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United States Patent Office Patented Dec 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.
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