SU346857A1 - METHOD OF OBTAINING ANYLIDES OF DIACYLOXYBENZENOIC ACID - Google Patents

Description

The invention relates to the field of the preparation of new derivatives of hydroxybenzoic acid, in particular diacyloxybenzoic acid anilides, which can be used in the medical industry.

A method for the preparation of diacyloxybenzoic acid anilides of the general formula O-CO-R B CO-NH O-CO-R is proposed, where X is hydrogen or halogen; R is a nitro group, trifluoromethyl group and (or) halogen atoms; R2 is lower alkyl, which in this case can be substituted by halogen, lower alkoxan or phenyl, hydrogen, alkenyl with 3-6 carbon atoms, cycloalkyl with 4-6 C atoms, phenyl, unsaturated heterocyclic 5- or 6-membered ring, alkylaminoyl dialkylamino in which the alkyl groups contain respectively 1-5 C atoms or together with the nitrogen atom can form a nirrolidine, piperidipic, morpholine or N-methylpiperazine ring.

The method of obtaining the above compounds, based on the known acylation reaction of hydroxyl groups, is that the dihydroxybenzoic acid anilide of the general formula: where X and R have the above values, is reacted with an acylating agent, a carboxylic acid, or carbamic acid, or their anhydride or acid chloride, or isocyanate in the presence of a condensing agent, followed by isolation of the target product by a known technique. The process can be carried out in an organic solvent medium with heating not exceeding the boiling point of the solvent. Tertiary amines, sulfuric acid, sulfonic acid, polyphosphoric acid or anhydrous zinc chloride are used as a condensing agent.

The compounds of formula I are crystalline, colorless substances, insoluble or slightly soluble in water.

 1. 4-Chloro1-1Ilide 3-nitro-2,6 lyacetoxybenzoic acid.

15.5 g of 4-chloroanilide 3-n1ggro-2,6-dihydroxy-isoic acid, 40 ml of acetic anhydride and three drops of endtitration and agglomerate 70 l to 85 ° C. After cooling, 120 ml of water are added, the precipitated crystals are sucked off, washed with 50 ml of water, dried and recrystallized from benzene. Obtain 15.2 g of 4-chloroanilide Z-nitro-2,6 diacetoxybenzoic acid, pour point 144 ° C.

Example 2. 3,5-Bnstrifluoromethylanilide 3-ytro-2,6-diacetoxybenzoic acid.

60 g of 3-nitro-2,6-dihydroxybenzoic acid, 5,6-bistrifluoromethylylide, 100 ml of acetic anhydride and 10 ml of acetyl chloride are heated together for 3.5 hours to 90 ° C. The solution is evaporated in vacuo and the oily residue is dissolved in double the volume of benzene. After evaporation of this solution, a solid residue is obtained, which is first recrystallized from benzene and then from methanol. 46 g of 3,5-bistrifluoroethyl anilide 3-nitro-2,6-diacetoxybenzoic acid are obtained, pouring point 169-170 ° C.

In a similar manner, 3,5-bistrifluoromethyl anilide of 3-nitro-2,6-dinropioyl-izoxy-isoic acid, yield point, is obtained.

Example 3. 3,5-Bistrifluoromethylanilide 3-nitro-2,6-dicapronyloxybenzoic acid 1L.

41 g of 3,5-bistrifluoromethyl anilide 3-nitro2, 6-dip1-hydroxybenzoic acid, 5 g of anhydrous zinc chloride, 150 ml of benzene and 55 g of caproic acid chloride are heated together with reflux for 7 hours. The still hot solution is filtered and evaporated in vacuo. The residue is non-recrystallized from the following: Ke volume of dinzonyl ether. 30 g of 3,5-bistrifluoromethylanilyl are obtained, and 3-nitro-2,6-dacapronyloxybenzoic acid, a pour point of 95 ° C.

PRI me R 4. 2,4,6-tri.chloroanilide 3-nitro2, 6-d | acetoxybenzoic acid.

In a mixture of 75 g of 2,4,6-trichloroanilide 3-i1ggro-2,6-digndrooxybenzoic acid, 160 ml of tetra.methylene sulfone and 15 g of anhydrous zinc chloride are instilled with stirring, 95 ml of acetic anhydride, so that the temperature does not exceed and mix further 3 hours at 85 ° C. After cooling, 600 ml of water is added, and the oil is precipitated, which after about 1 hour becomes solid. The crude product is filtered off with suction, washed with 300 ml of water and recrystallized with methanol. 46 g of 2,4,6-trnechloroanilide of 3-nitro-2,6-dnacetoxybenzoic acid are obtained, pouring point 191 ° C.

Example 5. 2,4,6-Trichloroanilide 3-nitro2, 6-dibenzoyloxybenzoic acid.

90 ml of tetramethylene sulfone, 30 ml of pyridine and 38 g of 2,4,6-trichloro nilide Z-nitro-2,6 dihydroxybenzoic acid are mixed together at 50 ° C. 34 g of benzoyl chloride are instilled into the resulting solution so that the temperature does not exceed 70 ° C, and stirred for another 2 hours at 50 ° C. After

cooling is diluted with 450 ml of water, the aqueous solution is poured, boiled with 200 ml of methanol and left to crystallize. The precipitated crystals are filtered off with suction, washed with 50 ml of methanol and recrystallized from methanol. 46 g of 2,4,6-trichloroanilide 3-nitro-2,6-dibenzoyloxybenzoic acid, yield point (decomposition) is obtained. PREMIER 6. 3,5-Bistrifluoromethylanilide

3-nitpo-2,6-di- (N-methylcarboxylic) - benzoic acid.

45 g of 3,5-bistrifluoromethyl anilide 3-nitro2, 6-dihydroxybenzoic acid, 350 ml of acetone, 0.5 ml of pyridine and 25 g of methyl isocyanate

heated together for 10 minutes to 40 ° C. A solution is first formed, and crystallization begins later, which ends at room temperature after 6 hours. The crystals are filtered off with suction and washed with 80 ml of acetone. Obtain 36 g of 3,5-bistrifluoromethylanilide 3-nitpo-2,6-di- (N - methylcarbamyloxy) -benzoic acid, pour point 226 ° C (decomposition). PRI me R 7. 3,5 ..Bistrifluoromethylanilide

3-HHTpo-2,6-6HC- (N, N - dimethylcarbamyloxy) benzoic acid.

50 g of 3,5-bistrifluoromethyl anilide of 3-nitro-2, 6-dihydroxybenzoic acid in 135 ml of pyridine are instilled with stirring in

for 25 minutes 45 g of acid chloride N, N-diethylcarbamic acid. Additionally stirred for 30 minutes at room temperature and 3 hours at 70 ° C. After cooling, the mixture is diluted with 800 ml of water, the solid product is filtered off with suction, washed with 150 ml of water and, after drying, recrystallized from diisopronyl ether. 45 g of 3,5-bistrifluoromethyl anilide of 3-nitro-2,6-bis- (N, N diethylcarbamyloxy) benzoic acid are obtained, pouring point 139-141 ° C.

Example 8. 4-Chloranilide 5-iodo-3-nitro2, 6-dimethoxybenzoic acid.

A. 30.8 g of 4-chloroanilide 3-nitro-2,6-dihydroxybenzoic acid, 230 ml of ice

acetic acid and 16.2 g of iodine monochloride are heated to 7 at 90 ° C while stirring. After cooling, the precipitated crystals are sucked off and washed with 50 ml of glacial acetic acid, then 50 ml of methanol. Get 34,2 e 4-chloroanilide 5-iodine-3-nitro2, 6-dihydroxybenzoic acid, pour point 190-19 HS.

Zinc is heated together for 20 minutes to 85 ° C. After cooling, almost colorless crystals are sucked off and washed with 8 ml of methanol. 7.5 g of 4-chloroanilide 5-iodo-Znitro-2, 6-diacetoxybenzoic acid are obtained, pouring point 201 ° C.

Example 9. 4-Bromoanilide 3-nitro-2,6-bis (furoidoxy) -benzoic acid.

In a mixture of 25 g of 4-bromoanilide Z-nitro-2,6 dihydroxybenzoic acid, 70 ml of tetramethylene sulfone and 30 ml of pyridine are instilled over 30 minutes with stirring 30 g of furan-2-carboxylic acid chloride, so that the temperature does not exceed 40 ° C. The mixture is stirred at room temperature for 2 hours. The mixture is diluted with 400 ml of water, the aqueous solution is poured and the remaining oil is stirred for 1 hour with 120 ml of methanol, and crystallization begins. The crystals are filtered off with suction and washed with 45 ml of methanol. Obtain 30 g of 4-bromoanilide-3-nitro-2,6bis- (furryloxy) -benzoic acid, a pour point 19GS.

Example 10. 3,5-Bistrifluoromethylanilide Z-nitro-2,6-bis - (piperidinocarbonyloxy) benzoic acid.

In 50 g of 3,5-bistrifluoromethyl anilide of 3-nitro-2, 6-dihydroxybenzoic acid in 135 ml of pyridine, 49 g of piperidine chloride of N-carboxylic acid are instilled with stirring so that the temperature is kept at 40-45 ° C. Finally, it is stirred for 2 hours at 70 ° C, cooled, diluted with 750 ml of water and the aqueous solution is poured. The residual oil is diluted with 100 ml of ethanol and crystallized. The crystals are sucked off and washed with 60 ml of ethanol. Get 50 g of 3,5-bistrifluoromethylanilide 3-nitro-2,6-bis - (piperidinocarbonyloxy) -benzoic acid, pour point 166 ° C.

Similarly, receive:

3,5-Bistrifluoromethylanilide Z-nitro-2,6 dibutyryloxybenzoic acid,

3,5-Bistrifluoromethylanilide - 3-nitro-2,6 diclohexyloxybenzoic acid,

3,5-Bistrifluoromethylanilide 3-nitro-2,6bistienyl- {3) -oxybenzoic acid.

3,5-Bistrifluoromethylanilide 3-nitro - 2,6 bispirprolidinecarbonyloxybenzoic acid.

Subject invention

The method of obtaining diacyloxybenzoic acid anilides, general, formula

0 O-CO-R

R

ten

j —co — NH;

O-CO-R

where X is hydrogen or halogen;

R - nitro group, trifluoromethyl group

and (or) halogen atoms;

R is lower alkyl, which in this case can be mixed, en halogen, lower

alkoxy or phenyl, hydrogen, alkenyl with 3-6 carbon atoms, cycloalkyl with 4-6 C atoms phenyl, unsaturated heterocyclic 5- or 6-membered ring, alkylamino or dialkylamino, in which the alkyl group

contain respectively 1-4 C atoms or, together with the nitrogen atom, can form a pyrrolidine, piperidine, morpholine or N-methylpiperazine ring, characterized in that the dihydroxybenzoic acid anilide of the general formula

HE

R

J CO-NH- C X OH

where X, R have the above meanings) is reacted with an acylating agent — carboxylic acid or carbamic acid, or their anhydride or acid chloride, or isocyanate in the presence of a condensing agent, followed by isolation of the target product by a known technique.

2. A method according to claim 1, characterized in that the process is carried out in an organic solvent medium at a temperature not higher than the boiling point of the solvent.