US2923737A - Benzoic acid amides showing antimy- - Google Patents

Benzoic acid amides showing antimy- Download PDF

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US2923737A
US2923737A US2923737DA US2923737A US 2923737 A US2923737 A US 2923737A US 2923737D A US2923737D A US 2923737DA US 2923737 A US2923737 A US 2923737A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom

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  • the present invention relates to benzoic acid amides" showing antimycotic action and a process for their manufacture, and it especially relates to compounds selected from the group consisting of benzoic acid amides of the general formula alkyl radicals containing an alkylene group with at most 2 carbon atoms, cycloalkyl and cycloalkylalkyl radicals containing 5-8 carbon atoms, R is a member selected from the group consisting of hydrogen and an alkyl group having at most 4 carbon atoms, and alkali metal salts of these compounds.
  • alkyl amides, halogenated in fl-position, of halogenated salicylic acids, particularly 3,5-dichloro-2-hydroxy-benzoic acid-B-chlorethyl amide can be used as preserving agent for wood or paper-pulp (compare French Patent 1,099,272).
  • R is a member selected from the group consisting of hydrogen and an alkyl group having at most 4 carbon atoms.
  • halogen substituents in the benzene nucleus of the 4-halogen-Z-hydroxy-benzoic acid derivatives used as starting substances according to the invention there may be used chlorine, bromine and iodine.
  • amines there can be used primary or secondary amines of straight-chained or branched, saturated or unsaturated aliphatic character, preferably primary amines with an aliphatic radical containing 3-6 carbon atoms.
  • ethylamine n-propylamine
  • isopropylarnine n.- butylamine
  • isobutylamine secondary butylamine, tertiary butylamine
  • n-pentylarnine isoamylamine
  • n-hexyl amine n-heptylamine
  • allylamine crotylamine
  • methylpropylamine and. di-n-propylamine.
  • Araliphatic amines such as benzylamine, fi-phenyl-ethylamine can also be used.
  • cycloalkylor cycloalkyl-alkylamines there can be used, for instance: Cyclo-pentylamine, cyclo-hexylamine, cycloheptylamine, cyclo-hexyl-methylamine and cyclohexyl-ethylamine.
  • the reac: tion conditions can be varied to a large extent.
  • the reactions can be carried out in the presence or absence of solvents or diluents, at low or at elevated temperatures, temperatures in the range from 70" C. to C. having proved to be favourable for the reactions of the 4-halogen-Z-hydroxy-benzoates with amines.
  • Tem-. peratures below +10 C. are chosen when 4-halogen-2- hydroxy-benzoic acid azides are used.
  • the amines can be used in an equimolar amount or in excess.
  • the products obtained according to the process of the invention are valuable medicaments and are, in particular, appropriate to be administered as antimycotics.
  • the concentrations indicated in 'y/ml. in the tables were sufiicient enough as to completely inhibit, in a solid culture medium, any growth of the fungi mentioned above, even after a period of 18 days.
  • the relative protein factors indicated constitute a ratio for the relative inactivation of the products claimed according to the invention by addition of serum and indicate the multiple by which the antimycotic action is reduced in the pres- .ence of protein,
  • the benzoic acid amides obtained according to the process of the invention and containing in the benzene nucleus bromine or iodine show the same action against .fungi pathogenic to humans as the chlorine compounds mentioned in the tables, irrespective of serum being added or not.
  • cut invention are characterized by a better activity, especially in the presence of protein, and by a low protein factor hitherto nearly unknown.
  • protein 4 therapeutical treatment were favourably influenced by a solution of 2% strength of, for instance, 4-chloro-2- hydroxy-benzoic acid-n-butylamide.
  • the benzoic acid amides obtainable according to the process of the present invention are very non-toxic substances.
  • 4-chloro-2-hydroxy-benzoic acidn-butylamide obtained according to the process of the present invention is tolerated in Swiss mice in doses up to 10 grams/kilogram in a suspension of 10% strength in starch mucilage.
  • the products of the process claimed are favourably judged as the test described by the following has shown.
  • a large number of male Swiss mice having a weight of 100 to 150 grams was fed 28 times within 38 days with a dose of 1 gram/kilogram each time of 4-chloro-2-hydroxy-benzoic acid-n-butylamide. All animals showed a normal behaviour and an increase in weight.
  • the new products can be administered in substance as well as in solution or emulsion, furthermore in the form of ointments or powders if desired in admixture with one another and/ or with other compounds showing an antimycotic or bactericidal action.
  • the products of the invention can also be used in the form of their salts or in the presence of substances which lead to the formation of their salts.
  • alkaline agents such as alkali metal hydroxides or alkaline earth metal hydroxides, furthermore physiologically tolerable organic bases can be used.
  • Alkali metal salts are particularly appropriate since they are characterized by a very good resistance to the air.
  • Example 1.4-chlor0-2-hydr0xy-benz0ic acid-n-butyl-amide A mixture consisting of 114 grams of 4-chloro-2- hydroxy-benzoic acid-n-butyl-ester, 64 grams of methanol and 130 grams of n-butyl-amine is heated for 22 hours at C.; then the parts volatile up to C. are distilled off under reduced pressure. The residue crystallizing in the cold is dissolved in 200 cc. of methanol and the solution obtained is slowly added dropwise and while stirring into dilute hydrochloric acid, if necessary, after treatment with animal charcoal. The precipitate which is at first semi-solid soon crystallizes completely.
  • the 4-chloro-2-hydroxy-benzoic acid-n-butylamide forms complex compounds which per 2 molecules of amide contain 1 molecule of amine.
  • the complex compound of 2 molecules of 4-chloro-2-hydroxybenzoic acid-,n-butylamide and -1 molecule of n-butylamine after recrystallization from chloroform melts at 98-100 C.
  • the reaction mixture obtained is cooled and introduced:dropwise,whilesstirring, into 0.1 N-hydrochloric acid.
  • the crystallized precipitate is filtered ofi with "suction, dissolved in 50 cc. of methanol, the solution is treated itwice with charcoal in order to be decolorized, the amide is again precipitated by intrdductiominto' 0.1 N-hydrochloric acid and dried at the air.
  • the 4-chloroQ-hydroxy-benzoic acid-allyl-amide melts at 9193 C.
  • Example 5 -4-chlar0-2 .hydroxy benzoic aci -nu yF amide .34 grams .of 4-cliloro-J2-hydroxyrbenzoicacid, ,51 grams of freshly distilled oxalyl chloride and 100 cc. .of absolute benzene are heated for 5 hours to boiling, while stirring, whereby slow decomposition of the acid sets in together with evolution of gaseous hydrogen chloride. The solution is boiled for 3 further hours and then distilled under reduced pressure so that the parts volatile up to 50" C. are removed as completely as possible. The residue which completely crystallizes :on cooling and after having been pressed on clay melts at about 150 C.
  • the finely pulverized product is triturated in several portions with water, dilute hydrochloric acid :and again with water, then filtered off with suction and dried in the air. .After having beenrccrystallized twice from carbon tetrachloride the 4-chloro-2-hydroxy benzoic ,acid-n butyl-amide is obtained in the form ofw'hite leaflets melting at -92 C.
  • Example 6.-4-br0,m0-2 hydr0xy1benz0ic acid-nebutylamide 23 grams of 4-bromo-2-hydroxy-benzoic acid-ethylester (prepared by esterification of 4-bromo-2-hydroxye benzoic acid of a melting point of 214-2l5 C. with ethanol in the'presence of concentrated sulphuric acid), 14.6 :grams of n-butylamine and 16 cc. of ethanol are heated for 20 hours at 80 C. The cooled reaction mixture'is introduced, while stirring, into dilute hydrochloric acid, and the crystalline precipitate is filtered off with suction.
  • 4-bromo-2-hydroxy-benzoic acid-ethylester prepared by esterification of 4-bromo-2-hydroxye benzoic acid of a melting point of 214-2l5 C. with ethanol in the'presence of concentrated sulphuric acid
  • 19.6 grams of 4-chloro-2- hydroxy-benzoic acid hydrazide are diazotised in water with a solution of 7.3 grams of sodium nitrite, and the 4-chloro2-hydroxy-benzoic acid azide obtained is reacted in an ethereal solution with 17 grams of allyl-ethyl-amine.
  • Example 9.4-chloro-2-hydroxy-benzoic acid-cyclohexyl-amide 18.6 grams of 4-chloro-2-hydroxy-benzoic acid methylester, 40 grams of cyclohexylamine and 20 cc. of methanol are heated for 24 hours at about 100 C. The cooled reaction mixture is introduced, while stirring, into 300 cc. of 1 N-hydrochloric acid. After having been allowed to stand for a short time the semi-solid precipitate crystallizes. The precipitate is filtered with suction, washed with water, the crystals are triturated with 2 N-hydrochloric acid, again filtered off with suction and washed again with water.
  • Example 10.-4-chloro-2-hydroxy-benzoic acid-cyclo-hexyI-methyl-amide 19.6 grams of 4-chloro-2-hydroxy-benzoic acid-hydrazide melting at 207-210 C. (prepared by reaction of 4-chloro-2-hydroxy-benzoic acid methylester with hydrazine hydrate in methanol) are suspended in 125 cc. of glacial acetic acid and 400 cc. of 2 N-hydrochloric acid.
  • the mixture is cooled to about -3 C. and diazotised, while stirring, with a solution of 7.3 grams of sodium nitrite in 50 cc. of water.
  • Example 11 -4-chloro-2-hydroxy-benzoic acid-n-heptyl-amide 75 grams of 4-chloro-Z-hydroxy-benzoic acid-hydrazide are suspended in 150 cc. of glacial acetic acid and 1000 cc. of 2 N-hydrochloric acid. The mixture is cooled to sulfate, 69 gra ms of n-heptyl-amine are added in portions. The ethereal solution is allowed to stand for .24

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Description

c 2,923,737 1C Patented Feb. 2,1961} BENZOIC ACID AMIDES SHOWING ANTDVIY! COTIC ACTION AND A PROCESS FOR THEIR MANUFACTURE Heinrich Ruschig, Bad Soden (Taunus), and Gerhard Korger, and Georg Nesemann, Frankfurt am Main, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormais Meister Lucius & Briining, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Application December 19, 1958 Serial No. 781,453
Claims priority, application Germany January 26, 1956 6 Claims. (Cl. 260559) The present invention relates to benzoic acid amides" showing antimycotic action and a process for their manufacture, and it especially relates to compounds selected from the group consisting of benzoic acid amides of the general formula alkyl radicals containing an alkylene group with at most 2 carbon atoms, cycloalkyl and cycloalkylalkyl radicals containing 5-8 carbon atoms, R is a member selected from the group consisting of hydrogen and an alkyl group having at most 4 carbon atoms, and alkali metal salts of these compounds.
It is known that for the treatment of mycoses in human beings a large number of medicaments can be used whose active components belong to quite different substance groups. In addition to inorganic active substances, there have been recommended, for instance, phenols, such as 2,2-dihydroxy-5,5'-dichloro-diphenyl sulphide fatty acids, dyestuifs, invert soaps, organic mercury compounds, antibiotics, quinoline derivatives, halogenated salicylic acid anilides, especially S-bromo-salicylic acid 4'-chloranilide (of. Deutsche Medizinische Wochenschrift, 79 (1954), page 1297).
It is further known that the calcium salt of S-bromosalicylic acid-isopropyl amide in admixture with sulphanilyl carbamide can be used for preparing an antiseptic vulnerary powder (cf. Zentralblatt, 1952, page 4657).
It is also known that alkyl amides, halogenated in fl-position, of halogenated salicylic acids, particularly 3,5-dichloro-2-hydroxy-benzoic acid-B-chlorethyl amide can be used as preserving agent for wood or paper-pulp (compare French Patent 1,099,272).
s it ing of alkyl and alkenyl radicals containing 2 -i7 carbon atoms, phenylalkyl radicals containing an alkylene group with at most 2 carbon atoms, cycloalkyl and cycloalkylalkyl radicals containing 5-8 carbon atoms, R is a member selected from the group consisting of hydrogen and an alkyl group having at most 4 carbon atoms. A
As reactive derivatives of 4-halogen-2-hydroxy-benzoic acids there are particularly suitable their esters with low molecular aliphatic alcohols or with phenols as well as the corresponding halides and azides.
As halogen substituents in the benzene nucleus of the 4-halogen-Z-hydroxy-benzoic acid derivatives used as starting substances according to the invention there may be used chlorine, bromine and iodine.
As amines there can be used primary or secondary amines of straight-chained or branched, saturated or unsaturated aliphatic character, preferably primary amines with an aliphatic radical containing 3-6 carbon atoms.
The following compounds may be mentioned, for instance: ethylamine, n-propylamine, isopropylarnine, n.- butylamine, isobutylamine, secondary butylamine, tertiary butylamine, n-pentylarnine, isoamylamine, n-hexyl amine, n-heptylamine, allylamine, crotylamine, methylpropylamine and. di-n-propylamine. Araliphatic amines, such as benzylamine, fi-phenyl-ethylamine can also be used.
As cycloalkylor cycloalkyl-alkylamines there can be used, for instance: Cyclo-pentylamine, cyclo-hexylamine, cycloheptylamine, cyclo-hexyl-methylamine and cyclohexyl-ethylamine.
According to the process of the invention the reac: tion conditions can be varied to a large extent. For instance, the reactions can be carried out in the presence or absence of solvents or diluents, at low or at elevated temperatures, temperatures in the range from 70" C. to C. having proved to be favourable for the reactions of the 4-halogen-Z-hydroxy-benzoates with amines. Tem-. peratures below +10 C. are chosen when 4-halogen-2- hydroxy-benzoic acid azides are used. The amines can be used in an equimolar amount or in excess.
Together with amines the products obtained according to the process of the invention form complex compounds which contain one mol of amine per each two mols of amide.
The products obtained according to the process of the invention are valuable medicaments and are, in particular, appropriate to be administered as antimycotics. As
such, in addition to very good tolerability, they are of considerable action and are especially characterized by a very low protein factor, whereby the partial or complete inactivation of antimycotic substances in the presence of protein is to be understood.
The antimycotic action of various products obtained according to the process of the invention on a large number of fungi pathogenic to humans, with or without ad.- dition of protein, are to be seen from Tables I and II.
The concentrations indicated in 'y/ml. in the tables were sufiicient enough as to completely inhibit, in a solid culture medium, any growth of the fungi mentioned above, even after a period of 18 days. The relative protein factors indicated constitute a ratio for the relative inactivation of the products claimed according to the invention by addition of serum and indicate the multiple by which the antimycotic action is reduced in the pres- .ence of protein,
The benzoic acid amides obtained according to the process of the invention and containing in the benzene nucleus bromine or iodine show the same action against .fungi pathogenic to humans as the chlorine compounds mentioned in the tables, irrespective of serum being added or not.
In contradistinction to comparable compounds showing antimycotic' act'ionwhich are hitherto known, the
cut invention are characterized by a better activity, especially in the presence of protein, and by a low protein factor hitherto nearly unknown. Generally, the protein 4 therapeutical treatment were favourably influenced by a solution of 2% strength of, for instance, 4-chloro-2- hydroxy-benzoic acid-n-butylamide.
Clinical tests also confirmed the good tolerability of factor of the known compounds showing antimycotic ac- 5 the products obtained according to the process of the tion amounts to more than and was found to be in the invention. Soon after the treatment with the benzoic range of 32 to 120 for the known S-bromo-salicyhc acidacid amides obtained according to the process of the 4'-chloro-anil1de, when examined under comparable coninvention has been started, the disagreeable pruritus disditions and with various fungi. appears. The good nonirritant tolerability of the prod- TABLE I [Active concentration in 'y/ml. for the preparations.]
4-ehloro-2-hydroxy-benzoic 4-chloro-2-hydroxy-beuzoic 4-chloro-2-hydroxy-benzoie 4-chloro-2-hydroxy-benzoic acid-n-butylamide acid-n-hexylarnide acid-n-pentylamide acid-allylaniide Fungi pathogenic to humans without with relative without with relative without with relative without with relative serum 20% protein serum 20% protein serum 20% protein serum 20% protein serum factor serum factor serum factor serum factor lllicrosporum gypseum 8 31 3. 8 4 31 7. 7 8 31 3. 8 16 31 1. 9 Microsporum canis 8 31 3. 8 4 16 4. 0 4 31 7. 7 4 8 2.0 Epidermophyton rubrum.- 8 31 3.8 4 31 7. 7 4 31 7. 7 8 31 3. 8 Trichophyton rotundum 4 16 4. 0 4 31 7. 7 4 31 7. 7 8 31 3. 8 Trichophyton mentagrophytesfl 8 31 3. 8 8 31 3. 8 8 31 3.8 16 31 1.9 Trichophyton plicutile 8 16 2.0 4 31 7. 7 4 31 7. 7 8 31 3. 8
TABLE II [Active concentrations for the preparations in 'y/mL] 4-0111oro-2-i1ydroxy-benzoic 4-ch1oro-2-hydroxy-benzoic 4-chloro-2-hydroxy-benzoie 4-chloro2-hydroxy-benzoic acid-cyclohexylamide acid-B-phenethylamide v acid-isopropylamide acid-isobutylamide Fungi pathogenic to humans without with relative without with relative without with relative without with relative serum 20% protein serum 20% protein serum 20% protein serum 20% protein serum factor serum factor serum factor serum factor Microsporu'm gz pseum 4 31 7. 7 8 62 7. 7 16 62 3. 8 8 31 3.8 Microsporum m'm'v 8 16 2.0 2 16 p 8.0 lldicrosporu'm lanosum 8 31 3.8 16 62 3. 7 Epidermophyton rubruvrl... 8 31 3.8 .8 62 7.7 16 62 3.8 8 16 2.0 Trichophyton rotundum 4 31 7. 7 8 62 7. 7 8 62 7- 7 4 16 4. 0 Trichophyton mentagrophytcs 8 62 7. 7 8 62 7. 7 16 62 3. 8 16 31 1. 9 Trichophyton plicatile 4 31 7. 7 8 62 7. 7 8 62 7. 7 4 16 4.0
The benzoic acid amides obtainable according to the process of the present invention are very non-toxic substances. For instance, 4-chloro-2-hydroxy-benzoic acidn-butylamide obtained according to the process of the present invention is tolerated in Swiss mice in doses up to 10 grams/kilogram in a suspension of 10% strength in starch mucilage. Also as regards the subchronic toxity, the products of the process claimed are favourably judged as the test described by the following has shown. A large number of male Swiss mice having a weight of 100 to 150 grams was fed 28 times within 38 days with a dose of 1 gram/kilogram each time of 4-chloro-2-hydroxy-benzoic acid-n-butylamide. All animals showed a normal behaviour and an increase in weight. After autopsy no visible pathological alteration was observed. The histological examination of the organs did not disclose any alteration which could be attributed to a damage caused by the product claimed according to the process of the invention. The compounds obtained according to the process of the invention are also well tolerated by the mucous membrane. When tested intracutaneously or epicutaneously in the rabbits ear, a solution of 10% strength of 4-chloro-2-hydroxybenzoic acid-n-butyl-amide did not cause any irritation. Also in the rabbits eye the solution was tolerated without causing irritation.
Clinical tests fully confirmed the antimycotic action of the products obtained according to the process of the invention, for instance of 4-chloro-2-hydroxy-benzoic acid-n-butylamide. Even in cases resistant to therapeutical treatment, for instance hyperkeratosic, obstinate interdigital-mycoses, scrotal mycoses, anal mycoses as well as in cases showing thrush (soor) character, very good results could be obtained. Also chronical epidermophytoses :existing'for a long time and, hitherto, resistant to all ucts obtained according to the process of the invention is of particular importance when treating anal mycosis.
The new products can be administered in substance as well as in solution or emulsion, furthermore in the form of ointments or powders if desired in admixture with one another and/ or with other compounds showing an antimycotic or bactericidal action. The products of the invention can also be used in the form of their salts or in the presence of substances which lead to the formation of their salts. For the salt formation alkaline agents, such as alkali metal hydroxides or alkaline earth metal hydroxides, furthermore physiologically tolerable organic bases can be used. Alkali metal salts are particularly appropriate since they are characterized by a very good resistance to the air.
The following examples serve to illustrate the invention, but they are not intended to limit it thereto:
Example 1.4-chlor0-2-hydr0xy-benz0ic acid-n-butyl-amide A mixture consisting of 114 grams of 4-chloro-2- hydroxy-benzoic acid-n-butyl-ester, 64 grams of methanol and 130 grams of n-butyl-amine is heated for 22 hours at C.; then the parts volatile up to C. are distilled off under reduced pressure. The residue crystallizing in the cold is dissolved in 200 cc. of methanol and the solution obtained is slowly added dropwise and while stirring into dilute hydrochloric acid, if necessary, after treatment with animal charcoal. The precipitate which is at first semi-solid soon crystallizes completely. It is filtered with'suction, washed with dilute hydrochloric acid, then thoroughly washed again with water, and the product obtained in good yield is dried in the air. After having been recrystallized twice from carbon tetrachloride the 4-.chloro-2-hydroxy-benzoic acidn-butylamide melts at 90-92 C.
Together with amines and in the same manner as the amides described below the 4-chloro-2-hydroxy-benzoic acid-n-butylamide forms complex compounds which per 2 molecules of amide contain 1 molecule of amine. The complex compound of 2 molecules of 4-chloro-2-hydroxybenzoic acid-,n-butylamide and -1 molecule of n-butylamineafter recrystallization from chloroform melts at 98-100 C.
Sodium .salt of 4-chloro-Z-hydraxybenzoic .acid-n-butyltamide 68.3 grams of 4-chloroi2 hydroxy benzoic acid-n-butylamide are dissolved in 300 cc. of 1 N-sodium hydroxide solution, while being warmed. On cooling, the sodium salt crystallizes 'as hydrate and in the form of white crystals. It is vigorously filtered with suction, the product obtained is dissolved, while heated, in '200 cc. of acetone, the pl-l is adjusted to about 8 by dropwise adding concentrated sulphuric acid, the mixture is filtered and ether is slowly added to the ,acetonic solution. Thereby the sodium salt of 4-chloro-2 hydroxy benzoic acid-nbutylamide precipitates in the form of snow white crystals as trihydrate. The anhydrous salt shows a melting point of 275-280 'C."Kwith decomposition). Example 2.-4-chlor0-2 hydroxy-benzoic acid-n-hexylamide 18.6 grams of 4-chloro-2 hydroxy-benzoic acid-methylester, 13 grams of methanol and 40 grams of n-hexylamine are reacted and worked up as described in Example 1. After having been recrystallized twice from cyclohexane 4-chloro-2=hydroxy benzoic 'acid-n-hexyl-amide is obtained in 'a good yield. The product melts *at 75- 76.5 "C.
In "an analogous manner the following amides were prepared:
Example 3.--4-chloro 2 hydroxy benzoic 'acid-allyl-amide' 20 grams of l=cliloro 2=hydr0xy-benzoic acid-ethylester, 18 grams of ethanol and L8 grams of allylamine= are heated for 20 hours at 100 'C. The reaction mixture obtained is cooled and introduced:dropwise,whilesstirring, into 0.1 N-hydrochloric acid. The crystallized precipitate is filtered ofi with "suction, dissolved in 50 cc. of methanol, the solution is treated itwice with charcoal in order to be decolorized, the amide is again precipitated by intrdductiominto' 0.1 N-hydrochloric acid and dried at the air. After:recrystallization 'from diiso-amyl-ether the 4-chloroQ-hydroxy-benzoic acid-allyl-amide melts at 9193 C. I
Example 4. 4-.chlor0=2-hydr0xy benz0ic acid-B-phenyl-- "ethyl amide Starting 'from 18.6 grams .of "4-chloroe2-hydroxy-ben-- zoic acid-methylester, 18 grams ofethanol'andrn grams of p-pheriyl-ethyl-amine the 4-chloro2=hydroxy benzoic acid-fl-phenyl-ethyl amide is prepared according to the description given in Example'S. After having bCCITIC' crystallized twice from carbon tetrachloride the amide melts at 95-99 .C'.
Example 5.-4-chlar0-2 .hydroxy benzoic aci -nu yF amide .34 grams .of 4-cliloro-J2-hydroxyrbenzoicacid, ,51 grams of freshly distilled oxalyl chloride and 100 cc. .of absolute benzene are heated for 5 hours to boiling, while stirring, whereby slow decomposition of the acid sets in together with evolution of gaseous hydrogen chloride. The solution is boiled for 3 further hours and then distilled under reduced pressure so that the parts volatile up to 50" C. are removed as completely as possible. The residue which completely crystallizes :on cooling and after having been pressed on clay melts at about 150 C. constitutes as crude product the 4-chloro-2 hydroxy-benzoic acid chlw ride and 'is reacted without having been purified again. It is dissolved in 120 cc. of absolute benzene. A solution of 33 grams of n-ibutylamine in cc. of benzene is added dropwise within 30 minutes to this solution, while stirring and cooling it with ice. Then it is heated for '2 hours :at '5060 C., :cooled, and to the resulting reaction mixture 1 litre of petroleum ether is slowly added. Thereby -a crystalline precipitate 'is separated which is filtered with suction and well dried. The finely pulverized product is triturated in several portions with water, dilute hydrochloric acid :and again with water, then filtered off with suction and dried in the air. .After having beenrccrystallized twice from carbon tetrachloride the 4-chloro-2-hydroxy benzoic ,acid-n butyl-amide is obtained in the form ofw'hite leaflets melting at -92 C.
Example 6.-4-br0,m0-2 hydr0xy1benz0ic acid-nebutylamide 23 grams of 4-bromo-2-hydroxy-benzoic acid-ethylester (prepared by esterification of 4-bromo-2-hydroxye benzoic acid of a melting point of 214-2l5 C. with ethanol in the'presence of concentrated sulphuric acid), 14.6 :grams of n-butylamine and 16 cc. of ethanol are heated for 20 hours at 80 C. The cooled reaction mixture'is introduced, while stirring, into dilute hydrochloric acid, and the crystalline precipitate is filtered off with suction. 'Then the precipitate is washed with water, triturated'in several tportions by means of dilute hydrochloric acid :and ifiltered sodium bicarbonate solution, and then the '4+bromo 2=hydroxy-benzoic .acid-n-butylamide vobtained in a very --good yield :and already :in a very pure state is dried at the air (melting point -1065 C.'). After recrystallization from cyclohexane the. melting point is within the-:range of 2106:5-107" C.
-1=1 grams.0f 4-iodo-.2 hydroxy-benzoic acid :hydrazide meltingat .186l88 C. (prepared by reaction of 4-iodoaehydroxy benzoic.Jacid methylester and hydrazine hydrate in methanol) are suspended .in 15 cc. of glacial acetic acidand 230cc. of 2 ,N-hydrochloric acid and diazotised, while cooled and stirred, with a solution of 2.7 grams of sodium nitrite in 20 cc. of water. The
spears? '7 Example 8.4-chIoro-Z-hydraxy-benzoic acid- (N-ethyl-N-allyl)-amide As described in Example 7, 19.6 grams of 4-chloro-2- hydroxy-benzoic acid hydrazide are diazotised in water with a solution of 7.3 grams of sodium nitrite, and the 4-chloro2-hydroxy-benzoic acid azide obtained is reacted in an ethereal solution with 17 grams of allyl-ethyl-amine. After having been correspondingly worked up, and recrystallized from cyclohexane, the 4-chloro-2-hydroxybenzoic acid-(N-ethyl-N-allyl)-amide, melting at 9395 C., is obtained.
Example 9.4-chloro-2-hydroxy-benzoic acid-cyclohexyl-amide 18.6 grams of 4-chloro-2-hydroxy-benzoic acid methylester, 40 grams of cyclohexylamine and 20 cc. of methanol are heated for 24 hours at about 100 C. The cooled reaction mixture is introduced, while stirring, into 300 cc. of 1 N-hydrochloric acid. After having been allowed to stand for a short time the semi-solid precipitate crystallizes. The precipitate is filtered with suction, washed with water, the crystals are triturated with 2 N-hydrochloric acid, again filtered off with suction and washed again with water. After drying, 23 to 24 grams of 4-chloro-2-hydroxy-benzoic acid-cyclohexyl-amide (90-94% of the theoretical yield) are obtained, which is already very pure and melts at 126-128" C. After recrystallization from cyclohexane it melts at 129-131 C.
When using cyclopentylamine the 4-chloro-2-hydroxybenzoic acid-cyclopentyl-amide melting at 107-1085 C. is obtained in an analogous manner.
Example 10.-4-chloro-2-hydroxy-benzoic acid-cyclo-hexyI-methyl-amide 19.6 grams of 4-chloro-2-hydroxy-benzoic acid-hydrazide melting at 207-210 C. (prepared by reaction of 4-chloro-2-hydroxy-benzoic acid methylester with hydrazine hydrate in methanol) are suspended in 125 cc. of glacial acetic acid and 400 cc. of 2 N-hydrochloric acid.
The mixture is cooled to about -3 C. and diazotised, while stirring, with a solution of 7.3 grams of sodium nitrite in 50 cc. of water.
It is again stirred for 10-15 minutes and then the mixture is shaken with about 800 cc. of ice-cooledether. The ethereal solution of the 4- chloro-Z-hydroxy-benzoic acid azide is shaken in several portions five times with ice water and twice with sodium bicarbonate solution and dried for 15 minutes over sodium sulphate. A solution of 22.6 grams of cyclohexylmethyl-amine in 15 cc. of absolute ether is added while cooling and shaking to the'dry ether solution. The-mixture is allowed to stand for 24 hours at C., then the ether is distilled 0E, finally under reduced pressure. The
crystalline residue is triturated in a mortar with 2 N- hydrochloric acid, the precipitate is filtered off with suction and washed with water. It is then triturated with a filtered sodium bicarbonate solution, again filtered with suction, washed with water and dried. The 4-chloro-2- hydroxy-benzoic acid-cyclo-hexyl-methyl-amide obtained -in.a good yield melts at 109-110 C. after having been recrystallized from cyclohexane.
Example 11 .-4-chloro-2-hydroxy-benzoic acid-n-heptyl-amide 75 grams of 4-chloro-Z-hydroxy-benzoic acid-hydrazide are suspended in 150 cc. of glacial acetic acid and 1000 cc. of 2 N-hydrochloric acid. The mixture is cooled to sulfate, 69 gra ms of n-heptyl-amine are added in portions. The ethereal solution is allowed to stand for .24
hoursand isthen shaken successively with dilute hydrochloric acid and sodium bicarbonate solution. The 4- chloro-2-hydroxy-benzoic acid-n-heptyl-amide that has formed is removed from the ethereal solution by means of dilute sodium hydroxide solution. .The alkaline solution so obtained is clarified with charcoal, acidified with hydrochloric acid, the precipitate is sucked off and recrystallized from about 5 liters of methanol of strength. The 4-chloro-2-hydroxy-benzoic acid-n-heptylamide so obtained melts at 6667 C.
In an analogous manner there are obtained: from 4- chloro-2-hydroxy-benzoic acid-azide and ethyl amine the 4-chloro-2-hydroxy-benzoic acid-ethyl amide, melting point 97-98 C. (from methanol of 60% strength); from 4-chloro-2-hydroxy-benzoic acid azide and crotyl amine the 4-chloro-2-hydroxy-benzoic acid-crotyl amide, melting point 113-115 C. (from methanol of 80% strength); from 4-chloro-Z-hydroxy-benzoic acid-azide and vdiethyl amine the 4-chloro-2-hydroxy-benzoic acid-diethyl amide, melting point 126-l28 C. (from methanol of 60% strength).
This application is a continuation-in-part of application Serial No. 635,109, filed January 22, 1957,.now abandoned.
We claim:
1. Compounds selected from the group consisting of benzoic acid-amides of the general formula HmQco-N CIQC O-NH-m-Oim 3. The compound of the formula Cl CO-NH-CHz-CQ 4. The compound of the formula 5. The compound of the formula 6. The compound of the formula References Cited in the file of this patent UNITED STATES PATENTS Bindler et al Mar. 1, 1955 Davies et al July 26, 1955 OTHER REFERENCES Way et al.: J. of Pharm. and Experimental Therapeutia va 19s 9 P 4

Claims (1)

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF BENZOIC ACID-AMIDES OF THE GENERAL FORMULA
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3102069A (en) * 1956-06-11 1963-08-27 Philips Corp Method of destroying plant harmful microorganisms
US3110670A (en) * 1959-08-03 1963-11-12 Sinclair Research Inc Lubricant composition
US4055640A (en) * 1975-07-14 1977-10-25 Nippon Kayaku Co., Ltd. Compositions and methods for controlling the growth of bacteria, fungi and algae using certain derivatives of N-(2,2-dichlorovinyl)salicylamides
US4055639A (en) * 1975-07-14 1977-10-25 Nippon Kayaku Kabushiki Kaisha Derivatives of N-(2,2-dichlorovinyl) salicylamide and use thereof as bactericides, fungicides and algicides for industry

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2703332A (en) * 1955-03-01 Poly halo-salicylanilioes
US2714082A (en) * 1955-07-26 New oxazoline derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2703332A (en) * 1955-03-01 Poly halo-salicylanilioes
US2714082A (en) * 1955-07-26 New oxazoline derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3102069A (en) * 1956-06-11 1963-08-27 Philips Corp Method of destroying plant harmful microorganisms
US3110670A (en) * 1959-08-03 1963-11-12 Sinclair Research Inc Lubricant composition
US4055640A (en) * 1975-07-14 1977-10-25 Nippon Kayaku Co., Ltd. Compositions and methods for controlling the growth of bacteria, fungi and algae using certain derivatives of N-(2,2-dichlorovinyl)salicylamides
US4055639A (en) * 1975-07-14 1977-10-25 Nippon Kayaku Kabushiki Kaisha Derivatives of N-(2,2-dichlorovinyl) salicylamide and use thereof as bactericides, fungicides and algicides for industry

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