Sovem ber I 909
1125
p&
R20 2
1
I
Experimental Sections 4- [5(3)-Methyl-3(5)-pyrazolyl]quinoline.-A mixture of 2.9 g (0.014 mole) of 4-acetoaretylqt1inoline2 and 5.8 ml (0.12 mole) of 100yo ?JH2KH2was stirred at room temperature for 15 min, heated on a steam bath for 15 min, and diluted with HaO. Filtration gave 2.1 g (66%) of tan crystals, mp 122-125". Sublimation gave yellow crystals, nip 123-126'. -1nal. ( C U H ~ ~ S ~ . H ? O )
C, H, N. 1-Methyl-4- [5(3)-methyl-3(5)-pyrazolyl] quinolinium 1odide.-
,
OR. 1. R,=SH; R-=H 2, R, = SH:R?= CH,C,,Hi 3. R, = KH2;R? = CH2C,,H., 4, R, =OH: R1 CH,C,,H-, a = a anomer b = B anomer Experimental Section'
.I wlution of 1.9 g (0.008 mole) of 4-[5(3)-methyl-3(5)-pyrazolyl]qiiinoline, 10 ml of MeI, and 100 ml of EtOH was heated under
Separation of 3a and 3b.-Column chromatography experiments with silica gel and alumina did not give good separation of reflux with stirring for 2 hr. The solvent was distilled, and the these anomers. However, Florid8 was satisfact,ory. A synthetic residue was tritiirated with Et20 to leave 2.1 g of ye1loTv crystals, mixture of 1.30 g of 3a and 1.43 g of 3b in 10 ml of warm toluene mp 180-185'. Two recrystallizations (EtOH) gave 1.6 g (55%) was placed on a 60-g column (2.2 X 47 cm) of 100-200 mesh of yellow crystals: mp 211-213" [Anal. ( C M H ~ J X ~ . O . ~ H , O )FlorisiP and eluted with E t 2 0 . The first fraction of 500 ml of C, H, I, S I ; uv (NeOH) 243 mp ( e 30,900) and 352 mp ( e 12,700), eluent was discarded. The nest. two fractions of 1.1 1. of E t 2 0 iiv (0.1 S S a O H ) 392 mp ( e 14,100). and 250 ml of EtOAc-EtuO (1:4) contained 1.32 g of 3b (92.5y0 recovery). The fourth fraction, 100 ml of EtOA4c-Et,O (1:4), (5) Melting points were determined in a Hershberg apparatus a n d are contained 0.09 g of 3a and 3b. The final two fractions of 500 ml uncorrected. Microanalyses vere performed by M r . L. M. Brancone and of EtOAc-Et20 (1:4) and 500 ml of EtOAc contained 1.21 g staff; where analyses are indicated only b y symbols of the elements, analy(93%) of 3s. The separation was followed by tlc in solvent 4 tical results obtained for those elements were within 0.4% of t h e theoretical values. U v spectra were determined with a Cary 11 spectrophotometer by wit,h RI 0.50 and 0.22 for 3b and 3a, respectively. l l r , JY. Fulmor and staff. This procedure was applied to the crude reaction mixtures of 3a and 3b5 from which about 10-15yo of the less soluble 3a had been firbt removed by fractional crystallization from toluene and ether. Some 9-(2,3,4-Tri-O-benzyl-p 9-(2,3,4-Tri-O-benzyl-~-arabinopyranosyl)hypoxanthine(4a and 4b ).--Stirring 1.0 g (1.9 mmoles) of 9-(2,3,4-tri-O-benzyl-aarabinopyranosy1)purines o-arabiiiopyraiios?.l)adenine (3a) with Kay02 (3.5 g, 40 mmoles) in 59 ml of .4cOH, 50 ml of HnO, and 2.5 ml of 1 A' HC1 for 24 hr A B E L 4 R D O P. AIARTIh.l.2, WILLIAM LEI,, of 4a: mp 150-131" after recrystallizat,ion from A N D LEOS c i O O D M . l S : : :A 250 mp ( e 11,200), nration with Et20; : : :A 249 (11,800),3',:A: 353 (13,600); [ C Y ] ~ ~ -13.6' D (C 1.38, Life Sciences Research, Stanford Research Instztute, CHsC12); Rf 0.10 in solvent ;2. Anal. (CalII:joN405) C, H, S . Menlo Park, California 94025 Compound 4b, similarly prepared in 66(;i; Field had mp 162231 mp ( e 11,200), : : :A 249 163" (trituraied with Et&); Received July 18, 1969 253 (13,800); [ C Y ] ~ ~+34.h0 D ( c 1.50, CH2Cle); (12,000), RI 0.34 in solvent A. Anal. (C31H&,05) C , H, K. 9-(2,3,4-Tri-O-benzyI-~-arabinopyranosyl)-9H-purine-6-thiol The arabinofuranoside of 6-mercapt'opurine (6-XP) ( l a and 2b).--A solntion of 0.50 g (0.93 mmole) of 4b and 1.7 g has inkresting antitumor actmivity.2To compare the of P& in 30 ml of dry C3HJ vas heated at)reflux for 3.5 hr under effect of a change in ring size, me recently synthesized T2 and then worked lip to afford 0.48 g (0370) of 2b, mp 177.5the a- and 6-arabinopyranosides of 6-hIP ( l a and l b ) . 3 , 4 179.0'. Recrystallization from EtOAc afforded 0.35 g (68%) of We have now prepared their 0-benzyl-blocked derivathe p anomer 2b: mp 199-200O; the solubility of 2b was too low for defermining ,,A, at pH 1 ;" : : :A 322 nip ( e 23,100), tives (2a and 2b), whose greatly altered solubility 313 (23,400); [ c Y ] ~ ~-21" D (c 0.50, DhIF); Rf 1.00 in solvent B. propert'ies may influence t,heir biological properties. .-ha/!. (cn13&404s) C , H, S . The synthesis of 2a and 2b became feasible when a The preparation of the cy anomer 2a was similar except that a pract'ical separation of their precursors 3a and 3b5 was larger amount of P& (3.0 g) for 0.30 g of 4a was required for found. The conversion of 3 by nit'rous acid to 4 and complete reaction. The yield was 0.37 g 172%) of the (Y anomer 323 mp ( e 20,300),: : :A 321 (19,300), 2a: mp 226-230";: : :A the thiation of 4 to 2 proceeded in good yields by 312 (21,600); [ ( Y ] * ~ D+23" i c 0.Z0 DJIF); Ri 0.81 in standard procedures. Compounds 2a, 2b, 4a, and 4b solvent B (Ri 0.31 for 4a). Anal. (C:~IH3PN404S) C, H, N .
w.
were inact.ive against leukemia L1210 in mice.6
(1) This work \vas carried out under the auspices of Chemotherapy, National Cancer Institute, National Institutes of Health, Public Health Service, Contract KO. PH-43-64-500. T h e opinions expressed in this paper are those of t h e authors and not necessarily those of the sponsoring agency. (2) A. P. Bimhall, G. .1.LePage. and R . Bowman. Cnn. J . Biochem., 44, 1753 (1964). (3) A. P. Martinez and TI-. K. Lee, J . O r y . Cirem.. 34, 416 (1Y60). (4) T h e formulas are written in t h e completely aromatic form for convenience, although the &hydroxy and 6-thiol derivatives exist as the keto tautomers. (5) A . P. Martinez, 1%'. W.Lee, and L. Goodman, ibid.. 34, 92 (1969). (6) These compounds were screened f o r antitumor activity by Chemotherapy, National Cancer Institute, according t o its protocol described in Cancer Chemotherapy R e p t . , 25, 1 (1962).
Acknowledgment.-The authors are indebted to -1Ir. 0. P.Cren-s, ,Jr., arid staff for the preparation of intermediates and to Dr. I'et'er Tim and staff for the spectra. ( i ) Melting points ivrrc drterniinrd in a Fisher-.Jolins apliaratiis and are iincorrectetl. TIC was run on silica gel IIF (E. l l e r c k .lG Darmstadt) in the followine solvents: .I, EtO.\c; E . l I e O l I - E t O . ~ c (1 : 9 ) . T h e spots \yere detected hy U T liglit. For tlie iiv spectra, tlie samples were dissolved in MeOH or Z-metliox>-etlianol and diluted either five- or tenfold with 0.1 2V HC1 p H 7 lrriffer or 0.1 S S a O H . as required. \There analyses are indicated only by symbol of the elements or functions. analytical results obtained for tlrose elements or fiinctions were within &0.-1% of the theoretical values. (8) Trade name for the magnesium silicate product of t h e Floridin Co.
