May 1969
NOTES
545
1-(2,3,5-Tri-0-benzyl-p-~-ribofuranosyl)-5-tr~fluoromet~iy~following solvent systems were used for tlc: -4, h O H - C s H s uracil (IX).-Compound T? (0.36 g, 2 mmoles) was refluxed with ( I :3, v / v ) ; B, lIe?CO-cyclohexane (1:1, v/v). 1-( 2-Deoxy-5-0- trityl-p-D-ribofuranosyl)-5-trifluoromethyl- hexamethyldisilazane ( 2 ml) and dichlorodimethylsilane (one drop) (bath temperature 170") in the absence of moisture. After uracil (II).---F3TDR ( I ) (4.72 g, 16 mmoles), twice evaporated 2 hr most of the ammonium salt, formed during the reaction, had from dry pyridine (5-ml portions), was dissolved in 45 ml of dry sublimed into the condenser and a colorless oil was left. This pyridine. Triphenylchloromethane (4.60 g, 16 mmoles) was was put on a rotary evaporator (bath temperature 50-60") and added and the solution was kept, under reflux for 40 min in the finally fractionated under high vacuum. His(0-trimethylsily1)absenre of moisture. Then the reaction mixture was cooled, and 5-trifluoromethyluracil (VII) distilled a t 5s O (1.5 mm), yield the contents were poured over ice water (400 ml) with constant 0.64 g (97%). 2,3,5-Tri-O-benzyl-~-ribofuranosyl bromide stirring. This aqueous mixture was extracted with CHC13 (300 (VIII) was prepared according to the method of Barker and ml), the CHC13 extract was dried (hIgSO1) and filtered, and the Fletcher1* (obtained from 1.12 g, 1.95 mmoles, of l-p-nitrobenfiltrate was evaporated t o a gum on a rotary evaporator. The zoyl-2,3,5-tri-O-benzylribofuranoside).To 1.111, VI1 was added gum was dissolved in Et20 (30 ml) and absorbed on a silicic acid (dry CHyClr used as a solvent for transfer) and the solvent was (100 mesh, llallinckrodt) column (5.5 X 30 em, packed with removed under reduced pressure. The residue was fused at 180" Skellysolve B ) ; the column was eluted with CsH,. and 40-ml frac(bath temperature) for 40 min. The resulting dark green mass tions were collected. The first 1200 nil of the eluate gave 1.2 g was cooled and then triturated with absolute EtOH ( 2 5 ml), and of a material which on tlc (silicic acid, system and B) had an some dark insoluble material was filtered. The filtrate was evapRt similar to that of an authentic sample of triphenylcarbinol. orated and the residual gum was again triturated with absolute The column was then eluted with 20To SIeOH in CGHP,. The EtOH (20 ml), when more insoluble material was obtained and product I1 came out in a single band of uv-absorbing material, filtered. The Et,OH filtrate was evaporated to a gum and then but on tlc it, showed slight traces of I as impurity. A11 fractions triturated with dry C& (15 ml). Some insoluble material containing I1 were collected and evaporated to a colorless gum. (shown t o be VI by tlc) was filtered, and the filtrate (20 ml) was The gum was crystallized from EtOH-HYO to give I1 as a coloradsorbed on an alumina (neutral Woelm, activity grade 11) less crystalline material (6.4 g, 74.453, which on tlc (silicic acid, column ( 2 X 28 cm). The column was eluted with C6H6 (400 system -4and B ) moved as a single homogeneous uv-absorbing ml), then loc; EtO& in CsH6 (1000 ml), followd by 30% component. It was recrystallized from Et?O-petroleum ether (bp 30-60") to give colorless needles: mp 134-156" (softens at E t 0 . 4 ~in C& (400 ml). During this period, most of the sugar derivatives were removed. Finally, I S was eluted with absolute 145"): uv,": : :A 262 mp ( E 9558). .4nal. (CI.sHnjF3XjzOj) MeOH (the elution was followed by tlc (silicic acid), in 10:; C, H, S . EtOhc in C&). The fractions containing I S were collect>ed, 1-(2-Deoxy-3-~-mesyl-5-~-tr~tyI-~-~-r~bofuranosy~)-5-tr~fludecolorized with charcoal, and evaporated to a gum. The gum oromethyluracil (HI).-Dry I1 (4.03 g, 7.5 mmoles) was dissolved gave one homogeneous uv-absorbing component on tlc in three in dry pyridine (25 ml) and the solution was cooled (-5'), different systems. Compound I S could not be crystallized and treated with lleS0,Cl (0.93 ml, freshly distilled), and kept in the was used as such without further purification; uv, refrigerator overnight in the ahsence of moisture. Absolute 261 mp, ",.A,: 231.5 mp. EtOH (3.5 ml) m-as added and the solution was maintained in the cold for another 1 hr. Then the pale contents of the reaction mix5-Trifluoromethyl-1- (p-D-ribofuranosyl)uraci~(X).--Conipound I S was dissolved in absolute MeOH (50 ml) and hydroture were poured over 700 nil of ice-water with vigorous stirring. genolyzed in the presence of P d catalyst (obtained from 0.5 g of I11 precipitated as a pale powder; it was filtered and washed with a large excess of H?O and dried in m c u o over PrOj. Crude I11 PdC12) a t 2 atm (room temperature) for 40 min. Then the catamoved as a single uv-absorbing component on tlc (silicic acid) in lyst was filtered and the filtrate was evaporated. The residual gum was dissolved in absolute EtOH (10 ml), some non-uvsystems and B. The yield was 4.615 g ( looc;): I11 was used as absorbing solid remained and was filtered. The filtrate was consuch without further purification: uv," : : :A 258 mp (shoulder a t 262.5), p 2:F 243 mp. The ir spectrum showed a band a t centrated and crystallized from EtOH-EtnO-petroleum ether. Three crops gave 0.188 g of S (over-all yield based on VI, 30.15; ). 1170 em-' corresponding to lIeSO?. 1-(5 - ~ - T r i t y ~ - 2 , 3 - d i d e o x y - ~ , 3 - d i d e ~ i y d r o - ~ - ~ - g ~ y c e ~ o - p e n tRecrystallization ofurfrom a small volume of absolute EtOH gave anosyl)-5-trifluoromethyluracil (IV).---Crude I11 (2.54 g, 4 colorless plates, mp 309-210". The compound gave a positive S a mmoles) was dissolved in anhydrous DJISO (40 ml) and KO-t-Bu fusion color test for F. A strong and positive Cotton effect in the (0.929 g, 8.3 mmoles) was added. The reaction mixture was ORD indicated the p-anomeric configuration. The nmr spectrum stirred at room temperature (absence of moisture) for 18 min, showed the anomeric proton as a doublet centered at 6 6.17 then the dark yellow solution was gradually poured over stirred (spectrum determined in D20); uv, A:!: 263 mp ( e 10,407) and ice-water (700 ml). To this solution phenolphthalein (two ' :!A: 262 mp (E 7002). Hydrolysis with 6 iV HC1 (loo", 3 h r ) drops) was added and the solution was made slightly acidic with gave IrI as identified by tlc and uv spect'ra. I n a l . (CIOHLIFSa few drops of 6 >Y AcOH. The product IV precipitated as a SzOs) C, H, S. gelatinous mass. It was filtered, washed with excess H10, and Acknowledgment.-We wish to acknowledge the dried in a vacuum desiccator. IT was recrystallized by dissolving in Et,O (charcoal) and precipitating with petroleum ether; mp skillful technical assistance of Miss Sharoii Ohlhorst 139-141" (resolidifies a t 150"); yield 1.42 g (6S.2%); uv, A$:") and Miss Marian Mitsche. '160 my ( E 8850). The ir spectrum showed no absorption a t 1170 cm-1 corresponding to lIeS02. The product' gave a positive test with molybdate spray, proving the presence of an unsaturated sugar.' The nmr spectrum (in CDCI,) showed the presence of two vinyl protons centered a t 6 5.S5 (3'-proton) and 6.25 (2'Pyrazoles. 111. Antileukemic Activity of 3-(3,3proton); the anomeric proton was a multiplet centered a t 6 6.90. Dimethyl-l-triazeno)pyrazole-4-carboxamidel Anal. ( C , ~ H Z , F , ~ Z O ~ . O , ~C,H H, , O )S . 1-(2,3-Dideoxy-2,3-didehydro-p-n-g~ycero-pentofuranosyl)-5trifluorometliyluracil (V).-Compound IT: (0.13 g, 0.25 mmole) c. \ v \ Y S E S O E L L I X D c. C. C H E X G was treated with ice-cold 98'1 formic acid. The mixture was swirled t o bring all particles in contact with the acid and then Jlzdwest Research Instatute, Kansas Czty, .llzssoitrz 641 10 (-1 min) the acid was distilled with an oil pump a t room temperature. The last trares of HCOzH were removed hy distillation IZeceaved .January 2, 1969 with dioxane (two 2-nil portions). The residue was extracted with warm H?O (5 ml) and the aqueous filtrate was evaporated to Treatment of 3-amiiiopyrazole-4-carl-loxainide2 with dryness under reduced pressure (bath temperature 35'). The nitrous acid yielded 3-dia~opyrazole-4-carboxamide.~ residue was dissolved in boiling anhydrous Et20 and filtered, and to the filtrate petroleum ether was added dropwise until slighl (1) This investigation was supported by the Cancer Chemotherapy National turbidity. The turbid solution was kept in a referigerator, and Service Center, National Cancer Institute of the National Institutes of Health, V crystallized out during a period of 7 days; mp 103-104"; Public Health Service, Contract PH-43-65-94. yield 35 mg (5O.S::;); uv,: : :A 260 mp ( e 8051), 238.5 mp ( e (2) R . K. Robins, J . .4m. Chem. Soc., 78, 784 (1956). 5511). 1' gave a purple color with molybdate spray.4 dnal. (3) C. C. Cheng, R . K. Robins, K. C. Cheng, and D. C. Lin, J . Pharm. Sci., 57, 1044 (1968). (CloHgFaSzOa.O.SH20) C, H, S .
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