Aug. 20, 1957
~ E N Z I h I I D X Z O L Y L24NA\LoGsOF E T H Y L PTEROYLGLUTAMATE
pler thiazolium salts. I n this case the final equilibrium absorbancy was measured. Because of the slow reaction rates in the neighborhood of pK,,, and slow secondary
[ C O X r R I B U l I O X F R O M T H E D E P A X T M E N T OF
Metabolite Analogs.
439 1
reactions, these particular p K estimates have an uneertainty Of as much as 1 0 . 2 unit. AYES, IOWA
CHEMISTRY O F THE
u N I V E R S I T Y O F PENNSYLVANIA]
VII. Preparation of Some Benzimidazolyl Analogs of Ethyl Pt eroy lglutamat e
BY 14’. RAYMOND SIEGART AND ALLANR. DAY RECEIVED JANUARY 15, 1957 Some benzimidazolyl analogs of ethyl pteroylglutamate have heen prepared. atom of the methylene bridge and in the benzene ring of the henzirnidazole
Substituents have been placed on the carbon
Two benzimidazolyl analogs of pteroylglutamic nitrobenzoyl chloride and glutamic acid. The acid have been reported previously, N- { 4- [ (2- nitro group was reduced by catalytic hydrogenabenzimidazoly1)-methylamino]- benzoyl} - glutamic tion over palladium and the corresponding aminoacid’ and N { 4- [(5-chloro-2-benzimidazolyl~ - benzoylglutamic acid converted to its diethyl ester. methylamino ]-benzoyl -glutamic acid. The first Preliminary work had shown that the final prodcompound was reported to retain a certain degree ucts, the benzimidazolyl analogs of folic acid, of growth-promoting activity’” and also to be a were most readily isolated and purified in the form weak growth antagonist.Ib The 5-chloro com- of their ethyl esters. The 2-hydroxyalkylbenzimidazoles were prepound was reported to be a stronger growth antagonist than the unsubstituted analog.Ib It seemed pared from the appropriate hydroxy acid and oto be desirable to extend this work, in several ways, phenylenediamine by the Phillips method3 or by in order to determine the possibility of obtaining fusing the reactants together. The hydroxy comstrong anti-folic activity in this type of compound. pounds were then converted to the corresponding In the present investigation, benzimidazolyl an- chloro compounds by treatment with thionyl chloalogs of folic acid have been synthesized containing ride. not only substituents in the benzene ring but also In order to reduce side reactions to a minimum, on the carbon atom of the methylene bridge. the hydrochlorides of the chloro compounds were Substituents have been placed on the methylene used for condensation with diethyl p-aminobenzoylbridge when there were no substituents on the ring glutamate. The condensations were carried out in and when there were substituents on the benzene dioxane solution in the presence of two equivalents ring. The choice of substituents in the benzene of triethylamine. The main side-reaction which ring was influenced by the work of Hoover and occurred to a greater or less extent, depending on Day.2 the nature of the chloro compound, was self conThe syntheses of the benzimidazolyl analogs of densation. It had been shown earlier4 that the pteroylglutamic acid involved four steps: (1) 2~-chloroalkylbenzimidazoles do not always unpreparation of diethyl p-aminobenzoylglutamate ; dergo normal anionic replacement reactions. They ( 2 ) preparation of 2-hydroxyalkylbenzimidazoles; show a marked tendency to undergo self-condensa( 3 ) preparation of 2-chloroalkylbenzimidazoles; tion t o form tetracyclic compounds. For example, and (4) finally, the condensation of the chloroalkyl 2-chloromethylbenzimidazole readily forms dicompound with the glutamate derivative. benzimidazo[ 1,2,-a, 1’,2’,-d ]piperazine. On several occasions during the course of the present work, high melting, crystalline compounds were isolated whose analyses indicated that they were tetracyclic. No attempt was made to purify these secondary products. Gummy materials also were separated _. COOCrHj from the reactions of the 2a-chloroalkylbenzimidazoles with ethyl p-aminobenzoylglutamate. They H?SCfiH*COHSCHCH*CH2COOC*H~ --+ were assumed to be linear polymers formed from H self-condensation of the chloro compounds. For testing purposes, two benzimidazolyl analogs of the ethyl ester of pteroic acid were prepared also. They were prepared by condensing the chloroalkyl benzimidazoles with ethyl p-aminop-Nitrobenzoylglutamic acid was prepared by a benzoate. modified Schotten-Baumann procedure from p All of the final products are being tested for ( 1 ) ( a ) P C . Edwards, D. Starling, A . hI. hIattork4 and H. E. physiological activity. The test results will be Skipper. S r i r n c e . 107, 114 (1918); (bi F. E . King, R . > f . Acheson. and published elsewhere. P
C. Spensley. A7aCwe, 162, 153 (1948); 1.Chem. Soc., 1401 (1944). ( 2 ) J R. E. Hoover a n d A. R. Day, THISJ O U R N A L 77. 4324 (1955): 7 7 , 5 6 5 2 (195.5): Progress Report, July 1955-January 1956,II.S.P.H.S G r a n t t-?18Q. Vniversity of Pennsvlvania.
(.O M A Phillips, J. Chem. Soc , 2393 (1928). ( 4 ) H Skolnik. I G Miller and A R n a y . THIS TOLTRNAI , 1854 (1943)
66,
4392
Tl$i,
Compouri d
I" 11" 111" 11.' 1-
1-1'
VII'. T'IIIC ISC
I
