DE1163805B - Process for the preparation of benzenesulfonylureas - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German class: 12 ο - 25

Number: 1163 805

File number: F 36246IV b / 12 ο

Filing date: March 10, 1962

Opening day: February 27, 1964

Subject of patent application F 33910 IVb / 120 is a process for the production of benzenesulfonylurea derivatives, by taking benzenesulfonylureas of the formula

- SO ₉ - NH - CO - NHo

wherein R ₁ and R ₂ denote hydrogen, alkyl or alkoxy radicals having 1 to 6 carbon atoms and / or halogen atoms, reacts with water-soluble tropylium salts and optionally hydrogenates the N-benzenesulfonyl-N'-cycloheptatrienyl-urea derivatives obtained.

It has now been found that benzenesulfonylureas which are also effective in lowering blood sugar can also be used good yields are obtained if, in a modification of the process according to patent application F 33910 IVb / 12 ο N-trifluoromethyl benzenesulfonyl ureas of the formula

CF _3x ._

* r- SO ₂ - NH - CO - NH,

with water-soluble tropylium halides to react and optionally the obtained Benzenesulfonyl-N'-cycloheptatrienyl urea derivatives hydrogenated in the usual way.

To react with the water-soluble tropylium salts, the sulfonyl group is turned away Side of the urea molecule unsubstituted trifluoromethyl-benzenesulfonyl-urea derivatives of the formula given above are used as starting materials. The trifluoromethyl radical can be in any position of the benzene nucleus, but above all the 4-position and then the 3-position is preferred. Consequently come into consideration as starting materials in the process according to the invention, for example: 2-, 3- or 4-trifluoromethyl-benzenesulfonyl-urea.

The reaction is carried out in the presence of acid-binding agents, such as alkali carbonates and alkali bicarbonates. The trifluoromethylbenzenesulfonylureas used as starting materials can also be used in the form of corresponding salts. Organic nitrogenous bases, such as pyridine or triethylamine, are also suitable as acid-binding agents. It is expedient to work in an aqueous medium, but aqueous-organic solvents, for example mixtures of dimethylformamide and water, acetone and water, or pure organic solvents, for example pyridine, can also be used. In response temperatures, especially temperatures around 2O ⁰ C are suitable. But you can also use a process for the preparation of benzenesulfonylureas

Addition to registration: F 33910 IV b / 12 ο -
Interpretation document 1157 605

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning, Frankfurt / M.

Named as inventor:
Dr. Walter Aumüller,
Kelkheim (Taunus) -Münster,
Dr. Karl Muth, Kelkheim (Taunus)

Cool and work at a moderately elevated temperature. Otherwise, the embodiments of the method according to the invention explained in more detail by the examples. The products obtained as process products N-trifluoromethyl-benzenesulfonyl-N'-cycloheptatrienylurea derivatives are remarkably pure. You can, if necessary, by recrystallization from alcohols or alcohol-water mixtures and other suitable solvents.

The hydrogenation to the corresponding N-trifluoromethyl-benzenesulfonyl-N'-cycloheptyl-urea derivatives is advantageous in alcoholic solution, in the case of poorly soluble compounds in the presence of dimethylformamide. But one can also use the alkali metal salts of N-trifluoromethyl-benzenesulfonyl-N'-cycloheptatrienyl-ureas dissolved in water hydrogenate directly. The catalysts which can generally be used are those which are used for the hydrogenation of olefinic double bonds come into consideration, for example palladium or platinum.

The desired N-trifluoromethyl-benzenesulfonyl-N'-cycloheptatrienylurea derivatives are obtained by the process according to the invention with the help of tropylium halides in remarkably pure crystalline form and with good yields.

It is possible, for example, by simply adding drops an aqueous N- (4-trifluoromethyl-benzenesulfonyl) -urea-sodium solution to an aqueous tropylium bromide solution at room temperature, in excellent yield N- (4-trifluoromethyl-benzenesulfonyty-N'-cycloheptatrienyl-urea to manufacture; the product separates immediately in crystalline form

409 510/551

off, can be vacuumed and, if necessary, processed further without further cleaning.

The method according to the invention leads to new compounds, which are easily carried out by an catalytic ^ hydrogenation in almost quantitative yield into corresponding N-trifluoromethyl-benzenesulfonyl-N'-cycloheptyl-ureas can be transferred with good blood sugar lowering effectiveness. For example, has N- (4-trifluoromethyl-benzenesulfonyl) -N'-cycloheptylurea with good tolerability an excellent, the well-known N- (4-methyl-benzenesulfonyi) -N'-n-butyl urea still superior blood sugar lowering effectiveness. The one achieved by a dose of 400 mg / kg in the rabbit Blood sugar drop reaches a maximum of 40% after 24 hours and returns after 72 hours return the initial values.

The products of the process should preferably be used to represent orally administrable preparations Hypoglycemic effects are used to treat diabetes mellitus and can be used as such or in In the form of their salts or in the presence of substances that lead to salt formation, are applied. To the Salt formation can be used, for example: Alkaline agents, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates.

example 1

a) N- (4-trifluoromethyl-benzenesulfonyl) -N'-cyclohaptatrienyl-urea

30th

26.1 g of 4-trifluoromethyl-benzenesulfonyl-urea are dissolved with 4.6 g of sodium hydroxide in 115 ecm of water and diluted with 900 ecm of water. A solution of 18 g of tropylium bromide in 700 ecm of water is added dropwise to this. During the dropping process, a constant weakly basic medium (pH 8) is used; if necessary, more caustic soda is added. The mixture is stirred for 1 hour and the reaction mixture is then acidified with acetic acid, filtered off with suction and recrystallized from alcohol. The N- (4-trifluoromethyl-benzenesulfonyl) -N'-cycloheptatrienyl-urea melts at 158-159 ⁰ C (with decomposition).

b) N- (4-trifluoromethyl-benzenesulfonyl) -N'-cycloheptylurea

45

16.4 g of N - ^ - trifluoromethyl-benzenesulfonyO-N'-cycloheptatrienyl-urea are dissolved in 400 ecm of absolute methanol and 60 ecm of dimethylformamide. After adding palladium black, the reaction solution is shaken in a duck at room temperature with hydrogen. The uptake of hydrogen has ended after one hour. The catalyst is filtered from, concentrates and precipitates the N- (4-trifluoromethyl-benzenesulfonyl) -N'-cycloheptyl-urea by adding water. Melting point 154 ° C (after recrystallization from alcohol).

Example 2

a) N - ^ - trifluoromethyl-benzenesulfonyO-N'-cycloheptatrienyl-urea

23.5 g of 3-trifluoromethyl-benzenesulfonyl-urea are dissolved using 4.15 g of sodium hydroxide and 100 ecm of water; the solution is diluted to a total volume of 900 ecm. A solution of 16.4 g of tropylium bromide in 600 ecm of water is added dropwise with stirring, the reaction mixture always being kept at about pn 8. The mixture is stirred for 1 hour, the reaction mixture is acidified with dilute acetic acid, the precipitate is filtered off with suction and recrystallized from alcohol-water. This gives N- (3-trifluoromethyl - benzenesulfonyl) -W- cycloheptatrienylharnstoff a melting point of 93 ⁰ C.

b) N-iS-trifluoromethyl-benzenesulfonyl-JN'-cycloheptyl urea

10 g of NP-trifluoromethyl-benzenesulfonyO-N'-cycloheptatrienyl-urea are hydrogenated with palladium in 200 ecm of methanol with the addition of 20 ecm of dimethylformamide. After the uptake of hydrogen has ended, it is worked up as usual. The N - (3 - trifluoromethylbenzenesulfonyl) - N '- cycloheptylurea with a melting point of 106 ^° C. (after recrystallization from alcohol-water) is obtained.

Claims (1)

Claim: Modification of the process for the preparation of benzenesulfonylurea derivatives of the formula - SO, —NH-CO —NH wherein R ₁ and R _{2 are} hydrogen, alkyl or alkoxy radicals with 1 to 6 carbon atoms and / or halogen atoms, according to patent application F33910IVb / 12o, characterized in that the starting materials used are trifluoromethylbenzenesulfonyl ureas of the formula CF, begins. - SO, - NH - CO - NH, 409 510/551 2.64 © Bundesdruckerei Berlin