DE1947948B2 - Process for the preparation of sulfanilamido-1,2,5-thiadiazole derivatives - Google Patents

Description

R ₁ -OC

Il

-C-Cl

(Ul

in which R ₁ is defined as indicated above. with SuIfanilamid or N ₄ -lower alkanoylsulfanilamide at elevated temperature in the presence of a solvent and of alkali compounds as acid-binding agent and optionally subsequent acidification of the reaction product and / or cleavage of the alkanoyl group by saponification, characterized in that the reaction of 1 mol of chlorothiadiazole compound of the general formula 11 1 mol of sulfanilamide or N ₄ - lower - alkanoylsulfanilamide and a maximum of 1.2 mol of alkali or alkaline earth metal hydroxides and / or carbonates are used and the reaction is carried out at temperatures of 115 to 160 ^° C. in the presence of dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide as solvent and is carried out with ongoing removal of the water formed with the aid of a water entrainer ^{boiling above 10O 0} C but below the boiling point of the amide used as solvent.

It is known that sulfanilamido-1,2,5-thiadiazole derivatives of the general formula I.

55

R ₁ OC-

Il

-CN-SO ₂

60

(D

65

in which R _{1 is} a lower alkyl radical, a lower alkoxyethyleneoxy radical, a lower alkenyl or alkynyl radical R, a hydrogen atom, an alkali metal 2nd S? AqäSnt d ~ s alkaline earth metal and R _{1 is} hydrogen or lower alkanoyl, possesses therapeutically valuable properties * SoM z . B. uTder Austrian patent 2 33 004 describes that * ethoxy or metfaoxy-3-sulfanilamido-lÄ5-thiadiazole are valuable sulfonamides with good antibacterial action, which are particularly good penetration into the interior of organs, eg. B. eyes, distinguish. The Austrian patent 2 40 853 reports on the good antibacterial properties of sulfonamides of the general formula I, in which R _{1 represents} a lower-alkoxy-äyleno-radical, and the Austrian Pateatsdirift 266 125 gives information about that compounds of the general formula I. in the R, is a lower alkenyl or aikinyl radical, develop not only a good antibacterial effect but also a good effect against coccidiosis.

For the preparation of these compounds, from the classical sulfonamide _{syntheses, the route via the coupling of N 4} -acyheric sulfamic acid chloride with the aminoheterocycle, which in principle is described in US Pat. No. 23,58031, was suggested. This is because the 3-amino-1,2,5-thiadia / ol and its 4-substituted derivatives were accessible in good yields by hydrolytic cleavage of diketothiapurines (Austrian patent 2 30 885). on the contrary? to 3-chloro-12 5-thiadiazole and its 4-substituted derivatives. For 5-thiadiazole derivatives, however, the reaction of 3-chloro-1,2,5-thiadiazoles _{, which are substituted in the 4-position by R 1} O (where R, has the abovementioned meaning), with sulfanilamide has also become of interest French patent specification 1503 797 or Austrian patent specification 2 66 125, it was necessary in this synthesis route to achieve reasonably good yields to 1 mol of chlorothiadiazole at least a 1 molar excess of sulfanilamide, but also up to 5 mol of this compound per mole chlorothiadiazole and min ^'4 -icns I molar equivalent of an acid-binding agent as excess, primarily potassium carbonate use, wherein at temperatures of 80 to 200 ^c C, preferably 110 to 175X, condensed. the default rule, the reaction is from 1 mole Chlorthiadi azole with 3 moles of sulfanilamide and 3 moles of potassium carbonate at 145 C. In spite of this large excess of sulfonamide, which puts a heavy burden on the process economically, the yields leave something to be desired, with 56%, based on the chlorothiadiazole used, ie not even 20%, based on the sulfanilamide used. can be specified.

Surprisingly, it has now been found that when reacting appropriately substituted chlorothiadiazoles with sulfanilamide or its N ₄ acyl derivatives for the purpose of preparing compounds of the general formula I, the economically very burdensome excess of sulfanilamide and acid-binding agent can be avoided and is possible, despite Conversion in equimolar amounts, yields of the compounds of the general formula I of around 80% of theory, based on both starting products, to be obtained when the reaction is carried out in certain solvents and selected

During the reaction, the water is continuously removed with the help of certain water entrainers.

The invention accordingly relates to a method 23JT Manufacture of sulfanilamido-1,2,5-thiadiazole derivatives of the general formula I.

R ₁ OC-

CN-SO ₂

NHR ₃

U)

in which R _{1 is} a lower alkyl radical, a lower i _S alkoxyäShylenoxy radical, a lower alkenyl or ABriiayl radical, R _{2 is} a hydrogen atom, an alkali metal or the equivalent of an alkaline earth metal and R _{3 is} hydrogen or lower alkanoyl, by reaction of 4-substitutes 3-chloro-1,2,5-thiadiazoles of the general formula II

R ₁ OC

Ii

C-Cl

Il

(Π)

is as defined above in which R _1, with sulfanilamide or N ₄ -nieder alkanoyl suifanilamid in ER- _J0 elevated temperature by in the presence of a solvent and of alkali metal compounds as the acid-binding agent and optionally followed by acidification of the reaction product and / or elimination of the alkanoyl group Saponification, which is characterized. that for the implementation of 1 mole of chlorothiadiazole compound of the general formula II 1 mole of sulfanilamide or N ₄ -lower alkanoylsulfanilamide and a maximum of 1.2 moles of alkali or alkaline earth metal hydroxide and / or carbonates are used and the reaction at temperatures of 115 to 160 ⁰ C in The presence of dimethylformamide, dimethylacetate or hexamethylphosphoric triamide as a solvent and with ongoing removal of the water formed with the aid of a water entrainer ^{boiling above 10O 0} C but below the boiling point of the amide used as solvent is carried out. An increase in the amount of sulfanilamide is not necessary and only leads to contamination. Since the implementation of practically completely is in sufficiently good speed in front of him, it is not necessary to apply a higher temperature than 160 ^0C. On the contrary, it has been found that higher temperatures have an adverse effect on the purity of the process product.

Particularly pure products and nevertheless optimal yields are obtained if the reaction temperature is less than or equal to from 125 to 135 ° C are maintained.

As a water entrainer toluene, xylene, chlorobenzene or a boiling between 100 and 140 ⁰ C gasoline fraction can be vei turns. The amount of the water entrainer should not be chosen too high, firstly in order to avoid segregation of the reaction mixture as far as possible, and also in order to maintain the desired reaction temperature; This is particularly important when the water entrainer boils significantly lower than the reaction temperature that must be adhered to in the reaction vessel. It is advisable to use just enough water entrainer that a constant reflux of entrainer is maintained during water separation.

Alkali carbonates, i.e. sodium carbonate and potassium carbonate, have proven to be very acidic well proven. However, ADcaB hydroxides can also be used or calcium carbonate can be used with success. The end of the reaction can be by stopping the Water separation can be recognized. It usually takes 3 to 8 hours to complete Implementation needed

The work-up of the reaction mixture is very simple, since significant amounts of unchanged starting materials do not have to be removed. It is advisable to first blow out the water entrainer with steam before the reaction mixture is acidified to precipitate the sulfonamides.If you _{want to split off existing N 4} acyl groups, this can be done at the same time as the water entrainer is removed by heating the mixture with sodium hydroxide solution. The salt can either be precipitated directly from this alkaline solution or the mixture can be acidified in order to liberate the free sulfonamide of the general formula I.

The process according to the invention will be explained in more detail with reference to the following examples.

example 1

164.0 g of 3-chloro-4-ethoxy-1,2,5-thiadiazole are _{heated to 130 ° C. for 8 hours with 172.2 g of sulfanilamide, 166.0 g of K 2} CO ₃ , 73 g of dimethylformamide and 40 ml of toluene. As the reaction proceeds, the internal temperature begins to decrease. The temperature is kept between 125 and 130 ^° C. by letting off toluene from the water separator. A total of 27 ml of a water-amine mixture are deposited (59% H ₂ O content). After the reaction has ended, the mixture is _{diluted with 500 ml of hot H 2} O and concentrated with 30 ml of HCl. neutralized. The toluene is blown off with steam, the reaction solution is cooled and introduced into dilute hydrochloric acid. When the addition is complete, the precipitate is filtered off with suction, washed with water and dried.

Yield: 279.7 g of 4-ethoxy-3- (4'-ammo-benzenesulfonamido) -1, 2,5-thiadiazole. this corresponds to a yield of 93.1% of theory.

By reprecipitation with aqueous ammonia and hydrochloric acid, 250 g of 4-ethoxy-3- (4'-aminobenzenesulfonamido) -l, 2,5-thiadiazole are obtained (83% of theory) from melting point 124 to 126 ° C.

Example 2

164 g of S-ChloM-ethoxy-US-thiadiazole, 172 g of sulfanilamide, 166 g of K ₂ CO ₃ and 73 g of dimethylformamide are heated to reflux with 40 ml of xylene. In 4V _{two hours} to 35.5 a water-amine mixture divorced from ml. After the water has stopped separating, 500 ml of hot water are added and the mixture is treated with conc. HCl neutralized. The xylene is blown over with steam and the cooled reaction solution is introduced into dilute hydrochloric acid. The resulting crystalline precipitate is filtered off with suction, washed with water and dried.

Yield: 278.2 g of 4-ethoxy-3- (4'-aminobenzenesulfonamido) -l, 2,5-thiadiazole, that's 90.8% of theory.

Example 3

164 g of S-chloro - ^ - ethoxy-IAS-thiadiazole, 214 g of 4-acetylsulfamlamide, 166 g of K ₂ CO ₃ and 110 g of dimethylformamide are heated with 10 ml of toluene at 130 ^° C. for 4 hours while stirring. 24.5 ml of a water-amine mixture are deposited. After the reaction has ended, 600 ml of 20% strength NaOH are added to the reaction mixture and the mixture is heated to boiling for 3 hours, the N ^ acetylamino group being saponified. At the same time, the toluene is blown over with steam. When the hydrolysis is complete, the mixture is cooled and the alkaline solution is introduced into dilute hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried.

Yield: 264 g of 4-ethoxy-3- (4'-aminobenzoI-sulfonamidoH , 2,5-thiadiazole, that is 87.9% of the

Example 4

15 ml HCl conc. neutralized and the toluene was distilled off with steam. Then with conc. HCl acidified, cooled, the precipitated product filtered off with suction, washed with water and dried.

Yield: 130.6 g of crude 4-methoxy-3 ^ (4'-aminobenzenesulfonamidoH, 2> 5-thiadiazole, that's 91.4% of theory.

After purification as described in Example 1, 4-methoxy-3- (4'-aminobenzenesulfonamido) -l, 2,5-thiadiazole with a melting point of 148 to 150 ^° C. is obtained in 81% yield

In an analogous manner, the following 4-alkoxy-3- {4'-aminobenzenesulfonamido) -1,2,5-thiadiazoles getting produced.

20th

208 g S-

172 g of sulfanilamide, 166 g of K ₂ CO ₃ and 73 ml of dimethylformamide are heated ^{to 130 °} C. with 40 ml of toluene for 7 hours. 30 ml of a water-amine mixture separate out (62% H ₂ O content). After the reaction has ended, 500 ml of hot H ₂ O are added, the mixture with conc. HCl adjusted to pH 7 and the toluene and unreacted 3-chloro-4- / i-ethoxyethoxy-1,2,5-thiadiazole blown off with steam. Then with conc. Hydrochloric acid is adjusted to pH 3.5, the mixture is cooled, the precipitate is filtered off with suction and washed with water. For further purification, the product is suspended in aqueous hydrochloric acid. The insoluble product is then filtered off with suction, washed and dried.

Yield: 323 g of 4- / i-ethoxyethoxy-3- (4'-aminobenzenesulfonamido) -l, 2,5-thiadiazole monohydrate, that's 89.1% of theory.

After reprecipitation from aqueous ammonia and acetic acid is obtained in 80% yield 4- / i-ethoxyethoxy-3- (4'-aminobenzenesulfonamido) -l, 2,5-thiadiazolmonohydrat of melting point 64 to 66 ⁰ C.

Example 5

75.0 g of i-ChloM-methoxy-1,2,5-thiadiazole, 86.0 g of sulfanilamide, 83.0 g of K ₂ CO ₃ and 37.0 ml of dimethylformamide are heated to 125 ° to 130 ° with 20 ml of toluene for 6 hours C heated.

14 ml of a water-amine mixture separate out. After the reaction has ended, 250 ml of H ₂ O are added to the mixture. This is then with

R. Bulge Fp. 157 i%, (Ο 187 CH ₃ -CH ₂ -CH ₂ - 73.0 156 CH ₃ - CH ₂ - CH ₂ - CH ₂ - 74.6 186 182 CH ₃
"CH-CH ₂ - CH ₃ 75.0 179 121 CH ₃ -O- C ₂ H ₄ - 82.0 120

Example 6

As in Example 1, 164.6 g of S-ethoxy ^ chloro-1,2,5-thiadiazole, 172.2 g of sulfanilamide, 165.8 g of potassium carbonate, 87 g of N, N-dimethylacetamide and 50 ml of toluene are used at 125 to 130 ⁰ C brought to reaction, with 19 ml of water-amide mixture (with a water content of 86%) separate out. After the mixture has been worked up as in Example 1, 269.8 g (corresponding to a yield of 90%) 3-ethoxy-4- (4'-aminobenzenesulfonamido) -l, 2,5-thiadiazole are obtained.

Example 7

Analogously to Example 6, 82.3 g of 3-ethoxy-4-chloro-1,2,5-thiadiazole, 86.1 g sulfanilamide, 82.9 g potassium carbonate, 89.6 g hexamethylphosphoric trisamide and 20 ml of toluene reacted and worked up. There are 103.3 g of 3-ethoxy-4- (4'-aminebenzenesulfonamido) -l, 2,5-thiadiazole corresponding to a yield of 68.8%.

Claims (1)

Claim: Process for the preparation of sulfanilamido-1 ^, 5-thiadiazole derivatives of the general formula I. -C IO in which! R _{1 is} a lower alkyl radical, a lower alkoxyethyleneoxy radical, a lower alkenyl or alkynyl radical, R _{2 is} a hydrogen atom, an alkali metal or the equivalent of an alkaline earth metal and R _{3 is} hydrogen or lower alkanoyl, by reaction of 4-substituted 3 -Chlor-1,2,5-thiadiazoles of the general formula II