5706 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
0.096 mmol), pyridine (8 µL, 0.099 mmol), and DMAP (0.5 mg)
Xu et al.
C. Compound 27 (58 mg, 76.3%) was obtained from 52 (50 mg,
0.184 mmol), pyridine (0.1 mL), crotonic anhydride (0.1 mL),
and DMAP (3 mg) in CH2Cl2 (2 mL) as a white solid. 1H NMR
(CDCl3) δ 7.69 (s, 1H), 7.10 ∼ 6.9 (m, 2H), 6.1 ∼ 5.7 (m, 2H),
4.4 ∼ 4.0 (m, 6H), 3.19 (s, 3H), 2.9 ∼ 2.7 (m, 1H), 1.91, 1.89 (d,
J ) 1.37 Hz, 3H).
Ben zoic Acid 2-ben zoyloxym eth yl-3-(2-ch lor o-6-m e-
th yla m in o-p u r in -9-yl)-p r op yl Ester (28). P r oced u r e C.
Compound 28 (28.2 mg, 80%) was obtained as a white solid
from 52 (20 mg, 0.074 mmol), pyridine (0.1 mL), benzoic
anhydride (50 mg, 0.221 mmol), and DMAP (0.5 mg) in CH2-
1
in CH2Cl2 (4 mL). H NMR (CDCl3) δ 8.2 ∼ 6.8 (m, 17H), 5.3
∼ 4.8 (m, 4H), 4.4 ∼ 3.7 (m, 6H), 3.05 (s, 3H), 2.8 ∼ 2.5 (m,
1H).
Ben zoic Acid 3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-
2-p h osp h on ooxym eth yl-p r op yl Ester , Am m on iu m Sa lt
(22). P r oced u r e D. Compound 22 (11.2 mg, 40.4%) was
obtained from 54 (36 mg, 56.7 mmol) and TMSBr (0.1 mL) in
CH2Cl2 (3 mL). 1H NMR (D2O) δ 8.05 (s, 1H), 7.6 ∼ 7.4 (m,
2H), 7.36 ∼ 7.05 (m, 3H), 2.9 ∼ 2.7 (m, 1H), 4.55 ∼ 4.4 (m,
1H), 4.4 ∼ 4.2 (m, 3H), 4.15 ∼ 3.95 (m, 2H), 2.61 (s, 3H); 31P
NMR (D2O) 0.814 (s); MS (FAB-): calcd: 456.0666/454.0701;
found: 456.0654/454.0683
1
Cl2 (2 mL). H NMR (CDCl3) δ 8.1 ∼ 7.9 (m, 4H), 7.78 (s, 1H),
7.65 ∼ 7.5 (m, 2H), 7.5 ∼ 7.35 (m, 4H), 6.05 ∼ 5.8 (br, 1H), 4.6
∼ 4.35 (m, 6H), 3.14 (s, 3H), 3.15 ∼ 2.95 (m, 1H). MS (FAB-):
calcd: 479.9; found: 480.3.
Car bon ic Acid 2-(bis-ben zyloxy-ph osph or yloxym eth yl)-
3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-p r op yl Ester Eth -
yl Ester (55). P r oced u r e C. Compound 55 (40 mg, 50%) was
produced from 51b (70 mg, 0.138 mmol), ethyl chloroformate
(16 µL, 0.167 mmol), Et3N (0.1 mL), and DMAP (1 mg) in CH2-
Cl2 (2 mL). The product was purified by column chromatog-
2-F lu or oben zoic Acid 2-(2-flu or oben zoyloxym eth yl-3-
(2-ch lor o-6-m et h yla m in o-p u r in -9-yl)-p r op yl E st er (29).
P r oced u r e C. Compound 29 (66 mg, 86.8%) was obtained
from 52 (40 mg, 0.148 mmol), pyridine (0.1 mL), 2-fluoroben-
zoic anhydride (116 mg, 0.443 mmol), and DMAP (3 mg) in
1
raphy on silica gel (iPrOH:CHCl3 ) 1:15). H NMR (CDCl3) δ
1
7.61 (s, 1H), 7.46 ∼ 7.28 (m, 10H), 5.91 (br, 1H), 5.4 ∼ 4.95
(m, 4H), 4.3 ∼ 3.8 (m, 8H), 3.16 (s, 3H), 2.8 ∼ 2.5 (m, 1H), 1.3
(t, J ) 7.14 Hz, 3H).
CH2Cl2 (2 mL) as a white solid. H NMR (CDCl3) δ 8.0 ∼ 7.9
(t, J ) 6.87 Hz, 2H), 7.79 (s, 1H), 7.65 ∼ 7.4 (m, 2H), 7.3 ∼ 7.0
(m, 4H), 6.19 (br, 1H), 4.7 ∼ 4.2 (m, 6H), 3.15 (s, 3H), 3.1 ∼
2.9 (m, 1H). Anal. calc for C24H20ClF2N5O4 (515.901): C, 55.87;
H, 3.81; N, 13.58; F, 7.37. Found: C, 55.95; H, 4.01; N, 13.53;
F, 7.24.
Ca r bon ic Acid 3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-
2-p h osp h on ooxym eth yl-p r op yl Ester Eth yl Ester , Am -
m on iu m Sa lt (23). P r oced u r e D. Compound 23 (7.3 mg,
34%) was obtained from 55 (35 mg, 0.061 mmol) and TMSBr
(0.1 mL) in CH2Cl2 (3 mL). 1H NMR (D2O) δ 8.09 (s, 1H), 4.4-
4.3 (m, 2H), 4.18 (d, J ) 5.1 Hz, 2H), 4.02 (q, J ) 7.2 Hz, 2H),
3.95-3.85 (m, 2H), 3.03 (s, 3H), 2.79-2.60 (m, 1H), 1.16 (t, J
) 7.2 Hz, 3H); 31P NMR (D2O) 1.106 (s); MS 424 (M-H-).
P h en yl-ca r b a m ic Acid 2-(b is-b en zyloxy-p h osp h or yl-
oxym eth yl)-3-(2-ch lor o-6-m eth ylam in o-pu r in -9-yl)-pr opyl
Ester (56) (P r oced u r e E). To a solution of 51a (60 mg, 0.113
mmol) in dry CH2Cl2 (4 mL), Et3N (5 uL) and phenylisocyanate
(15 uL, 0.138 mmol) were added and the mixture was stirred
overnight under N2. The solvent was removed under reduced
pressure and the residue was subjected to column chromatog-
raphy on silica gel (CH3OH:CHCl3 ) 1:10) gave 56 (50 mg,
2,6-Diflu or ob en zoic Acid 2-(2,6-d iflu or ob en zoyloxy-
m eth yl-3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-p r op yl Es-
ter (30). P r oced u r e C. Compound 30 (37 mg, 91%) was
obtained as a white solid from 52 (20 mg, 0.074 mmol),
pyridine (0.1 mL), 2,6-difluorobenzoic anhydride (50 mg, 0.168
1
mmol), and DMAP (1 mg) in CH2Cl2 (2 mL). H NMR (CDCl3)
δ 7.72 (s, 1H), 7.6 ∼ 7.35 (m, 2H), 7.1 ∼ 6.9 (m, 4H), 5.92 (br,
1H), 4.7 ∼ 4.2 (m, 6H), 3.17 (s, 3H), 3.1 ∼ 2.9 (m, 1H).
P h en yla cetic Acid 3-(2-ch lor o-6-m eth yla m in o-p u r in -
9-yl)-2-p h en yla cetoxym eth yl-p r op yl Ester (31). P r oce-
d u r e C. Compound 31 (34.5 mg, 92%) was obtained from 52
(20 mg, 0.074 mmol), pyridine (0.05 mL), phenylacetic anhy-
dride (45 mg, 0.177 mmol), and DMAP (2 mg) in CH2Cl2 (2
1
1
68%). H NMR (CDCl3) δ 7.63 (s, 1H), 7.45 ∼ 7.24 (m, 13H),
mL) as a white solid. H NMR (CDCl3) δ 7.5 ∼ 7.2 (m, 10H),
7.14 ∼ 7.02 (m, 1H), 6.9 ∼ 6.78 (m, 1H), 5.95 (br, 1H), 5.3 (s,
1H), 5.15 ∼ 4.95 (m, 4H), 4.25 ∼ 3.85 (m, 6H), 3.16 (s, 3H),
2.7 ∼ 2.55 (m, 1H).
7.16 (s, 1H), 6.03 (s, 1H), 4.15 ∼ 3.85 (m, 6H), 3.63 (s, 4H),
3.16 (s, 3H), 2.8 ∼ 2.55 (m, 1H).
P h en ylca r ba m ic Acid 3-(2-ch lor o-6-m eth yla m in o-p u -
r in -9-yl)-2-ph en ylcar bam oyl-oxym eth yl-pr opyl Ester (32).
P r oced u r e E. Compound 32 (75.1 mg, 80%) was obtained as
a white solid from 52 (50 mg, 0.184 mmol), phenylisocyanate
(48 µL, 0.441 mmol), and Et3N (20 µL) in dry CH2Cl2 (2 mL)
under N2. 1H NMR (CDCl3) δ 7.83 (s, 1H), 7.50 ∼ 7.2 (m, 10H),
7.1 (s, 2H), 6.36 (s, 1H), 4.40 ∼ 4.1 (m, 6H), 3.12 (s, 3H), 2.9 ∼
2.7 (m, 1H). MS calcd: 509.950; found: 510.2
P h en yl-ca r ba m ic Acid 3-(2-ch lor o-6-m eth yla m in o-p u -
r in -9-yl)-2-p h osp h on ooxy-m eth yl-p r op yl Ester , Am m o-
n iu m Sa lt (24). P r oced u r e D. Compound 24 (13.5 mg, 58%)
was obtained from 56 (30 mg, 0.046 mmol) and TMSBr (0.1
1
mL) in CH2Cl2 (3 mL). H NMR (D2O) δ 8.08 (s, 1H), 7.45 ∼
7.1 (m, 2H), 7.1 ∼ 6.9 (m, 3H), 4.34 (s, 2H), 4.23 (s, 2H), 3.96
(s, 2H), 2.75 (s, 4H). 31P NMR (D2O) 1.25 (s); MS (FAB-):
calcd: 470.806; found: 471.2.
Ca r bon ic Acid 3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-
2-p h en oxyca r bon yloxy-m eth yl-p r op yl Ester P h en yl Es-
ter (33). P r oced u r e C. Compound 33 (21.1 mg, 56%) was
obtained from 52 (20 mg, 0.074 mmol), Et3N (41 µL), phenyl
chloroformate (20 µL, 0.159 mmol), and DMAP (1 mg) in CH2-
Cl2 (2 mL) as a white solid. The product was purified by column
P r op ion ic Acid 3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-
2-p r op ion yloxym eth yl-p r op yl Ester (25). P r oced u r e C.
A mixture of 52 (20 mg, 0.074 mmol), pyridine (0.1 mL),
propionic anhydride (28.5 mg, 0.221 mmol), and DMAP (0.5
mg) in CH2Cl2 (2 mL) was stirred at room temperature
overnight. After worked up, it gave compound 25 (25 mg,
1
chromatography on silica gel (iPrOH:CHCl3 ) 1:15). H NMR
1
88.5%) as a white solid. H NMR (CDCl3) δ 7.71 (s, 1H), 6.08
(CDCl3) δ 7.77 (s, 1H), 7.5 ∼ 7.0 (m, 10H), 6.11 (s, 1H), 4.5 ∼
(br, 1H), 4.26 (d, J ) 6.9 Hz, 2H), 4.2 ∼ 4.0 (m, 4H), 3.18 (s,
3H), 2.8 ∼ 2.65 (m, 1H), 2.36 (q, J ) 7.5 Hz, 4H), 1.15 (t, J )
7.5 Hz, 6H). MS (FAB-): calcd: 383.832; found: 384.1
2,2-Dim eth yl-pr opion ic Acid 3-(2-ch lor o-6-m eth ylam in o-
p u r in -9-yl)-2-(2,2-d im et h yl-p r op ion yloxym et h yl)-p r o-
p yl Ester (26). P r oced u r e C. Compound 26 (0.112 g, 73.6%)
was obtained from 52 (94 mg, 0.346 mmol), pyridine (0.1 mL),
pivalic anhydride (0.1 mL), and DMAP (1 mg) in CH2Cl2:DMF
4.1 (m, 6H), 3.18 (s, 3H), 3.0 ∼ 2.9 (m, 1H).
Su ccin ic Acid m on o-[2-(3-ca r boxy-p r op ion yloxym eth -
yl)-3-(2-ch lor o-6-m eth yla m in o-p u r in -9-yl)-p r op yl] Ester
(34). Compound 52 (50 mg, 0.184 mmol) was dissolved in dry
pyridine (2 mL) and succinic anhydride (92 mg, 0.919 mmol)
was added under stirring at room temperature. Stirring was
continued overnight under exclusion of humidity. The volume
was reduced in vacuo and the residue was extracted with
CHCl3 (3 × 10 mL) which gave 34 (23 mg, 25%) as a brown
solid. 1H NMR (CD3OD) δ 8.04 (s, 1H), 7.72 (s, 1H), 4.5 ∼ 4.25
(m, 2H), 4.25 ∼ 4.0 (m, 4H), 3.08 (s, 3H), 2.8 ∼ 2.6 (m, 1H),
2.6 (s, 8H). MS (CI): calcd: 471.9 (M+); found: 472.0 (M+H).
Dit h ioca r b on ic Acid S-b en zyl E st er O-[2-b en zylsu l-
fa n ylth ioca r boxyoxym eth yl-3-(2-ch lor o-6-m eth yla m in o-
p u r in -9-yl)-p r op yl] Ester (35). To a solution of 52 (50 mg,
0.184 mmol) and CS2 (0.5 mL) in DMSO (1 mL), maintained
1
(1:1) (2 mL) as a white solid. H NMR (CDCl3) δ 7.70 (s, 1H),
6.0 ∼ 5.8 (br, 1H), 4.23 (d, J ) 7.14 Hz, 3H), 4.08 (dd, J )
7.69, 2.19 Hz, 4H), 3.19 (s, 3H), 2.85 ∼ 2.65 (m, 1H), 1.22 (s,
18H); MS (FAB-): calcd: 439.94; found: 440.3. Anal. calc for
C
20H30ClN5O4 (439.94): C, 54.60; H, 6.87; N, 15.92. Found: C,
54.35; H, 6.97; N, 15.33.
Bu t-2-en oic Acid 2-bu t-2-en oyloxym eth yl-3-(2-ch lor o-
6-m eth yla m in o-p u r in -9-yl)-p r op yl Ester (27). P r oced u r e