216
X.-Z. Fu et al. / European Journal of Medicinal Chemistry 49 (2012) 211e218
1.48(d, J ¼ 7.6 Hz, 3H, COCHCH3), 1.45e1.42(m, 1H, CHCH2[1H]CH3),
1.23e1.18(m, 1H, CHCH2 [1H]CH3), 0.94e0.87(m, 12H, 4 ꢃ CH3). IR
(KBr,cmꢁ1): 3674.8(N-H), 3650.4 (N-H), 1733.4(C]O), 1648.6(C]
O); ESI-MS (m/z): 677.3 [M þ H]þ. HRMS calcd for C32H50N6O8P
[M þ H]þ 677.3349, found 677.3435.
4.25e4.18(m, 6H, 2 ꢃ OPOCH2CH2, CH2OCO), 4.11e4.05(m, 2H,
CH2CH2O), 3.88e3.86(m, 2H, NCH2CH2O), 3.77e3.74(m, 4H, OCH2P,
COCHCH3, CHNH2), 3.10e3.06 (m, 1H, NH2CHCH2[1H]Ar),
2.89e2.85(m, 1H, NH2CHCH2[1H]Ar), 1.96e1.91(m, 2H, OCH2CH2
CH2O), 1.53(d, J ¼ 7.2 Hz, 3H, COCHCH3); IR (KBr,cmꢁ1): 3673.9(N-
H), 3651.5 (N-H), 1733.6(C]O), 1682.1(C]O); ESI- MS (m/z):749.2
[M þ H ]þ; HRMS calcd for C37H43FN6O8P [M þ H]þ 749.2786,
found 749.2809.
5.2.3. 3-({{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}[3-
(L-valylthio)propoxy]phosphoryl}oxy)propyl 2-(4-isobutylphenyl)
propanoate (6c)
Compound 6c was light yellow oil, yield 17.8%. Rf 0.53(dichloro-
methane: methanol 20:1(v/v)). 1H NMR(CDCl3): 8.33 (s, 1H, 2eH),
7.92 (s, 1H, 8eH), 7.27 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.09 (d, J ¼ 7.6 Hz,
2H, Ar-H), 6.11(brs, 2H, purine-NH2), 4.37 (m, 2H, NCH2), 4.16e4.12
5.2.7. 3-({{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}[3-(L-isoleu-
cylthio)propoxy]phosphoryl}oxy)propyl 2-(2-fluorobiphenyl-4-yl)
propanoate (7c)
Compound 7c was light yellow oil, yield 15.6%. 1H NMR(CDCl3):
(m, 2H, CH2OCO), 4.05e4.00(m, 4H,
2
ꢃ
P(O)OCH2CH2),
d
¼ 8.33 (s, 1H, 2-H), 7.91 (s, 1H, 8eH), 7.54e7.51 (m, 2H, Ar-H),
3.92e3.89(m, 2H, NCH2CH2O), 3.77e3.68(m, 3H, OCH2P, COCHCH3),
3.36(d, J ¼ 4.8 Hz, 1H, CHNH2), 2.91e2.87(m, 2H, CH2SCO), 2.43(d,
J ¼ 7.2 Hz, 2H, ArCH2CH), 2.15e2.09(m, 5H, 2 ꢃ CH2CH2CH2O,
CH(CH3)2), 1.48(d, J ¼ 6.8 Hz, 3H, COCHCH3), 0.98(d, J ¼ 6.8 Hz, 3H,
NH2CHCH3), 0.89e0.87(m, 9H, NH2CHCH3, 2 ꢃ CH(CH3)2); IR
(KBr,cmꢁ1): 3673.1(N-H), 3649.5 (N-H),1733.1(C]O),1648.0(C]O);
ESI- MS (m/z): 693.3 [M þ H ]þ. HRMS calcd for C32H50N6O7PS
[M þ H]þ 693.3121, found 693.3181.
7.44e7.33 (m, 3H, Ar-H), 7.32e7.25(m, 4H, Ar-H), 7.20e7.10(m, 4H,
Ar-H), 5.81 (brs, 2H, purine-NH2), 4.39e4.37 (m, 2H, NCH2),
4.25e4.21(m, 2H, CH2CH2O), 4.19e4.12(m, 4H, 2 ꢃ OPOCH2CH2),
4.10e4.05(m, 2H, CH2OCO), 3.89e3.72(m, 4H, OCH2P, NCH2CH2),
3.43(m, 1H, CHNH2), 2.89e2.85(m, 2H, CH2SCO), 2.43(d, J ¼ 7.2 Hz,
2H, ArCH2CH), 1.95e1.81(m, 5H, 2 ꢃ CH2CH2CH2O, CH(CH3)2),
1.52(d, J ¼ 7.2 Hz, 3H, COCHCH3), 1.47e1.38(m, 1H, CHCH2[1H]CH3),
1.23e1.12(m, 1H, CHCH2[1H]CH3), 0.98(d,
J
¼
6.8 Hz, 3H,
NH2CHCH3), 0.92e0.87(m, 9H, NH2CHCH3, 2 ꢃ CH(CH3)2); IR
(KBr,cmꢁ1): 3673.6(N-H), 3650.5 (N-H), 1733.4(C]O), 1682.3(C]
O); ESI- MS (m/z):745.3 [M þ H ]þ; HRMS calcd for C35H47FN6O7PS
[M þ H]þ 745.2870,found 745.2904.
5.2.4. 3-({{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}[3-
(L-isoleucylthio)propoxy]phosphoryl}oxy)propyl 2-(4-isobutylphenyl)
propanoate (6d)
Compound 6d was light yellow oil, yield 21.4%. Rf 0.65(dichloro-
methane: methanol 20:1(v/v)). 1H NMR(CDCl3): 8.34 (s, 1H, 2eH),
7.92 (s, 1H, 8eH), 7.27 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.09 (d, J ¼ 8.0 Hz,
2H, Ar-H), 5.82(brs, 2H, purine-NH2), 4.38 (m, 2H, NCH2), 4.16e4.13
5.2.8. 3-({{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}[3-(L-pheny-
lalanylthio)propoxy]phosphoryl}oxy)propyl 2-(2-fluorobiphenyl-4-
yl)propanoate (7d)
(m, 2H, CH2OCO), 4.05e4.00(m, 4H,
2
ꢃ
P(O)OCH2CH2),
Compound 7d was light yellow oil, yield 16.7%. Rf 0.66(dichloro-
3.91e3.88(m, 2H, NCH2CH2O), 3.76e3.68(m, 3H, OCH2P, COCHCH3),
3.39(d, J ¼ 4.8 Hz, 1H, CHNH2), 2.91e2.87(m, 2H, CH2SCO), 2.43(d,
J ¼ 7.2 Hz, 2H, ArCH2CH), 1.92e1.79(m, 5H, 2 ꢃ CH2CH2CH2O,
CH(CH3)2), 1.49(d, J ¼ 7.2 Hz, 3H, COCHCH3), 1.48e1.39(m, 1H,
CHCH2[1H]CH3),1.21e1.09(m,1H, CHCH2[1H]CH3), 0.97(d, J ¼ 6.8 Hz,
3H, NH2CHCH3), 0.91e0.87(m, 9H, NH2CHCH3, 2 ꢃ CH(CH3)2); IR
(KBr,cmꢁ1): 3674.2(N-H), 3649.5 (N-H), 1733.4(C]O),1682.6(C]O);
ESI- MS (m/z): 707.3 [M þ H ]þ. HRMS calcd for C33H52N6O7PS
[M þ H]þ 707.3278, found 707.3339.
methane: methanol 20:1(v/v)). 1H NMR(CDCl3):
d
¼ 8.31 (s,1H, 2-H),
7.90 (s, 1H, 8eH), 7.53e7.51 (m, 2H, Ar-H), 7.45e7.34 (m, 3H, Ar-H),
7.32e7.24(m, 4H, Ar-H), 7.22e7.10(m, 4H, Ar-H), 5.76 (brs, 2H,
purine-NH2), 4.39e4.37 (m, 2H, NCH2), 4.23e4.20(m, 2H, CH2CH2O),
4.17e4.13(m, 4H, 2 ꢃ OPOCH2CH2), 4.08e4.03(m, 2H, CH2OCO),
3.88e3.74(m, 4H, OCH2P, NCH2CH2), 3.46(m, 1H, CHNH2),
3.15e3.11 (m, 1H, NH2CHCH2[1H]Ar), 2.89e2.85(m, 2H, CH2SCO),
2.80e2.74(m, 1H, NH2CHCH2[1H]Ar), 1.98e1.91(m, 2H, OCH2CH2
CH2O), 1.87e1.83(m, 3H, CH2CH2CH2S, CH(CH3)2), 1.54(d, J ¼ 7.2 Hz,
3H, COCHCH3); IR (KBr,cmꢁ1): 3674.2(N-H), 3649.5 (N-H),1733.4(C]
O), 1682.3(C]O); ESI- MS (m/z):779.2 [M þ H ]þ. HRMS calcd for
C38H45FN6O7PS [M þ H]þ 779.2714,found 779.2795.
5.2.5. 4-{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}-11-(2-
fluorobiphenyl-4-yl)-4-oxido-10-oxo-3,5,9-trioxa-4-phosphadodec-
1-yl -isoleucinate (7a)
L
Compound 7a was colorless oil, yield 23.1%. Rf 0.65(dichloro-
methane: methanol 20:1(v/v)). 1H NMR(CDCl3): 8.32 (s, 1H, 2-H),
7.89 (s, 1H, 8eH), 7.52e7.50 (m, 2H, Ar-H), 7.44e7.34 (m, 4H, Ar-H),
7.15e7.11(m, 2H, Ar-H), 6.04 (brs, 2H, purine-NH2), 4.36e4.34 (m,
5.2.9. 4-{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}-11-(4-benzoyl-
phenyl)-4-oxido-10-oxo-3,5,9-trioxa-4-phosphadodec-1-yl L-valinate
(8a)
Compound 8a was colorless oil, yield 16.2%. Rf 0.47(dichloro-
2H, NCH2), 4.29e4.15(m, 6H,
2
ꢃ
OPOCH2CH2, CH2OCO),
methane: methanol 20:1(v/v)). 1H NMR(CDCl3):
d
¼ 8.32 (s, 1H,
4.07e4.02(m, 2H, CH2CH2O), 3.86e3.83(m, 2H, NCH2CH2O),
3.82e3.76(m, 1H, COCHCH3), 3.78(d, J ¼ 7.6 Hz, 2H, OCH2P), 3.38(m,
1H, CHNH2), 1.95e1.89(m, 2H, OCH2CH2 CH2O), 1.72e1.71(m, 1H,
NH2CHCH(CH3)), 1.54(d, J ¼ 7.6 Hz, 3H, COCHCH3), 1.46e1.43(m, 1H,
CHCH2 [1H]CH3), 1.22e1.15(m, 1H, CHCH2 [1H]CH3), 0.93e0.86(m,
2-H), 7.91 (s, 1H, 8eH), 7.80e7.76 (m, 3H, Ar-H), 7.61e7.41 (m, 6H,
Ar-H), 6.03 (brs, 2H, purine-NH2), 4.38e4.36 (m, 2H, NCH2),
4.31e4.14(m, 6H, 2 ꢃ OPOCH2CH2, CH2OCO), 4.03e4.02(m, 2H,
CH2CH2O), 3.91e3.89(m, 3H, OCH2P, COCHCH3), 3.83e3.74(m, 2H,
NCH2CH2O), 3.33(m, 1H, CHNH2), 2.03e1.91(m, 3H, OCH2CH2CH2O,
NH2CHCH(CH3)2), 1.54(d, J ¼ 6.8 Hz, 3H, COCHCH3), 0.99(d,
J ¼ 7.2 Hz, 3H, CHCH3), 0.90(d, J ¼ 6.8 Hz, 3H, CHCH3); IR
(KBr,cmꢁ1): 3674.1(N-H), 3649.4 (N-H), 1733.4(C]O), 1648.4(C]
O); ESI- MS (m/z): 711.2 [M þ H ]þ. HRMS calcd for C34H44N6O9P
[M þ H]þ 711.2829,found 711.2911.
6H,
2
ꢃ
CH3). IR (KBr,cmꢁ1): 3673.4(N-H), 3649.6 (N-H),
1733.4(C]O), 1648.8(C]O); ESI- MS (m/z):715.2 [M þ H ]þ; HRMS
calcd for C34H45FN6O8P [M þ H]þ 715.2942,found 715.3029.
5.2.6. 4-{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}-11-(2-
fluorobiphenyl-4-yl)-4-oxido-10-oxo-3,5,9-trioxa-4-phosphadodec-
1-yl
L
-phenylalaninate (7b)
5.2.10. 4-{[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl}-11-(4-
benzoylphenyl)-4-oxido-10-oxo-3,5,9-trioxa-4-phosphadodec-1-yl
Compound 7b was colorless oil, yield 17.9%. 1H NMR(CDCl3):
d
¼ 8.31 (s, 1H, 8-H), 7.88 (s, 1H, 2eH), 7.53e7.51 (m, 2H, Ar-H),
L
-isoleucinate (8b)
7.44e7.34 (m, 4H, Ar-H), 7.29e7.23(m, 2H, Ar-H), 7.19e7.12(m, 5H,
Ar-H), 6.04 (brs, 2H, purine-NH2), 4.35e4.30 (m, 2H, NCH2),
Compound 8b was colorless oil, yield 22.3%. 1H NMR(CDCl3):
d
¼ 8.31 (s, 1H, 8-H), 7.95 (s, 1H, 2eH), 7.79e7.76 (m, 3H, Ar-H),