DE1020971B - Process for the preparation of carbamic acid esters of 2,4,5-trichlorophenol - Google Patents

Description

GERMAN

R-NH-COO-

-Cl

The well-known good fungi ^ j ^ h ^ effect of 2,4,5-1 richlorphenols because of the strong irritating effect of this phenol has medicinal properties (7 B to combat mycoses the skin or the mucous membranes) has no practical relevance obtained the ester of 2,4,5-trichlorophenol, especially the N-disubstituted carbamic acid esters, are better contractual, but the fungistatic Effectiveness for the needs of practice is not This also applies sufficiently to the known N-monoalkyl-substituted Carbamic acid ester of 2,4,5-trichlorophenol to

The present invention is concerned with the task To produce derivatives of 2,4,5-trichlorophenol, the one have good fungistatic effectiveness and at the same time are well contractually compliant with these conditions the so far not described N-monoarvl-substituted 2,4,5-chlorophenyl carbamate of the formula

Cl

Method of manufacture
of carbamic acid esters
of 2,4,5-trichlorophenol

Applicant:

E. Merck Aktiengesellschaft,
Darmstadt, Frankfurter Str. 250

where R is phenyl or substituted phenyl.

Such N-monoaryl-substituted 2,4,5-chlorophenyl carbamate can be obtained by implementing a Dr Otto Zima, Darmstadt-Eberstadt,
and Dr Ernst Jacobi, Darmstadt,
have been named as inventors

primary amine with the 2,4,5-Trichlorphcnylester Chloroformic acid, carbonic acid or cyanoformic acid as well as by addition of 2,4,5-trichlorophenol to an isocyanate or by reacting said phenol with N-monoaryl-substituted urea or Carbammic acid chloride or bromide are produced These reactions proceed in accordance with the following reaction equations, where R is phenyl or substituted phenyl and R 'represents the 2,4,5-chlorophenyl radical

1 R-NH ₂ C = O + Cl-COOR ' 2 R-N = -CO- + RAW 3 R-NH- + RAW 4th R-NH ₂ + N- C-COOR ' 5 R-NH ₂ -CO- + CO = (OR ') a 6th R -NH- + RAW -Cl -MH ₂

-> R - NH- COOR '+ HCl

- "R —NH-COOR"

-> R-NH -COOR '4- HCl

-> R NH-COOR'-r HCN

-> R -NH-COOR '+ ROH

-> R —NH-COOR '+ NH,

Reactions 7u 1 and 2 sounded particularly smooth and are therefore preferably suitable for the preparation of the N-monoaryl-substituted 2,4,5-chlorophenyl carbamic acid ester

example 1
iN-Phenylcarbammsaure ^^^ - tnchlorphenylester]

19.8 g of 2,4,5-trichlorophenol are isocyanate with 11.9 g of phenyl added After the addition of a drop of Tnathylamm, the reaction starts with warming. After completion the reaction is cooled and recrystallized from benzene petroleum ether. 28.0 g of N-phenylcarbic acid are obtained 2,4,5-chlorophenyl ester at the melting point 125 to 132

Example 2
IN-m-Tolylcarbammsaure ^^ S-trichlorophenyl ester]

Are added to a solution \ on 21.4 g m-Toluidm in 200 cc of absolute ether while stirring slowly 26.0 g of chloroformic acid ^^. S-tnchlorphenylester in 100 cc of absolute ether / ugetropft, wherein the reaction mixture is slightly heated mixture is then still ^lf ₂ Heated under reflux for an hour, cooled, poured onto ice water, the ethereal phase separated, the aqueous layer breathed out, the purified ethereal solutions dried over calcium chloride, filtered over charcoal and the ether distilled off 132 ° yield 26.5 g

709 810/336

Example 3

The mixture of 14.5 g of chloroformic anilide and 27.5 g of 2,4,5-trichlorophenol takes about 1 to 2 hours Heated at 60 to 70 °. After cooling, it is recrystallized twice from cyclohexane and washed with petroleum ether. The obtained N-phenylcarbic acid ^^. S-trichlorophenyl ester melts at 125 to 132 ° and shows, in addition to correct analysis, no melting point depression with a other way of producing samples.

Example 4

21.0 g of the carbonic acid ester of 2,4,5-trichlorophenol are dissolved in 200 ecm aniline and heated to about 80 ° for a short time. After separating the excess'? WI ^ | s, z. B. via the hydrochloride, the resulting Reak ^ LonSk product recrystallized from ethyl acetate. The resulting N-Phenylcarbamic acid ^^. S-trichlorophenylestej 'w urJjr by melting point, mixed melting point and A'riSfyse identified.

In addition to the carbamic acid esters mentioned, the following compounds, inter alia, were produced using the specified methods produced in good yields:

N - ρ - chlorophenylcarbamic acid - 2,4,5 - trichlorophenyl ester, M.p. 135 °.

N-m-chlorophenyl ^^. S-trichlorophenyl ester, m.p. 144 up to 145 °,

N-o-Tolylcarbarnic acid 2,4,5-trichlorophenyl ester, melting point 128 to 130 °,

N-p-Tolylcarbamic acid ^^. S-trichlorophenyl ester, m.p. 144 °,

N - ρ - nitrophenylcarbamic acid - 2,4,5 - trichlorophenyl ester, M.p. 182 °.

All of these compounds have undergone an exposure test as well as a test for fungicidal and fungistatic Subject to properties. The study of tolerability and acute oral toxicity at the Mouse was compared with N-disubstituted and N-monoalkyl-substituted carbamic acids ^^ S-trichlorophenyl esters carried out; the N-monoaryl-substituted carbamic acid esters were found on oral administration about half as toxic as the disubstituted esters and about ten to twenty times as well tolerated such as 2,4,5-trichlorophenol. In skin irritation tests on the rabbit ear and in mucous membrane irritation tests on the The N-monoaryl-substituted compounds are also much better tolerated by rabbit conjunctiva than the N-disubstituted and N-monoalkyl-substituted derivatives as well as 2,4,5-trichlorophenol. While with the N-monoalkyl-substituted esters show clear, sometimes severe reddening of the conjunctiva rabbits treated with N-monoaryl-substituted esters showed no findings.

The germ-inhibiting effect of the N-monoaryl-substituted products is against CoIi and Paratyphus bacteria, hemolyzing staphylococci and streptococci about ten times as strong and compared to the skin pathogens Fungi Trichophyton mentagrophytes and Candida albicans about two to ten times as strong as that of the N-disubstituted substances.

The fungicidal effect of the N-monoaryl-substituted derivatives on the soil fungus Rhizoctonia solani (Filter plate method) is about fifty times as large as that of the N-disubstituted carbamic acid ^^. S-trichlorophenyl ester and about the same size as that of tetramethylthiuram disulfide.

Also the fungi Fusicladium dentriticum and Alternaria spec, are much more strongly inhibited in growth by the compounds according to the invention than by the disubstituted esters.

The fungistatic test was also carried out on the pathogenic fungi Epidermophyton floccosum and Sporotrichon Schenckii, Trichophyton rubrum, and Microsporon Andonini, and here too the N-monoaryl-substituted Compounds on average two to ten times as effective as the N-dialkylated carbamic acid 2,4,5-trichlorophenyl ester.

The compounds mentioned are thus well tolerated and show very good fungicidal and fungistatic properties Efficacy, especially against skin pathogens and soil fungi.

Claims (1)

PATENT CLAIM: Process for the preparation of carbamic acid esters of 2,4,5-trichlorophenol, characterized in that that you have a primary amine of the formula R-NH ,, wherein R = Phen3'l or substituted phenyl, with Chloroformic acid ^ AS-trichlorophenyl ester, carbonic acid di-2,4,5-trichlorophenyl ester or 2,4,5-trichlorophenyl cyanoformate is reacted, or 2,4,5-trichlorophenol is reacted with an isocyanate of the formula R-N = C = -O attached or with an N-monoaryl-substituted carbamic acid halide of the formula R -NH-CO-X or with an N-monoaryl-substituted urea of the formula R-NH-CO-NH ₂ reacted, where R has the meaning given above and X is bromine or chlorine. Considered publications:
Chem. Abstr., 49, 4224 d 11955]. © 709 810/336 12. 57