1936 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 10
Pontikis et al.
(98 mg, 0.25 mmol) was deprotected with 0.60 mL of aqueous
solution of 4 N sodium hydroxide to give compound 30c′ as a
white solid (70 mg, 74% yield): TLC (CH2Cl2/EtOH: 9/1) Rf
4,6-dimethoxy-1,3,5-triazine (1.1 equiv). After the mixture was
stirred for 3 h at 0 °C, a solution was added, in DMF, of the
amino derivative 9, 21a , 21b, 25, 30a ′, or 30b′ (≈1.0 equiv).
After 20 h, the solvent was removed in vacuo, and the residue
was chromatographed.
1
0.07; mp 234-235 °C; H NMR (DMSO-d6) δ 0.81 (t, 3H, J )
7 Ηz, CH2CH3), 1.69-1.86 (m, 2H, CH2-10), 2.19 (s, 3H, CH3-
6), 2.23 (s, 6H, Ar-CH3), 2.23-2.39 (m, 6H, CH2-9, CH2-11,CH2-
CH3), 3.74 (s, 2H, CH2Ar), 6.76 (s, 2H, Ar-H), 6.81 (s, 1H, Ar-
H), 8.97 (s, 1H, CO2H), 11.74 (br s, 1H, NH-1). Anal.
(C22H28N2O4) C, H, N.
3′-Azid o-3-[N-15-[6-(3,5-d im eth ylp h en ylth io)-5-eth yl-1-
(5-oxop en t yl)u r a cil]-4,15-d ia za -3-oxop en t a d eca n yl]-3′-
d eoxy-5′-O-(th exyld im eth ylsilyl)th ym id in e (14). From the
nucleoside 9 (160 mg, 0.252 mmol) and HEPT analogue 13
(95 mg, 0.250 mmol) was obtained compound 14 as a white
solid (150 mg, 60% yield) after flash chromatography (EtOAc/
3-(9-Ca r boxyn on a n oyl)a m in o-4-(3,5-d im eth ylben zyl)-
5-eth yl-6-m eth ylp yr id in -2(1H)-on e (30d ′). Compound 29d
(200 mg, 0.43 mmol) was deprotected with 1.0 mL of aqueous
solution of 4 N sodium hydroxide to give compound 30d ′ as a
white solid (188 mg, 97% yield): TLC (CH2Cl2/EtOH: 9/1) Rf
1
MeOH: 98/2): mp 93-95 °C; H NMR (DMSO-d6) δ 0.13 (d,
6H, J ) 2.5 Ηz, (CH3)2Si), 0.84-0.94 (m, 15H, (CH3)2C × 2,
CH2CH3), 1.24 (br s, 12H, CH2-7* to CH2-12*), 1.30-1.45 (m,
8H, CH2-6*, CH2-13*, CH2-8′′, CH2-9′′), 1.60 (m, 1H, (CH3)2CH),
1.84 (s, 3H, CH3-5), 1.99 (m, 2H, CH2-10′′), 2.25 (s, 6H, Ar-
CH3), 2.25-2.40 (m, 4H, CH2-2′, CH2-2*), 2.50 (CH2CH3 with
DMSO), 2.99 (m, 4H, CH2-5*, CH2-14*), 3.75-3.90 (m, 5H, CH-
4′, CH2-5′, CH2-7′′), 4.00 (m, 2H, CH2-1*), 4.37 (m, 1H, CH-
3′), 6.12 (t, 1H, J ) 6 Hz, CH-1′), 6.91 (s, 2H, Ar-H), 6.93 (s,
1H, Ar-H), 7.20 (t, 1H, J ) 5.5 Hz, NHCO), 7.51 (s, 1H, CH-
6), 7.88 (t, 1H, J ) 5.5 Hz, NHCO), 11.60 (br s, 1H, NH-3′′);
MS (ESI) m/z 874.5 (M + Na)+, 852.5 (M + H)+.
1
0.14; mp 134-135 °C; H NMR (DMSO-d6) δ 0.81 (t, 3H, J )
7 Ηz, CH2CH3), 1.20 (br s, 8H, CH2-11 to CH2-14), 1.44-1.64
(m, 4H, CH2-10, CH2-15), 2.15 (s, 3H, CH3-6), 2.22 (s, 6H, Ar-
CH3), 2.15-2.36 (m, 6H, CH2-9, CH2-16,CH2CH3), 3.74 (s, 2H,
CH2Ar), 6.76 (s, 2H, Ar-H), 6.81 (s, 1H, Ar-H), 8.94 (s, 1H,
CO2H), 11.75 (br s, 1H, NH-1). Anal. (C27H38N2O4‚0.25H2O)
C, H, N.
3′-Azid o-5-(2-ca r b oxyet h yl)-2′,3′-d id eoxyu r id in e (31).
To a solution of methyl ester 20 (403.0 mg, 1.18 mmol) in
MeOH (5 mL) was added 2 mL of 2 N NaOH dropwise at 0
°C. After being stirred for 3 h at room temperature, the
mixture was neutralized with Dowex 50X2-200 mesh ion-
exchange resin. After filtration and evaporation, the residue
obtained was rinsed with CH2Cl2 and dissolved in MeOH, and
the product 31 (365 mg, 95% yield) precipitated by adding
diethyl ether: TLC (EtOAc/MeOH: 8/2) Rf 0.35; mp 170-172
°C; [R]20D +35° (c 1.1, MeOH); IR (KBr) 3600-3200, 2109, 1703,
3′-Azido-2′,3′-dideoxy-5-[N-9-[6-(3,5-dim eth ylph en ylth io)-
5-et h yl-1-(5-oxop en t yl)u r a cil]-4,9-d ia za -3-oxon on a n yl]-
u r id in e (22). From the nucleoside 21a (54 mg, 0.144 mmol)
and HEPT analogue 13 (58 mg, 0.146 mmol) was obtained
compound 22 as a white solid (62 mg, 57%) after flash
chromatography (EtOAc/MeOH: 90/10) and recrystallization
1
from EtOAc/MeOH: mp 120-123 °C; H NMR (DMSO-d6) δ
0.91 (t, 3H, J ) 7.5 Ηz, CH2CH3), 1.30-1.45 (m, 8H, CH2-12*,
CH2-13*, CH2-8′′, CH2-9′′), 1.98 (m, 2H, CH2-10′′), 2.20-2.40
(m, 10H, CH2-2′, CH2-2*, Ar-CH3), 2.42 (m, 2H, CH2-1*), 2.50
(CH2CH3 with DMSO), 3.00 (m, 4H, CH2-5*, CH2-8*), 3.63 (m,
2H, CH2-5′), 3.83 (m, 3H, CH-4′, CH2-7′′), 4.41 (m, 1H, CH-3′),
5.25 (br s, 1H, OH), 6.10 (m, 1H, CH-1′), 6.90 (s, 2H, Ar-H),
6.92 (s, 1H, Ar-H), 7.63 (s, 1H, CH-6), 7.72 (br s, 1H, NHCO),
7.79 (br s, 1H, NHCO), 11.35 (br s, 1H, NH), 11.60 (br s, 1H,
NH); MS (ESI) m/z 751 (M + Na)+. Anal. (C35H47N9O8S) C, H,
N.
1
1665 cm-1; H NMR (DMSO-d6) δ 2.25-2.40 (m, 6H, CH2-2′,
CH2-7, CH2-8), 3.55-3.65 (m, 2H, CH2-5′), 3.83 (m, 1H, CH-
4′), 4.41 (m, 1H, CH-3′), 6.09 (m, 1H, CH-1′), 7.71 (s, 1H, CH-
6), 11.20 (br, 2H, NH, COOH).
3′-Azid o-2′,3′-d id eoxy-5-[[[3-(m eth oxyca r bon yl)p r op yl]-
a m in o]-3-oxop r op yl]u r id in e (32). To a cooled solution of 130
mg (0.40 mmol) of 31 and 60 µL (0.54 mmol) of N-methylmor-
pholine (NMM) in DMF (3 mL) was added 2-chloro-4,6-
dimethoxy-1,3,5-triazine (70 mg, 0.40 mmol). After the mixture
was stirred for 3 h at 0 °C, NMM (60 µL, 0.54 mmol) and
methyl-γ-aminobutyrate hydrochloride55 (63 mg, 0.41 mmol)
were added successively. After 20 h, the solvent was removed
in vacuo, and the residue was purified by flash chromatogra-
phy (EtOAc/MeOH: 94/4) to give 32 as a white solid (130 mg,
3′-Azid o-2′,3′-d id eoxy-5-[N-15-[6-(3,5-d im eth ylp h en yl-
t h io)-5-e t h yl-1-(5-oxop e n t yl)u r a cil]-4,15-d ia za -3-oxo-
p en ta d eca n yl]u r id in e (23). From the nucleoside 21b (71 mg,
0.148 mmol) and HEPT analogue 13 (58 mg, 0.146 mmol) was
obtained compound 23 as a white solid (71 mg, 57% yield) after
flash chromatography (EtOAc/MeOH: 95/5) and recrystalli-
zation from EtOAc: mp 98-100 °C; 1H NMR (DMSO-d6) δ 0.90
(t, 3H, J ) 7.5 Ηz, CH2CH3), 1.20 (br s, 12H, CH2-7* to CH2-
12*), 1.35-1.45 (m, 8H, CH2-6*, CH2-13*, CH2-8′′, CH2-9′′),
1.97 (m, 2H, CH2-10′′), 2.20-2.35 (m, 10H, CH2-2′, CH2-2*, Ar-
CH3), 2.40 (m, 2H, CH2-1*), 2.50 (CH2CH3 with DMSO), 2.98
(m, 4H, CH2-5*, CH2-14*), 3.61 (m, 2H, CH2-5′), 3.80 (m, 3H,
CH-4′, CH2-7′′), 4.40 (m, 1H, CH-3′), 5.23 (br s, 1H, OH), 6.08
(t, 1H, J ) 6.5 Hz, CH-1′), 6.89 (s, 2H, Ar-H), 6.91 (s, 1H, Ar-
H), 7.61 (s, 1H, CH-6), 7.67 (t, 1H, J ) 5.5 Hz, NHCO), 7.77
(t, 1H, J ) 5.5 Hz, NHCO), 11.35 (br s, 1H, NH), 11.60 (br s,
1H, NH); MS (ESI) m/z 860 (M + Na)+, 838 (M + H)+. Anal.
(C41H59N9O8S) C, H, N.
2′,3′-Did eoxy-4-N-[N-13-[6-(3,5-d im eth ylp h en ylth io)-5-
eth yl-1-(5-oxop en tyl)u r a cil]-13-a za d od ecyl]cytid in e (26).
From the nucleoside 25 (74 mg, 0.180 mmol) and HEPT
analogue 13 (68 mg, 0.181 mmol) was obtained compound 26
as a white solid (98 mg, 69% yield): mp 116-118 °C; 1H NMR
(DMSO-d6) δ 0.92 (t, 3H, J ) 7.5 Ηz, CH2CH3), 1.25 (m, 16H,
CH2-3* to CH2-10*), 1.30-1.50 (m, 8H, CH2-2*, CH2-11*, CH2-
8′′, CH2-9′′), 1.75-1.90 (m, 3H, CH-2′a, CH2-3′), 1.98 (m, 2H,
CH2-10′′), 2.20-2.25 (m, 7H, CH-2′b, Ar-CH3), 2.50 (CH2CH3
with DMSO), 2.99 (m, 2H, CH2-12*), 3.19 (dt, 2H, J ) 6.5, 6.5
Hz, CH2-1*), 3.54 (dd, 1H, J ) 12, 4 Hz, CH-5′a), 3.66 (d, 1H,
J ) 12 Hz, CH-5′b), 3.82 (m, 2H, CH2-7′′), 4.02 (m, 1H, CH-
4′), 5.00 (br s, 1H, OH), 5.70 (d, 1H, J ) 7.5 Hz, CH-5), 5.93
(dd, 1H, J ) 6.5, 3 Hz, CH-1′), 6.90 (s, 2H, Ar-H), 6.93 (s, 1H,
Ar-H), 7.61 (t, 1H, J ) 5.5 Hz, NH), 7.72 (t, 1H, J ) 5.5 Hz,
NHCO), 7.84 (d, 1H, J ) 7.5 Hz, CH-6), 11.60 (br s, 1H, NH-
76% yield): mp (EtOAc) 128-130 °C; [R]20 +27.5° (c 1.0,
D
MeOH); IR (KBr) 3406, 3322, 1735, 1710, 1676, 1658 cm-1
;
1H NMR (DMSO-d6) δ 1.64 (m, 2H, CH2-12), 2.25-2.45 (m,
8H, CH2-2′, CH2-7, CH2-8, CH2-13), 3.04 (m, 2H, CH2-11), 3.58
(s, 3H, OCH3), 3.60 (m, 2H, CH2-5′), 3.84 (m, 1H, CH-4′), 4.41
(dd, 1H, J ) 11.5, 5.5. Hz, CH-3′), 5.20 (br s, 1H, OH), 6.09 (t,
1H, J ) 6 Hz, CH-1′), 7.64 (s, 1H, CH-6), 7.86 (t, 1H, J ) 5.5
Hz, NH-10), 11.37 (br s, 1H, NH-3); MS (CI-NH3) m/z 425 (M
+ H)+. Anal. (C17H24N6O7) C, H, N.
3′-Azido-5-[[(3-car boxypr opyl)am in o]-3-oxopr opyl]-2′,3′-
d id eoxyu r id in e (33). To a solution of methylester 32 (100
mg, 0.23 mmol) in MeOH (4 mL) was added 0.5 mL of 2 N
NaOH at 0 °C dropwise. After being stirred for 4 h at room
temperature, the mixture was neutralized with Dowex 50X2-
200 ion-exchange resin. After filtration and concentration, the
residue obtained was rinsed with CH2Cl2, then recrystallized
in MeOH to give 33 as a white solid (71 mg, 73% yield): TLC
(EtOAc/MeOH/AcOH: 9/1/0.02) Rf 0.16; mp 155-156 °C; [R]20
D
+30° (c 1.0, MeOH); IR (KBr) 3405, 3353, 2123, 1703, 1683,
1642 cm-1; 1H NMR (DMSO-d6) δ 1.60 (m, 2H, CH2-12), 2.15-
2.45 (m, 8H, CH2-2′, CH2-7, CH2-8, CH2-13), 3.03 (m, 2H, CH2-
11), 3.61 (m, 2H, CH2-5′), 3.81 (m, 1H, CH-4′), 4.40 (dd, 1H, J
) 11.5, 5.5 Hz, CH-3′), 5.20 (br s, 1H, OH), 6.08 (t, 1H, J )
6.5 Hz, CH-1′), 7.63 (s, 1H, CH-6), 7.84 (t, 1H, J ) 5.5 Hz,
NH-10), 11.35 (br s, 1H, NH-3), 12.10 (br, 1H, COOH).
Gen er a l P r oced u r e for th e Syn th esis of Heter od im er s
14, 22, 23, 26, 34-37. To a cooled solution of carboxylic acid
compound 13, 31, 33, 30c′, or 30d ′ (1.0 equiv) and N-
methylmorpholine (1.5 equiv) in dry DMF was added 2-chloro-