulfanilamido- 5- ethoxy- 6- n- propoxy- pyrimidine. 40 g of 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine is converted, as described above, with 6.9 g of sodium in 300 ml of n-propanol to 4-sulfanilamido-5-ethoxy-6-n-propoxy-pyrimidine. Yield: 22 g; melting point 162°C (from butyl acetate).

Example 8.

4- sulfanilamido- 5- ethoxy- 6- isopropoxy-pyrimidine.

By reacting 4-sulfanilamido-5-ethoxy-6-chloro-pyrimidine with a solution of sodium in isopropanol in the manner described above, 33 g of crude 4-sulfanilamido-5-ethoxy-6-isopropoxy-pyrimidine are obtained with a melting point of 178-182°C.

Example 9.

a) 4-(N4- acetylsulfanilamido)- 5, 6- dimethoxypyrimidine. In a three-necked flask with a stirrer, thermometer and chlorcalcium tube, 62 g of 4-amino-5,6-dimethoxy-pyrimidine are dissolved in 160 ml of absolute pyridine and 130 g of p-acetaminobenzene sulfochloride are introduced into the solution over the course of 3 hours under ice-cooling on such way that the reaction temperature does not exceed 2-3°C. The solution is stirred for 16 hours at 1-2°C and then 350 g of ice is added under ice-cooling, whereby the temperature rises to approx. 9°C. It is then distilled off in a vacuum at 40°C bath temperature approx. 250 ml pyridine-water mixture, whereby crystallization follows. The crystal slurry is added once more to 200 ml of water and 150 ml of this is distilled off to remove as much pyridine as possible. The rest is then scraped off and washed with ice water. The yield of crude 4-(N4-acetyl-sulfanilamido)-5,6-dimethoxy-pyrimidine with melting point 216-224°C is 126 g (90 per cent of the theoretical). When redissolved from glacial acetic acid, the melting point rises to 230-231°C. 4-(N4-acetyl-sulfanilamido)-5,6-dimethoxy-pyrimidine can also be obtained from the same starting compounds as follows: 1 g of 4-amino-5,6-dimethoxy-pyrimidine (6.45 mmol) and 1, 55 g of p-acetaminobenzene sulfochloride (6.6 mmol), dissolved in 6 ml of absolute pyridine, is heated for one and a half hours while excluding moisture on the boiling water bath. After normal work-up, 730 mg of crude 4-(N4-acetylsulfanilamido)-5,6-dimethoxy-pyrimidine is obtained. After two recrystallizations from glacial acetic acid/water (1:1) with the addition of animal charcoal, an almost pure white product with a melting point of 217-222°C is obtained. The compound is soluble in dilute lye. b) 4-sulfanilamido-5,6-dimethoxy-pyrimidine.

In a three-necked flask with a stirrer and thermometer, 126 g of crude 4-(N4-acetyl-sulfanilamido)-5,6-dimethoxy-pyrimidine are stirred in 1155 ml of 2 N caustic soda for one and a half hours at 83-85°C. The clear solution is cooled with ice and 130 ml of ice-cold concentrated hydrochloric acid is added, so that the temperature does not exceed 25°C and the solution still reacts clearly phenolphthalein-alkaline. The solution is stirred with animal charcoal and then filtered. The clear, almost colorless filtrate is neutralized under ice-cooling by the introduction of carbon dioxide, whereby the excretion of crystallized 4-sulfanilamido-5,6-dimethoxy-pyrimidine quickly begins. The introduction of carbon dioxide is continued until the solution shows pH=7. The white precipitate is filtered off, washed with water and dried in a vacuum at 40°C. 101 g (91 per cent of the theoretical) of pure 4-sulfanilamido-5,6-dimethoxy-pyrimidine with a melting point of 201-202°C are thus obtained.

Example 10.

a) . Bis-(acetaminobenzenesulfonyl)-4-amino-5,6-dimethoxy-pyrimidine.

A suspension of 1.55 g (10 mmol) of 4-amino-5,6-dimethoxy-pyrimidine and 4.7 g of p-acetamino-benzenesulfochloride (20.0 mmol) in 10 ml of dry methylene chloride is heated with stirring to reflux. To this suspension is added 7 ml of a 20% solution of trimethylamine in absolute benzene. After five hours of heating under reflux and stirring, the mixture is evaporated under vacuum. 2.94 g (53.5 percent of the theoretical) of crude bis-(acetamino-benzenesulfonyl)-4-amino-5,6-dimethoxy-pyrimidine are thus obtained. The compound begins to decompose from 195°C during yellowing, without melting through before 230°C. The compound is insoluble in cold dilute lye. b) 4-sulfanilamido-5,6-dimethoxy-pyrimidine.

2.94 g of the thus obtained crude bis-(acetaminobenzenesulfonyl)-4-amino-5,6-dimethoxy-pyrimidine are suspended in 20 ml of 10% caustic soda and heated under reflux. After an hour and a half animal charcoal is added, the solution is filtered hot and the cooled filtrate is acidified to pH=5 with glacial acetic acid. 1.01 g (61 percent of the theoretical) of 4-sulfanilamido-5,6-dimethoxy-pyrimidine with a melting point of 195-198°C is thus obtained.

Example 11.

a) 4-( N 4- acetyl- sulf anilamido)- 5- methoxy- 6- ethoxy- pyrimidine.

To 40 g of 4-amino-5-methoxy-6-ethoxy-pyrimidine in 200 ml of absolute pyridine, 77 g of p-acetaminobenzene sulphochloride are added at 3-4°C over the course of 2 hours. The reaction mixture is stirred overnight at the same temperature. The reaction solution is then added to 200 g of fine ice and then evaporated in a vacuum at 40 °C bath temperature. After adding approx. 100 ml of water is added to the crystallisate, washed with water and recrystallized from glacial acetic acid. 69 g of 4-(N4-acetyl-sulfanilamido)-5-methoxy-6-ethoxy-pyrimidine with a melting point of 201-202°C are thus obtained. b) 4-sulfanilamido-5-methoxy-6-ethoxy-pyrimidine. 60 g of 4-(N4-acetyl-sulfanilamido)-5-methoxy-6-ethoxy-pyrimidine are heated in 600 ml of 2 N caustic soda for 12 hours at 85-90°C. The cooled to 25°C solution is made phenolphthalein-alkaline with concentrated hydrochloric acid, treated with animal charcoal, filtered and adjusted to pH=6 with CO2 gas. In this case, 4-sulfanilamido-5-methoxy-6-ethoxy-pyrimidine crystallizes out. The yield is 48 g (90 per cent of the theoretical). Melting point 170-171°C (from dimethylformamide/water).

Example 12.

a) 4- ( N4- acetyl- sulphanilamido) - 5- methoxy - 6- n- propoxy- pyrimidine.

To 20 g of 4-amino-5-methoxy-6-n-propoxy-pyrimidine in 100 ml of absolute pyridine, 38.5 g of p-acetamino-benzene sulphochloride are added at 3-4°C over the course of 2 hours. The reaction mixture is stirred overnight at the same temperature. After the usual work-up, 38 is obtained 4-(N4-acetyl-sulfanilamido)-5-methoxy-6-n-propoxy-pyrimidine with melting point 186-187°C (from glacial acetic acid). b) 4-sulfanilamido-5-methoxy-6-n-propoxy-pyrimidine. 35 g of 4-(N4-acetyl-sulfanilamido)-5-methoxy-6-n-propoxy-pyrimidine is heated in 350 ml of 2 N caustic soda for 1 and 2 hours at 85-90°C. After cooling, the solution is made phenolphthalein-alkaline with concentrated hydrochloric acid, treated with animal charcoal, filtered and adjusted to pH=6 with CO2 gas. 28 g (88 per cent of the theoretical) of 4-sulfanilamido-6-methoxy-6-n-propoxy-pyrimidine with a melting point of 142-143°C (from acetonitrile) are thus obtained.

Example 13.

a) 4-( N 4- acetyl- sulf anilamido)- methoxy- 6- isopropoxy- pyrimidine. 20 g of 4-amino-5-methoxy-6-isopropoxy-pyrimidine in 100 ml of absolute pyridine is reacted, as described above, with 38.5 g of p-acetamino-benzenesulfochloride to 4-(N4-acetyl-sulfanilamido)-5-methoxy - 6 -isopropoxy-pyrimidine. Yield: 37 g. Melting point 195-197°C (from glacial acetic acid). b) 4-sulfanilamido-5-methoxy-6-isopropoxy-pyrimidine. 34 g of 4-(N4-acetyl-sulfanilamido)-5-methoxy-6-isopropoxy-pyrimidine are saponified, as described above, to 4-sulfanilamido-5-methoxy-6-isopropoxy-pyrimidine. Yield: 27 g. Melting point 136-137°C (from acetonitrile).

Claims (3)

1. Process for the preparation of therapeutically effective sulfonamides with the following general formula: in which Ri and R2 mean lower alkyl or alkenyl residues, as well as salts of such sulfonamides, characterized by (a) condensing a pyrimidine with the general formula: in which R 1 means the same as above, and R 3 and R 4 stand for a halogen atom or an R 20 group, with an alkali salt of a benzenesulfonic acid amide, which in the para position exhibits a free or protected amino group, and then replaces a in condensation pro - the optionally present halogen atom is fused with an R20 group, as well as fragments of an optionally present protecting group, or that one (b) condenses a pyrimidine with the general formula: in which R2 and R3 have the same meaning as stated above, with a benzenesulfonhalide, which in the para-position exhibits a substituent convertible to the amino group, and after condensation, replaces any halogen atom present with an R20 group, as well as converting the para-substituent to the amino group, and, if desired, converts the obtained compounds into their salts in a manner known per se. 2. Method according to claim 1 (a), characterized in that the condensation of the pyrimidine component, preferably a 4,6-dihalogeno-5-alkoxy-pyrimidine, is carried out with an alkali salt of sulfanilamide or of N4-acylsulfanilamide in the presence of dimethylformamide at a temperature of between 80 and 120°C, in particular between 90 and 100°C. 3. Method according to claim 1 (b), characterized by carrying out the condensation of the pyrimidine component, preferably a 4-amino-5,6-dialkyloxy-pyrimidine, with the sulfohalide component of absolute pyridine while cooling, preferably at a temperature below 5°C.