DE1017171B - Process for the preparation of 5-acylamino-í¸-1, 3,4-thiadiazoline-2-sulfonamides substituted in the 4-position - Google Patents

Description

Process for the preparation of 5-acylamino- A'- 1, 3, 4-thiadiazoline-2-sulfonamides substituted in the 4-position. The present invention relates to a process for the preparation of new sulfonamides.

The sulfonamides have gained particular importance in recent years through the discovery of C 1 ap p and R ob 1 in (US Pat. No. 2,554,816) that certain heterocyclic sulfonamides are valuable diuretics because of their ability to remove the enzyme carbonic anhydrase «To inhibit. Because of this property, these agents have found use in the treatment of diseases associated with fluid retention in the body, such as congestive heart failure. The new sulfonamides according to the invention are 5-acylimine, o-4-substituted-A-1, 3, 4-thiadia, zoline-2-sulfonamides of the general formula In. In this formula, R denotes hydrogen or a low molecular weight alkyl or a monocyclic aralkyl radical and R2 denotes a low molecular weight alkylode, r monocyclic aralkyl radical. Examples of low molecular weight alkyl radicals are: methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Benzyl, α-phenetyl, phenylpropyl and phenylbutyl may be mentioned as suitable aralkyl substituents.

These new sulfonamides are also capable of "calcium anhydrase" to inhibit. Studies of these compounds. in vivo showed that they were longer acting Inhibitors are and that the therapeutic levels of these substances over, longer Periods of time can be sustained, thereby achieving greater diuresis will. The investigations also showed that these compounds are capable of working in the Penetrate cerebrospinal fluid by breaking the blood Liquo.r barrier, and into the ocular fluid by breaking the blood-aqueous barrier. Because of this, they are known to others. Compounds of this class at the Treat glaucoma and epilepsy superior.

According to the invention, these new sulfonamides are produced by that chlorine gas either through a suspension or through a solution of an S-acylimino-4-substituted-2-benzylmercapto-d = -1, 3, 4-thiadiazoline, s passes in an aqueous acid and then the corresponding formed Sulfonyl chloride derivative with ammonia to form a sulfonamide of the above formula to react. Working in an aqueous acidic solution is to be preferred because this is the case the point at which the reaction is complete is easily identified by a color change can be seen from colorless to yellow, while this point is difficult to determine, when a suspension is used. The sulfonyl chloride derivative thus obtained becomes then converted into the corresponding sulfonamide by treatment with ammonia in Form of liquid ammonia or ammonium hydroxide. Dilute with water, filter and acidifying the solution with a mineral acid such as hydrochloric acid or sulfuric acid.

The preferred medium for chlorinating the starting material is an aqueous acetic acid solution containing 10% water in which the starting materials are completely soluble. As stated above, it is because of the ease of use Prefer handling to use solutions of the starting material. Others and Likewise usable media are hydrobromic acid and hydrochloric acid, as well as low molecular weight media Fatty acids such as formic, propionic or butyric acid. The mineral acids, such as sulfuric acid, Hydrochloric acid and phosphoric acid are also applicable for this purpose. the starting materials used according to the invention, namely the 5-acylimino-4-substituted-2-benzylmercapto-42-1, 3,4-thiadiazo.line can be obtained by alkylating the corresponding 2-acylamino-5-benzylinercapto-1, 3, 4-thiadiazoles with an alkyl halide under suitable reaction conditions. getting produced. Methyl iodide. and benzyl bromide are examples of alkylating agents, that can be used. The reaction is preferably carried out in the presence of a sodium alcoholate, such as sodium methylate.

The following examples are intended to explain the present invention in more detail. All parts are parts by weight unless otherwise specified. serves and the Mixture chlorinated for 30 minutes at 5 °. The solid sulfonyl chloride derivative was filtered off, washed with water and dissolved in 50 parts by volume of ether. The solution was dried and added to about 10 parts by volume of liquid ammonia. The excess of ammonia and solvent was removed by distillation and the residue in cold Water again dissolved. By acidifying this solution, the crude 5-propionylimino-4-ynethyl-J2-1, 3, 4-thiadiazoline-2-sulfonamide precipitated as a colorless solid substance. The product was by two recrystallizations from 50% ethanol and then from one Purified mixture of ethyl acetate and petroleum ether. F. 177 to 178 °. example 1 A suspension of 6 parts of 5-acetylimino 4-ynethyl-2-benzylinercapto-42-1, 3, 4-thiadiazoline in 180 parts by volume 33fl / ®iger aqueous acetic acid was 30 minutes chlorinated at 5 °. The solid substance was filtered off, dried and in portions to 100 parts by volume. added to liquid ammonia. The ammonia was under one removed dry nitrogen stream. The solid residue became partially in 10 parts by volume Dissolved water, filtered and used to form 5-acetylimino-4-methyl-42-1, 3, 4-thia.diazoline-2-sulfonamide acidified. The product was purified by two recrystallizations from hot water. F. 212 to 214 °. Example 2 A sample of 1.18 parts of 5-acetylimino-4-benzyl-2-benzylmercapto-42-1, 3, 4-thiadiazoline was suspended in 30 parts by volume of 33% strength acetic acid and the mixture is chlorinated for 30 minutes at 5 °. The solid sulfonyl chloride derivative was filtered off, washed with water and dissolved in 50 parts by volume of ether. The solution was dried and added to about 10 parts by volume of liquid ammonia. The excess of ammonia and solvent was removed by distillation and the residue redissolved in cold water. By acidifying this solution, the crude 5-acetyl-imino-4-benzyl-42-1, 3, 4-thiadiazoline-2-sulfonamide precipitated as a colorless solid substance. The product was by recrystallizing twice from 50% ethanol and then from one Purified mixture of ethyl acetate and petroleum ether. F. 195 to 196 °. Example 3 A suspension of 6 parts of 5-acetylimino-4-ethyl-2-benzylmercapto-42-1, 3, 4-thiadiazoline in 180 parts by volume of 33% aqueous acetic acid was chlorinated for 30 minutes at 5 °. The solid substance was filtered off, dried and 100 parts by volume in portions added to liquid ammonia. The ammonia was under a stream of dry nitrogen removed. The solid residue was partially dissolved in 10 parts by volume of water and filtered and acidified to form 5-acetylimino-4-ethyl-42-1, 3, 4-thiadiazoline-2-sulfonamide. The product was purified by two recrystallizations from hot water. F. 155.5 to 156.5 degrees.

Example 4 A sample of 1.18 parts of 5-propionylimino-4-methvl-2-benzylmercapto-42-1, 3, 4-thiadiazoline was suspended in 30 parts by volume of 3.3% acetic acid. Example 5 A suspension of 6 parts of 5- Propionylimino-4-ethyl-2-benzylmercapto-42-1, 3, 4-thiadiazoline in 180 parts by volume of 33% aqueous acetic acid was chlorinated at 5 ° for 30 minutes. The solid substance was filtered off, dried and added in portions to 100 parts by volume of liquid ammonia. The ammonia was removed under a stream of dry nitrogen. The solid residue was partially dissolved in 10 parts by volume of water, filtered and acidified to form 5-propionylimino-4-ethyl-1, 3, 4-thiadiazoline-2-sulfonamide. The product was purified by recrystallizing twice from hot water. Example 6 14 parts of 5-acetylimino-4-methyl-2-benzylmercaptod2-1, 3, 4-thiadiazoline were dissolved in a solution which contained 150 parts by volume of glacial acetic acid and 50 parts by volume of water. The mixture was chlorinated with chlorine gas for 10 minutes at 10 to 15 ° until the colorless solution turned a steady yellow color. The reaction mixture was poured into a mixture of 100 parts by volume of water and 100 parts of ice. A white solid substance separated out immediately and was filtered off. The dried solid product was added to 75 parts by volume of liquid ammonia and the excess NH3 was evaporated off under nitrogen. The reaction mixture was diluted with 100 parts by volume of water, a cloudy solution remaining. After acidification with hydrochloric acid, solid 5-acetylimino-4-methyl-42-1, 3, 4-thiadiazoline-2-sulfonamide separated out, which was filtered off and dried. F. 212 to 214 °. Example 7 According to the process described in Example 6, 5-acetylimino-4-benzyl-2-benzylmercapto-42-1, 3, 4-thiadiazoline can be dissolved in a 75% strength acetic acid solution and the mixture can be chlorinated with chlorine gas for 10 minutes at 5 ° until the solution turns a steady yellow color. The sulfonyl chloride derivative is thereby. obtained by pouring the reaction mixture into a mixture of 100 parts by volume of water and 100 parts of ice. The precipitated white solid substance is filtered off. The dry solid product is added to 75 parts by volume of liquid ammonia and the excess NH "is evaporated off under nitrogen. When diluting with 100 parts by volume of water, a cloudy solution remains which, when acidified with hydrochloric acid, 5-aoetylimino-4-benzyl-42-1, 3 , 4-thiadiazoline-2-sulfonamide, which is filtered off and dried. M.p. 195 ° to 196 °. The compounds listed below can be prepared according to the process described in Example 1, the starting material being the corresponding 5-acylimino-4- substituted-2-benzylmercapto-d2-1, 3, 4-thiadiazoline is used. 5-Formylimino-4-methyl-A-1, 3, 4-thiazodine-2-sulfonamide, 5-butyrylimino-4-methyl-A- 1, 3, 4-thiadiazoline-2-sulfonamide, 5-butyrylimino-4-benzyl-A-1, 3, 4-thiadiazoline-2-sulfonamide, 5-acetylimino-4-p-nitrobenzyl-A-1, 3, 4-thiadiazoline-2-sulfonamide, 5-acetylimino-4-butyl-A-1, 3, 4-thiadiazoline-2-suilfonamid, 5-propionylimino-4-butyl-A-1, 3, 4-thiadiazoline 2-sulfonalnide.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of 5-acylimino-A-1, 3, 4-thiadiazoline-2-sulfonamides of the general formula which are substituted in the 4-position where Ri is hydrogen or a low molecular weight alkyl or monocyclic aralkyl radical and R2 is a low molecular weight alkyl or monocyclic aralkyl radical, characterized in that chlorine gas is passed through a suspension or solution of a 5-acylimino-4-substituted-2-benzylmercapto-A -1, 3, 4-thiadiazoline passes in an aqueous acid and then reacts the corresponding sulfonyl chloride derivative formed with ammonia. 2. The method according to claim 1, characterized in that that an acetic acid solution with a content of 10% water is used as the aqueous acid will.