DE1303920B

DE1303920B -

Info

Publication number: DE1303920B
Application number: DE19661303920
Authority: DE
Priority date: 1966-01-15
Filing date: 1966-01-15
Publication date: 1974-11-14
Also published as: DE1303920C2

Claims

Patent claims:

1. Resorcylic anilides of the general formula

OH

<^> - CO -NH

EAR

dl

in which R 1 denotes a halogen atom and R denotes hydrogen, a halogen atom or a methyl group. ■ _s

2. Process for the Hersldluxig of ^ ResorcylsSure-aniliden of the general formula I, thereby characterized dal) one in a known manner

10

a); -Resorcylsäore or their reactive functional derivatives with amine derivatives of general formula 11

H ₁ N - <^> -

(H)(H)

converts or b) compounds of the general formula ΠΙ

OX

<foN — CO -NH - <(VV-R,

OY

around

JJ

in which X and Y are low molecular weight alkyl, aralkyl or acyl groups, with ether-splitting agents treated and / or hydrolyzed.

45

From the Journal of Scientific and Industrial Research of India IIB, 292 (1952), γ-resorcylic acid anilides are (= 2,6-dihydroxybenzoic acid aniItde) known.

A process for the preparation of) <- resorcylic acid anilides of the general formula I has now been developed

5)

OH

EAR

(I)

60

in which R ₁ denotes a halogen atom and R denotes hydrogen, a 6s halogen atom or a methyl group, which is characterized in that one is carried out in a manner known per se

a) --Resorcylic acid or its reactive functional derivatives with aniline derivatives of the general formula II

implements or
b) compounds of the general formula III

, (IN)

»5 in the X and Y low molecular weight alkyl. Aralkyl or acyl groups mean with ether-splitting Agents treated and or hydrolyzed.

According to the invention, the starting materials for the procedure described under a) are anilines in question whose benzene nucleus is substituted by at least one halogen atom in p-Stelhmg. The benzene ring can additionally be substituted by a methyl group or a halogen atom, all of which Halogens come into question, but chlorine and bromine are preferred.

The method according to al is e.g. B. carried out in the manner. that one reacts resorcylic acid with an aniline derivative in the presence of a suitable condensing agent. The reaction is advantageously carried out in an inert solvent. z. B. in an aromatic hydrocarbon such as benzene. Toluene and xylene, or in an ether such as diethyl ether or diisopropyl ether. Phosphorus halides are advantageously used as the condensing agent. Phosphorus trichloride or phosphorus oxychloride are particularly suitable. To accelerate the reaction, the reaction is carried out at elevated temperatures, advantageously at the boiling point of the solvent used. The reaction is generally complete in a few hours. For the isolation of the resulting _y ~ -resorcylic acid anilide-treating the Reaktioosgemisch, optionally after having previously distilling off the solvent. with water and the insoluble product is filtered off.

It is often advantageous not to use free; -resorcylic acid, but rather one of its functional, reactive ones To implement derivatives with the corresponding aniline. Suitable bind for this z. B. Acid Halides. Acid anhydride c or acid esters.

Aromatic esters react particularly smoothly, e.g. 3. the phenyl ester, with the aniiines. In this case the reaction components are mixed with one another and heated to elevated temperatures for a short time, preferably to 160 to 200 ° C. After cooling, the solid reaction product is rubbed expediently with an inert solvent and can then isolate the anilide by filtration. Advantageous the reaction of the aromatic i'-resorcylic acid esters with aniiines can also be carried out in the presence

3 ^V 4

perform high-boiling inert solvents. You can protect those on the hydroxyl groups aromatic hydrocarbons are suitable for this purpose, also with isocyanates or resorcylic acid derivatives or halogenated hydrocarbons, such as xylene tetralin isothiocyanates of the formulas VI or VII and TrichIorbenzoL

Mixed internal anhydrides, which are reactive derivatives of; -Resorcy! Acid for acylation the anilines can be used are, for. B. 2-chloro-5-hydroxy-4H-1,3J-dioxaphosphorom-4-one

of the formula IV and 5-Hydroxv- [1,3] -bcnzodioxan- R 2,4-dione of the formula V ίο

OH

R ₁ - <(o ^> - N = C = S

(VII)

(IV)

co

IV)

They arise from the action of phosphorus trichloride or phosgene on; -resorcylic acid. The implementation with an aniline is advantageously carried out in the presence of an inert solvent, e.g. B. benzene, Toluene, dioxa or dibutyl ether, by heating the reaction mixture to elevated temperatures, preferably heated to the boiling point of the solvent. Treated after completion of implementation the reaction mixture is washed with water and the anilide is isolated in a conventional manner.

The products of the process can be prepared in accordance with the method of operation of the method according to the invention described under b) also prepared by converting compounds of the formula III in which the hydroxyl groups of resorcylic acid through lower Alkyl, aralkyl or acyl radicals are protected, these protective groups by treatment with ether-cleaving Agents or split off by hydrolysis.

The production of these protected resorcytanilides serving as starting materials for the claimed process of the formula III can be carried out, for example, in the manner described above by using from correspondingly substituted formic acid derivatives goes out. This procedure is particularly suitable if the very reactive acid halides are used as resorcylic acid derivatives. As suitable Protecting group be z. B. low molecular weight alkyl groups, such as the methoxy or ethoxy group, or Aralkyl radicals, e.g. B. the benzyl radical called. Low molecular weight acyl radicals are also used as protective groups, such as the acetyl or propionyl radical, in question, as well as aromatic acyl radicals, such as the benzoyl radical or the Carbomethoxy radical.

The acid derivatives protected in this way can in the manner described above with the aniline derivatives to be converted to the compounds of formula III.

in which R, for a halogen atom and R for hydrogen. Stand halogen or methyl, implement. The reaction is expediently carried out between 80 and 160 ° C. in inert solvents, the corresponding anilides of the formula III being formed _{with elimination of CO 2 or COS.}
The protective graves are split off after

ij usual method depending on the nature of the protecting groups. Acyl residues can be z. EL by hydrolysis remove as by treating with dilute alkalis. Alkyl groups can for example by Heating with hydrobromic or hydroiodic acid or other ether-splitting agents such as aluminum chloride or broroid. be split off. Aralkyl groups can be replaced by hydrobromic or hydroiodic acid or by catalytic hydrogenation.

The substances obtained by the process according to the invention are crystalline colorless bodies, which are very sparingly soluble in water. Allow by recrystallization from suitable solvents they generally clean themselves well.

The new anilides of; -resorcylic acid are characterized by a pronounced anthelmintic effectiveness the end. It is particularly directed against tapeworms and surpasses the effect of the tapeworm agent practically used 5-chlorosalicylic acid-2'-cblor-4'-nitroaniltd. Let these superior properties can be read off from Table I below, in which the results of experimental chemotherapeutic experiments for p .. of the process products in comparison with * · ·. .ilicylic acid - 2 '- chloro - 4' - nitroanilide (Niclost. R i. 'Compiled rind. The tests were carried out on for experimental purposes experimentally with Tapeworms infected rats or mice stirred, the compounds to be tested the Animals were administered once perorally in Tylose-Suspenston. The rats were infected with five each cysticercoid from Hymenolepis diminuta obtained from Tribolium comfusum. The infection of the Mice were carried out with 100 eggs each from Hymenolepis fraterna, which were obtained from ripe, crushed proglottids became. After the end of the priority period, the attack on the infection was in each case through Controlled fecal examinations. The success of the treatment was confirmed by repeated faecal examinations on the third and fifth days and by dissecting the animals on the seventh day after treatment. Dose durativa minima is the smallest amount of active ingredient required to completely eliminate the worms led.

1

Table I.

Chemotherapeutic examination for cestodes

WirtxlafT

According to the invention:
2,6-DHBS-4'-chloro-anilide
2. i-DHBS-4'-bromo-an "did
2,6-DHBS-2 \ 4'-dichloro-amlide
2,6-DHBS-4'-iodo-anilide
2,6-DHBS-2 \ 4'-difluorani] id
2,6-DHBS-3'-metbyl-4'-iodanilide

Known:
Niclosamide

Oasis airativa minima, mg fcg

Rough hymenal dimine.

25 16 20 40 24 28

50

Msui

Hymn !, fralcnra

200 175 250 400 200 250

'5

350 κ

In contrast to the 5-CnIomucylic acid-2'-chk> r-4'-nitroanilide known as tapeworm material The anthelmintic effectiveness of the process products also affects other intestinal parasites such as $ 2 Oxyurs. Table II contains the results of studies on mice that were experimentally carried out with each 200 eggs of Aspiculuris tetraptera were innziert. The Tesl substances were given to the animals in TyIose suspended three times administered orally. The success of the treatment was confirmed by faecal examinations after the end of the prepatent period, as well as on the third and fifth day, also by dissecting the animals determined on the seventh day after treatment. The curativa minima dose was that dose.

920 ^BC

new after the three applications of which there were no more worms present.

Table Il

Chemo-therapeutic investigations in oxyurs

Really Dot cur. min.
mgtc
mouse
Aspicitl
tctrapL According to the invention: 2,6-DHBS-4'-fluoro anilide 3-200 2.6-DH BS-4'-cblor-anilide 3 125 2,6-DH BS-4'-bromo-anflid 3-400 Z6-DH BS-4 -iodo anifide 3-400 Known: Niclosamide ineffective

The values given indicate that the products of the process are valuable pharmaceuticals. Sic are primarily suitable for combating tapeworm infestation in humans and domestic or nutritious animals. In addition, they can also be used successfully as therapeutic agents in the presence of mixed nifeclions with several intestinal parasites.

DicausJoumal of Scientificand Industrial Research of India Π Β. 292 (1952). known; -resorcylaniltdc. which, unlike the products of the process, contain no halogen substituents in the studies described no anti-helminal efficacy.

Table III

Contribution
No. material Dosk
lolcm ma *.
(Mouse l
ms kg Disü
Rane
HymenoL
dimine. curaliva minima.
Msib
HymcnoL
Itatcnu mg / kg
mouse
Aspic
lelr. 1 2,6-DHBS-4'-fluoro anilide > 5000 400 3-200 2.11.12 2,6-DHBS-4-chloro-anilide > 2500 25th 200 3 125 3 2,6-DHBS-4'-bromo-anilide > 5000 16 175 3-400 4.6 2,6-DHBS-2 \ 4'-dicWor-anilide > 5000 20th 250 5 2,6-DHBS-2'-methyl-4'-chloro-anilide 750 10 450 3,200 8.10 2.6-DHBS-3 ', 4'-dichlc.r-anilide > 5000 50 9 2.6-DHBW-jud-anihd > 2500 40 400 3-400 Known 5-chlorosalicylic acid-2'-chl or-4'-nitro- 1250 50 350 ineffective aniltd

Example I 2,6-Dihydroxybenzoic acid-4 ^, -n'u oranilide

35 g of 2,6-dihydroxybenzoic acid phenyl ester and 18 g of 4-fluoroaniline are heated together to 195 ° C. for 5 minutes. The reaction product is then cooled to about 20 ° C., the crystalline mass is triturated with 40 ml of benzene, the crystals are filtered off with suction and washed with 80 ml of ethanol. Manerhail 3 "g of 2,6-dihydroxybenzocic acid" (^ Ti ^lid · ^ρ · " ^{224 to 225.1}

_b / "^^ Dihydroxybenzocsiiurephenylcslcr (I ^;: .« 96 ' ^c ' ^{, aBl sic Hau} »2,6-Dihydroxybenzoic acid and phenol by the action of phosphorus oxychloride).

Example 2

Z6-Hydroxybenzocic acid c-4'-cWoranilide

92 g of phenyl 2,6-dihydroxybenzoate and 60 g of 4-chloroaniline are taken together for 10 minutes Heated to 180 ° C. The reaction product is then cooled to about 20 ° C. and the crystalline mass is triturated with 80 ml Benzene, sucks off the crystals. washes them with 60 ml of benzene and 80 ml of ethanol. 101 g of 2,6-dihydroxybenzoic acid-4'-chloroanilide are obtained. F. = 223 to 225 C.

I 303

20th

Example 3
2,6-dihydroxybenzoic acid c-4'-bromometrilide

69 g of 2,6-dihydroxybenzoic acid phenyl chloride and 62 g of 4-bromamline are heated together to 190 ° C. for 10 minutes. Then cool the reaction product to about 20 ° C the crystalline mass ₁ is triturated with 60 ml of benzene, the crystals filtered off, washed with 40 ml of benzene and 100 ml of ethanol. 84 g of 2,6-dihydroxybenzoic acid-4'-bromanilide are obtained. F. = 229 to 230 ° C.

In an analogous way, bulges of equal quality are created:

Example 4 ' ^s

2,6 - Dihydroxybenzoic acid - 2 ', 4' - dichloroanilide, m.p. 240 to 241 "C

Example p

2 ^ -Dihydroxyben20c acid-2'-methyl-4'-chlorariilide, m.p. 209-21 "C

Example 6
2,6-dihydroxybenzoic acid-2 ', 4'-dichloroanilide

IOS g of 2,6-dihydroxybenzoic acid phenyl ester, 75 g of 2,4-dichloroaniline and 90 ml of trichlorobenzene heated together to 195 ° C for 10 minutes. After cooling, the precipitated crystals suctioned off, washed with 100 ml of ethanol and recrystallized from tetrahydrofuran. 68 g are obtained 2,6 - Dihydroxybenzoic acid - 2 ', 4' - dichloroanilide. F. = 241 to 242 ° C

35

Example 7

In an analogous manner, 2,6-dihydroxybenzoic acid-3 *, 4'-dichloroanilide is obtained F. = 267 to 268 ° C.

Example 8
Z6-Dibydroxybenzoic acid-3 ', 4'-dichloroanilide

15.4 g of 2,6-dihydroxybenzoic acid. 33 g of 3,4-dichloroaniline, 450 ml of anhydrous toluene and 15.7 g of phosphorus tricbloride are refluxed together with stirring for 7 hours. Then the toluene is im Distilled off in vacuo, the residue boiled four times with 300 ml of water each time, the undissolved crude product is suctioned off each time. For purification, the crude product is recrystallized from diraan. You get 8 g of 2,6-dihydroxybenzoic acid 3 ', 4'-dichloroaniride. F. = 267 ° C.

Example 9
2,6-Dihydroxybenzoic acid-4-iodanilide

21 g of 2-chloro-5-hydK> xy-4H-lJ.2-benzodioxaphosphorin-4-one, 42 g of 4-iodoaniline and 150 ml of anhydrous benzene are refluxed together for 1 hour. The benzene is distilled off in vacuo, the residue is heated with 250 ml of water for 30 minutes, the dissolved product is filtered off and leached three times with 150 ml of hot water each time. For purification, the crude product is recrystallized twice from glacial acetic acid. 15 g of 2-6-dihydroxybenzoic acid are obtained. F. = 226 ^e C (Z).

(2-chloro-5-hydroxy -4H -13,2-dioxaphosphorin-4-one can be obtained from 2,6-dihydroxybenzoic acid and Produce phosphorus trichloride. It is a colorless Dl, soluble in petroleum ether, which turns with water to form 2,6-dihydroxybenzoic acid implements.)

Example 10
2,6-dihydroxybenzoic acid 3 ', 4'-dichloroanilide

a) 13 g of 3,4-dichloroaniline and U g of triethylamine are dissolved in 65 ml of anhydrous tetrahydrofuran. A solution of 16.1 g is added dropwise to this solution with stirring and cooling (5 ° C. within 5 minutes 2,6-DtmethoxybenzoyIchlorid in 45 ml anhydrous tetrahydrofuran. It is followed by 1 hour, distilled Tetrahydrofuran off, the residue is triturated with 150 ml of water, the crystals are filtered off with suction and triturated successively with 150 ml of 2 u hydrochloric acid and 2 η sodium hydroxide solution, each time suctioning off and washing with 40 ml Water after. The crude product is recrystallized from methanol. 174 g of 2j6-dimethoxybenzoic acid 3 ', 4'-dichloroanilide are obtained obtain. M.p. 181 to 183 ° C.

b> Mg of 2,6-dimethoxybenzoic acid-3 \ 4'-dichloroanilide and 8 ml of 57% hydroiodic acid heated together under reflux for 40 minutes. The reaction product is then cooled and diluted it with 30 ml of water, sucks off the crystals, washes them with 15 ml of water and recrystallizes them from dioxane. 1.1 g of 2,6-dihydroxybenzoic acid-3 ', 4'-dichloroanehd are obtained. F. 267 "C.

55 Example 11
2,6-Dihydroxybenzoic acid-4'-chloroanilide

a) 3.1 g of 2,6-DiroethoxybenzoeuTe and 2.7 g of 4-chlorophenyl isocyanate are heated together in 15 ml of! ^ - dichlorobenzene for 4 hours at 160 ° C. The hot solution is nitrated in vacuum, evaporated the residue is triturated with 15 ml of sodium hydroxide solution , the solid product is filtered off with suction with 15 ml of water and recrystallized twice from methanol to give 2J6 g ZO-Dimethoxybcnzoesäure-4'-chloroanilide. F. 210-21 I ^e C

b) IX g of 2Jü-dimethoxybenzoic acid-4'-chloroanilide are heated under reflux for 40 minutes with 10 ml of 57% strength iodine hydrochloric acid. The reaction mixture is then cooled. dilute it with 30 ml of water, siphon off the crystals. wash them with 15 ml of water and recrystallize them from methanol. 12 g of Z6-dihydroxybenzoic acid-4'-chloranilide are obtained. F. = 223 «8 225-0.

Example 12
2,6-Dihydroxybenzic acid-4'-chloroanilide

a) Ug W-dimethoxybenzoic acid and 1.4 g of 4-CMorphenyliMthiocyanat are together in 8 ml 1.2-dichlorobenzene heated to 160 ° C. for 4 hours. The hot solution is nitrated and evaporated in vacuo the residue is triturated with 15 ml of sodium hydroxide solution, the solid product is filtered off with suction, with 10 ml of water washed and recrystallized from methanol. Yield QjB g 2 ^ DrmrthOTybenzoesäujT-4'-cbIoianflid. F. 210 to 21 rC.

b) The methoxy groups are split off as described in Example 10b).

409 54V356

Example 13 β c ■ a μ ■ c ι ι · »

2.6 Dihydroxyben oesäure.2 _Z ', 4'Klifl _UO ranilid 2,6-Dihyd _ro XYB n2oesäure _{e-3'-melhyM'-jodanilid}

From 12 g of 2-chloro-5-hydroxy-4H-1,3,2-benzo-dioxa-

Obtained from 36 g of 2,6-dihydroxybenzoic acid and 20 g of 2,4-di-5 phosphorin-4-one and 29 g of 3-methyl-4-iodaniline

Auoraniline is obtained by the method described in Example 3 by the method described in Example 9

benen method 37 g of 2,6-dihydroxybenzoic acid- 10g 2,6-dihydroxybcnzoic acid-3'-methyI-4'-iodine-

2 ', 4'-difluoraniKd. M.p. = 242 to 244 ° C anilide. F. - 216 "C.