Journal of Medicinal Chemistry, 1970, Vol. 13, iVo. 3 407
6-(N-ALKYLN-ARYLAMINO)PYRI~IIDIN6$
Synthesis of 6-(N-Alkyl-N-arylamino)pyrimidines As Potential Antimetabolites' P. L. WARNER, JR.,*p3 AND T. J. BARDOS4 Depaitment of Medicinal Chemistry, School of Phomiacy, State Unzversity of ,Yew York at Buffalo, Buffalo, iYew York 14214 Received October 13, 1969 Thirty-eight new 6-(X-alkyl-li-arylamino)pyrimidines were prepared as open-chain analogs of riboflavin that lack the Nlo atom of the central ring. Nost of these compounds were prepared by simple coupling reaction between the appropriate 2,4-disubstituted 6-chloropyrimidine and an N-alkylaniline, usually under fusion conditions, except in the case of the derivatives where C1 was sufficiently activated to react in refluxing EtOH, EtaN, or DRIF. Several of the compounds showed in vitro activity against Sarcoma 180 cells, 2,4-diamino-6(~V-ethy1-3,4-dimethylanilino)pyrimidine~ HC1 (34)being the most active.
It has also been observed that a mammalian 2,4-Diamino-6,7-dimethyl-2,4-dideoxyalloxazine (I) flavokinase was inhibited in vitro by a homologous series has been found to antagonize both riboflavin (11) and and it of 9-(w-hydroxyalkyl)-6,7-dimethylisoalloxazines, folinic acid in several microbiological test systems6f' appeared that the alkyl chain a t the 9 position of the and to inhibit the growth of transplanted tumors in heterocyclic ring system contributed to the binding of m i ~ e . ~However, !~ the poor tissue absorption properties the inhibitor to the ensyme.l3 Thus, we were enof I limited further in vivo studies with this compound. couraged to prepare a variety of 2,4-disubstituted 6It mas felt that introduction of various alkyl and hy(N-alkyl-N-ary1amino)pyrimidines (111, R = alkyl ; droxyalkyl chains in the S,position of I might lead R' = H or CH,), including some which were substituted to compounds with increased solubility and better in the 5 position of the pyrimidine moiety with a nitro absorption proper tie^.^ Such compounds would also or nitroso group. bear a greater structural resemblance to 11. However, While 6-(N-alkyl-3,4-dimethylanilino)pyrimidines direct alkylation of I resulted in substitution in the SI (111, R = alkyl; R' = CH,) would bear the greateat positio~i,~and our attempts to react dimeric 4,5structural resemblance to riboflavin (11), several 6dimethyl-o-benzoquinone6 with a variety of 4-sub(N-alkylani1ino)pyrimidines (111, R = alkyl; R' = H) led to stituted 6-alkylamino-2,3-diaminopyrimidines'0 were also prepared, making use of the commercial condensation products which were difficult to purify. availability of N-benzyl-, N-ethyl-, and N-methyl"2 Q anilines. The reaction of 2 mol of 3,4-dimethylaniline with 1 mol of the appropriate acyl chloride gave a series of 3',4'-dimethylanilides (IV, Scheme I ; 1-5, Table I) which were reduced by the method of Brown and Heim14 in good yield to the corresponding NI &H,(CHOH),CH,OH alkyl-3,4-dirnethylaniliries (V,It' = CH,, Scheme I ; I1 6-10, Table 11). By treating 2-amino-4,G-dichloropyrimidine with the N-alkyl-N-arylamines in a fusion reaction similar to that described by O'Brien and coworkers,'; a series of 2-amino-4-chloro-6-(N-alliyl-Nary1amino)pyrimidines (VI, Scheme I ; 11-18, Table 111) was obtained. Contrary to previous reports of III similar condensations,'j l6 we found the addition of Cheng, O'Brien, arid coworkers reported the aiitit,umor mineral acid to be unnecessary. The 4-chloro derivaactivities of various 5-nitro- (and 5-nit'roso)-2,4-ditives were readily converted into the 4-hydroxy analogs amino-6-arylaminopyrimidines,and noted t.he struc(VII, Scheme I ; 19-26, Table 111) by treating the tural resemblance of 6-arylaminopyrimidines t80 riboformer with powdered NaOH in ethylene glycol at elevated temperatures. l5 (1) This research mas supported b y Grant S o . C.i 06695-7 from the Kah series of 6-(N-alkyl-N-arylami1io)uracils (IX, tional Cancer Institute, National Institutes of Health, U. S. Public Health Service. Scheme 11; 27-32, Table 111) were prepared by fusing (2) Present address: Westwood Pharmaceuticals, Inc., Buffalo, N. Y. 6-chlorouracil'7 (VIII) with the N-alkyl-N-ar~lamiiie~. 14213. Similarly, we synthesized a series of 2.4-diamino-G(3) Taken in part from t h e dissertation submitted by P. L. \V,,Jr., in partial fulfillment of the requirements for a P h . D. degree, S t a t e u n i v e r s i t y (N-alkyl-N-arylamino) pyrimidines (XI, Scheme I1; of h'ew York a t Uuffao, I3uffalo. N. Y . , M a y 1969. (4) T o whom communications should be directed. ( 5 ) T. J. Bardos, D . B. Olsen, a n d T. Enkoji, J . Amer. Chem. SOC.,79, 1704 (1957). (6) T . J. Bardos and D. B. Olsen, 129th Kational Meeting of t h e American Chemical Society, Dallas, Texas, April 1956. Abstracts, p 3 M . ( 7 ) J. L. Ambrus, C . Jl. Ambrus, a n d N. Back, Pharmacologist, 1, 80 (1959). (8) J. L. .Lmbrus a n d A. Segaloff, Proc. Amer. Ass. Cuncer R e s . , 3, 2 (1Y 59).
(9) 8. 1,. Alukherjee, Z. F. Ctimielewics, and T. J. Uardos, J . Phurm. S c i . , 67, 516 (1968). (10) P. L. Warner, Jr. and T. J. Uardou, J . M e d . Ckem., 9, Y77 (lY6ti).
(11) D. E. O'Brien, F. Baiocchi, R. E;. Robins, and C. C. Clieng, J . M e d . Pharm. Chem., 6 , 1085 (1962). (12) D. E. O'Urien, C. C. Cheng. a n d W. Pfleiderer, J . X e d . Chem., 9, 573 (1966). ( 1 3 ) B. hl. Chassy. C. Arsenis, and D . B. hIcCormick, J . B i d . Chem.. 240, 1338 (1965). (14) H. C . Brown and P. Heim. J . Amer. Chem. Soc.. 86, 3566 (1964). (15) D. E. O'Brien, F. Baiocchi, R. li. Robins, a n d C. C. Cheng, 3 . Org. Cliem., 27, 1104 (1962). (16) C . K. Dank% J . Amer. Chem. Sue., 66, 1127, 1131 (1944). ( l i ) R. Jl. Creasnell and H. C. S. Wood, J . Chem. Soc. 4768 (19601.
sCIiER11:
I
TABLE I11 6-(ly-*kLKYL--v- \RYL)AMINOPYRIIMIDINES
Y I
R NO.
x
Yield, Y
c/o"
Recrystn solvent
M u . oc
EtOAc176-178' cyclohexane 72.6 Cyclohexaiie 12 2" C1 13 5- 156 EtOH, HLO 84.6 C1 166-165 13 NH2 67.2 C1 EtOAc 179-lhl NHL 14 38.1 C1 Heptane KH? 157-158.5 15 73.2 Heptane 2" C1 1 ,j7- 158 16 49.3 EtOAc 212.3-2 14 NHL C1 17 60.h 1s e1 Heptane 2" 200-202 67.1 OH 3IeOH 19 274-273. .i NH, 84.0 OH EtOH 20 273-276 2" OH RIeOH hb.7 21 NH? 248 .i-250 38.1 22 2" OH 25.5-257 NeOH 53.0 XIeOH-HA0 23 2" OH 24.5246. j 3LeOH OH 43.7 24 KH2 239.3-241, .i 2.j 42.2 2" OH 241.3-243 5 EtOH OH 2" 58.7 EtAc 26 218-220 98.1 27d OH OH 1IeOH 265-287 dec 28 11lIF-3IeOH b3.4 OH OH 2h4. .52S6 OH OH 71.3 29 EtOH-H2O 269-270 dec OH OH 76.9 30 EtOH 235-237 OH OH 84.7 31 EtOH 231.5-233.5 OH OH 32 58.7 EtOH 240 5-242 2" 83.0 33" 2" EtOH-HLO 157-15s 34e NH1 70.4 2" 262.5-263.3 CaHs NHr SH, 78.3 35. Xcetoiie-EtOAc 203, ;i-205. 3 XH? XH? 37.8 36e EtOH-EtOAc 163-163 ?iH2 %6.6 37 RIeOH-E tOAc149.5-132.3 NHr Heptane Recrystallized product. Except for compound 11 which was not analyzed, satisfactory analysis were obtained for C, H , and N. c Reportedlj mp: 177-178". B. 11.Baker and W. lizeszotarski. J . .)led. Chern., 10,1109 (1967) report mp 287-289" for this compound. e As the HCl salt. 11
NHz
C1
(.500 ml). The reactioii mixture was theti briefly heated a t reflux and filtered t,o remove the amine.HC1. The salt wab washed with hot CeHa (50 ml), t,he filtrat,e and washings were combined, and the C6Hs was removed by heating in z'acuo on the steam bath. The crude amide was dissolved it1 a minimum amourit of hot EtOH and poured with stirring into cold H20 (500 ml); the crude product was separated by filtratioii, washed with cold HSO, and dried. .V-Alkyl-3,4-dimethylanilines(6-10, Table II).-Esseiitially the procedure of Brown arid Heim14 was followed. A solution of the amide (0.175 mol) in a minimum amourit, of freshly distilled T H F was added dropu-ise with stirring to the cold boraneTHF solution (375 ml, l M ) > in the course of 0.5-0.75 hr (S2 atm). The mixture was refluxed for 2 hr, followed by cooling t o 5-10'. HCl (6 IY,50 ml) was added to the cold, stirred reaction mixture (water-cooled condenser) cautioztsly, followed by the rapid addition of HgO (50 ml). After removal of the T H F by distillat,ion, hot HZ0 was added (100-300 ml), then the mixture was cooled arid made strongly basic with XaOH. The crude amine was extracted into t,hree 100-ml portioiis of Et.zO. After dq-iiig (Na2SOd), Et20 was removed in uacuo and the product purified by distillation. 2-Amino-4-chloro-6-( S-alkyl-,L~-arylamino)pyrimidines( 11-18, Table III).--A mixture of the .Y-alkyl-.Y-arylamine (0.02 mol) and 2-ami1io-4,B-dichloropyrimidiiie (0.02 mol) was placed i n a 2.3 X 10 cm test tube which was then partially inimeried i l l a bath preheated to 195". The reaction mixture was stirred ruitil soliitioii occurred, followed by a stroiig exothermic reactioii i i i which gab W V R evolved. ~ Heatiiig war coiitiiiued f o i , 0.5
78.0
SCHEME
X
VIII, X =OH; Z = H X, X = NHe; Z = H XII, X = OH; Z = NO2 XIV, X=NH2; Z = NOe
11
X
R M, X=OH; Z = H XI, X=NH2; Z = H XIII, X = O H Z = NO, XV, X = NHz; Z = NOz
hr, aiid sufficient, hot, ethylene glycol was added to dissolve the yellow oil. The hot solution was poured with vigorous stirring into dilute NHiOH (400 ml). Xfter staridiiig overnight, the crude solid was collected by filtration, washed with HIO, aiid dried. 2-Amino-6-(,\~-alkyl-S-arylamino)-4-pyrimidinols ( 19-26, mixtiire of the chloropyrimidine (0.01 mol), Table III).--A powdered XaOH ( 2 . 0 g ) , mid ethylene glycol (30 ml) was heated (as above) at 165'. The reactioii was stirred occasionally until solution was effected. (If Pome of the chloropyrimidine was undiisolved after heatiirg 0.3 hr, siifficieiit additioiial hot glycol n-ah added to dissolve the compound.) Heating was eoiitiiiued for a total of 1.5 hi, atid the hot reactioii mixture was poured, with vigirous stii,riiigj i l l t o H.0 ( 2 5 0 nil). The f i l l i , a t e was atijiihted
'i I
