DE1143205B - Process for the preparation of 3, 5-diiodosalicylhydroxamic acid - Google Patents

Description

GERMAN

PATENT OFFICE

F34460IVb / 12q

REGISTRATION DATE: JULY 18, 1961

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: FEBRUARY 7, 1963

The invention relates to a process for the preparation of the therapeutically valuable 3,5-diiodosalicylhydroxamic acid.

This compound is prepared according to the invention by methods known per se, either S by iodination of salicylhydroxamic acid or by conversion of a reactive 3,5-diiodosalicylic acid derivative, such as B. a halide or a suitable ester, with hydroxylamine. Particularly smooth the reaction succeeds with 3,5-diiodosalicylic acid azide and hydroxylamine. Implementation will be in this Fall at 0 to 5 ° C in a suitable solvent, such as. B. ethanol, tetrahydrofuran or dioxane, carried out and the reaction product isolated in the usual manner.

The 3,5-diiodosalicylhydroxamic acid has a good one antifungal effect and in this regard surpasses both salicylhydroxamic acid and its Mono- or dichloro or mono- or dibromine substitution products. Furthermore it was surprising found that 3,5-diiodosalicylhydroxamic acid had its antifungal effect even after oral administration unfolds and thus in principle differs from all known antifungal salicylic acid derivatives differs.

The 3,5-diiodosalicylhydroxamic acid (II) prepared according to the invention shows the same fungistatic acid in vitro Same effect as the well-known 3,5-diiodosalicylamide (I).

However, there is a significant difference in in vivo experiments, where the 3,5-diiodosalicylhydroxamic acid is better absorbed or less inactivated and the urine has a higher fungistatic effect. Are z. For example, if 500 mg / kg of I are administered to rabbits, total urine is fungistatic Activity up to a 1: 100 dilution; while in the parallel experiment with II a fungistatic effect up to a dilution of 1: 300 is achieved.

The compatibility of both compounds is about equally good.

DL ₅₀ rat po

for I 3.5 g / kg

for II 3.0 g / kg

example 1

50.0 g (0.123 mol) of 3,5-diiodosalicylic acid hydrazide are distributed in 500 ml of dioxane, a solution of 12.5 g (0.18 mol) of sodium nitrite in 25 ml of water is added and this suspension is heated to 5 to 10 ^° C. cooled down. A mixture of 100 ml of glacial acetic acid and 16 ml of concentrated hydrochloric acid is then added with vigorous stirring

Method of manufacture
of 3,5-diiodosalicylhydroxamic acid

Applicant:

Paint factories Bayer Aktiengesellschaft,
Leverkusen

Dr. Horst Böshagen, Haan (RhId.),

Dr. Ernst Schraufstätter, Wuppertal-Elberfeld,

and Dr. Maria Brömmelhues, Wuppertal-Sonnborn, have been named as the inventor

slowly added dropwise, the temperature between 5 and 10 ⁰ C is kept. The hydrazide goes completely into solution. The mixture is stirred for a further 15 minutes and then 450 ml of water are added. The azide slowly crystallizes out. After about an hour, the product is filtered off with suction, washed well with water and dried in a desiccator.

45 g of 3,5-diiodosalicylic acid azide are obtained, which is 88% of theory.

The azide forms yellowish crystals which fizzle out when suddenly heated. The compound can be recrystallized from ethyl acetate and then forms yellowish needles with a melting point of 112 ° C .; the substance then solidifies again and then melts again at 259 to 260 ^° C. (decomposition).

24.6 g (0.38 mol) of hydroxylamine hydrochloride are dissolved in 800 ml of ethanol (99%) and a solution of 20.3 g (0.38 mol) of sodium methylate in 150 ml of ethanol (99%) is slowly added with stirring. The thus prepared ethanolic hydroxylamine solution is cooled to -5 ⁰ C, and then slowly added dropwise a solution of 80.0 g (0.191 mol) of 3,5-Dijodsalicylsäureazid in 170 ml of tetrahydrofuran under vigorous stirring. The reaction temperature is kept at 0 to -5 ° C. by occasional cooling. The mixture is then stirred at 25 ° C. for 2 hours to complete the reaction.

The reaction solution is concentrated to half its volume in vacuo and then added to water. The 3,5-diiodosalicylhydroxamic acid precipitates out as a thick paste. The connection is sucked off, good washed with water and dried. The crude product obtained is then made from about 100 ml of acetone recrystallized.

309 508/272

Claims (1)

3 4 61.5 g are obtained, that is 79.5% of theory, 3.5-50 ° C. 97.2 g (0.3 mol) of 50% chloroiodine / HCl are added dropwise. Diiodosalicylhydroxamic acid in beautiful, colorless Na- The reaction mixture is 18 hours at 50 ⁰ C ge delchen, which melt at 199.5 ° C with decomposition. stirs. It is then cooled and the formed Mixture of 5-iodine and 3,5-diiodo-saücylh.ydroxam- Example 2 ₅ acid suctioned off. The reaction product becomes hot with 10.0 g (0.144 mol) of hydroxylamine hydrochloride are treated with methanol and the poorly soluble 5-ioddenine 100 ml of water is dissolved and slowly a solution of salicylhydroxamic acid (9.0 g), melting point after Um-9.6 g (0.240 mol) of sodium hydroxide in 100 ml of water, crystallization from dimethylformamide 244 ° C (Admitted. Settlement in the hydroxylamine solution prepared in this way). The filtrate is evaporated in vacuo at 25 ° C with vigorous stirring within a ίο and the crude 3,5-diiodosalicylhydroxam hour a solution of 20.0 g (0.048 mol) of 3,5-diiodic acid several times from a little Recrystallized acetone, ethyl salicylate added dropwise to 100 ml of dioxane. 12.2 g of 3,5-diiodosalicylhydroxamic acid are obtained.
touched. One draws now in a vacuum (bath temperature 40 ° C) largely removes the added dioxane and acidifies it. the aqueous solution with concentrated hydrochloric acid. An oil initially precipitates out, but this quickly becomes a process for the production of 3,5-diiodosalicylic crystalline solidified. The reaction product is ab- hydroxamic acid, characterized in that sucked, washed well with water and dried a) that one in a conventional manner either (~ 17 g). After recrystallization from acetone, 20 salicylic hydroxamic acid is iodized or one 10.5 g of 3,5-diiodosalicylhydroxamic acid as coloring b) a reactive functional derivative of loose needles of melting point 199.5 ⁰ C. 3,5-diiodo-salicylic acid with hydroxylamine environmental r. ■ ■ 1 τ ^sets - Example 3 13.7 g (0.1 mol) of salicylated hydroxamic acid are used in 25 publications considered: 50 ml of concentrated hydrochloric acid suspended and in Chemical Abstracts, Vol. 52 (1958), p. 8087L © 309 508/272 1.63