NO117492B - - Google Patents

Description

Process for the preparation of basic heterocyclic ethers.

The present invention relates to a

process for the preparation of basic heterocyclic ethers, which are derived from acridine, xanthene and thiaxanthene. In the following it is used in "The Ring Index" by Paterson and Capell, New York 1940, for acridine under System-No. 1973, for the xanthine below. System-No. 2000 and for the tiaxant under System-No. 2019 specified nomenclature.

The method according to the invention consists in reacting a compound of the general formula

in which Z means NH, O or S and one or I two of the symbols R' means OH and the others mean hydrogen, alkyl or halogen, however at most two of the groups R' means halogen, with a dialkylaminoalkyl halide in the presence of an acid binding agent , whereupon the formed basic heterocyclic ether of the general formula

in which Z means NH, O or S and one or two of the symbols R means dialkylamino-alkoxy and the others mean hydrogen, alkyl or halogen, with at most two of the groups R meaning halogen, can be transferred in normal or quaternary salts.

When in the two formulas I and II the letter Z means a divalent imino group, then the corresponding compounds derive from the basic skeleton 9-[10 H]-acridone according to the formula below:

When the designation Z means an oxo group, the corresponding compounds are derived from - the basic skeleton 9-xanthone according to the following formula:

When Z means a divalent thio group, the corresponding compounds are derived from the basic skeleton 10-thiaxanthone according to the following formula:

It should be noted that the numbering of the thiaxanthone molecule differs somewhat from the numbering of the 9-[10 H]-acridone or the 9-xanthone molecules in accordance with the numbering system from

"The Ring Index".

The halogenated starting compounds of the general formula I, in which Z represents an imino group, can e.g. is obtained by reacting o-chlorobenzoic acid or from a halogenated o-chlorobenzoic acid with a primary arylamine, which contains an ether group, such as e.g. o-aminoanisole or a core halogenated aminoanisole. In the formed acridones, the ether groups can be transferred by hydrolysis, e.g. in the presence of aluminum chloride, in free oxygen groups. The halogenated thiaxanthones of the general formula I can in turn be prepared by reaction of o-mercaptobenzoic acid or of a halogenated o-mercaptobenzoic acid with a halogenated ether, such as e.g. p-Chloranisole. According to another extraction method for these starting compounds, o-chlorobenzoic acid or a halogenated o-chlorobenzoic acid can be condensed with a mercaptoether or a halogenated mercaptoether, such as 4-chloro-2-mercaptoanisole. The ether groups present can then be converted into oxy groups in the usual manner as indicated above by hydrolysis.

The reaction of heterocyclic bases of the general formula I with the dialkyl-aminoalkyl halides conveniently takes place by heating in an inert organic solvent in the presence of an alkali alcoholate, such as sodium methylate. Alcohols, such as methanol, ethanol, or halogenated benzenes, such as chlorobenzene, etc. are advantageously used as solvents. The recovered bases of the general formula II can, by reaction with acids, e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, oxalic acid, citric acid, ethanolsulphonic acid, etc. are transferred in the normal salts, or by reaction with quaternizing agents, such as alkyl halides (e.g. methyl bromide, ethyl iodide, n -butyl chloride), dialkyl sulphates (e.g. dimethyl sulphate), aralkyl halides (e.g. benzyl bromide) etc. are transferred in the corresponding quaternary salts.

The basic heterocyclic ethers with

the general formula II and their salts can be used as chemotherapeutic agents, e.g. against worms (such as Syphacia obvelata), against fungal infections (e.g. with Tricho-phyton mentagrophytes or Microsporon lanosum) and against protozoeninf ex ions (e.g. with Trypanosoma equiperdum or Trichomonas vaginalis).

Example 1:

A mixture of 38.5 g of 4-oxy-9(10 H)-acridone, 400 ems of chlorobenzene, 12 g of sodium methylate and 50 ems of methanol is heated with stirring until the methanol has distilled off and the temperature of the reaction mass has reached 130°. The reaction mixture is then cooled to 100° and 30 g of p-diethylaminoethyl chloride is added. While stirring, it is heated for 4 hours under reflux. 250 cm" of water and 10 cm" of 40% sodium hydroxide solution are then added. 100° and continue stirring for another half hour. The reaction mixture is then allowed to stand, the chlorobenzene layer is separated, dried over sodium sulphate and concentrated in vacuo. The remaining oil is digested with ether, and the precipitated crystallized product is recrystallized from a mixture of benzol and petroleum ether. The 4-(f3-diethylaminoethoxy)-9(10 H)-acridone thus obtained is a yellowish-brown substance with a melting point of 62°, which is insoluble in water; however soluble in acids, e.g. n-hydrochloric acid, n-sulphuric acid, acetic acid and propionic acid.

The water-soluble dihydrochloride of the above-mentioned base is a pale yellow powder with a melting point of 236-238°.

On standing a solution of 6 g of the base in 35 cm" of acetone with a 23% acetone methyl bromide solution, 10-methyl-4-((3-diethylaminoethoxy)-9(10 Hj-acridonium bromide) is formed with a melting point of 229-230 °, which is soluble in water.

Example 2:

A mixture of 29 g of 2-oxy-9(10 H)-acridone, 350 ems of chlorobenzene, 10 g of sodium methylate and 50 ems of methanol is reacted as indicated in example 1 with 25 g of diethylaminoethyl chloride. The 2-(|3-diethylaminoethoxy)-9(10 H)-acridone thus obtained consists, after recrystallization from chlorobenzene, of pale yellow crystals with a melting point of 209-211°. The product is insoluble in water and easily soluble in alcohol. It forms a water-soluble dihydrochloride with melting point 183°.

Example 3:

A mixture of 32 g of 1-methyl-4-oxy-9(10 H)-acridone, 10 g of sodium methylate, 350 ems of chlorobenzene and 50 cm" of methanol is reacted as in example 1 with 25 g of 5-diethylaminoethyl chloride. The 1-methyl-4-(p-diethylaminoethoxy)-9(10 H)-acridone thus obtained is a yellow-brown substance with a melting point of 147-148°, and which is insoluble in water. This base forms a yellow dihydrochloride, which after recrystallization from 95 per cent ethanol and drying in an oven at 95° loses one mole of hydrochloric acid and turns into monohydrochloride with a melting point of 234-236°.

Example 4:

A mixture of 29 g of 2-oxy-9(10)H)-10 g of sodium methylate, 300 cm» of chlorobenzene and

40 cm" of methanol is heated while stirring until the methanol distills off and the mixture has reached a temperature of 130°. The mixture is then cooled to approximately 100° and 25 g of f5-diethylaminoethyl chloride are added. Stir under reflux for 5 hours at 130° and then cool to 100°. 250 cm3 water and 10 cm3 40% sodium hydroxide solution are added and the mixture is stirred for a further hour. The chlorobenzene layer is then separated, dried over sodium sulphate and concentrated in vacuo. The remaining oil is dissolved in ether, cooled

— 5° and add 25 cm» of 35% ethanolic hydrochloric acid. The crude hydrochloride that forms is recrystallized from alcohol. 4-(|3-Diethylaminoethoxy)-9-xanthone hydrochloride

melts at 236° and is soluble in water.

Example 5:

25 g of 2-oxy-9-xanthone, 10 g of sodium methylate, 300 cm" of chlorobenzene, 40 cm" of methanol and 25 g of p-diethylaminoethyl chloride are left to react with each other as described in example 4. After recrystallization from ethanol, the formed 2-( |3-diethylaminoethoxy)-9-xanthone hydrochloride at 194-195°. It consists of white crystals and is soluble in water.

Example 6:

23 g of 2,7-dioxy-9-xanthone, 16 g of sodium methylate, 350 cm'! chlorobenzene and 60 cm" of methanol are allowed to react as described in Example 4 to form the disodium salt. The latter is condensed with 33 g of 3-diethylaminoethyl chloride by heating to 130° under reflux for 5 hours. The reaction mixture is then cooled to 100°, 300 cm" of water and 10 cm" of 40% sodium hydroxide solution are added.

ning and stir for half an hour. The chlorobenzene sol layer is then separated, dried over sodium sulphate and concentrated in vacuo. The remaining oil is dissolved in 300 cm" of ether, filtered, the filtrate is cooled to -5° and 30 cm" of 35% ethanolic hydrochloric acid is added. The 2,7-bis-([3-diethylaminoethoxy)-9-xanthone dihydrochloride thus obtained is recrystallized from methanol, melting point 229°. It forms white, water-soluble crystals.

Example 7: 30 g of 4-methyl-8-oxy-10-thiaxanthone, 10 g of sodium methylate, 350 cm" of chlorobenzene and 50 cm" of methanol are heated with stirring to 130°, whereupon part of the methanol distills off. The reaction mixture is then cooled to 100°, 27 g of p-diethylaminoethyl chloride are added and heated for 4 hours, with stirring and reflux. The mixture is then cooled to 100°, 250 cm" of water and 10 cm" of 40% sodium hydroxide solution are added and the mixture is stirred for half an hour. The chlorobenzene sol layer is then separated, dried over sodium sulphate and concentrated in vacuo. The remaining oil is dissolved in 300 cm" of ether and 20 cm" of 35% ethanolic hydrochloric acid is added. After recrystallization from a mixture of acetone and alcohol, the obtained 4-methyl-8-((3-diethylaminoethoxy)-10-thiaxanthone hydrochloride consists of pale yellow crystals with a melting point of 212-214°, which are soluble in water and in alcohol.

Example 8:

A mixture of 52 g of 1-methyl-4-oxy-6-chloro-9(10 H)-acridone, 500 cm" of chlorobenzene, 100 cm" of methanol and 16 g of sodium methylate is heated with stirring until 131° until the methanol is heated under stirring as long as 131° until the methanol has distilled off. The reaction mixture is then cooled to 100° and 35 g of (3-diethylaminoethyl chloride) is added. The mixture is then heated for 4 hours under reflux to 130°. After cooling to less than 100°, 500 cm" of water and 20 cm" of sodium hydroxide (40 percent .) and heat the mixture again to 90°. The chlorobenzene layer is separated, dried over sodium sulfate and concentrated in vacuo. Light yellow crystals of 1-methyl-4-(p-diethylaminoethoxy)-6-chloro-9(10 H)-acridone are recovered with melting point 175-176°.

Example 9:

A mixture of 62 g of 1-chloro-4-oxy-acridone, 500 cm" of chlorobenzene, 120 cm" of methanol and 18 g of sodium methylate is heated while stirring to 130° until the methanol has distilled off. The mixture is then cooled to 100° and 45 g of (3-diethylaminoethyl chloride) is added. The mixture is then heated for 4 hours under reflux to 130-32°. After cooling to less than 100°, 500 cm" of water and 25 cm" of sodium hydroxide (40 per cent), stir for a further hour, separate the chlorobenzene layer and concentrate in vacuo. The residue is extracted with 60 cm" of concentrated hydrochloric acid and 600 cm" of water on a steam bath. 5 g of activated charcoal is added and filtered hot. The filtrate is cooled then to 10° and the 1-chloro-4-((3-diethylaminoethoxy)-9(10 H)-acridone is separated with 70 cm" of sodium hydroxide (40 per cent). The product is crystallized from 80 per cent alcohol. The thus obtained pale yellow crystals melting at 115d.

Example 10:

A mixture of 59 g of 1-chloro-4-oxy-. thiaxanthone, 16 g of sodium methylate, 500 cm" of chlorobenzene and 100 cm" of methanol are heated to 130°, whereupon the methanol is distilled off. The mixture is then cooled to 100°, 45 g of (3-diethylaminoethyl chloride) is added and heated for 4 hours under reflux to 130-132°. It is then cooled to below 100° and 20 cm" of sodium hydroxide (40 percent) and 400 cm" of water are added After further stirring for half an hour, the chlorobenzene layer is separated and concentrated in vacuo, 1-chloro-4-((3-diethylaminoethoxy)-thiaxanthone remaining as a yellow oil. The monohydrochloride melts at 227°, the tartrate at 185 -187°.

Example 11:

A mixture of 54 g of 1,6-dichloro-4-oxy-acridone, 500 cm" of chlorobenzene, 15 g of sodium methylate and 100 cm" of methanol is reacted with 45 g of (3-diethylaminoethyl chloride as described in Example 10. The free base formed is crystallized from ethanol The light brown crystallized 1,6-dichloro-4-(p-diethylaminoethoxy)-9(10 H)-acridone melts at 174-175°.

Example 12:

42 g of thiosalicylic acid and 32 g of 4-chloro-3-methyl-anisole are introduced under vigorous shaking into 360 g of sulfuric acid (96 per cent). The mixture is stirred for 4 hours at 45-50°. 50 cm" fuming sulfuric acid (5 per cent anhydride) is added, and the mixture is heated for another half hour to 80°. The mixture is then poured onto a mixture of ice and water and filtered. The 1-chloro-2-methyl-4-methoxy-thiaxanthone thus obtained is then heated with 35 g of aluminum chloride in 250 cm" of chlorobenzene for 3 hours to reflux. 1-Clpr-2-methyl-4-oxy-thiaxanthone is formed.

A mixture of 28 g of 1-chloro-2-methyl-4-oxy-thiaxanthone, 350 cm of chlorobenzene, 60 cm of methanol and 9 g of sodium methylate is heated with stirring, whereby the methanol distills off. The distillation is finished as soon as the temperature has reached 131°. The mixture is then cooled to 95°. 20 g of |3-diethylaminoethyl chloride are added, and the mixture is heated for 4 hours under reflux. Then 10 cm" of sodium hydroxide (40 per cent) and 300 cm" of water at 100° are added. stir for half an hour, separate the chlorobenzene layer and concentrate it in vacuo. The residual oily 1-chloro-2-methyl-4-((3-diethylaminoethoxy)-thiaxanthone is dissolved in 300 cm" of acetone and filtered. The filtrate is cooled to 0° and add 15 cm" of ethanolic hydrochloric acid (30 per cent). The 1-chloro-2-methyl-4-diethyl-aminoethoxy)-thiaxanthone hydrochloride separates as crystals. After recrystallization from 90 per cent ethanol it melts at 240—242°.

Example 13:

60 g (0.31 mol) of the potassium salt of o-chloro-benzoic acid and 52 g (0.3 mol) of 2-chloro-4-methoxy-5-aminotoluene are heated for 9 hours with 4.5 g of potassium carbonate and 2 g of copper powder in 225 cm»- amyl alcohol to boil under reflux.

After standing overnight at room temperature, 30 cm" of sodium hydroxide (40 per cent) and 60 cm" of water are added. The amyl alcohol is removed by steam distillation. The aqueous residue is filtered hot. The filtrate is poured with stirring into a mixture of ice and water, which contains 50 cm" of concentrated hydrochloric acid. After stirring for half an hour, the crude condensation product is filtered off, washed acid-free with cold water and sucked off. 2-(2-Methoxy-4-chloro 5-methylanilino)-benzoic acid is recrystallized from a mixture of 1150 cc of glacial acetic acid and 500 cc of water; melting point 200—202°. 65 g (0.22 mol) of 2-(2-methoxy-4-chloro-5-methylanilino)-benzoic acid are heated for 9 hours with 650 g of polyphosphoric acid on a steam bath. After cooling to room temperature, the mixture is diluted drop by drop while cooling with 800 cm3 of water and finally poured onto 2500 cm3 of an ice and water mixture. After stirring for one hour, the crude 1-methyl-2-chloro-4-methoxy-9(10 H)-acridone is filtered off, washed acid-free with cold water and sucked off. The crude product is heated for half an hour with 1000 cc of water and 15 cc of sodium hydroxide (40 per cent) to 85°. The solid mass is filtered off, washed free of alkali, sucked off and then dried in vacuum. After recrystallization from chlorobenzene, the compound melts at .193—195°. 58 g (0.216 mol) of 1-methyl-2-chloro-4-methoxy-9(10 H )-acridone is heated for 5 hours with 95 g of aluminum chloride in 450 cm<:i >chlorobenzene under reflux to boiling. After cooling to room temperature, carefully crushed ice is added to the mixture. The chlorobenzene sol is removed by steam distillation and the crude 1-methyl-2-chloro-4-oxy-9(10 H)-acridone is filtered off. The crude product is dissolved in a mixture of 1000 cc of water and 100 cc of sodium hydroxide (40 per cent) at 85°, precipitated with acetic acid and recrystallized from ethanol; melting point 312—314°. 49 g (0.19 mol) of 1-methyl-2-chloro-4-oxy-9(10 H )-acridone is heated in 600 cm» of chlorobenzene with 35 g (0.26 mol) of (3-diethylaminoethyl chloride and 13 g of .24 mol) of sodium methylate for 4 hours under reflux to boiling. 150 cm" of water and 25 cm" of sodium hydroxide (40 per cent) are then added. The reaction mixture is cooled in ice and the separated crystalline product is filtered off. The 1-methyl-2-chloro-4-((3-diethylaminoethoxy)-9(10 H)-acridone formed is recrystallized from Ligroinbenzene; melting point 143-145°. The hydrochloride melts at 241-243°. 5 g of 1-methyl- 2-Chloro-4-p-diethylaminoethoxy)-9(10H)-acridone is dissolved in 50 cm» of acetone. The mixture is filtered and the filtrate is added at 10-15° 10 cm" of a 25% solution of methyl bromide in acetone. After standing for 24 hours, 1,10-dimethyl-2-chloro-4-(p-diethylaminoethoxy-9(10 H)-acridonium bromide crystallizes out.

Example 14: A mixture of 19 g of 1,7-dichloro-4-oxy-thiaxanthone (derived from 2-mercapto-4-chlorobenzoic acid and p-chloroanisole according to the method described in Example 12), 360 cm3 of chlorobenzene, 60 cm» methanol and 6 g of sodium methylate are heated to 132°, whereby the methanol distills off. The mixture is then cooled to 100°, 15 g of (3-diethylaminoethyl chloride) are added and heated for 4 hours to 130-132° to reflux. After cooling to below 100°, 300 cm" of water and 10 cm" of sodium hydroxide (40 percent .) The mixture is stirred for half an hour, the chlorobenzene layer is separated and after drying over sodium sulfate is concentrated in vacuo. The oily residue of 1,7-dichloro-4-(|3- diethylaminoethoxy)-thiaxanthone is dissolved in 1,300 cc of acetone and 10 cc of 25% ethanolic hydrochloric acid is added. 1,7-Dichloro-4-(1-diethylaminoethoxy)-thiaxanthone hydrochloride separates out in pale yellow crystals, which are recrystallized from 96 per cent.-ig. aqueous alcohol;

melting point 222—224°.

Claims (1)

Process for the preparation of basic heterocyclic ethers of the general formula in which Z means NH, O or S and one or two of the symbols R means dialkylamino-alkoxy and the others mean hydrogen, alkyl or halogen, with at most two of the groups R means halogen, and salts thereof, characterized by reacting a compound with the general formula: in which Z means NH, O or S and one or two of the symbols R' means OH and the others mean hydrogen, alkyl or halogen, although at most two of the groups R' means halogen, with a dialkylaminoalkyl halide in the presence of an acid binding agent, whereupon the heterocyclic ethers formed are, if desired, transferred to common or quaternary salts.