DE1094265B - Process for the preparation of 5-sulfanilamidopyrazoles - Google Patents

Description

Process for the preparation of 5-sulfanilamidopyrazoles The preparation of heterocyclically substituted sulfanilamides is usually carried out by reaction of a sulfonic acid halide which can be converted into the amino group in the p-position Rest carries, with a heterocyclic amino compound or by reacting the corresponding heterocyclic halogen compound with a sulfonamide or its Alkali salt (see German patent specification 952 809 and Belgian patent specification 557 254).

However, these known methods have various disadvantages. So is z. B. the second-mentioned method does not apply to all halogen-substituted heterocycles applicable; in the case of the 5-halopyrazoles it fails z. B. completely. With the former Method, however, there is a risk that the sulfonyl halide also with the ring nitrogen reacts and thus either the isomerically substituted in the nucleus of the desired sulfonamides Connections arise or double substitution occurs. In some cases The amino-heterocycles are only weak bases that react directly with the sulfonyl halide are not accessible, so that an auxiliary base is added must be, z. B. pyridine.

In many cases, however, much stronger bases (such as trimethylamine) be applied; this usually results in compounds that have two sulfonyl radicals wear on the amino group. The conversion of these isomeric or doubly substituted Sulphonamides in the desired compounds requires special measures and is often associated with the loss of half the amount of sulfonyl halide used. In the case of the 5-sulanilamido-pyrazoles, there is also the fact that they are used as starting materials required aminopyrazoles are sometimes very difficult to access.

It has now been found that the therapeutically interesting 5-sulfanilamido-pyrazoles can be produced by a new process, which the above Avoids disadvantages and in particular a secure position of the sulfonamide group guaranteed on the pyrazole ring.

The method of the present invention consists in that in the methylene group optionally substituted N1-acylacetyl-sulfonamides with hydrazine or monosubstituted hydrazines or their reactive derivatives in acidic Condensed environment.

To explain the process according to the invention, the preparation of 5-sulfanilamido-3-methyl-1-phenylpyrazole from sulfanilic acid acetoacetylamide and phenylhydrazine is shown in the following equation: X = amino group or a radical which can be converted into the amino group (e.g. nitro or acylamino group).

The feasibility of this ring closure reaction is surprising to call. The ß-ketoacyl-sulfonamides have two oxygen functions, which appear to be suitable per se for reaction with hydrazines.

However, it is known that the pyrazole ring closure of β-keto acid derivatives generally the residue on the acid group (ester or amide group) is blasted off, resulting in the formation of 5-oxy-pyrazoles (= pyrazolones). This was also to be expected in the present case, all the more so as a sulfonamide group a substituent that can be split off particularly easily represents an acid group. Indeed was also able to date in the implementation of Nl-acylacetyl-sulfonamides with phenylhydrazine only the formation of oxy-pyrazoles and sulfamides can be observed (Chem. Ber., 83, 555 [1950]).

When the process according to the invention is carried out, the acylacetyl sulfonamides expediently reacted with a small excess of the hydrazines.

The preferred reaction temperatures are between O "C and room temperature (Ice cooling). The free hydrazines and their reactive ones can be used as the hydrazine component Derivatives (e.g. hydrazones, acylhydrazines, semicarbazides, azines and those by reaction from Diket or aldazines iii quaternary ammonium compounds obtained with reactive alkyl esters) be used. In the latter case, the ring closure takes place with elimination of the residue on the hydrazine group (i.e. it becomes, for example, the aldehyde or the ketone free). The reaction can be carried out with all common acidic condensing agents be performed; she succeeds z. B. already when using the hydrazine hydrochloride or sulfates. If the free hydrazines are used as starting materials (i.e. the ring closure takes place with elimination of water), considerably increased values are obtained Yields if you have an acidic condensing agent with the ability to bind of the water of reaction formed is used; has proven to be particularly advantageous proved to be a mixture of phosphoric acid and phosphorus pentoxide. However, can also others for carrying out condensation reactions in an anhydrous medium use suitable condensation agents, such as strong water-attracting acids or Lewis acids. The only prerequisite for the feasibility of the reaction is that the acidic condensation agent sufficient solubility for both reactants or obtain them by adding a suitable inert solvent.

The starting materials for the process of the present invention Nl-acylacetyl-sulfonamides used are except for those in Chem. Ber., 83, p. 556 (1950), representatives described new compounds. You can through implementation the sulfonamide alkali salts with ß-ketocarboxylic acid phenyl esters according to the German Patent 926491 for the preparation of N1-acyl-sulfonamides described Procedures are obtained. For the acetoacytyl sulfonamides there is also the Diketone method available (cf. Chem. Ber., 83, p. 558 [1950]).

The ring closure reaction according to the present invention can both with the free N1-acylacetyl-sulfanilamides be carried out as well as with such Benzenesulfonamides, which in the p-position can subsequently be converted into the amino group Remainder (nitro or acylamino group, especially acetyl and carboxyethylamino group) wear. Because of the easy saponifiability of the ketocarboxylic acid sulfonamide bond However, it is advantageous to use the acylamino group, which is probably the most commonly used technically to be converted into the free amino group only after the ring formation has taken place.

The novel process according to the invention should be based on the following Examples are explained.

1. 5-sulfanilamido-3-methyl-1-phenyl-pyrazole 85 cc anhydrous phosphoric acid 21 cc of phenylhydrazine are added in an ice bath. After stirring for 30 minutes it has the phenylhydrazine phosphate is dissolved, and 32.4 g of acetylsulfanilic acid-acetoacetylamide are added at 10 ° C (M.p. 205 to 207 ° C) too. After stirring for one hour at 100 ° C., the mixture is cooled with ice 18.7 g of phosphorus pentoxide were added. The gradually toughening mixture is stirred another 3 hours at 10 ° C and then work up as follows: By adding 375 ccm Most of the 5-acetyl-sulfanilamido-3-methyl-1-phenyl-pyrazole can be dissolved in water fail. The aqueous solution can be neutralized or shaken out with ethyl acetate a further 5 to 10% can be obtained. F. 108 to 110 ° C.

The saponification is carried out by heating with 3 mol of 4N sodium hydroxide solution the steam bath. The 5-sulfanilamido-3-methyll-phenyl-pyrazole can be obtained from the saponification mixture (F. 178 to 180 ° C) are precipitated with dilute hydrochloric acid. Yield (based on on acetylsulfanilic acid acetoacetylamide used) about 70% of theory.

2. The following 5-sulfanilamido-pyrazoles can be prepared in a manner analogous to that described in the example: Total- Yield 5-sulfanilamido-pyrazole FF of the acetyl comments link 3-methyl- 252 to 254O C 247 to 2480 C use of hydrazine phosphate 55% 3-phenyl- .............. 251 to 253 ° C 227 to 228 ° C F. des acetylsulfanilic acid-benzoyl-acetyl- amids: 168 to 1720 C 6001o 3-Phenyl-l-methyl- ...... 209 to 210 ° C 248 to 251 ° C Use of methyl hydrazine sulfate 52% 1,3-Dimethyl4-ethyl- 182 to 185 ° C 229 to 230 ° C F. des Acetylsulfanilicäure- (ethyl-aceto- acetyl) amides: 210 "C 54010 3. 5-sulfanilamido-1,3-dimethylpyrazole 126 ccm of anhydrous phosphoric acid are mixed with 32 g of methyl hydrazine sulfate in an ice bath. After stirring for 30 minutes, 45 g of acetylsulfanilic acid aceto-acetylamide are added at 10 ° C. (mp 205 ° to 207 ° C.). The mixture is stirred for 1 hour at 10 ° C. and 27 g of phosphorus pentoxide are added while cooling with ice. The mixture, which gradually becomes tough, is stirred for a further 3 hours at 10 ° C. and then mixed with water and so much concentrated ammonia that it only reacts slightly acidic. The 5-acetyl-sulfanilamido-1,3-dimethyl-pyrazole precipitates in a yield of 75.5% of theory; F. 199 to 200 ° C.

The saponification of this acetyl compound is carried out by means of heating 3 moles of 4N sodium hydroxide solution on the steam bath. From the saponification mixture can the 5-sulfanilamido-1,3-dimethyl-pyrazole are precipitated with dilute hydrochloric acid; F. 213 to 215 "C. Yield 870% of theory.

4. 5-sulfanilamido-3-propyl-1-methyl-pyrazole 0.15 mole of acetylsulfanilic acid butyroacetylamide (F. 177 to 1800 C) and 0.22 mol of methyl hydrazine sulfate are under analogous conditions, as described in Example 3, brought to condensation. F. des 5-Acetylsulfanilamido-3-propyl-1-methyl-pyrazole: 142 up to 145 ° C.

Yield 73010 of theory. The saponification carried out in the usual way gives the 5-sulfanilamido-3-propyl-1-methyl-pyrazole from F. 168 to 169 "C.

5. 5-sulfanilamido-3-methyl-1-butyl-pyrazole If this is done in the example 3 using 0.15 mol of acetylsulfanilic acid acetoacetylamide and 0.18 mol of butylhydrazine, 5-sulfanilamido-3-methyl-1-butyl-pyrazole is obtained in about 700% yield from the mp 173 to 1750 C (mp of the acetyl compound 145 to 148 ° C).

6. 5-sulfanilamido-3-methyl-1-cyclohexyl-pyrazole 0.15 mole of acetylsulfanilic acid-acetoacetylamide and 0.18 mol of cyclohexylhydrazine hydrochloride are as described in Example 3, brought to implementation. F. of the obtained acetyl compound: 230 to 2310 C. F. des 5-sulfanilamido-3-methyl-1-cyclohexyl-pyrazole: 220 to 223 ° C. Overall yield 69 0t0 of the theory.

7. The following 5-sulfanilamido-pyrazoles are obtained in an analogous manner: 5-sulfanilamido-pyrazole m.p. of the acetyl processes link 1-ethyl-3-propyl- ....... 140 to 141 ° C 144 to 147 ° C analogous to example 3 from acetylsulfanilic acid-butyroacetyl- amide + ethyl hydrazine sulfate l-propyl-3-methyl- ...... 193 to 195 ° C 148 to 152 ° C analogous to example 3 from acetylsulfanilic acid acetoacetyl amide + propylhydrazine l-Isopropyl-3-methyl- .... 176 to 178 ° C 169 to 1700C analogous to Example 3 from acetylsulfanilic acid acetoacetyl amide + isopropylhydrazine hydrochloride l-ethyl-3-methyl- ....... 166 to 168 ° C 148 to 152 ° C analogous to example 3 from acetylsulfanilic acid acetoacetyl amide + ethyl hydrazine sulfate

Claims (1)

PATENT CLAIM: Process for the preparation of 5-sulfanilamidopyrazoles, which can be substituted in the 1-, 3- and / or 4-position of the pyrazole ring, characterized in that N1-acylacetyl-sulfonamides of the formula optionally substituted in the methylene group in which X denotes an amino group or a radical which can be converted into the amino group, condenses with hydrazine or monosubstituted hydrazines or their reactive derivatives in an acidic medium, and optionally then converts X into the amino group in a manner known per se.