4592
JOEIN
X.R~ONTGOMERY.ZND CARROLL TENPI,E, JR.
[ C O S T R I I X W I O X FROM T I E KETTERISG-hIEYER
LABORATORY,' S O C T H E R N
Synthesis of Potential Anticancer Agents. XXIII. Compounds
l7Ol. 82
RESEARCH IXSTITUTE, BIRMISGIIAM 3, '\LA.
1
9-Aminohypoxanthine and Related
BY JOHN A. MONTGOMERY AND CARROLL TEMPLE, JR. RECEIVED MARCH 7, 1960 The reaction of 5-amino-4-hydrazinopyritnidines with formic acid has been found to give 9-aminopurines rather than the isomeric 1,2-dihydropyrimido[5,4-e]-as-triazines,Some l-alkyl-1,2-dihydropyrirnido[5,4-e]-as-triazines were prepared from 4-( l-alkylhydrazino)-5-aminopyrimidines.
The behavior of 5-amino-4-hydrazinopyrimi-the N-H bandsg (3450, 3250 and 1645) that would dines when treated with reagents such as anhydrous be expected from that structure, and the ultraviolet formic acid2 or ethyl orthoformate-acetic anhy- spectrum agrees well with t h a t of 9-ethylhypoxandride3, normally used to prepare purines from 4,5- thine1° (see Table I). diaminopyrimidines, poses an interesting chemical TABLE I problem, since one would assume that the reaction is R# equally likely to give 9-aminopurines4or 1,2-dihydropyrimido- [5,4-e]-as-triazines.6 Either product could be utilized in the preparation of potential anticancer agents; the former compounds might interfere with purine metabolism and the latter with the one-carbon transfers involvi~igfolic or folinic ,pH 7 - 7 -0.1 N SaOH-0.1 .v HCIA,nax, e Am*x, e A*.%, acid. mp XlO-3 nip X 10-3 mp X10-3 R? RI To investigate the reaction, we prepared 5-amino- H CzHa 2G3 7 .82 2G1.5 5.85 263 7.82 ... 264 5.05 2Gj.5 4-chloro-6-hydrazinopyrimidine (IV) from 5-amino- H ?" ... 262.5 250 12.4 250 11.7 250 10.8 4,6-dichloropyrimidine (111) and anhydrous hy- O H CzHs 12 0 254 249 11.0 250 10.4 OH drazine.' Reaction of ILr with anhydrous formic O H S=CHCeHj 250 254 ., , 254 21.1 ... acid gave a product (XI) which on treatment with 289 ., . 2% 22.8 284 , . . 255 13.2 12.2 250 dilute acid or base yielded 9-aminohypoxanthine O H NHCH2CsHs 250 11.4 266 9.4 266 9.4 9.6 265 ( X I X ) . The identity of XIX was established in CI C?Ha 266 ... 263 . . . 262 ... NHCOCHI CI a number of ways. First, treatment of X I X with S H CrHa 310 21.8 320 20.0 325 10.6 aqueous nitrous acid gave a good yield of hypoxan- s Fr NHCOCHi 311 21.2 316 20.0 321 23.9 thine (XIII), as did fusion with sulfur. Secondly, The hydrolysis of the chlorine atom of IV during X I X was synthesized by an unequivocal route. ;i-Xmino-4-chloro - 6- benzylidenehydrazinopyrirnid- ring closure was expected for this is a well docuSince the ine (VII) was prepared by the reaction of 5-amino- mented reaction in the purine 1,6-dichloropyrimidine (111) and benzaldehyde hy- ring closure gave 9-formamidohypoxanthine (XI) drazone and also by the reaction of ~-amino-4-chloro- instead of the isomeric 1,2-dihydropyrimido[5,4G-hydrazinopyrimidine (IV) and benzaldehyde. P ] -as-triazin-5-01, it seems reasonable t o assume Treatment of VI1 with formic acid gave R-benzyli- that, although formylation of the terminal amino denearninohypoxanthine (X) which, on heating in group of the hydrazino group of I V probably took dilute aqueous acid or base, was hydrolyzed to X I X . place first, diformylation occurred in the large exCompound X I X reacted with benzaldehyde to give cess of anhydrous formic acid t o give V I I I , which X. Further, X was reduced catalytically t o 9-ben- would surely cyclize in the observed manner. 5-Aknino-4-chloro-6-hydrazinopyrimidine ( 1 1 7 ) zylamiriohypoxanthiiie ( X I I ). In addition to these chemical proofs of structure, the infrared spectrum was reduced catalytically12to j-a1nino-4-hydrazitloof X I X shows the carbonyl hand9 (1690 cm.-l) and pyrimidine (VI), which on treatment with formic acid gave 9-aminopurine (IX). ( I ) Affiliated with t h e Sloan-Kettering Institute. This work was Treatment of IV with ethyl orthoformate-acetic supported by f u n d s from t h e C F. Kettering Fuundation and t h e anhydride3 gave crude 9-acetamido-6-chloropurine Cancer Chemotherapy h-:itionaI Service Center. h-ational Cancer Institute, h-ational Institutes of IIralth, Cimtract No. SA-vh-1740. ( I ) , which was hydrolyzed in acid to 9-aminohypoPart XXII. J . A. .\IontgoinerJ- 2nd C . 'l'cniple, J r . , J. 0i.g ( h t m . , xanthine and treated with thiourea to give 0-acet25, 393 (1960). L;midopurine-O(lH)thione (11). ( 2 ) G. B. Elion, E. Burgi and (2. H . Hitchings, THISJ O U R N A L , 74, j-Amino-4,6-dichloropyrimidine was allowed to 411 (1952). (3) E. Richter a n d E. C. Taylor, A n g ~ wChiiit., 67, 303 (1%>5); react with methylhydrazine and benzylhydrazine to 1.A. Montgomery, T H I S .ioUn:~AL, 1 8 , 1!)28 ( 1 9 j G ) give 5-amino-4-chloro-6-(1-methylhydrazinc;) -py(4) E C . Taylor recently reported the synthesis
