162
Prabhpreet Singh
38.0 mmol) was dissolved in dry methanol (100 mL). sulphate, filtered and evaporated to get pure product
To this solution SOCl2 (6.92 mL, 95.0 mmol) was added 11 as light green solid (1.70 g, 89.5%yield). Rf
drop-wise at time interval of 2 h, maintaining the tem- 0.2 (dichloromethane:methanol, 90:10), 1H NMR
perature at 0◦C. The reaction was further stirred for (300 MHz) (DMSO-d6): δ 1.33 (quintuplet, J1
=
=
5 h at room temperature. The methanol was evaporated 7.2 Hz, J2 = 14.7 Hz, 2H, CH2), 1.54 (quintuplet, J1 =
under vacuum and resulting solid was co-evaporated 7.2 Hz, J2 = 14.7 Hz, 4H, CH2); 2.20 (t, J = 7.2 Hz, 2H,
with diethyl ether several times to isolate the com- CH2); 3.27 (q, J = 6.9 Hz, 2H, CH2); 8.06 (dd, J1 =
pound 9 as white solid, (6.59 g, 95.6% yield). 1H NMR 9.0 Hz, J2 = 2.1 Hz, 2H, ArH); 8.28 (dd, J1 = 9.0 Hz,
(300 MHz) (CDCl3): δ 1.44 (quintuplet, J1 = 6.6 Hz, J2 = 2.1 Hz, 2H, ArH); 8.73 (t, J = 5.7 Hz, 1H, NHCO)
J2 = 14.7 Hz, 2H, CH2), 1.66 (quintuplet, J1 = 7.2 Hz, ppm. 13C NMR (75 MHz) (DMSO-d6): δ 24.16, 25.94,
J2 = 14.7 Hz, 2H, CH2); 1.80 (broad quintuplet, J = 28.58, 33.52, 39.22, 123.40, 128.55, 140.23, 148.81,
6.3 Hz, 2H, CH2); 2.33 (t, J = 8.7 Hz, 2H, CH2); 3.01, 164.35, 174.36 ppm. LC-MS m/z 281.1 [M+H]+.
(bt, 2H, CH2); 3.66 (s, 3H, OCH3); 8.26 (bs, 3H, NH+3 )
ppm. 13C NMR (75 MHz) (CDCl3): δ 24.04, 25.78,
2.2d Synthesis of N-(6-(2-(6-amino-9H-purin-9-
27.01, 33.48, 39.66, 51.43, 173.74 ppm. LC-MS m/z
yl)ethylamino)-6-oxohexyl)-4-nitrobenzamide (13): A
solution of compound 11 (2.0 g, 7.0 mmol) in dry
dichloromethane:dimethylformamide (1:1) (20 mL)
was cooled to 0◦C and HOBt (N-hydroxybenzotriazole)
(1.158 g, 8.5 mmol) was added, followed by addi-
tion of EDC·HCl (1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride) (1.643 g, 8.5 mmol).
After 1 h the mixture was allowed to come at
room temperature and then adenine amine as
TFA salt 12 (3.174 g, 7.8 mmol) dissolved in
dichloromethane:dimethylformamide (1:1) (20 mL)
was added, followed by addition of diisopropylethyl-
amine (4.35 mL, 24.9 mmol). The reaction mixture
was stirred for 24 h. The solvent was evaporated under
high vacuum and ethyl acetate (100 mL) was added.
The ethyl acetate layer was washed with 10% NaHCO3
solution (2 × 40 mL), and finally with saturated
brine solution (2 × 20 mL). The collected organic
layer was dried over anhydrous sodium sulphate and
organic layer was evaporated under vacuum to get the
crude compound (2.89 g). The crude product obtained
was further column chromatographed on silica using
15–25% gradient of methanol in dichloromethane to
give pure 13 as yellow solid (2.02 g, 64.4%yield).
Rf = 0.5 (dichloromethane:methanol, 80:20). 1H NMR
259.2 [M + TFA]+.
2.2b Synthesis of methyl 6-(4-nitrobenzamido)
hexanoate (10): 4-Nitrobenzoyl chloride (1.0 g,
5.4 mmol) was dissolved in dry toluene (50 mL)
and to this solution amine 9 (1.07 g, 5.9 mmol) also
dissolved in dry toluene (10 mL) was added imme-
diately under Ar atmosphere followed by addition
of triethylamine (0.97 mL, 7.0 mmol). The reaction
mixture was stirred for 12 h at 65◦C under Ar atmo-
sphere. After completion of the reaction (TLC), the
mixture was cooled to room temperature and diethyl
ether was added. The solid precipitate was filtered off,
washed with diethyl ether and dried under vacuum.
The residue was column chromatographed on silica
using gradient of 0.5–5% methanol in dichloromethane
to isolate pure 10 as white solid (1.18 g, 67%). Rf =
0.74 (dichloromethane:methanol, 98:2). 1H NMR
(300 MHz) (CDCl3): δ 1.43 (quintuplet, J1 = 7.2 Hz,
J2 = 15.9 Hz, 2H, CH2), 1.61–1.73 (m, 4H, CH2),
2.34 (t, J = 7.2 Hz, 2H, CH2); 3.49 (q, J = 6.9 Hz,
2H, CH2); 3.66 (s, 3H, OCH3); 6.46 (bs, 1H, NHCO);
7.94 (dd, J1 = 9.0 Hz, J2 = 2.1 Hz, 2H, ArH); 8.27
(dd, J1 = 9.0 Hz, J2 = 2.1 Hz, 2H, ArH) ppm. 13C
NMR (75 MHz) (CDCl3): δ 24.10, 26.18, 28.85, 33.62,
39.89, 51.48, 123.61, 128.10, 140.26, 149.36, 165.45,
174.06 ppm. LC-MS m/z 295.1 [M+H]+.
(300 MHz) (DMSO-d6): δ 1.21 (quintuplet, J1
=
6.6 Hz, J2 = 15.0 Hz, 2H, CH2); 1.40–1.54 (m, 4H, 2
x CH2); 2.00 (t, J = 7.5 Hz, 2H, CH2); 3.25 (q, J =
6.9 Hz, 2H, CH2); 3.45 (q, J = 6.6 Hz, 2H, CH2); 4.17
(t, J = 6.0 Hz, 2H, CH2); 7.16 (s, 2H, NH2 of adenine);
2.2c Synthesis of 6-(4-nitrobenzamido)hexanoic acid 7.91 (t, J = 6.0 Hz, 1H, NHCO); 8.01 (s, 1H, ArH-C2
(11): The compound 10 (2.0 g, 7.0 mmol) was of adenine); 8.06 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 2H,
dissolved in minimum volume of methanol and ArH); 8.13 (s, 1H, ArH-C8 of adenine); 8.30 (dd, J1 =
NaOH (0.033 g, 8.0 mmol) as its 1N solution was 9.0 Hz, J2 = 2.4 Hz, 2H, ArH); 8.77 (t, J = 5.4 Hz,
added and stirred for 24 h. Then, methanol was 1H, NHCO) ppm. 13C NMR (75 MHz) (DMSO-d6):
evaporated under vacuum and 20 mL of water was δ 24.83, 26.03, 28.65, 35.21, 42.64, 45.48, 39.28,
added in ice cold condition. The solution was acidi- 118.71, 123.38, 128.58, 140.24, 140.9, 148.80, 149.60,
fied to pH 2–3 and extracted with ethyl acetate. 152.23, 155.85, 164.39, 172.39 ppm. LC-MS m/z 441.2
The organic layer was dried over anhydrous sodium [M+H]+.