w i i s w a a h t d \\ith \\nter. dried. and evaporated in I'UCUIJ. 'l'he ~ i r i ~ d u c1.89 t . g i l l pale yellow oil. was crystallized from benzenelight petroleum mixtures to give 0.994 p of colorless crystals melting at 11.4- 116.5". (i-i.~:.~lethyl)amino-2,J,l-trimethoxyben~ocycloheptane i Ih). 'l'ht. carhamate l i 1820 mg 2.1 mmoli dissolved in 15 mi ot drx, tetrahydrofuran was slowly added dropwisr t ( i l . : i g (Li-4 mmtrli or Li,4iH4 suspended in 15 mi of drq tetrahydrofuran cooled t i l 0. _ . I he mixture was 3tirred Cj.5 hr at 0" after which time it wah ri'tlusrtl t o r 2 hr. T h e reaction was terminated h y adding 1 :I 1111 r i t {cater in 10 nil of' tetrahydrofuran and made filterable Irith 5 m i ( I t 12% S a O H . After filtering. drying. and evaporating 64;; nig (:Il'ki of yellow oil was obtained. The compound was isolated iiq 1 hi. oxalate. nip 195-205'. 3-,j-('yano-li-oxo--',R,1-trimethoxyben~oc~-cloheptane ( l!J). ' I ~ t i i - c,onipound \vas made as already descrihedl* t'rom t h e ketone 12 in 98% crude yield. Recrystallization from ethanol pave a pro& uct meltingat 107-110" (lit. m p 110.5-111.2"). ,?-(fi-Oxo-2,:1,4-trimethoxybenzocycloheptan-5-y1)propionic Acid (20). Comp~iuncl20 war in cyiino ketone 19 by methods alrea tali\!, yield. The ir -jiectrum ah
8,k :lo; 1 .
1.4
,?-~3-(6-H~droxy-~,3,.i-trimethox~benzoc~clohepten-~-yl) 1propionic Acid &Lactone (21). This product was made troni the k e t o acid 20 hy previously described methods*? in 59Yc yield 01 niitterial melting at 105-107 (lit.nip 104 103"). ,~-~~-(6-Hydroxy-2,4,-L-trimethox~benzocyclohepten-5-~1) 1propionic Acid h-.V-Methyllactam ( 2 2 ) . The crude keto acid 20 (. not exceeding 0.01 ml g o t hririy ht. 'i'ehting ~ ) r o t ~ ~ciinsisteti c~ii (JI3uapending or di-holving all emp impound^ in w a t e r t ~ r11.5% ineth>icellulose. Approximate 0..5 log-spaced doses were employed t i i characterize a "no effect" t i i l ~ l O % lethal response. Four animalh \vere used at each d i i s level. E;ic,h animal \vas evaluated for hignificant activit\ at .i. 10. 13. :io. anti 60 min pcistinjection a n d thereaiter at 2 , t. and 2 i hr. The - t a l i5t ical methoti. employed tor tht, calculation r i t L11,~o anti is that described by WeiI.'* The MED5o shown in Table et1 on the fir>t pharmacological et'i'ect shown in the "elf e c , t - " c.iilumn; other eftec,ts !thoht= s h o \ v n atter the c o m m a ) ma! rlr may n ~ ) ttie ritikerved a t t h e LIEI)5~ldose T h e LIEDROi> liaietl o i l t tic pharmaci)logicaI etiecl ihou 11 'it t h e llei-Temp and are corm l ) . To this solution was added 3.56 g (23.0 mmol) of 6-chloro rected. Optical rotations were measured at ambient temperatures purine. 2.90 g (11.5 mmol! of H g ( C S ) * . and 2.0 g ot Drierite. anti with a Perkin-Elmer 141 automatic polarimeter. n m r with a Varthe mixture was heated under retlux for 2 hr. 'The reaction mixian A-60D spectrometer, ir with a Perkin-Elmer 237B spectropho ture was filtered hot. and the filter rake was extracted tw4c.e witti tometer, and uv with a Cary 14 recording spectrophotometer. A n hot MePiOz and refiltered. The combined tiitrares were e v a p o alytical results were determined by M - H - W Laboratories. Garden rated under aspirati)r L'acuum ( H C T ' j at 50' and then .(I7 combined, dried (Drierite). and evaporated in L ' U P U ( I at 40". A i q ) iH-2 and H-81. 6.00 ( d . 1. J = 1.6 Hz. H - 1 ' ) . -1.60 ( d d . 2 small amount of solid was removed from the oily product by a d - 2 ' ) . 4.29 itid. 1. J2 ,j = 5 3 Hz. = 1.6 Hz. J2 , 3 = 5 . 2 Hz. dition of EtOAc (30 m l ) followed by filtration. The filtrate was = 10,7 H z . H-9 I. :]A$ IS. NMe2). 2.05 ( s . 3 , N C O C H ~ II.. . concentrated in vacuo t o a light orange oil. 19.4 g. Distillation ot' :3, .I4 .$ = 5.5 Hz. >'-('Hl ( t ] * * r i -11,O' i! 0.99.1,leOH).. A n d the oil gal-e 13.5 g of ketone 3 as a light yellow oil. bp 49-57' (0.50 IC14H2oS603) C y . H. X . m m ) . This product was shown by n m r to contain 5% DMSO. Concentration ot The above EtOAr filtrate to 13 mi and cooling To 12.3 g (7.14 mmol) of 3 and 16.0 g (231 mmoll of hydroxyl1-ielded a solid mixture of the I t . and ,,'-nucleosides (162 nig). This amine hydrochloride in water (44 mlj &-as added 43.3 ml of 10W mixture wa5 separated on a preparative silica gel plate (HrinkS a O H . T h e mixture was stirred at 65" for 2 hr and then extractman. F-2,311 by developing three times with IOL7c MeOH in ed with CH2C12 ( 3 X 80 ml). T h e combined organic extracts were CHCl3, A n additional X5 mg of t h e $nucleoside was removed washed with saturated NaCl solution (120 ml). dried (Drierite), from the plate hy extraction of the band at K , 0.61 itotal !ieltl and concentrated in t'acuo t o a syrup. Trituration with petroleum 40.9%). The : I nucleoside was obtained from the band at H i 0.49: ether ( b p 60-70") gave the white solid oxime 4. 11.7 g, m p 85--87". ?-ield 51,:3 mg ~ 2 . 1 5I . The ,i-nucleoside was crystallized :rr)rn An analytical sample was prepared b>- crystallization from petroMeOH and gave an an ample as the monohydratc. hi11:leum ether and gave white needles. m p 89" (lit. m p 90.5-91'1." ens at l;i;7'. melts at 1 ~ v ~ i, n,m, l ~ipH ~ 1 267. i p H 71 .)" Anal ( C R H I ~ T OC, ~ )H. N. - 1 3 . i p H 13) 27.5: nnir :3-Acetamido-R,5-dideoxg1,2-0-isopropylidene-ci-I,-ribofuranose (6).T o a solution of 8.61 g (49.7 mmol) of 3-amino-3.5-dideoxy-1,2-O-isopropylidene-ii-o-ribofuranose ( 5 ; prepared from 1 as described in ref 9) in pyridine (75 ml) was added 14 ml (149 f i - D i m e t h y l a m i n o - 9 - ( : ~ ' - a m i n o - : ~ ' . ~ ' - d i d e o x ~bofuranu-,~-~~-ri mmol) of AczO. T h e mixture was stirred a t ambient temperature sy1)purine (12). A solution of 925 mg (2.89 mmol) of' 1 1 and 4 1 mi for 17 hr and t h e volatile materials were removed in t acuo at 40". of 0,%5 .V Ba(OH12 was heated at 85" for 3.5hr. Absolute E t O H 115 The orange syrup product was dissolved in CHC13 (400 ml) and mll was added to the cooled reaction mixture and the solution washed with 5% HC1 (250 ml), saturated S a H C O 3 (250 1x11). and was neutralized with excess Dry Ice, The solid was removed by saturated NaCl (250 mlj, respectively. The CHC13 layer was filtration and washed with E t O H (20 m l ) . The filtrate was evapodried (Drierite) and evaporated in ~ ' a c u oto a n orange syrup. Perated ; n i'acuo to a white solid. The solid was mixed with hot troleum ether ( b p 30-60") was added, and the mixture was evapoE t O H (40 mli and filtered. T h e filter cake was washed with hot rated ~n racuo to a light yellow solid. 8.89 g. Crystallization from E t O H (40 mi!. and the filtrate was ex-aporated to a white solid. E t 2 0 gave the analytical product 6 as white crystals: 7.88 g This process wab repeated, and the white solid residue \vas di*(74%); m p 106-107": j n ] 2 2 ~ +169" ( e 2.12. L'IeOH). A n n / solved in EtOAc (50 ml). Refrigeration of the EtOA(, sollit ion ( C i o H i i N O d C . H. Y. gave 12 as a white powder which was removed by tiltration: > ieltl :bhcetamido-3,5-dideoxy-r>-ribose ( i ) .T o a solution of 4.50 g 369 nip: m p 200-201". The filtrate was evaporated and the - i , i i t i (20.9 mmol) of 6 in H2O (150 mli at 60" was added 58 ml 1110 residue (321nig, was treated with 15 mi 0 . i h'Ba(Of-l), uhin:: lhc mequiv) of IR-120 acidic resin (Amberlite. Mallinckrodt 1 in water same work-up as above. An additional 228 1ng of 12 (100 ml), and the mixture was stirred at 60" for 1 hr. The resin The t w o fractions of product were combined and was removed by filtration. and the filtrate was evaporated in horn EtOAc and gave pure 12: vield 543 rng ( 6 7 . t'ucuo to a yellow solid. 3.43 g (this material could be used in suh2005"..-lna/ 1C12H16S602) C. H. N. sequent reactions without loss o f yields). Crystallization from 6-Dimethylamino-9-[ 3'-(benzyloxycarbonyI-p-methox\EtOAc gave a n analytical sample of 7 as white crystals. m p 119phenyl-~-alanylamino)-3',5'-dideox~-~-~-ribofuranos~~]purin~~ 121". .qnU/. ( C ~ H 1 3 N 0 4c) , H,5 . ( I f ) . A mixture of 200 mg (0.719 mmol) of 12. 249 mg
