Eovember 1965
2-E'LGOROETHPL.4MINES.
2-Fluoroethylamines,
11
711
11." Biological Evaluation and Synthesislb
ABELARDO P. MARTINEZ, WILLIAMW,LEE, ASD LEONGOODMAN L i f e Sciences Research, Stanford Research Institute, Menlo Park, California Received A p r i l '7, 1965 Sitrogen mustards containing fluorine were attached to ciiinamic acid, hydrocinnamic acid, and phenylbutyric acid as carrier groiips. These fluoro mustards and others, synthesized earlier, that were attached to benzaldehyde, phenylpyruvic acid, and phenylalanine, together with some intermediates were screened for antitiimor activity. T h e majority were screened against Walker 256 in rat and KB cell cdture. Selected mustards were screened against Sarcoma 180, lymphoid leukemia L1210, and Lewis lung carcinoma in mice. I n general, replacement of chlorine by fliiorine resulted in increased toxicity and the compounds did not meet the criteria for activitv.
CHARTI 2-Fluoroethylamines have been studied the least of CH=CHCOzRi CHO all 2-hal~ethylaniines~ as potential anticancer agents. CH2 (COzH)2 However, the recent report of the remarkable clinical or application of "ftorpan" [3-(2-chloroethyl-2-fluoro(CeH5)3P= CHCOzEt ethylamin0)-6-niethyluracil] has spurred interest iii NCHzCHzF the synthesis of 2-fluoroethylamines in this laboraTCHzCHzF I CHZCHzR CHzCHzR tory'& and else~vhere.~R e report here the synthesis I I1 I1 I,, R II = =H Et and biological evaluation of the fluorine analogs of p-cinnamic acid niustardb,; chlorambucil,6 and re( C H Z ) ~ C O Z M ~ (YH2)nC02H lated compounds. I For the synthesis of the bisfluoro and the chlorofluoro mustards outlined in Chart I, we used either the intermediates or the general methods reported preHNCHzCHiF NCHZCHiF viously.1" p-[Bis(2-fl~oroethyl)aniino]benzaldehyde~~ RiNRz I VHCI (Ia) reacted with malonic acid under either acid or base CHpCHzR catalysis. In the presence of acetic acid, the reaction IV-IX Y,n = 2 XI1 proceeded slowly to give a low yield of p-[bis(2-fluoroXI, n = 3 ethyl)amino]cinnamic acid (IIa) of analytical purity. With the use of an equivalent amount of piperidine as catalyst, the condensation afforded much higher yields of IIa. S o condensation of Ia with malonic acid took place under the milder conditions (room temperature, less piperidine) found suitable for p - [bis(2-chloroethyl)aniino]ben~aldehyde.~The product, IIa, was apparently a mixture of cis and trans isomers that gave two spots on paper chromatograms. I t was not converted to a single isomer by iodine in refluxing benzene ethoxyiiiethyleriephosphorane.8 The cinnaniate ester and could not be separated by recrystallization. HyIIIa that resulted was hydrolyzed to afford a fair yield drogenation of this mixture afforded the homogeneous of IIa, also a mixture of isomer
