Arylaminoheterocycles. II. Arylaminopyrimidines

Abstract

Relatively few di-(ary1amino)-pyrimidines and amino-arylaminopyrimidines are recorded in the literature.1.2~a~4~6 These compounds were prepared by reawing a halo-or ethylmercapto-pyrimidine in the liquid amine and were limited to those containing simple.ary1 groups such as phenyl and tolyl. In the precedipg paper of this series,6 the condensation of 2-amino-4-chloropyrimidine and aniline was studied to detennine the rate of reaction under varying conditions of alkalinity and acidity. The compound formed, 2-amino-Panilinopyrimidine, was isolated and studied pharmacologically. It caused a 'presser response in anesthetized dogs equal to that of benzedrine but of shorter duration. It also appeared to have analgetic activity.' Since the structure of this compound differs ' widely from other compounds having similar pharmacological activity, a number of compounds having substituents in the benzene ring were prepared.All of the arylamines and halo-aminopyrimidines used are commercially available or adequately described in the literature. The condensation of amine and heterocycle was carried out under the optimum reaction conditions previously described.6 The yields were nearly theoretical. Morpholine was also condensed with 2amino-4-chloropyrimidine, using the same procedure, in yields of 66-75%. The compounds so formed are now being studied for pharmacological activity.Experimental 2-Amino4anilinopyrimidinrimidine-tenth mde of aniline, 0.1 mole of 2-amino-4-chloropyrimidine and 1 ml. of hydrochloric acid in 100 ml. of water were refluxed for thirty minutes. A clear solution was formed, which was charcoaled (Darco) and filtered while hot. A test for unreacted amine indicated that over 99% reaction had occurred. The filtrate was cooled, made strongly alkaline with 10 N sodium hydroxide and the precipitated product filtered off and recrystallized from alcohol-water. The over-all yield was 92%. The monoacetate salt was formed by dissolving the base in hot dilute acetic acid and cooling. The diacetate was prepared by solution of the base in glacial acetic acid and precipitating with anhydrous ether. These compounds were dried in ULUW (1 mm.) for twentyfoy: hours at room temperature. The diacetate loses one mole of acetic acid when heated in wcuo. The hydrochloride was formed by solution of the base in alcoholic Pharmacological work under the supervision of Drs. C. C. PfeifIer and E R. Loew of our laboratories.hydrochloric acid, addition of five volumes of butyl acetate and crystallization started by scratching. The crys; tals were filtered off and dried twenty-four hours at 100 WGW. Similar procedures were followed in preparing compounds 3, 15, 16, 17, 18 and '19 of the table. The remainder were prepared by carrying out the condensation in the same manner but after charcoaling and filtering, an equal volume of concentrated hydrochloric acid was added and the solution chilled in an ice-bath. The produit.was filtered off and recrystallized from dilute hydrochloric acid. To obtain the free bases of these hy ochlorides, aqueous...

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines

“…[20] Furthermore, protonation of a nitrogen atom of a heteroaromatic ring can enhance the rate of a S N Ar reaction. [10][11][12][13] However, addition of an acid may deactivate the nucleophilic component of the reaction. The aniline needs to be in its non-protonated form, and thus increasing the amount of TFA will augment the population of unreactive protonated aniline.…”

“…An investigation, in which various acid catalysts and solvents were explored, led to the identification of trifluoroacetic acid‐2,2,2‐trifluoroethanol (TFA‐TFE) as a convenient and efficacious combination for effecting S N Ar reactions with purines and pyrimidines 5. 7, 9 The benefit of acidic catalysis for S N Ar reactions of appropriate heterocycles had already been recognised long ago by Banks10, 11 and Chapman,12, 13 and subsequent to our initial studies, further quantified by Liu and Robins 14. The use of acidic catalysis in S N Ar reactions employed for the scale‐up synthesis of drugs is increasingly commonplace 4.…”

Potential antitumor agents. 23. 4'-(9-Acridinylamino)alkanesulfonanilide congeners bearing hydrophilic functionality

“…In an extension of promising inhibitory results in vitro against Histoplasma capsulatum, correlated earlier using substituent constants developed by regression analysis with 77 disulfides, one symmetrical and 14 unsymmetrical disulfides were prepared (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). About half were active in vitro against H. capsulatum (and one against Candida albicans).…”

The Role of Phenol in the Reaction of 2-Amino-4-Chloro-6-Methylpyrimidine with Piperidine

“…It is also unreasonable to consider that the weakly acidic phenol could activate the chloropyrimidine in the fashion demonstrated by Banks (3,4). It is believed now that phenol must exert its beneficial influence on the displacement reaction under discussion by a solvolytic pull on the chlorine atom according to the method elaborated by Swain (5).…”