Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12 2477
DMSO-d6) δ 8.29 (d, 1H, C7-H, J ) 1.9 Hz, long-range coupled
to F), 7.93 (s, 1H, C4-H), 6.44 (dd, 1H, 1′-H, J 1′,F ) 17.7 Hz,
J 1′,2′ ) 4.5 Hz), 6.02 (d, 1H, 3′-OH, D2O exchangeable), 5.31-
5.35 (m, 1.5 H, 5′-OH and 0.5 of 2′-H, 5′-OH D2O exchange-
able), 5.25 (dm, 0.5 H, 2′-H, J 2′,F ) 53.2 Hz, J 2′,3′ ) 2.7 Hz),
MeOH (95:5 followed by 9:1 then 2:1 and finally 1:1; v/v). The
product containing fractions were combined and the solvents
removed in vacuo to give 0.54 g (67%) of a white solid 20: MS
(FAB+) m/z 321, M + 1. Anal. Calcd for C12H11Cl2FN2O3‚
0.05CHCl3‚0.1CH3OH: C, H, N.
4.42 (dm, 1H, 3′-H, becomes ddd on D2O wash with J 3′,F
)
5,6-Dich lor o-1-(2-d eoxy-3,5-d i-O-a cetyl-2-flu or o-â-D-r i-
bofu r a n osyl)ben zim id a zole (22). Compound 20 (0.45 g, 1.4
mmol) was dissolved in pyridine (20 mL) and concentrated in
vacuo to remove water. The solution was chilled to 0 °C in an
ice bath. Acetic anhydride (260 µL, 2.9 mmol, 2 eq.) was added
and the reaction was allowed to warm to room temperature
while stirring overnight. Methanol (3 mL) was added and the
solvents removed in vacuo. Residual pyridine was removed by
coevaporation with toluene (3 × 10 mL). The residue was
partitioned between water and ethyl acetate. The ethyl acetate
solution was dried with MgSO4, filtered, and the solvent
removed in vacuo. The product 22 was used without further
purification: yield 0.56 g, 98%; MS (FAB+) m/z 405, M + 1.
24.2 Hz, J 2′,3′ ) 2.7 Hz and J 3′,4′ ) 5.9 Hz), 3.71-3.86 (m, 3H,
4′-H and 5′-H); 13C NMR (90 MHz, DMSO-d6) δ 140.81,
140.60, 134.07, 126.07, 125.68, 119.88, 115.61, 97.38 (2′C, J 2′C,F
) 192.5 Hz), 84.98 (1′C, J 1′C,F ) 17.4 Hz), 82.89 (4′C), 73.25
(3′C, J 2′C,F ) 24.4 Hz), 59.05 (5′C, J 5′C,F ) 9.9 Hz); HRMS m/z
calcd for C12H10Cl3FN2O3 353.9741, found 353.9735. Anal.
Calcd for C12H10Cl3FN2O3: C, H, N.
2,5,6-Tr ich lor o-1-(3,5-d i-O-ben zoyl-2-d eoxy-2-flu or o-â-
D-a r a bin ofu r a n osyl)ben zim id a zole (17) a n d Its r-Isom er
16. The 2-fluoro sugar 1414 (1.20 g, 2.6 mmol) was dissolved
in CH2Cl2 (10 mL) and then a 33% HBr in CH3COOH solution
was added (2.64 mL, 10.4 mmol). The reaction mixture was
stirred in a stoppered flask for 6 h. Additional CH2Cl2 (100
mL) was added to the reaction mixture and the organic phase
was washed sequentially with ice cold saturated NaHCO3 (100
mL) and ice cold water (100 mL). The CH2Cl2 solution was
dried over magnesium sulfate, filtered and the solvent was
removed under reduced pressure to give a colorless syrup of
15. This syrup was dissolved in dry ClCH2CH2Cl (10 mL) and
added to a previously prepared solution containing 6 (0.6 g,
2.6 mmol) in ClCH2CH2Cl (10 mL) and activated 4A sieves.
The resulting mixture was heated at 80 °C under an inert
atmosphere for 2 days. Then CH2Cl2 (100 mL) and a saturated
NaHCO3 solution (100 mL) were added to the reaction mixture.
The organic phase was separated and washed with water (100
mL), then dried over magnesium sulfate, filtered and the
solvent was removed in vacuo. The resulting solid was purified
by flash chromatography (EtOAc/hexane: 1:2, 4 cm × 15 cm)
with the fractions containing the faster moving nucleoside
being pooled, concentrated to dryness and recrystallized from
MeOH/H2O and then from EtOH to give 0.12 g (8%) of 16 as
white crystals. The fractions containing the slower moving
nucleoside were contaminated with a small amount of 6. These
contaminated fractions were pooled, concentrated to dryness
and rechromatographed on a second column (5% MeOH in
CHCl3, 4 cm × 15 cm) to give after pooling appropriate
fractions and removing solvent under reduced pressure a white
solid which after recrystallizations from MeOH/H2O gave 1.0
g (72%) of 17. 17: mp 88-90 °C; Rf 0.36 (EtOAc/hexane 1:2);
Rf 0.67 (5% MeOH in CHCl3); HRMS m/z calcd for C26H18Cl3-
FN2O5 562.0265, found 562.0254. Anal. Calcd for C26H18Cl3-
FN2O5: C, H, N. 16: mp 78-80 °C; Rf 0.60 (EtOAc/hexane
2-Br om o-5,6-d ich lor o-1-(2-d eoxy-2-flu or o-â-D-r ibofu r a -
n osyl)ben zim id a zole (23a ) a n d 2-Br om o-5,6-d ich lor o-1-
(5-O-a cet yl-2-d eoxy-2-flu or o-â-D-r ib ofu r a n osyl)b en zim -
id a zole (23b). Compound 22 (0.55 g, 1.4 mmol) was dissolved
in dioxane (25 mL) and boiled to remove water. The solution
was heated to reflux in a 120 °C oil bath. NBS (0.48 g, 2.8
mmol, 2 equiv) was added and the reaction mixture heated at
reflux for 4 min. A second portion (0.48 g, 2.89 mmol, 2 eq.)
was then added and heating at reflux was continued for an
additional 6 min. The reaction was removed from the heat
source, diluted with chloroform (40 mL) and cooled to room
temperature. The solution was washed with saturated sodium
bicarbonate (2 × 75 mL), dried (MgSO4) and filtered. The
solvents were removed in vacuo and the residue purified by
flash chromatography (ethyl acetate/hexane 1:1, v/v). The
product containing fractions were combined and the solvents
removed in vacuo to give 2-bromo-5,6-dichloro-1-(2-deoxy-3,5-
di-O-acetyl-2-fluoro-â-D-ribofuranosyl)benzimidazole (21). A
removal of the acetyl groups was accomplished by treatment
of 21 in methanol and ethanol (17 mL each) with sodium
carbonate (0.22 g, 2.1 mmol, 2 equiv) dissolved in 4.2 mL
water. The reaction was stirred at room temperature for 18
h. The solution was diluted with water (40 mL) and the product
was extracted with ethyl acetate (2 × 75 mL). The ethyl acetate
solution was dried with MgSO4, filtered, and the solvent
removed in vacuo. The residue was purified by chromatogra-
phy on 75 g of silica gel. The column was eluted with ethyl
acetate/hexane (1:4, v/v) followed by ethyl acetate/hexane
(1:2, v/v). The faster eluting product was the 5′-acetyl com-
pound 23b (0.17 g). The second product to elute was 2-bromo-
5,6-dichloro-1-(2-deoxy-2-fluoro-â-D-ribofuranosyl)benzimida-
zole (23a ; 0.03 g): MS (FAB+) m/z 399, M + 1; 1H NMR
(DMSO-d6) δ 8.46 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 6.22 (dd,
1H, H-1′, J 1′,2′ ) 5.4 Hz, J 1′,F ) 14.5 Hz), 5.82 (d, 1H, OH-3′, J
) 5.6 Hz), 5.45 (t, 1H, OH-5′, J ) 4.5 Hz), 5.29 (dt, 1H, H-2′,
J ) 5.2 Hz, J 2′,F ) 53 Hz), 4.3 (m, 1H, H-3′), 4.0 (m, 1H, H-4′),
3.7 (m, 2H, H-5′).
1:2); Rf 0.9 (5% MeOH in CHCl3); HRMS m/z calcd for C26H18
Cl3FN2O5 562.0265, found 562.0276. Anal. Calcd for C26H18
Cl3FN2O5: C, H, N.
-
-
2,5,6-Tr ich lor o-1-(2-d eoxy-2-flu or o-â-D-a r a bin ofu r a n o-
syl)ben zim id a zole (11). Compound 17 (0.5 g, 0.9 mmol) was
dissolved in methanolic ammonia and the solution was stirred
at room temperature for 6 h. The solvent was removed in vacuo
and the residue purified by flash chromatography (EtOAc/
hexane 5:1, 2 cm × 15 cm), appropriate fractions pooled and
evaporated to dryness to give after crystallization from MeOH,
0.23 g (74%) of a white solid identical to the previously
characterized 11.
5,6-Dich lor o-1-(2-deoxy-2-flu or o-â-D-r ibofu r an osyl)ben -
zim id a zole (20). 2′-Deoxy-2′-fluorouridine21 (19; 0.99 g, 4
mmol) was dissolved in 800 mL of 50 mM pH 6.0 citrate buffer.
5,6-Dichlorobenzimidazole4 (18; 0.30 g, 1.6 mmol) was added
and the reaction was placed in a 50 °C water bath. N-
Deoxyribofuranosyl transferase, 60 000 units,22 was added and
the reaction was gently shaken overnight. 5,6-Dichlorobenz-
imidazole (0.30 g, 1.6 mmol) was again added and the reaction
continued for 2 days. The enzyme was precipitated by heating
to 80 °C then cooling to room temperature. Celite (50-60 g)
was added and the reaction filtered. The product was extracted
with ethyl acetate (3 × 100 mL). The ethyl acetate was
removed in vacuo and the residue purified by chromatography
on 75 g of basic alumina. The column was eluted with CHCl3/
2-Br om o-5,6-d ich lor o-1-(5-O-a cetyl-2-d eoxy-2-flu or o-â-
D-r ibofu r a n osyl)ben zim id a zole (23b): 1H NMR (DMSO-
d6) δ 8.00 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 6.25 (dd, 1H,
H-1′, J 1′,2′ ) 5.1 Hz, J 1′,F ) 16.5 Hz), 5.95 (d, 1H, OH-3′, J ) 6
Hz), 5.40 (dt, 1H, H-2′, J ) 5.3 Hz, J 2′,F ) 53 Hz), 4.4-4.1 (m,
4H, H-3′,4′,5′), 2.13 (s, 3H, acetyl-CH3).
5,6-Dich lor o-2-isop r op yla m in o-1-(2-d eoxy-2-flu or o-â-D-
r ibofu r a n osyl)ben zim id a zole (24). Compound 23b (0.06 g,
0.14 mmol) was dissolved in ethanol (4 mL) and isopropy-
lamine (Fluka; 1.3 mL) was added to this solution. The reaction
was heated in a sealed tube in a 90 °C oil bath for 17 h. The
solvents were removed in vacuo and the residue purified by
chromatography on silica gel (6 g). The column was eluted with
chloroform/methanol (95:5). The product containing fractions
were combined and the solvents removed in vacuo to afford
1
0.03 g (57%) of 24: MS (APCH+) m/z 378, M + 1; H NMR
(DMSO-d6) 7.66 (s, 1H, Ar-H), 7.37 (s, 1H, Ar-H), 6.92 (d,
1H, NH, J ) 7.7 Hz), 6.17 (dd, 1H, H-1′, J 1′,2′ ) 5.3 Hz, J 1′,F
)
15.4 Hz), 5.73 (d, 1H, OH-3′, J ) 5.7 Hz), 5.63 (t, 1H, OH-5′,