DE1173100B - Process for the preparation of new 4-sulfanilamido-dialkoxypyrimidines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C07d

German KL: 12 ρ -7/01

Number: 1173 100

File number: H 43194IV d / 12 ρ

Filing date: July 21, 1961

Opening day: July 2nd, 1964

The invention relates to a process for the preparation of new 4-sulfanilamido-dialkoxypyrimidines the general formula

R ¹ O

OR ²

H-N-

- SOONH

N-

wherein R ¹ and R ^{2 are} low molecular weight alkyl or alkenyl radicals, in particular those with up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, hexyl and allyl groups, and salts of such sulfonamides.

The process is characterized in that either (a) a pyrimidine is used in a manner known per se the general formula

R ¹ O

R ⁴ -

R ³

II

Method of making new
4-sulfanilamido-dialkoxypyrimidineii

Applicant:

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr. G. Schmitt, lawyer,

Loerrach (Bad.), Friedrichstr. 3

Named as inventor:

Dr. Hermann Bretschneider,

Wilhelm Richter, Innsbruck (Austria)

Claimed priority:
Switzerland of 9 August 1960 (8994),
dated March 17, 1961 (3267)

wherein R ^{3 is} an R ² O group or a halogen atom, e.g. B. a chlorine, bromine or iodine atom, and R ^{4 is} a halogen atom, in particular a chlorine atom, is condensed with an alkali salt of a benzenesulfonic acid amide which has a free or protected amino group in the p-position, e.g. B. an acylamino or carbalkoxyamino group, and the halogen atom which may be present in the condensation product is replaced by an R ² O group and the protective group which may be present is split off or (b) a pyrimidine of the general formula

R ¹ O

HoN-

N--

OR ²

III

condensed with a benzenesulfohalide, which can be converted into an amino group in the p-position Has substituents and the p-substituents of the condensation product, if necessary Cleavage of bis-benzenesulfonyl compounds too Monobenzenesulfonyl compounds, into the amino group converts.

According to a preferred embodiment of process variant (a), the starting material used is pyrimidines of the general formula II in which R ^{3 is} a halogen atom, in particular a chlorine atom,

z. B. 4,6-dichloro-5-methoxypyrimidine, 4,6-dichloro-5-ethoxypyrimidine or 4,6-dichloro-5-n-propoxypyrimidine. This 4,6-dihalo-5-alkoxypyrimidines is condensed, for example with Sulfanilamidnatrium, N ₄ -Acetylsulfanilamid sodium or ₄ N sodium -Carbäthoxysulfanilamid. The corresponding 4-sulfanilamido-5-alkoxy-6-halopyrimidines or their N ₄ -acyl derivatives are obtained as the condensation product. The condensation reaction is conveniently carried out in the presence of a solvent or diluent such as dimethylformamide, at temperatures between 80 and 12O ⁰ C, particularly at about 90 to 100 ⁰ C.

In a second stage, the halogen atom in the 6-position of the condensation product obtained is replaced by an R ² O-ReSt, in particular by a methoxy, ethoxy, n-propoxy, isopropoxy or allyloxy group. For this purpose, the condensation product obtained is heated with an alkali metal alcoholate of the corresponding alcohol, e.g. B. with a methanolic solution of sodium methylate, to reflux. The reaction with the alkali metal alcoholate can also be carried out under pressure at higher temperatures, for example at about 120 to 130.degree. _{Any N 4} acyl group present in the condensation product can be present

409 628/312

or after the alcoholysis operation easily by heating the N ₄ acyl compound with dilute acids or alkalis, e.g. B. with dilute sodium hydroxide solution, are split off. If the alcoholysis reaction is carried out under pressure at higher temperatures, any N ₄ acyl group which may be present is generally split off at the same time.

The 4,6-dihalo-5-alkoxypyrimidines which are particularly preferred as starting materials for process variant (a) can e.g. B. can be obtained as follows:

A methyl alkoxyacetate is made using dimethyl carbonate converted into the corresponding dimethyl alkoxymalonate and this ester with ammonia into the corresponding alkoxymalone

4,6-dihydroxy-5-alkoxypyrimidine cyclized, from which by halogenation with a phosphorus oxyhalide, z. B. with phosphorus oxychloride, the 4,6-dihalo-5-alkoxypyrimidine can be obtained.

The 4-halo-5,6-dialkoxypyrimidines which can also be used as starting materials for process variant (a) can be from the just mentioned 4,6-dihalo-5-alkoxypyrimidines by replacing one

one z. B. easily win from the above-mentioned 4,6-dihalo-5-alkoxypyrimidines by reaction with ammonia and then with an alkali metal alcoholate. The ammonia can be used in the form of a solution in an organic solvent or, expediently, in undiluted, liquid form. So you can z. B. in a solution of 4,6-dihalo-5-alkoxypyrimidine in dimethylformamide at a temperature of about 8O ⁰ C ίο anhydrous ammonia gas. When using liquid ammonia, it is advantageous to work at about room temperature and to carry out the reaction in a closed vessel, expediently in a shaking autoclave. The 4-amino acid diamide thus obtained is converted. This diamide is easily converted into the corresponding 4-amino-5,6-dialkoxypyrimidine by reacting formamide in the presence of sodium ethylate with an alkali metal alcoholate by means of 5-alkoxy-6-halo-pyrimidine. This reaction is expediently carried out at the boiling point of the reaction mixture. The reaction can also be carried out in a closed vessel at temperatures above 100 ^° C., e.g. B. at about 110 to 140 ° C can be made.

For the deposition of the pyrimidines of the general formula I obtained as end products from aqueous of the two halogen atoms obtained by alkoxy. 25 alkaline solutions, it has been found to be particularly useful - the replacement of the halogen atoms by alkoxy - moderately, the alkaline solution initially with groups can be converted by reacting the halopyrimidine with the corresponding alkali metal alcoholate,
z. B. with sodium methylate, ethylate, n-propylate or

isopropylate, optionally using 30 from 6 to 7. Pressure, accomplish. The sulfonamides obtainable according to the process of

For process variant (b), the starting materials are used of the general formula III z. B. 4-Amino-5,6-dimethoxypyrimidine, 4-Amino ~ 5-methoxy-6-eth-

oxypyrimidine or 4-amino-5-ethoxy-6-methoxypyr- 35 bicarbonates, converted into salts, imidine. Examples of p-substituents from benzene - The products of the process prove to be effective against

sulfohalide are the acylamino, in particular tion of the most diverse pathogens, such as staphylococci, Acetylamino, carbalkoxyamino, such as carbethoxy pneumococci, E. coli and Salmonella, as high amino, carbobenzyloxyamino and nitro groups. active. They are also characterized by long-lasting These p-substituents can take effect after the condensation has taken place. You can use as a remedy z. Am sation in a manner known per se by hydrolysis form of pharmaceutical preparations use or reduction into the free amino group.

leads to be. Compared to the Austrian patent

For the condensation reaction, the usual font 175 895 known 4-SulfaniIamido-2,6-dimeth-Kondensationstionsmittel can be used, z. B. 45 oxypyrimidine (II) is the anhydrous pyridine obtained according to the process or a benzene solution of 4-sulfanilamido-5,6-dimethoxypyrimidine (I) in more of trimethylamine. superior in multiple respects. Judged according to the CD ₅₀ -

Depending on the amount of benzenesulfo- value Gene curative dose in mg / kg, which is at half halids can suppress condensation products with one of the animals which set infection) is that or two benzenesulfonyl radicals are obtained. 50 4-sulfanilamido-5,6-dimethoxypyrimidine at Sta-Works equimolar amounts of pyrimidine phylococcal nephritis in rats and in pneumo- and sulfohalide component, main coccal sepsis in the mouse is obtained about twice, in the mainly monobenzenesulfonyl compounds; coli sepsis is about three times in mice and that in mice However, the molar ratio is 1: 2, so in typhoid fever is about seven times more effective than the vorbe coupling product the bis-benzenesulfonyl compound knew 4-sulfanilamido-2,6-dimethoxypyrimidine (cf. gen.Table I).

The condensation of the aminopyrimidine compound The toxicity of the obtained according to the method

with the sulfohalide component, both 4-sulfanilamido-5,6-dimethoxypyrimidines are as low as temperatures down to low as those of the previously known 4-sulfanil to the boiling point of the reaction mixture, 60 amido-2,6-dimethoxypyrimidine. Both will combine. When using p-acetaminophen, the DL ₅₀ (mouse, po) is over 20 g / kg, benzene sulfochloride as the sulfohalide component and compared to the same previously known sulfonamide

of pyridine as solvent, it has been found particularly sulfanilamido-4-5-äthvorteilhaft proven to be the method according obtained at low temperatures, oxy-6-allyloxypyrimidin (III) superior in that preferably at temperatures below ezwa 5 ⁰ C, 65 in infections with Salmonella typhimurium to work on. Mouse shows the same effect as the double

The starting dose of the previously known comparison substance (cf. 4-Amino-5,6-dialkoxypyrimidines can be found in Table II).

concentrated mineral acids, e.g. B. with hydrochloric acid, and then to the still phenolphthalein alkaline Solution carbon dioxide up to a pn value

General formula I can be used both with stronger acids, such as hydrochloric acid or sulfuric acid, as well with bases such as alkali hydroxides, carbonates or

Table I.

infection

Pneumococcal Sepsis (Mouse)

Staph nephritis (rat)

Coli sepsis (mouse)

S. typhimurium (mouse)

S.typhosa P 58 a (mouse)

S. schottmuelleri (mouse)

CD ₅₀ , mg / kg *) compound

I: II

31.25

3.3 2.75 99.0 1.4 9.4

70.5

10.2

696.0

15.2

67.8

*) Calculation according to Reed and Muench (J. Am. Hyg. ' Vol. 27, 1938, p. 493). The experiments were carried out according to the methods of B. Fust, E. Böhni, G. Zb in den and A. S tüder (HeIv. Med. Acta, Vol. 23, 1956, p. 714) and B. Fust,

Table II

Effect against

Infections with

Salmonella typhimurium in the mouse

Compound III
Compound II.

Dose six times mg / kg; per os

250 500

For the process for the preparation of the compounds used as starting materials of the general In the context of the invention, no protection is sought for formulas II and III.

example

a) 4-sulfanilamido-5-methoxy-6-chloropyrimidine 42.7 g of sulfanilamide sodium (0.22 mol) are in

rapid filtration crystallizes 4-sulfanilamido-5-methoxy-6-chloropyrimidine in completely colorless leaflets.

The crystallizing in the form of leaflets Material> is a labile modification, which merges with partial melting at 19O ⁰ C in prisms and needles. These melt at 198 to 202 ^° C. with decomposition. A still from ethanol-water (1: 1) sample recrystallized (melting point: 200-202 ° C) is ίο after drying at 11O ⁰ C under a pressure of 0.5 mm of analytical purity.

The pure white 4-sulfanilamido-5-methoxy-6-phlorpyrimidine is sparingly soluble in water and ether, somewhat soluble in hot water but soluble in alcohol and acetone. In alkalis as well as soda and bicarbonate solutions it is soluble with salt formation, likewise in stronger mineral acids.

The new 4,6-dichloro-5-methoxypyrimidine used as starting material can be obtained as follows: 16.1 g of formaemidine hydrochloride (0.2 mol) are in an ice-cold solution of 13.8 g sodium (0.6 gram atoms) in 200 ml absolute methanol

registered. After adding 32.4 g of methoxymalone

acid dimethyl ester (0.2MoI) the mixture remains effect, ° / " ₂₅ under exclusion of moisture V ₂ hours in an ice bath and a further 48 hours at room temperature left to itself, with plenty of sodium salt of 4,6-dihydroxy-5-methoxypyrimidine as a white, coarse crystals separate. After this time, 30 is suction filtered, the filtrate brought to dryness in vacuo and washed with ether and crystallized together with the evaporation residue at HO ⁰ C dried.

The finely powdered material is cooled with ice in small portions in 170 ml of phosphorus oxychloride entered, a violent reaction taking place with strong heating of the mixture. After addition 15 ml of dimethylaniline are refluxed for 1 hour heated, with most of the solid material going into solution. The bulk of the excess

8th day

35 39

Small proportions in 140 ml of absolute dimethylform- 40 phosphorus oxychloride are then introduced in vacuo. The resulting slurry is distilled under and the residue is heated ^{to 95 ° C. with stirring to 200 g of stirring.} Then 19.7 g of ice are poured. The 4,6-dichloro-5-methoxypyrimidine (0.11 mol) 4,6-dichloro-5-methoxypyrimidine in portions separates out after a short time in the form of small reddish colors. The rapidly occurring reaction is colored needles and becomes the strongly acidic water exothermic. It will be ensured that the ring 45 loading phase extracted by shaking with ether in the reaction mixture temperature from 90 to 100 ⁰ C (pH = 1). The combined organic phases are carried. Washed free of acid after completion of the addition the Pyrimidinverbin- with bicarbonate, dried and fertilize is concentrated at 40 to 50 ⁰ C. bath temperature for a further 5 minutes while stirring at. 90 ^° C. is obtained. 3 hours of heating on the boiling point so 28.9 g of 4,6-dichloro-5-methoxypyrimidine. This water bath is completed with the exclusion of moisture and is sufficiently pure for further processing. The implementation melts away. The point after this time in the vacuum: 53 to 58 ⁰ C, sublimation from 40 ° C; Yield of solvents distilled off as completely as possible 81% of theory. Sublimation at a pressure a brownish crystalline residue leaves, of 0.5 mm of, triturated with 60 ml of water, in large part in Luftbads analytically pure, white material with solution gives proceeds at 60 to 8O ⁰ C temperature. The majority of the excess 55 melting point 57 to 58 ° C.

The sulfanilamide used separates after a short time. The compound is in water in the cold and in

Time off and is sucked off, hardly soluble with a little water in the heat, but soluble in lower wash and dry. Alcohols, ethyl acetate, ether, benzene and petroleum ether.

The brownish colored filtrate is diluted with glacial acetic acid. At room temperature it is considerably volatile and Ph 6 acidified, the 4-sulfanilamido-5-meth-60 exerts on skin and eyes when handled for a long time oxy-6-chloropyrimidine in a tough honey-like consistency has a strong irritant effect. fails. Decant and grind the precipitate with.

A little aqueous alcohol quickly leads to crystalline ^b -> 4-sulfanilamido-5,6-dimethoxypynmidm

sation. Yield: 29.1 g (84% of theory); Melting 15.75 g of pure 4-sulfanilamido-5-methoxy-6-chloro

point: 189 to 198 ^° C. For purification, 15 g of 65 pyrimidine (0.05 mol) are added to a solution of this product in 250 ml of glacial acetic acid-water (1: 1) 5.75 g of sodium (0.25 gram atom) dissolved in 100 ml absoin the heat, added 5 g animal charcoal and added pure methanol and left in the autoclave for 10 minutes in the hot water bath. Heated to 125 ^° C. after 4 hours. After cooling it will

the solvent is drawn off in vacuo and the residue from evaporation is taken up in 50 ml of water. After treatment with animal charcoal, a clear yellow filtrate is obtained, which when acidified with glacial acetic acid amorphous 4-sulfanilamido-5,6-dimethoxypyrimidine separates. The latter is done by rubbing quickly crystalline. After filtration and drying in vacuo, an almost colorless product is obtained. Melting point: 182 to 190 ° C.

To clean it, it is brought into solution in about 150 ml of glacial acetic acid-water (1: 1) in the heat, treated with animal charcoal, quickly filtered and the solution left to crystallize. 10.6 g of pure white 4-sulfanilamido-5,6-dimethoxypyrimidine, melting point: 190 to 194 ^° C. (yield: 78.2% of theory) are obtained.

The pure white compound is not very soluble in cold water and ether. It is soluble in something Alcohol, better in acetone. In alkalis as well as in soda and bicarbonate solution it dissolves with salt formation, likewise in stronger mineral acids.

Example 2

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

2.36 g of _{sodium N 4} -acetylsulfanilamide (0.01 mol) are mixed with 7 ml of anhydrous dimethylformamide to form a paste. After heating to 95 ⁰ C are added with stirring 0.895 g of 4,6-dichloro-5-methoxypyrimidine (0.005 mol) in portions and the temperature maintained in the reaction mixture between 90 and 100 ° C. 5 minutes after the addition has ended, the mixture, which has become thin, becomes fluid

c) 4-sulfanilamido-5,6-dimethoxypyrimidine

0.35 g of sodium (about 0.015 gram atom) are dissolved in 8 ml of absolute methanol and 1.07 g of crude 4- (N ₄ -acetylsulfanilamido) -5-methoxy-6-chloropyrimidine (0.003 mol) are added. The mixture is kept in the glass autoclave for 3 hours at 115 to 125 ⁰ C and after this time Evaporation obtained by distilling off the solvent residue in 10 ml of water was added. After treatment with animal charcoal in a boiling water bath, it is filtered and acidified with 50% acetic acid; 4-sulfanilamido-5,6-dimethoxypyrimidine separates out in amorphous form. Decanting and digesting with a little aqueous alcohol quickly leads to crystallization. The raw material collected after standing for one hour in the refrigerator weighs 760 mg (82.5% of theory) when vacuum-dried. Melting point 172 to 187 ⁰ C.

The compound, which is soluble in mineral acids, melts after being recrystallized twice from methanol. Water (4: 1) with the addition of animal charcoal at 192 to 194 ° C (corrected).

Example 3

4-sulfanilamido-5-methoxy-6-alyloxypyrimidine

31.4 g of 4-sulfanilamido-5-methoxy-6-chloropyrimidine are added to a solution of 5.75 g of sodium in 200 ml of allyl alcohol. After 3 hours of cooking the allyl alcohol is distilled off, the residue is dissolved in 150 ml of water and treated with concentrated hydrochloric acid added with the addition of ice until a practically clear solution is obtained. After treatment with animal charcoal and filtration, the solution is slowly

with exclusion of moisture for 1 hour on the boiling monia on Ph 6 and sucked the crystals,

40

heated the water bath, with most of the solid material going into solution. The solvent, which has been completely distilled off in vacuo after this time, leaves a syrupy brown residue; Rubbed with a little water, this separates most of the N ₄ -acetylsulfanilamide used in excess as colorless crystals. This is removed by filtration.

The filtrate is brought to pn 5 with 50% acetic acid, _{whereupon 4- (N 4} -acetylsulfanilamido) -S-methoxy-o-chloropyrimidine separates out as a viscous, rubbery substance which rapidly crystallizes when rubbed. The pale yellowish product filtered off with suction weighs 1.65 g (92.5% of theory) after drying in vacuo. Recrystallization from methanol with the addition of carbon leads to a pure white product melts at 210 to 212 ⁰ C (the conversion at 198 ° C).

The pure white, odorless compound is very sparingly soluble in water and alcohol; soluble in alkalis and soda solution.

b) 4-sulfanilamido-5-methoxy-6-chloropyrimidine washed with water and dried. The received 4 - sulfanilamido - 5 - methoxy - 6 - allyloxypyrimidine melts at 135 ° C (from butyl acetate).

Example 4

a) 4-sulfanilamido-5-ethoxy-6-chloropyrimidine

320 g of dry sodium sulfanilamide are introduced into 1030 g of dimethylformamide within half an hour. The mixture is stirred intensively ^{at 100 ° C. for 1 hour.} Then, 160 g of 4,6-dichloro-5-äthoxypyrimidin added so that the temperature remains at 100 ⁰ C. The reaction mixture is stirred for a further 3 hours at 100.degree. C. and then freed as completely as possible from dimethylformamide in vacuo at a bath temperature of 65.degree. The residue is ^{dissolved in 600 ml of water at 40 °} C. and the solution is adjusted to pH 7.1 with about 45 ml of 1η hydrochloric acid. After 2 hours of standing at 0 to 5 ⁰ C, the excess of sulfanilamide crystallizes out. This is suction filtered, the light yellow filtrate is mixed with 300 ml of ethyl alcohol and adjusted to pH 5 with glacial acetic acid. This gives 217 g of 4-sulfanilamido-5-ethoxy-6-chloropyrimidine with a melting point of 215 to 216 ° C (from

55

150 mg of 4- (N ₄ -acetylsulfanilamido) -5-methoxy-6-chloropyrimidine are dissolved in 10 ml of 0.5N sodium hydroxide solution (60 dimethylformamide water) and heated in a boiling water bath for _{2 hours.} When the solution, which has been treated with animal charcoal in the heat, is acidified with 50% acetic acid, 4-sulfanilamido-5-methoxy-6-chloropyrimidine precipitates, which, after standing for 1 hour in the refrigerator, is filtered off with suction, washed with water and dried in vacuo

will. Yield: 100 mg of raw material (75.8% of the Theory). Melting point 196 to 198 ° C with decomposition.

b) 4-sulfanilamido-5-ethoxy-6-methoxypyrimidine

40 g of 4-sulfanilamido-5-ethoxy-6-chloropyrimidine are in a solution of 6.9 g of sodium in 300 ml Methanol entered. The reaction mixture is refluxed for hours. Then 250ml Methanol is distilled off. The remaining solution is refluxed for a further 18 hours. To

Evaporation, the residue is dissolved in 200 ml of water and 130 ml of concentrated hydrochloric acid, with animal charcoal filtered and adjusted to pH 5 to 6 with ammonia. There are so 26 g of 4-sulfanuamido-5-ethoxy-6-methoxypyrirnidine obtained from melting point 224 to 227 ° C. After recrystallization from acetonitrile the melting point is 228 to 229 ° C.

Example 5

4-sulfanilamido-5,6-diethoxypyrimidine

40 g of 4-sulf anilamido-S-ethoxy-o-chloropyrimidine are, as described above, with 6.9 g of sodium in 300 ml of absolute ethanol to form 4-sulfanilamido-5,6-diethoxypyrimidine implemented. Melting point: 173 to 174 ° C (from dimethylformamide-water).

Example 6
4-sulfanilamido-5-ethoxy-6-allyloxypyrimidine

40 g of 4-sulfanilamido-5-ethoxy-6-chloropyrimidine are mixed with a solution of 6.9 g of sodium in 300 ml Allyl alcohol boiled for 4 hours. After distilling off 200 ml of allyl alcohol, the remaining Reaction mixture boiled for a further 5 hours, then the allyl alcohol is distilled off and the residue in 190 ml of water and 130 ml of concentrated hydrochloric acid dissolved. The acidic solution is treated with animal charcoal, nitrated, the filtrate with 160 ml of concentrated sodium hydroxide solution placed with the addition of ice to Ph 5 and extracted with ethyl acetate. The ethyl acetate solution will dried, evaporated in vacuo. and the residue suspended in 300 ml of water. After adding the solution is treated with animal charcoal from about 60 ml of 3 η sodium hydroxide solution, filtered and with carbon dioxide gas neutralized. The crystalline precipitating 4-sulf anilamido-5-ethoxy-6-allyloxypyrimidine Melts at 151 to 152 ° C. After redissolving from butyl acetate, the Melting point 152 ° C. Yield: 24 g.

Example 7
4-sulf anilamido-5-ethoxy-6-n-propoxypyrimidine

40 g of 4-sulf anilamido-S-ethoxy-o-chloropyrimidine are, as described above. with 6.9 g of sodium in 300 ml of n-propanol to form 4-sulfanilamido-5-ethoxy-6-n-propoxypyrimidine implemented. Yield: 22 g; Melting point 162 ° C (from butyl acetate).

Example 8
4-sulf anilamido-S-ethoxy-o-isopropoxypyrimidine

By reacting 4-sulfanilamido-5-ethoxy-6-chloropyrimidine with a solution of sodium in isopropanol in the manner described above 33 g of crude 4-sulfanilamido-5-ethoxy-6-isopropoxypyrimidine with a melting point of 178 bis are obtained 182 ° C. After redissolving from butyl acetate, the melting point is 181 to 183 ° C.

Example 9
a) 4-Amino-5-methoxy-6-chloropyrimidine

480 g of 4,6-dichloro-5-methoxypyrimidine and 1700 g of liquid ammonia are placed in a 5-1 shaking autoclave and the reaction mixture is shaken overnight at room temperature after applying nitrogen (20 atmospheres). The ammonia is then blown off, the solid residue is made into a paste with water, suction filtered and dissolved in 2η hydrochloric acid. The hydrochloric acid solution is treated with animal charcoal and then filtered. The filtrate is neutralized with soda solution. The 4-amino-5-methoxy-6-chloropyrimidine which separates out is filtered off with suction, washed and dried. Yield 351 g (82 ° / ₀ of theory). Melting point 176 to 178 ° C. In another approach using liquid ammonia

ίο, the yield is 92 ° / ₀ of theory of pure white product of melting point 179 to 181 ⁰ C.

4-Amino-5-methoxy-6-chloropyrimidine can also be obtained as follows: In a solution of 2.51 g 4,6-dichloro-5-methoxypyrimidine in 15 ml of absolute dimethylformamide is at 80 ° C. for 7 hours Bath temperature dry ammonia gas introduced. The ammonium chloride which has crystallized out is filtered off with suction and the filtrate evaporated at 60 ° C bath temperature. This gives 1.51 g (68% of theory) pure 4-amino-5-methoxy-6-chloropyrimidine with a melting point of 175 ° C. After recrystallization from

Ether-petroleum ether, the melting point of 178 to 18O ⁰ C.

4-Amino-5-methoxy-6-chloropyrirnidine is somewhat soluble in cold water; it is soluble in hot water. It is also soluble in lower alcohols, ethers and ethyl acetate. There is very little in petroleum ether soluble. In dilute mineral acids it dissolves with salt formation.

b) 4-amino-5,6-dimethoxypyrimidine

170 g of 4-amino-5-methoxy-6-chloropyrimidine are introduced into a solution of 29.4 g of sodium in 1070 ml of absolute methanol. The solution is refluxed for 18 hours. About 800 ml of methanol are then distilled off, after which the residue is boiled for a ^{further 1} l for _{2 hours.} The solvent is then completely removed in vacuo and the residue is treated with boiling ether. The remaining undissolved sodium chloride is dissolved in cold water and the aqueous solution is extracted with ether. The combined ethereal solutions are dried, treated with animal charcoal, filtered and then evaporated. The residue is dissolved in hot isopropyl ether. 155 g (94% of theory) of 4-amino-5,6-dimethoxypyrimidine with a melting point of 88 to 89 ° C. crystallize out of the solution.

4-Amino-5,6-dimethoxypyrimidine can by performing the methanolysis in a closed vessel can also be obtained as follows: In a solution of 0.1 g of sodium in 5 ml of absolute methanol 638 mg of crude 4-amino-5-methoxy-6-chloropyrirnidine were added. The mixture is in the autoclave during Heated for 4 hours to 120 to 130 ° C and then evaporated in vacuo. 440 mg (62% theory) pure white 4-amino-5,6-dimethoxypyrimidine with a melting point of 90 to 92 ° C (sublimation from 50 ° C). The twice sublimed product melts at 92 to 93 ° C.

4-Amino-5,6-dimethoxypyrimidine is readily soluble in water, as well as in alcohols, ethers and ethyl acetate. In dilute mineral acids it dissolves with salt formation.

c) 4- (N ₄ -acetylsulfanilamido) -5,6-dimethoxypyrimidine

62 g of 4-amino-5,6-dimethoxypyrimidine are placed in a three-necked flask equipped with a stirrer, thermometer and calcium chloride tube dissolved in 160 ml of absolute pyridine

409 628/312

11 12

and in the solution within 3 hours 130 g of theory) crude bis (acetaminobenzolsulfonyl) -4-amino-

p-acetaminobenzene sulfochloride so 5,6-dimethoxypyrimidine while cooling with ice. The connection begins

entered that the reaction temperature 2 to 3 ° C from 195 ° C to decompose with yellowing without up

does not exceed. The solution is durchzuschmelzen 23O ⁰ C for 16 hours. The connection is in

stirred at 1 to 2 ^° C. and then insoluble in the cold with 5 dilute alkalis while cooling with ice.
350 g of ice are added, the temperature increasing to about 9 ^° C.

increases. This is followed by distillation in vacuo at 40 ° C. t>) sulfanilamido-5,6-dimethoxypyrimidine
Bath temperature about 250 ml pyridine-water mixture

from, whereby crystallization occurs. The crystal slurry 2.94 g of the crude bis (acetaminobenzene-

is added again with 200 ml of water, and io sulfonyl) -4-amino-5,6-dimethoxypyrimidines are in

150 ml are distilled off, suspended as much as possible 20 ml of 10% sodium hydroxide solution and under

Remove pyridine. The residue is then heated to reflux. After 1 1 ¹ ₂ hours it becomes animal charcoal

sucked and washed with ice water. The yield was added, the solution was nitrated while warm and that cooled

on crude 4- (N ₄ -acetylsulfanilamido) -5,6-dimethoxy filtrate acidified to pH 5 with glacial acetic acid. You get so

pyrimidine with a melting point of 216 to 224 ^° C. is 1.10 g (61% of theory) of 4-sulfanilamido-5,6-di-

126 g (90% of theory). By dissolving methoxypyrimidine from glacial acetic acid with a melting point of 195 to 198 ^° C., the melting point rises to 230 to 23 ° C.

4- (N ₄ -Acetylsulfanilamido) -5,6-dimethoxypyrimidine Example 11

can also be obtained from the same starting compounds. ....

Obtained as follows: 1 g of 4-amino-5,6-dimethoxypyr-20 ^a ) 4-amino-5-methoxy-6-athoxypynm ₁ din

imidine (6.45 mmol) and 1.55 g of p-acetaminobenzene- 50 g of 4-amino-5-methoxy-6-chloropyrimidine

sulf chloride (6.6 mmol) dissolved in 6 ml of anhydrous in a solution of 9.4 g of sodium in 450 ml of absolute

Pyridine, are boiled for ₂ hours under moisture IV 18_Stunden ethyl alcohol under reflux,

exclusion heated on the boiling water bath. Then the ethyl alcohol is distilled off, the return

Customary work-up gives 730 mg of crude 25 standing in ether and the ether solution

4- (N ₄ -acetylsulfanilamido) -5,6-dimethoxypyrimidine. washed with water, dried with sodium sulfate

After two recrystallization from glacial acetic acid and evaporated. 43 g of 4-amino

Water (1: 1) with the addition of animal charcoal gives 5-methoxy-6-ethoxypyrimidine with a melting point of 64

an almost pure white product with a melting point of up to 65 ° C (from isopropyl ether).

217 to 222 ° C. The compound is in dilute 30

Soluble alkalis. b) 4- (N ₄ -acetylsulfanilamido) -5-methoxy-

6-ethoxypyrimidine
d) 4-sulfanilamido-5,6-dimethoxypyrimidine

To 40 g of 4-amino-5-methoxy-6-ethoxypyrimidine in

In a three-necked flask with a stirrer and thermo-35 200 ml of anhydrous pyridine at 3 to 4 ° C meters are 126 g of crude 4- (N ₄ -acetylsulfanilamido) - 77 g of p-acetaminobenzenesulfochloride within 5,6-dimethoxypyrimidine in 1155 ml of 2 N sodium hydroxide solution was added for 2 hours. The reaction mixture is stirred while I ¹ Z ₂ hours at 83 to 85 ⁰ C. Stirred the night at the same temperature. The clear solution is cooled with ice and 130 ml of action solution is then mixed with 200 g of fine ice of ice-cold concentrated hydrochloric acid, so that the bath temperature does not rise above 25 ° C ^{and then in vacuo at 40 0 C and the solution is evaporated.} After adding about 100 ml of water, the phenolphthalein reaction is still clearly alkaline. The crystals are sucked off, washed with water, the solution is stirred with animal charcoal and then filtered. and recrystallized from glacial acetic acid. Are thus obtained 69 g The clear, almost colorless filtrate is neutralized under ice-cooling ^ (N ^ Acetylsulfanilamido ^ S-rnethoxy-o-äthoxypyrimidurch introducing carbon dioxide to give 45 din of melting point 201-202 ⁰ C.
the deposition of crystallized 4-sulf-

anilamido-5,6-dimethoxypyrimidine is used. The one- _c) 4-sulfanilamido-5-methoxy-6-ethoxypyrimidine
Conduction of carbon dioxide continues until the

Solution shows a pH of 6 to 7. The white 60g4- (N ₄ -acetylsulfanilamido) -5-methoxy-6-ethoxy-

Precipitate is filtered off with suction, washed with water. 50 pyrimidine are dissolved in 600 ml of 2N _{sodium hydroxide solution for 1V for 2 hours}

and dried in vacuo at 4O ⁰ C. The heated at 85 to 90 ° C. is obtained in this way. The cooled to 25 ⁰ C.

101 g (91% of theory) of pure 4-sulfanilamido solution is phenolic with concentrated hydrochloric acid

5,6-dimethoxypyrimidine from melting point 201 to phthalein-alkaline, treated with animal charcoal,

202 ⁰ C. filtered and adjusted to Ph 6 with carbon dioxide gas.

55 4-sulfanilamido-5-methoxy-

Example 10 6-ethoxypyrimidine from. The yield is 48 g

a) Bis-iacetaminobenzenesulfonylH-amino- (90% of theory). Melting point: 170 to 171 ^° C

,,,. ,. .,. (from dimethylformamide-water).

5,6-dimetnoxypynmidine

A suspension of 1.55 g (10 mmol) of 4-amino-60 Example 12

5,6-dimethoxypyrimidine and 4.7 g of p-acetaminobenzene- ". . . , _r ....

sulfochloride (20.2 mmol) in 10 ml of anhydrous a) 4-Ammo-5-methoxy-6-n-propoxypynnudine

Methylene chloride will be refluxed with stirring 50 g of 4-amino-5-methoxy-6-chloropyrimidine

temperature heated. This suspension is 7 ml in a solution of 9.4 g of sodium in 600 ml of n-protein 20% solution of trimethylamine in ab- 65 panol refluxed for 18 hours. Then it will be added to solid benzene. After 5 hours of heating, the n-propanol is distilled off, _ the residue with the ether mixture is evaporated under reflux and stirring and the ether solution is added to water in a vacuum. This gives 2.94 g (53.5% of the washed, dried with sodium sulfate and

steamed. Are thus obtained 44 g of 4-amino-5-methoxy-6-n-propoxypyrimidine a melting point of 70-71 ⁰ C (from isopropyl ether).

b) 4- (N ₄ -acetylsulfanilamido) -5-methoxy-

6-n-propoxypyrimidine

To 20 g of 4-amino-5-methoxy-6-n-propoxypyrimidine in 100 ml of anhydrous pyridine 38.5 g of p-Acetaminobenzolsulfochlorid at 3 to 4 ⁰ C over 2 hours was added. The reaction mixture is stirred at the same temperature overnight. After the usual work-up, 38 g of 4- (N ₄ -acetylsulfanilamido) -5-methoxy-6-n-propoxypyrimidine with a melting point of 186 ° to 187 ° C. (from glacial acetic acid) are obtained.

c) 4-sulfanilamido-5-methoxy-6-n-propoxypyrimidine

35 g of 4- (N ₄ -Acetylsulfanilamido) -5-methoxy-6-n-prop-ao oxypyrimidine are heated in 350 ml of 2 N sodium hydroxide IV2 hours at 85 to 9O ⁰ C. After cooling, the solution is made phenolphthalein-alkaline with concentrated hydrochloric acid, treated with animal charcoal, filtered and adjusted to pH 6 with carbon dioxide gas, as 28 g (88% of theory) of 4-sulfanilamido-5-methoxy-6-n- propoxypyrimidine of melting point 142-143 ⁰ C (from acetonitrile).

Example 13

a) 4-Amino-5-methoxy-6-isopropoxypyrimidine

50 g of 4-amino-5-methoxy-6-chloropyrimidine are, as described above, with 9.4 g of sodium in 600 ml of isopropanol converted to 4-amino-5-methoxy-6-isopropoxypyrimidine. Yield: 44 g; Melting point 111 to 112 ° C (from isopropyl ether).

b) 4- (N ₄ -acetylsulfanilamido) -5-methoxy-

6-isopropoxypyrimidine

As described above, 20 g of 4-amino-5-methoxy-6-isopropoxypyrimidine in 100 ml of anhydrous pyridine are reacted with 38.5 g of p-acetaminobenzene _{sulfochloride to give 4- (N 4} -acetylsulfanilamido) -5-methoxy-6-isopropoxypyrimidine . Yield: 37 g; Melting point: 195 to 197 ⁰ C (from glacial acetic acid).

c) 4-sulfanilamido-5-methoxy-6-isopropoxypyrimidine

34 g of 4- (N ₄ -acetylsulfanuamido) -5-methoxy-6-isopropoxypyrimidine are saponified as described above to give 4-sulfanilamido-5-methoxy-6-isoρropoxypyrimidine. Yield: 27 g; Melting point: 136 to 137 ° C (from acetonitrile).

Claims (2)

Patent claims: 1. Method of making new 4-sulfanilamido-dialkoxypyrimidines of the general formula R ¹ O OR ² H ₂ N-, V- SO ₂ NH - ; n wherein R ¹ and R ^{2 are} low molecular weight alkyl or alkenyl radicals, and salts of such sulfonamides, characterized in that either (a) a pyrimidine of the general formula is used in a manner known per se R ¹ OR ⁸ R ⁴ - / where R ^{3 is} an R ² O group or a halogen atom and R ^{4 is} a halogen atom, condensed with an alkali salt of a benzenesulfonic acid amide which has a free or protected amino group in the p-position, and then the halogen atom which may be present in the condensation product is replaced by a R ^a O- Group replaces and the protective group which may be present is split off or (b) a pyrimidine of the general formula R ¹ O OR ² H ₂ N- ; n III condensed with a benzenesulfohalide, which can be converted into an amino group in the p-position Has substituents and the p-substituent of the condensation product, if necessary after cleavage of bis-benzenesulfonyl compounds to monobenzenesulfonyl compounds, converts into the amino group and that one the resulting reaction product of the formula I, if appropriate with an acid or a base in a salt transferred. 2. The method according to claim 1, characterized in that the condensation of the pyrimidine component of the general formula III, with the sulfohalide component in the presence of anhydrous pyridine in the cold, preferably at a temperature below 5 ⁰ C, is carried out. Documents considered: German Patent No. 967 884; Austrian patent specifications No. 201 595, 175 895.