3,781,358 United States Patent Office Patented Dec. 25, 1973

1. 2 FORMUL.A. I. FORMULA III 3,781,358 H B INTERMEDIATES FOR PREPARING ACRIDINES N N Elvin L. Anderson, 246 Nicholson Drive, Moorestown, / N / N N.J. 08057, and Harold Graboyes, 1506 Sheffield Lane, Philadelphia, Pa. 19151 5 R4 R3 - R. R No Drawing. Application Feb. 25, 1971, Ser. No. 118,976, now Patent No. 3,692,834, which is a continuation-in part of application Ser. No. 732,869, May 29, 1968, \ ONNEISO-Air \on now Patent No. 3,625,945. Divided and this applica tion June 30, 1972, Ser. No. 267,852 10 R2 int, C. C07e 119/00 U.S. C. 260-566 B 2 Claims /Ns ABSTRACT OF THE DISCLOSURE R Diphenyl-2-carboxaldehyde derivatives, prepared by re 5 acting a diphenylamine - 2 - carboxylic acid benzenesul fonylhydrazide with a base and hydrazine, semicarbazide, in which: thiosemicarbazide or phenylhydrazine, are reacted with a R is hydrogen, halogen having an atomic weight of less mineral acid to produce acridines. The acridines are use 20 than 80, lower alkyl, lower alkoxy, trifluoromethyl, tri ful as intermediates for preparing 9-aminoalkylacridans fluoromethylsulfonyl, dimethylsulfamoyl or lower alkyl having pharmacodynamic activity. thio; R3 and R4 are hydrogen, halogen having an atomic weight This is a division of application Ser. No. 118,976, filed of less than 80, lower alkyl, lower alkoxy, trifluoro Feb. 25, 1971, now Pat. No. 3,692,834 which is a con 25 methyl, trifluoromethylsulfonyl, dimethylsulfamoyl or tinuation-in-part of Ser. No. 732,869, filed May 29, 1968, lower alkylthio, at least one of Ra and R4 being hydro now Pat. No. 3,625,945. geal This invention relates to new diphenyl-2-carboxalde hyde derivatives which are useful as intermediates for R2 is O preparing acridines. 30 in NH&NH; The acridines prepared from the intermediates of this invention are represented by the following formula: M R Rs Eormula (I) 35 YN/ /NS H. R S NA NH&NH, or NH-( > and in which R1 is hydrogen, halogen having an atomic weight of less than 80, lower alkyl, lower alkoxy, tri 40 fluoromethyl, trifluoromethylsulfonyl, dimethylsulfanoyl Ar is phenyl, tolyl preferably p-tolyl or dihalophenyl pref or lower alkylthio. erably 2,5-dichlorophenyl. The acridines of Formula I are useful as intermediates for preparing 9-aminoalkylacridans having pharmaco The intermediates of this invention are represented by dynamic activity as described in U.S. 3,131,190. Briefly, 45 Formula III above. an acridine of Formula I is reacted with an alkylamino Preferred intermediates of this invention are repre propyl magnesium halide in an inert organic solvent such sented by Formula III above when R2 is as an ether at about 35-100° C. for about 30-180 min utes to give a 9-aminoalkylacridan which is, or is an in termediate for, a pharmacodynamically active compound 50 as described in U.S. 3,131,190. These pharmacodynami cally active 9-aminoalkylacridans have central nervous system activity and are useful as tranquilizers, ataractics, antidepressants, antiemetics, antihistaminics, antispas modics and antiinflammatory agents. 55 An advantageous compound of Formula I is that in which R is chloro, in particular, in the 2-position, that compound being 2-chloroacridine. This acridine is an in termediate in the preparation of 9-aminoalkyl-2-chloro and one of R and R4 is chloro and the other is hydrogen, acridans, in particular, 2-chloro-9-dimethylaminopropyl 60 the chloro substituent being in the position para to the acridan which is a known tranquilizing agent, Simpson et attachment of the nitrogen atom. al., Current Therapeutic Research 8:447-451 (1966) and According to the above process, a diphenylamine-2- Claghorn et al., Psychosomatics 8:212-215 (1967). carboxylic acid benzenesulfonylhydrazide of Formula II The process for preparing the acridines of Formula I is reacted with a base such as an alkali metal hydroxide, using the intermediates of this invention is represented 65 for example, sodium or potassium hydroxide, or an alkali schematically as follows: metal carbonate, for example sodium or potassium car 3,781,358 3 4. bonate, and a member selected from the group consisting and the insoluble solid is removed by filtration and dried of hydrazine, semicarbazide, thiosemicarbazide and phen in vacuo to give 4'-trifluoromethyldiphenylamine-2-car ylhydrazine to give a diphenylamine - 2 - carboxaldehyde boxylic acid p-toluenesulfonylhydrazide. derivative of Formula III. This reaction is carried out in A mixture of 272 g. of 4'-trifluoromethyldiphenyl an organic solvent preferably a hydroxylic solvent such amine-2-carboxylic acid p-toluenesulfonylhydrazide, 120 as, for example, 6-ethoxyethanol, B-methoxyethanol, eth ml. of 10 N sodium hydroxide, 1.1 liter of 3-ethoxyeth ylene glycol, butanol or amyl alcohol, advantageously in anol, 680 ml. of water and 36.5 g. of 85% hydrazine hy an aqueous solution with a water miscible hydroxylic sol drate is heated at reflux with mechanical stirring for two vent such as 6-ethoxyethanol or 3-methoxyethanol. The hours. The mixture is cooled and the solid removed by reaction is carried out at elevated temperature prefera 0 filtration and dried in vacuo to give 4'-trifluoromethyldi bly about 100-200 C, conveniently at reflux tempera phenylamine-2-carboxaldehyde azine. ture. A mixture of 90 g. of 4'-trifluoromethyldiphenylamine The above prepared diphenylamine-2-carboxaldehyde 2-carboxaldehyde azine, 270 ml. of glacial acetic acid and derivatives are reacted with a mineral acid such as, for 73 ml. of concentrated hydrochloric acid is heated at example, hydrochloric acid, sulfuric acid or phosphoric reflux with mechanical stirring for one hour. The solution acid to give the acridines. The reaction is carried out in is diluted with ice and water and basified with sodium an organic solvent, for example, a lower alkanoic acid hydroxide solution. The solid material is removed by fil Such as acetic or formic acid or a hydroxylic solvent such tration and dried in vacuo to give 2-trifluoromethylacri as 6-ethoxyethanol, B-methoxyethanol or ethylene glycol, dine. preferably a lower alkanoic acid. Preferably, the reaction EXAMPLE 3 is carried out at elevated temperature, such as, for exam ple, about 100-200 C. A mixture of 156.5 g. of o-chlorobenzoic acid, 167.2 The diphenylamine-2-carboxylic acid benzenesulfonyl g. of p-(n-butyl)aniline, 69 g, of potassium carbonate, 1 hydrazide compounds are prepared as follows: g. of copper-bronze powder and 350 ml. of isoamyl alco hol is heated at reflux with mechanical stirring for four (1) by reacting a diphenylamine-2-carboxylic acid with hours. During this time the water which formed is re a chlorinating agent, for example, thionyl chloride, to moved by azeotropic distillation. The inorganic salts are give the corresponding carboxylic acid chloride and reacting the acid chloride with a benzenesulfonyl hy removed by filtration and 30 ml. of glacial acetic acid drazine or is added to the filtrate. After cooling, the solid material 30 is removed by filtration and dried in vacuo to give 4'-(n- (2) by reacting a lower alkyl ester of a diphenylamine butyl) diphenylamine-2-carboxylic acid. 2-carboxylic acid with hydrazine and benzenesulfonyl A mixture of 26.9 g, of 4'-(n-butyl) diphenylamine-2- chloride. carboxylic acid, 13.2 g. of thionyl chloride and 270 ml. of The diphenylamine-2-carboxylic acids are either known benzene is heated at reflux with mechanical stirring for to the art or are prepared by known methods, for ex one hour. The solution is cooled to 40-45° C. and 20.5 ample, by reacting an aniline with an o-halobenzoic acid g. of p-toluenesulfonylhydrazine is added. The resulting or by reacting an o-aminobenzoic acid with a haloben mixture is heated at reflux for six hours, cooled to 5. 2ee 10 C. and the insoluble solid removed by filtration and dried in vacuo to give 4'-(n-butyl) diphenylamine-2-car The following examples are not limiting but are ill 40 boxylic acid p-toluenesulfonylhydrazide. lustrative of this invention. A mixture of 25 g. of 4'-(n-butyl) diphenylamine-2-car EXAMPLE 1. boxylic acid p-toluenesulfonylhydrazide, 11.5 ml. of 10 A mixture of 247.5 g. of 4'-chlorodiphenylamine-2- N Sodium hydroxide, 100 ml. of g-ethoxyethanol, 60 ml. carboxylic acid, 135 g. of thionyl chloride and two liters of Water and 3.5 g. of 85% hydrazine hydrate is heated of cyclohexane is heated at reflux for one hour with me at reflux With mechanical stirring for two hours. The mix chanical stirring. The resulting solution is cooled to 40 ture is cooled and the solid removed by filtration and 50 C. and 223 g. of p-toluenesulfonylhydrazine is added. dried in vacuo to give 4'-(n-butyl) diphenylamine-2-car The mixture is then heated under reflux for six hours with boxaldehyde azine. stirring, then cooled and filtered. The solid materialis A mixture of 7 g. of 4'-(n-butyl) diphenylamine-2-car dried in vacuo to give 4'-chlorodiphenylamine-2-carbox 50 boxaldehyde azine, 25 ml. of glacial acetic acid and 10 ylic acid p-toluenesulfonylhydrazide. ml. of concentrated hydrochloric acid is heated at reflux A mixture of 104 g. of 4'-chlorodiphenylamine-2-car with mechanical stirring for one hour. The solution is boxylic acid p-toluenesulfonylhydrazide, 50 ml of 10N diluted with ice and water and basified with sodium hy Sodium hydroxide, 400 ml. of g-ethoxyethanol, 250 ml. droxide solution. The solid material is removed by filtra of Water and 15 g. of 85% hydrazine hydrate is heated at 55 tion, dissolved in ether and the residue is crystallized reflux for two hours with mechanical stirring. The mix from hexane to give 2-(n-butyl)acridine. ture is cooled and filtered. The solid material is dried in vacuo to give 4'-chlorodiphenylamine-2-carboxaldehyde EXAMPLE 4 aZe A mixture of 131 g. of 4'-chlorodiphenylamine-2-car 60 A mixture of 85 g. of 2'-chlorodiphenylamine-2-car boxaldehyde azine, 400 ml. of glacial acetic acid and 122 boxylic acid, 47.4 g. of thionyl chloride and 850 ml. of ml. of concentrated hydrochloric acid is heated at reflux benzene is heated at reflux with mechanical stirring for with mechanical stirring for one hour. The solution is one hour. The solution is cooled to 40-50° C., 76.5 g. diluted with ice and water, basified with sodium hydroxide of p-toluenesulfonylhydrazine is added and the resulting Solution and filtered. Drying the solid material in vacuo 65 mixture is heated at reflux with stirring for six hours. The gives 2-chloroacridine. mixture is cooled to 5-10 C. and the solid material is removed by filtration and dried in vacuo to give 2'-chlo EXAMPLE 2 rodiphenylamine-2-carboxylic acid p-toluenesulfonylhy A mixture of 50 g. of 4'-trifluoromethyldiphenylamine drazide. 2-carboxylic acid, 24 g. of thionyl chloride and 500 ml. 70 A mixture of 138 g. of 2'-chlorodiphenylamine-2-car of cyclohexane is heated at reflux with mechanical stir boxylic acid p-toluenesulfonylhydrazide, 66.2 ml. of 10 N ring for one hour. The solution is cooled to 40-50° C. sodium hydroxide, 550 ml. of 6-ethoxyethanol, 250 ml. and 37.2 g. of p-toluenesulfonylhydrazine is added. The of water and 19.5 g. of 85% hydrazine hydrate is heated resulting mixture is heated for six hours at reflux, cooled 5 at reflux with mechanical stirring for two hours. The mix 3,781,358 5 6 ture is cooled and the solid material is removed by filtra The above prepared thiosemicarbazone is refluxed with tion and dried in vacuo to give 2'-chlorodiphenylamine glacial acetic acid and concentrated hydrochloric acid by 2-carboxaldehyde azine. the procedure of Example 6 to give 3-bromoacridine and A mixture of 51.5 g. of 2'-chlorodiphenylamine-2-car 1-bromoacridine. boxaldehyde azine, 155 ml. of glacial acetic acid and 48 5 EXAMPLE 8 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for one hour. The solution is A mixture of 140 g. of 4'-chlorodiphenylamine-2-car diluted with ice and water and basified with sodium hy boxylic acid p-toluenesulfonylhydrazide (prepared as in droxide solution. The precipitate is removed by filtration Example 1), 27g of sodium hydroxide, 36.4g. of phenyl and dried in vacuo to give 4-chloroacridine. O hydrazine, 500 ml. of 6-ethoxyethanol and 200 ml. of water is heated at reflux with mechanical stirring for two EXAMPLE 5 hours. The mixture is cooled and the solid material is re A mixture of 155 g. of 2 - trifluoromethyldiphenyl moved by filtration and dried in vacuo to give 4'-chloro amine-2-carboxylic acid, 76.5 g. of thionyl chloride and diphenylamine-2-carboxaldehyde phenylhydrazone. 1600 ml. of benzene is heated at reflux with mechanical 5 A mixture of 80 g. of 4'-chlorodiphenylamine-2-car stirring for one hour. The solution is cooled to 40-50 boxaldehyde phenylhydrazone, 200 ml. of glacial acetic C., 123 g. of p-toluenesulfonylhydrazine is added and the acid and 33 ml. of concentrated sulfuric acid is heated at resulting mixture is heated under reflux with stirring for reflux with stirring for one hour. The solution is diluted six hours. The suspension is cooled and the insoluble solid with ice and water, basified with sodium hydroxide solu is removed by filtration and dried in vacuo to give 2'-tri 20 tion and filtered to give 2-chloroacridine. fluoromethyldiphenylamine-2-carboxylic acid p - toluene sulfonylhydrazide. EXAMPLE 9 A mixture of 166 g. of 2 - trifluoromethyldiphenyl A mixture of 52 g. of 4'-methylthiodiphenylamine-2- amine-2-carboxylic acid p-toluenesulfonylhydrazide, 74 carboxylic acid, 26.4 g. of thionyl chloride and 600 ml. ml. of 10 N sodium hydroxide, 665 ml. of (3-ethoxyethanol, 25 of benzene is heated at reflux with stirring for one hour. 415 ml. of water and 22 g. of 85% hydrazine hydrate is The solution is cooled to 40-50° C. and 41 g of p-tolu heated at reflux with mechanical stirring for two hours. enesulfonylhydrazine is added. The resulting mixture is The mixture is cooled and the insoluble solid is removed heated at reflux with stirring for five hours, cooled and by filtration and dried in vacuo to give 2'-trifluoromethyl the solid material removed by filtratition and dried in diphenylamine-2-carboxaldehyde azine. 30 vacuo to give 4 - methylthiodiphenylamine-2-carboxylic A mixture of 37.5 g. of 2 - trifluoromethyldiphenyl acid p-toluenesulfonylhydrazide. amine-2-carboxaldehyde azine, 113 ml. of glacial acetic A mixture of 75 g. of 4'-methylthiodiphenylamine-2- acid and 30 ml. of concentrated hydrochloric acid is carboxylic acid p-toluenesulfonylhydrazide, 35 ml. of 10 heated at reflux with mechanical stirring for one hour. N sodium hydroxide solution, 320 ml. of 3-ethoxyethanol, The solution is diluted with ice and water and basified 200 ml. of water and 10 g. of 85% hydrazine hydrate is with sodium hydroxide solution. The insoluble solid is heated at reflux with stirring for two hours. The mixture removed by filtration and dried in vacuo to give 4-tri is cooled and the solid material is removed by filtration fluoromethylacridine. and dried in vacuo to give 4'-methylthiodiphenylamine-2- 40 carboxaldehyde azine. EXAMPLE 6 A mixture of 7 g. of 4'-methylthiophenylamine-2-car A mixture of 416 g. of 4' - chlorodiphenylamine-2-car boxaldehyde azine, 25 ml. of glacial acetic acid and 7.5 boxylic acid p-toluenesulfonylhydrazide (prepared as in ml. of concentrated hydrohcloric acid is heated at reflux Example 1), 120 g. of sodium hydroxide, 1600 ml. of 6 with stirring for one hour. The solution is diluted with ethoxyethanol, 1200 ml. of water and 114.5 g. of semicar 45 ice and water and basified with sodium hydroxide solu bazide hydrochloride is heated at reflux with mechanical tion. The insoluble solid is removed by filtration and dried stirring for 1.5 hours. To the hot solution is added an ad in vacuo to give 2-methylthioacridine. ditional 600 ml. of water and the mixture is cooled. The solid material is removed by filtration and dried in vacuo EXAMPLE 10 to give 4'-chlorodiphenylamine-2-carboxaldehyde semi 50 A mixture of 35 g. of 4'-methyldiphenylamine-2-car carbazone. boxylic acid, 24 g. of thionyl chloride and 500 ml. of A mixture of 72 g. of 4' - chlorodiphenylamine-2-car cyclohexane is heated at reflux with stirring for two hours. boxaldehyde semicarbazone, 200 ml. of glacial acetic acid The solution is cooled and 48 g. of 2,5-dichlorobenzene and 61 ml. of concentrated hydrochloric acid is heated at sulfonylhydrazine is added. The resulting mixture is reflux with stirring for one hour. The reaction mixture 55 heated at reflux for six hours, then cooled and filtered to is worked up as in Example 1 to give 2-chloroacridine. give 4'-methyldiphenylamine-2-carboxylic acid 2,5 - di chlorobenzenesulfonylhydrazide. EXAMPLE 7 A mixture of 27 g. of the above prepared 2,5-dichloro A mixture of 29.2 g. of 3' - bromodiphenylamine-2-car benzensulfonylhydrazide, 6.4 g. of sodium carbonate, 110 boxylic acid, 13.5 g. of thionyl chloride and 200 ml. of 60 ml. of 3-ethoxyethanol, 68 ml. of water and 3.7 g. of 85% cyclohexane is heated at reflux for one hour with stirring. hydrazine hydrate is heated at 100 C, with stirring for The solution is then cooled to 40-50 C. and 20.6 g. of three hours. The mixture is cooled and filtered to give 4'- benzenesulfonylhydrazine is added. The resulting mixture methyldiphenylamine-2-carboxaldehyde azine. A mixture of 7 g. of the above prepared azine, 25 ml. is heated at reflux for six hours with stirring, cooled and 65 of formic acid and 10 ml. of phosphoric acid is heated at filtered to give 3'-bromodiphenylamine-2-carboxylic acid reflux for two hours. The solution is diluted with ice and benzensulfonylhydrazide. water, basified with sodium hydroxide and filtered to give A mixture of 44 g. of 3' - bromodiphenylamine-2-car 2-methylacridine. boxylic acid benzensulfonylhydrazide, 12 g. of sodium hy EXAMPLE 11 droxide, 160 ml. of (3-ethoxyethanol, 120 ml. of water and 70 12.8 g. of thiosemicarbazide hydrochloride is heated at A mixture of 43 g. of 2'-methoxydiphenylamine-2-car reflux with stirring for two hours. An additional 60 ml. of boxylic acid, 24 g. of thionyl chloride and 500 ml. of water is added to the hot solution. The mixture is cooled cyclohexane is heated at reflux with stirring for one hour. and filtered to give 3'-bromodiphenylamine-2-carboxalde The solution is cooled to 45° C. and 34.4 g. of benzene hyde thiosemicarbazone. 75 sulfonylhydrazine is added. The mixture is heated for six 3,781,358 7 8 hours at reflux, then cooled and filtered to give 2'-me EXAMPLE 1.5 thoxydiphenylamine-2-carboxylic acid benzensulfonylhy drazide. A mixture of 118 g. of 2-bromo-5-chlorobenzoic acid, A mixture of 13 g. of the above prepared benzenesul 93 g. of aniline, 69 g. of potassium carbonate, 6 g. of fonylhydrazide, 3.8 g. of potassium hydroxide, 3.6 g. of copper-bronze powder and 500 ml. of water is heated phenylhydrazine and 50 ml. of ethylene glycol is heated at reflux for five hours with mechanical stirring. The mix at 200 C. (with stirring for two hours. The mixture is ture is cooled slightly and clarified by filtration. The fil cooled and filtered to give 2'-methoxydiphenylamine-2- trate is cooled and acidified with concentrated hydro carboxaldehyde phenylhydrazone. chloric acid. The solid which precipitates is filtered off, washed with water, dried and recrystallized from toluene A mixture of 7.9 g, of 2'-methoxydiphenylamine-2- 10 to give 5-chloro-N-phenylanthranilic acid. carboxaldehyde phenylhydrazone, 10 ml. of concentrated A mixture of 24.9 g, of 5-chloro-N-phenylanthranilic sulfuric acid and 50 ml. of ethylene glycol is heated at acid, 12.0 g. of thionyl chloride and 250 ml. of benzene 150° C. for one hour. The solution is diluted with ice is heated at reflux with mechanical stirring for one hour. and water, basified with sodium hydroxide solution and The resulting solution is cooled to 40-50° C. and 18.6 g. filtered to give 4-methoxyacridine. of p-toluenesulfonylhydrazine is added. The resulting mix EXAMPLE 12. ture is heated at reflux with stirring for four hours and cooled. The solid material is filtered off, washed with ben A mixture of 34.5 g. of 4'-trifluoromethylsulfonyldi zene, dried and recrystallized from methanol to give 5 phenylamine-2-carboxylic acid, 13.5 g. of thionyl chloride 20 chloro-N-phenylanthranilic acid p-toluenesulfonylhydra and 200 ml. of cyclohexane is heated at reflux with stirring zide. for one hour. The solution is cooled to 40-50° C. and A mixture of 17 g. of 5-chloro-N-phenylanthranilic acid 22.3 g of p-toluenesulfonylhydrazine is added. The mix p-toluenesulfonylhydrazide, 8 ml. of 10 N sodium hy ture is heated at reflux with stirring for six hours, then droxide, 70 ml. of (3-ethoxyethanol, 50 ml. of water and cooled and filtered to give 4'-trifluoromethylsulfonyldi 3 g. of 85% hydrazide hydrate is heated at reflux with phenylamine - 2 - carboxylic acid p-toluenesulfonylhydra mechanical stirring for two hours. The mixture is cooled zide. and the solid material is filtered off, washed with water, A mixture of 12.8 g. of the above prepared p-toluene dried and recrystallized from dimethylformamide to give sulfonylhydrazide, 3.5 g. of potassium carbonate, 45 ml. 4-chlorodiphenylamine-2-carboxaldehyde azine. of 3-methoxyethanol, 25 ml. of water and 1.5 g. of 85% 30 A mixture of 4.6 g. of 4-chlorodiphenylamine-2-car hydrazine hydrate is heated at reflux for two hours with boxaldehyde azine, 15 ml. of glacial acetic acid and 5 stirring. The mixture is cooled and filtered to give 4'- ml. of concentrated hydrochloric acid is heated at reflux trifluoromethylsulfonyldiphenylamine - 2 - carboxalde with mechanical stirring for one hour. The resulting solu hyde azine. tion is quenched in a mixture of ice and water and basi A mixture of 8.8 g. of the above prepared azine, 7.5 35 fied with ammonia. The solid material is filtered off, ml. of concentrated hydrochloric acid and 20 ml. of 6 washed with water and dried to give 2-chloroacridine. ethoxyethanol is heated at reflux for one hour. The solu tion is diluted with ice and water, basified with sodium EXAMPLE 16 hydroxide solution and filtered to give 2-trifluoromethyl A mixture of 75 g. of 2-bromo-4-trifluoromethylben sulfonylacridine. 40 zoic acid, 55 g. of aniline, 41.5 g. of potassium carbon EXAMPLE 13 ate, 4 g. of copper-bronze powder and 500 ml. of water is heated under reflux with mechanical stirring for two A mixture of 47 g. of 4'-(N,N-dimethylsulfamoyl)- hours. The mixture is clarified by filtration and the filtrate diphenylamine-2-carboxylic acid benzenesulfonylhydra 45 is acidified to pH 1-2 with concentrated hydrochloric zide (prepared from 4'-(N,N-dimethylsulfamoyl) diphenyl acid. The solid material is filtered off, washed with water, amine-2-carboxylic acid by the procedure of Example 7), dried and recrystallized from toluene to give 4-trifluoro 12.0 g. of sodium hydroxide, 160 ml. of B-ethoxyethanol, methyl-N-phenylanthranilic acid. 120 ml. of water and 11.4 ml. of semicarbazide hydro A mixture of 24 g. of 4-trifluoromethyl-N-phenyl chloride is heated at reflux with stirring for two hours. 50 anthranilic acid, 10.4 g. of thionyl chloride and 300 ml. Water (60 ml.) is added to the hot solution and the mix of benzene is heated at reflux with mechanical stirring for ture is cooled and filtered to give 4'-(N,N-dimethylsulfam one hour. The resulting solution is cooled to 40-50° C. oyl) diphenylamine-2-carboxaldehyde semicarbazone. and 16.2 g of p-toluenesulfonylhydrazine is added. The A mixture of 36 g. of the above prepared semicarba mixture is heated at reflux with mechanical stirring for Zone, 150 ml. of glacial acetic acid and 48 ml. of concen four hours and then cooled. The solid material is filtered trated hydrochloric acid is heated at reflux with stirring off, separated, washed with benzene, dried and recrystal for one hour. The solution is diluted with ice and water, lized from 5-ethoxyethanol to give 4-trifluoromethyl-N- basified with sodium hydroxide solution and filtered to phenylanthranilic acid p-toluenesulfonylhydrazide. give 2-(N,N-dimethylsulfamoyl)acridine. A mixture of 18 g. of 4-trifluoromethyl-N-phenyl 60 anthranilic acid p-toluenesulfonylhydrazide, 8 ml. of 10 EXAMPLE 1.4 N sodium hydroxide, 70 ml. of 6-ethoxyethanol, 50 ml. of water and 3 g. of 85% hydrazine hydrate is heated at A mixture of 9.5 g. of diphenylamine-2-carboxylic acid reflux for two hours with mechanical stirring. The mix p-toluenesulfonylhydrazide, 5 ml. of 10 N sodium hy ture is cooled and the solid material is filtered off, washed droxide, 1.5 g. of 85% hydrazine hydrate, 50 ml. of (3- 65 with water, dried and recrystallized from 6-ethoxyethanol methoxyethanol and 20 ml. of water is heated at reflux to give 5-trifluoromethyldiphenylamine-2-carboxaldehyde with stirring for two hours. The mixture is cooled and aZ11e. filtered to give diphenylamine-2-carboxaldehyde azine. A mixture of 5.3 g. of 5-trifluoromethyldiphenylamine A mixture of 5.7 g. of diphenylamine-2-carboxaldehyde 2-carboxaldehyde azine, 16 ml. of glacial acetic acid and azine, 7.5 ml. of concentrated hydrochloric acid and 100 70 4 ml of concentrated hydrochloric acid is heated at re ml. of 6-methoxyethanol is heated at 100° C. for two flux with mechanical stirring for one hour. The resulting hours. The solution is diluted with water and ice, basified solution is quenched in ice and basified with ammonia. with aqueous sodium hydroxide solution and filtered to The solid material is filtered off, washed with water and give acridine. 75 dried to give 3-trifluoromethylacridine. 3,781,358 9 10 What is claimed is: oyl or lower alkylthio, at least one of R and R being 1. A compound of the formula: hydrogen. H 2. A compound according to claim 1, said compound N being 4'-chlorodiphenylamine-2-carboxaldehyde phenyl / N 5 hydrazone. R R References Cited Yoh Chemical Abstracts, vol. 52, col. 20120(b) (1958). N BERNARD HELFIN, Primary Examiner NH-( ) 10 G. A. SCHWARTZ, Assistant Examiner in which R3 and R4 are hydrogen, halogen having an U.S. C. X.R. atomictrifluoromethyl, weight of trifluoromethylsulfonyl, less than 80, lower alkyl, dimethylsulfam lower alkoxy, 260-556 B, 397.7 UNITED STATES PATENT OFFICE . CERTIFICATE OF CORRECTION patent No. 3,781,358 Dated December 25, 1973 Inventor(s) Elvin L. Anderson et al. It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: Column 1, 1ine 5, after "19151" insert -- , as Signors to SmithKline Corporation, Philadelphia, Pa. --.

Signed and sealed this 15th day of October 1974.

(SEAL) Attest: McCOY M. GIBSON. J.R. C. MARSHALL DANN Attesting Officer Commissioner of Patents

For M Po-1050 (10-69) US COMMs to c 6037 6so 69 U.S. GOVERNMEN PRINTNG OFFICE: 869 - 930