2-Fluoroeth) laniincs. lII.la Sonle Alkylating Agents Derived f r o m Uracil1')
oAN2 H
UrN(CH,CH,OR,),
H
12, RL= C1; R, = F
15, R,
13,RL= RJ = OH 14, R2= OH; R, t F
16, R,= tosyl
I
,CH,CH,OH UrN
=
UrN(CH,CH,F)-
'CH,CH,OR-
17
18, R,= mesyl 19, R2= tosyl 0
Ur =
a. R , = H b, R, = benzyl c.
R = benzhydryl
d. R,= trityl Z = carbobenzylos\i
e. R, = CH,CH.F
3%
NOTES
cRACIL Coniwl
T,b
5, 3d 6h Bc 6d ia
2, id 8b Oil
!)I) !)e 1o n 101) 10e
yo
Rlp. " C
14i.S-148.0 91-92 139-141 181-183 118-120 148-140 (138-140) 239-240 139.0-130.5 142-143 (133-136) 119.3-120.0 >300 188-101 169.3-1i0. .i 184-1 6.5 ( 14U- I .-)I ) 120-12s 141-142 148.5-140. .5 62.5-63.0 16.5.3-166.0 165-17.5 10'2-103 163.5-164.0 12.5-127 Oil
i 1 64
79 (92) 64 60 (83) (29) 61 (79) 2.5 (82) 64 (98) 56
no
TABLE I FLUORO J I U S T A R D S .4ND Solventb
1L A
A A
E
d
CS
C D E C A TC A B
ns
-1 A
DS F A
w
e
.f
(-56) (80)
.4F AI{: 1>F
67 30 (96)
,4
(no)
INTERMEDI.1TES
ChromatoprayliSC Soirent Ri
0.01 0.93 0.24 0.9.5
0.22 0.41 0.82 0.61 0.93 0.64 0.04 0.38 ( I . 67 0.43 0.53 0.40 0.11 0.24 0,56
4
c c C C C C TJ1 C
inallses
c, rr, I\: C, H, r\' C, H, K C, H, X C, H
c,E,HI
C,H C, H, S C, €I, T C, H, F C, H, S , F C, I T , K, F c, ir, E,FA c,TI, s,F' C, I T , F C, H , N, F C, H, C1, F C, H, C1, F C, TT, N, C1 C, H, F C, H , N c, I T , N, C1 C, H, S , S C, IT, F C, I T , ti c, IT, s
4 EP 1l b A 1:3sn C (21) 81 14b -4 1.5b (j3) DS 1.id nP TE 130) 0.42 16R 19 .f TN 0.91 1i b 47 h TC 0.48; 148-349 18d 6.5 (88) T TF 0.36 1Od 118-1 19 32 F TF 0.59 11 1Ieltirig poiiits and yields are for analytical samples. Corresponding valiies enclosed in parenthe s are for other samples that are homogeneoiiw, biit less purified, and suitable for use in the next step. Solvents iised for crystallixat ns are A, E t O H ; C , CHC1,; I), CH2C12;E, E t O h c ; F, EtpO; AI, AIeOH; P, petroleum ether 30-60"; 8,Skellysslve B ; T, toluene; R, H,O; and CS for CHCls-SkellyChromatography solvent systems are those in ref 14. solve B, etc. Decomposed diiring chromatography. e Precipitated from HzO by adjusting aqueous solution of 9a.HBr to p H 5 with NH4OH. X o t recrystallized: 9b.HBr was washed with EtzO; 16a was tritiirated with H 2 0 and toluene. 13x Denotes l-trityl-S-[bis(2-hydroxyethyl)amino] uracil, the N1 isomer of 13d. h The analytical sample was obtained by thick layer chromatography on a silica gel plate, CHC1, as solvent. 1 By miiltiple development tinder coriditions where 16b had Rr 0.20. j H: calcd, 5.98; foiind, 5.53. F: calcd, 16.5; foiind, 15.9. F : calcd, 8.75; foiind, 8.23.
'
derivatives 14b and 13b, for their nmr spectra showed the C-G proton split into a doublet b y coupling with the N-1 proton. On the basis of these results, it seems that the preparation of 4 could not be achieved through the use of benzyl blocking groups. The benzhydryl series was examined briefly; 5c and 6c were prepared in the same way as their benzyl analogs. The benzhydryl series was abandoned when attempts to remove both benzyhydryl groups of 6c to give 6a failed. By using the trityl blocking groups, the sequence 5d + 6d --c 7d +8d mas carried out in a manner similar to the benzyl series. The trityl groups proved t o be quite labile. Partial loss of trityl groups occurred when the nitro compound 5d was heated or recrystallized from methanol; 5d was more stable in other solvents. For good yields in the reduction of 5d to 6d, it was necessary to replace part of the methanol in the solvent mixture with 1,2-dimethoxyethane. The trityl groups on the amine 6d were less labile; 6d could be recrystallized from ethanol. When the fluoro mustard 8d was treated with HBr in acetic acid, all of the blocking groups were removed, and 5-(2-fluoroethylamino)uracil (9a) was the product. This was hydroxyethylated to 10a and treated with phosphoryl chloride to give 4. The synthesis of the bisfluoro mustard 17a was explored without success. All attempts to tosylate 5- [(2hydroxyethyl) (2-fluoroethyl)amino]uracil (loa) failed. j-(Bishydroxyethyl) aminouraci12 (15a) was readily
tosylated to give 16a, which, however, could not be converted to 17a. Parallel experiments in the benzyl series demonstrated that the conversion of 15b through 16b to 17b proceeded smoothly. It was apparent that blocking of the uracil ring was necessary. Use of the trityl blocking group posed problems at two points. First, synthesis of the bishydroxyethylamine 15d was difficult. Hydroxyethylation of 6d did not take place under the conditions tried. Only a low yield of 1Sd could be obtained by the tritylation of E a . Second, the bis(2-hydroxyethy1)amine 15d could be converted only to the monosulfonyloxy derivatives 18d and 19d, in contrast to the ready formation of the bistosyloxy derivatives 16a and 16b. A few other 2-fluoroethylamines mere prepared. Fluoroethylation of 5-(benzyloxycarbony1amino)uracil (7a) afforded the tris(2-fluoroethyl) compound 8e, an unanalyzed oil which mas converted through 9e to 10e. The mustard 4 and a number of the other possible alkylating agents were screened for antitumor activity by the Cancer Chemotherapy Xational Service Center (CCSSC) according to its protocol." The results were all negative, although 8b and 9a caused some reduction in tumor growth in Sarcoma 180, and 16a caused some increase in survival time in leukemia 1,1210. The other test systems and compounds tested were Walker 256 subcutaneous (4, 17b), Walker 236 intramuscular (11) Cancer Chemotherapy R e p t . , 26, 1 (1962).
357
KOTER
llarch 1968
was diluted wit,h an eqiial voliime of petroleiim ether, t o afford 2.12 g (30%) of the crude 15d in two crops, mp 161-162 and 138.3l.jO..io, idelltical by iiifiared spectra arid thiii layer chlomatography. h port i o i i was c.hrciiiia~og~al)Iietl o t i H (hick I a y ~ rplxlc of silica gel, developing with EtOAc-CITCla (1 : 1) 10 af%ord15d that was crystallized oric*efor the aiinlytical $ample. 1,3-Ditrityl-5- [( 2-hydroxyethyl)( 2-mesy1oxyethyl)aminoJ uracil (18).-h 1.04-g (9.1 mmole3) portion of AIeS02C1was added t o :t cold (-lo"), stirred soliition of 2.00 g (2.86 Inmoles) of the bishydroxyethyIamirioIiraci1 15d. The soliltion \vas stirred for 2 hr at 2 O , then partitioned betffeen 200 ml of toluene and 300 ml of H&. The organic layer was washed with two 200-ml portions of H&, dried, concentrated to ea. 20 ml, then diluted with an equal volume of petroleum ether to afford 1.95 g ( 8 8 % ) of 18. In a similar way, 19 was prepared from 15d and p-toluenesulfonyl chloride. The same procedure, when applied to 15a arid 15b, gave the bistosyl derivatives 16a and 16b, respectively. 1,3-Dibenzyl-5- [bis(2-fluoroethyl)amino]uracil (17b).-By the literature procedure,8 a mixtlire of 5.0 g of anhydrous K F and 5.00 g (7.1 mmoles) of 1,3-dibenzyl-5-[bis(2-tosyloxyethy1)amino] uracil (16b) in i . 5 g of N-methyl-2-pyrrolidone was heat,ed a t 160-175" for 40 min to afford 2.69 g (9655) of rritde 17b which was piirified by plate chromatography.
Acknowledgment.-We are indebted t o \: [r. Osborne P. Crews, Jr., and his staff for the large-scale preparation of many intermediates and to Dr. Peter Lim and his staff for the spectra and paper chromatograph y .
Pyrimidines. XXII. 2,4-Diamino-6-arj-lamino-5-pyrimidinecarboxaldehydes and Related Compounds' DARRELL E. O'BRIES, LOUIST. WEINSTOCK, AND C. C. CHEW
Jf idwest Research Institute, Kansas City, Jf issouri 64110 Received September 30, 1967
The synthesis and antitumor evaluation of a number of 2,4-diamino-6-arylaminopyrimidi1ies bearing various functions substituted a t position 5 of the pyrimidine moiety (I) have been reported from our laboratories in
As a continuation of this study, synthesis of the corresponding 5-carboxaldehyde derivatives was initiated. search iii the literature rcvc:iled that) 3-l)yriiiiidiiiccarboxaldchydes majr be 1)rel)ared bj. ozo~iol~.sis of of riitromethj.1 ethylenic groups,5 by h\.drol\ arid by proper conversion of cy~t110,~ c:irboxy,* trichloroh~,droxycthyl,gand hj,droxymet hyIio groulm 120rnq.l groups have also been int,roduced directly by acylation reactions, l 1 - I 3 arid by the Reimer-Tiemann reaction. l 4 Recently, it was reported by Iilotzer and Herberz that 2-ami1io-4,G-dichloro-5-p~rimidi1iecarboxaldehyde (IIa) was prepared in good yield from 2-amino-4,6-1 dinediol by a modified Vilsmeier-Haacli synth This material was t'herefore used as the starting material for the present investigation. When IIa was stirred wit'h ethanolic ammonia at room temperature, 2,4-diamino-G-chlor0-5-pyrimidinecarboxaldehyde (IIb) was obtained in good yield. Treatment of the intermediate I I b with 2 equiv of a subst'ituted aniline iii refluxing et hano1 yielded the ariils of 2,4-diamino-G-(substitutcd aniliiio)-j-pyrimidiiie-carboxaldehyde (111), with characteristic ultraviolet absorption maxima in the 350-3GO-mp region at 1)H 1 and 11. The desired 2,4-diamino-G-(subst'ituted anilino)-5-pyrimidinecarboxaldehydes (11;) were readily obtained by acid hydrolysis of I11 in 0.1 N HCl. These products do not possess any ultraviolet absorption maxima above 340 mp in either pH 1 and 11.
R IIa, R = C1 b,R = NH2
k I11
NH2 IV NH*
I
recent ears.^-^ Among these compounds, the 6-(halogen-substituted ani1ino)pyrimidines with a 5-nitroso group demonstrated int'eresting activity against Adenocarcinoma 755 tumor system.2 For the retention of biological activity, available information indicates that substitution a t position 5 is restricted to a particular size (comparable t o -K=O) and its electronic effect (electron withdrawing). This is illustrated by the fact that the corresponding 5-cyario3 and 5-nitro4derivat'ives possess similar biological activity but the 5-ethyl, 5-bromo, and 5-carbamoyl derivatives were i n a ~ t i v e . ~ (1) This investigation was supported b y t h e Cancer Chemotherapy National Service Center, National Cancer Institute. National Institutes of Health, Public Health Service. Contract PH-43-65-94. (2) D. E. O'Rrien, F. Baiocchi, R . K. Robins, and C. C. Clieng, J . M e d . Pharm. Chem., 6, 1085 (1962). (3) D. E. O'Brien. F. Baiocchi, R. K. Robins, and C. C. Cheng, ibid.. 6, 467 (1963). (4) ll. E. O'Brien, C. C. Cheng, and W. Pfleiderer, ibid., 9, 573 (1966).
These 5-pyrimidinecarboxaldehydes (IT) displayed no significant anticancer activity against leukemia L1210 and Walker carcinosarcoma 256. (5) (a) H. Kondo and A I . Yanai, J . P h a r n . Soe. J a p a n , 67, 747 (1937): (b) E. Ochiai and AI. Tanai, ibid., 68, 397 (1938). (6) F. E. King and T. J. King, J . Chen. Soc., 943 (1947). (7) AI. Delepine and K. -1. Jenaen, Bull. Soc. Chim. F r a n c e , 6 , 1663 (1939). (8) D. Price, E. L. M a y , and F. D. Pickel, J . A m . Ciiem. Soc., 62, 2818 (1940). (9) R . Hull, J. Chem. Soc., 4845 (1957). (10) R. E. Cline, R. R l . Fink, and K. Fink, J . A m . C h e m . Soc., 81, 2.521 (1959). (11) RI. Ridi and P. Papini, Gam. Chi". Ital., 76, 376 (1916). (12) RI. Ridi, ibid., 79, 175 (1949). (13) JV. Pfleiderer and G. S t r a w s , Ann., 612, 173 (1958). ' . Yamamoto, J . Org. Chem., 26, 1906 (1960). (14) R. H. Wiley and 1 (15) W. Klotzer and 31. Herherz, .Uonatsh. Chem., 96, 1.567 (1965); cf. A . Vilsmeier and A . Haack, Ber., 60B,119 (1927). (16) A similar preparation of 4 , 6 - d i c h l o r o - ~ - p ~ r i m i d i n e c a r b o x a l d e h ? d e b y the reaction of 4,6-dihydroxg.pyrimidine v i t l i a mixture of pliosgene and dimethylformamide was recently reported by H. Bredereck, G. Simchen, A. Santos, and H . Tt-agner, Angew. Chem., 78, 717 (1966), el. Z. Arnold, Collection Czsch. Chem. Comnun., 24, 4048 (1959).
