6596 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Jones et al.
Purification by flash chromatography using hexane and EtOAc
(5:2) as eluent yielded product as white crystals (0.3 g, 84.3%); mp
54-56 °C. HRMS: C18H20O8 [M þ Na]þ requires 387.1056;
found 387.1069. 1H NMR δ (CDCl3): 1.19 (3H, t, J = 8.04 and
7.52 Hz), 2.37 (3H, s), 2.44 (2H, q, J = 7.52, 8.04, and 7.52 Hz),
3.86 (1H, q, J = 5.52, 4.52, and 5.04 Hz), 3.98 (1H, q, J = 5.52,
4.04, and 6.0 Hz), 4.08 (2H, m), 4.59 (1H, d, J = 4.52 Hz), 4.91
(1H, t, J = 5.0 and 5.04), 5.20 (1H, q, J = 5.04, 6.0, and 5.52 Hz),
5.43 (1H, d, J = 3.0 Hz), 7.12 (1H, dd, J = 1.0 and 1.0 Hz), 7.33
(1H, t,J=1.0, 6.56, and8.0 Hz), 7.59(1H, t,J=6.0and6.52Hz),
8.01 (1H, dd, J = 1.48 and 2.0 Hz).
Isosorbide-2-aspirinate-5-pentanoate (5g). 5b (0.25 g, 0.82 mmol)
was reacted with valeroyl chloride (0.108 g, 0.9 mmol) according to
GP2 to give a yellow oil, which was purified by flash chromato-
graphy using hexane and EtOAc (4:1) as eluent yielding 5g as a
yellow oil (0.25 g, 65%). HRMS: C20H24O8 [M þ H]þ requires
393.1549; found 393.1559. Anal. C20H24O8 requires C 61.22,
H 6.16; found C 61.35, H 6.02. 1H NMR δ (CDCl3): 0.97 (3H, t,
J = 8 Hz), 1.40 (2H, m), 1.65 (2H, m), 2.37 (3H, s), 2.41 (2H, t, J =
8 Hz), 3.95 (2H, m), 4.1 (2H, m), 4.60 (1H, d, J= 5 Hz), 4.95 (1H, t,
J = 5 Hz), 5.20 (1 H, q, J = 4.5 Hz), 5.45 (1 H, d, J = 3 Hz), 7.13
(1H, d, J = 8 Hz), 7.34 (1H, t, J = 8 Hz), 7.60 (1H, dt, J = 8 Hz,
2.5 Hz), 8.05 (1H, dd, J = 8 Hz, 2 Hz).
Isosorbide-2aspirnate-5-(4-phenylbenzoate) (5s). Isosrbide-
2-aspirinate 5b (200 mg, 0.6 mmol) and 4-phenylbenzoylchlor-
ide (0.156 g, 0.72 mmol) were reacted together to give 5s (0.185 g,
65%) as a colorless oil after flash chromatography using hexane
and EtOAc (4:1) as eluent. HRMS C28H24O8, [M þ H]þ requires
489.4933; found 489.5021. Anal. C28H24O8 requires C 68.85, H
4.95; found C 68.88, H 5.08. 1H NMR (CDCl3, 400 MHz) δ 2.4
(3H, s), 4.1 (4H, m), 4.65 (1H, d, J = 5 Hz), 5.05 (1H, t, J =
5 Hz), 5.45 (2H, m), 7.1 (1H, d, J = 8.5 Hz), 7.35 (1H, dt, J =
6.5 Hz, 1 Hz), 7.45 (1H, t, J = 8 Hz), 7.5 (2H, t, J = 7.5 Hz),
7.6 (1H, dt, J = 8 Hz, 1.5 Hz), 7.65 (2H, d, J = 7 Hz), 7.7
(2H, d, J = 8.5 Hz), 8.0 (1H, dd, J = 8 Hz, 1.5 Hz), 8.2 (2H, d,
J = 8.5 Hz).
Isosorbide-2-aspirinate-5-nicotinate (5v). 5b (0.3 g, 0.98 mmol),
was reacted with nicotinic acid (0.12 g, 0.98 mmol) according to
GP1 to give product as a crude oil (0.95 g). Purification by flash
chromatography using DCM and EtOAc (95:5) as eluent yielded
compound 5p as white crystals (0.12 g, 29.7%); mp 94-96 °C.
HRMS: C21H19NO8 [M þ Na]þ 436.1008; found 436.1011. Anal.
C21H19NO8 requires C 61.02, H 4.63, N 3.39; found C 61.13, H
4.28, N 3.45. 1H NMR δ (CDCl3): 2.36 (3H, s), 4.11 (9H, m), 6.64
(1H, d, J = 4.52 Hz), 5.05 (1H, t, J = 5.04 and 5.52 Hz), 5.46 (2H,
dd, J = 2.0 and 2.52 Hz), 7.11 (1H, d, J = 8.52 Hz), 7.32 (1H, q,
J = 6.52, 8.04, and 8.52 Hz), 7.43 (1H, q, J = 6.53, 8.04, and
8.52 Hz), 7.59 (1H, t, J = 6.04 and 6.52 Hz), 8.00 (1H, dd, J =
1.52and2.0Hz), 8.34 (1H, m), 8.82 (1H, dd, J = 2.0 and 1.48 Hz),
9.28 (1H, d, J = 2.0 Hz).
Isosorbide-2-aspirinate-5-iso-nicotinate (5w). 5b (0.2 g, 0.65
mmol) was reacted with isonicotinic acid (0.08 g, 0.65 mmol)
according to GP1 to give compound 5w (0.17 g, 63.1%) as white
crystals following purification by flash chromatography using
DCM and EtOAc (95:5) as eluent. mp 86-88 °C. HRMS:
C21H19NO8 [M þ Na]þ requires 436.1008; found 436.1004. 1H
NMR δ (CDCl3): 2.37 (3H, s), 4.09 (5H, m), 4.65 (1H, d, J =
4.52 Hz), 5.05 (1H, t, J = 5.52 and 5.04 Hz), 5.46 (2H, dd, J =
5.52 and 5.04 Hz), 7.12 (1H, d, J = 7.04 Hz), 7.33 (1H, m), 7.59
(2H, t, J = 6.04 and 6.04 Hz), 7.90 (1H, d, J = 5.04 Hz), 8.01 (H,
dd, J = 2.0 and 1.52 Hz), 8.84 (1H, s), 8.98 (1H, s).
Isosorbide-2-aspirinate-5-cyclopropanoate (5h). 5b (0.506 g,
1.6 mmol) was reacted with cyclopropane carbonyl chloride
(2 mmol) according to GP2 to followed by purification by flash
chromatography using hexane and EtOAc (2:1) as eluent to give
5h as a clear oil (0.396 g, 65%). 1H NMR δ (CDCl3) 0.9-1.18
(m, 4H), 2.32 (3H, s), 3.78 (m, 1H), 3.9 (m, 1H), 4.06 (2H, m), 4.5
(1H, d, J = 5 Hz), 4.83 (1H, t, J = 5 Hz), 5.12 (1H, q, J =
4.5 Hz), 5.38 (1H, s), 7.06 (1H, d, J = 8 Hz), 7.26 (1H, dt, J = 8,
2.5 Hz), 7.52 (1H, t, J = 8 Hz), 7.95 (1H, dd, J = 8, 2 Hz).
Isosorbide-2-aspirinate-5-benzoate (5i). 5b (1.0 g, 3.25 mmol)
was reacted with benzoic acid (0.59 g, 4.88 mmol), according to
GP1 to give colorless oil, which was recrystallized in ethanol to
afford 5i as white crystals (1.13 g, 84.3%); mp 80-82 °C. HRMS:
C22H20O8 [M þ H]þ requires 413.1236; found 413.1226. Anal.
1
C22H20O8 requires C 64.07, H 4.89; found C 63.99, H 4.96. H
NMR δ (CDCl3): 2.37 (3H, s), 4.07 (1H, m), 4.11 (3H, m), 4.65
(1H, d, J = 5.0Hz), 5.05 (1H, t, J = 5.5and 5.0Hz), 5.56 (1H, m),
7.13 (1H, d, J = 8.04 Hz), 7.27 (1H, t, J = 8.04 and 6.52 Hz), 7.33
(1H, d, J = 7.56 Hz), 7.49 (2H, t, J = 7.52and 7.56 Hz), 8.01 (1H,
d, J = 7.56 Hz), 8.12 (2H, d, J = 7.52 Hz).
Isosorbide-2-aspirinate-5-(-4-methyl-1,2,3-thiadiazole-5-oate)
(5aa). 5b (0.2 g, 0.65 mmol) and 4-methyl-1, 2, 3-thiadiazole-5-
carboxylic acid were reacted together according to GP1 to give
5aa (0.228 g 83%) as a pale-pink foam after flash chromato-
graphy using hexane and EtOAc (3:1) as eluent. HRMS
C19H18N2O8S [M þ Na]þ requires 457.0682; found 457.0679.
1H NMR δ (CDCl3) 2.4 (3H, s), 3.05(3H, s), 4.1 (4H, m), 4.65
(1H, d, J = 5.5 Hz), 5.05 (1H, t, J = 5 Hz), 5.5 (2H, m), 7.15
(1H, d, J = 8.5 Hz), 7.35 (1H, t, J = 1 Hz), 7.7 (1H, dt, J = 8 Hz,
1.5 Hz), 8.1 (1H, d, J = 8 Hz).
Isosorbide-2-aspirinate-5-(1-methyl-(1H)-pyrazole-5-carboxylate)
(5bb). 5b (0.15 g, 0.48 mmol) and 1-methyl-(1H)-pyrazole-5-car-
boxylic acid (0.055 g, 0.44 mmol) were reacted according to GP1 to
give 5bb (60 mg 30%) as a yellow oil after flash chromatography
using hexane and EtOAc (1:1) as eluent. HRMS: C20H20N2O8
[M þ Na]þ requires 439.1117; found 439.1113. 1HNMR δ(CDCl3)
2.37 (3H, s), 3.87 (1H, q, J = 5.55, 4.52 Hz), 4.05 (1H, q, J = 6.05,
3.52 Hz), 4.13 (5H, m), 4.63 (1H, d, J = 4.52 Hz), 4.95 (1H, t, J =
5.00 Hz), 5.30 (1H, m), 5.44 (1H, d, J = 5.52 Hz), 6.95 (1H, d, J =
2.01 Hz), 7.15 (1H, dd, J = 8.04, 1.00 Hz), 7.35 (1H, dt, J = 7.56,
1.00 Hz), 7.55 (1H, d, J = 2.01 Hz), 7.59 (1H, m), 8.05 (1H, dd, J =
6.05, 2.0 Hz).
Isosorbide-2-aspirinate-5-(2-nitroxymethyl)benzoate (7c).
Phthalide (37 mmol) and dichlorotriphenylphosphorane (38
mmol) were heated at 180 °C for 4 h with stirring. Color change
from green to brown was seen over the course of 4 h. 2-Chloro-
methylbenzoyl chloride (600 μL) was reacted with compound 5b
(0.52 g, 1.7 mmol) according to GP2, producing 769.5 mg of a
brown/green oil. Thiswas purified by flashchromatography using
hexane and EtOAc (2:1) as eluent to give (0.419 g, 51%) of a white
solid. 1H NMR δ (CDCl3) 400 MHz: 2.38 (3H, s), 4.03 (4H, m),
4.66 (1H, d), 5.04 (2H, m), 5.10 (1H, s), 5.42 (2H, m), 7.12 (1H, d),
Isosorbide-2-aspirinate-5-(2-methylbenzoate) (5j). 5b (0.2 g,
0.65 mmol) was reacted with 2-toluoyl chloride (0.09 mL, 0.72
mmol) according to GP2 to give 0.41 g of crude product as
brown oil. Purification by flash chromatography using hexane
and EtOAc (2:1) as eluent gave product as yellow oil. This was
recrystallized in ethanol to yield 5j as a white solid (0.11 g,
39.6%); mp 104-106 °C. HRMS: C23H22O8, [M þ Na]þ
requires 449.1212; found 449.1238. Anal. C23H22O8 requires C
64.78, H 5.20; found C 64.78, H 5.29. 1H NMR δ (CDCl3): 2.38
(3H, s), 2.65 (3H, s,), 4.01 (1H, dd, J = 5.52 and 5.52 Hz), 4.12
(3H, m), 4.66 (1H, d, J = 4.52 Hz), 5.04 (1H, t, J = 5.04 and
5.0 Hz), 5.41 (1H, q, J = 5.52 Hz), 5.47 (1H, d, J = 2.0 Hz),
7.13 (1H, dd, J = 1.0 and 1.0 Hz), 7.33 (1H, t, J = 7.0 and
6.52 Hz), 7.59 (1H, t, J = 6.52 and 6.52 Hz), 8.02 (1H, dd, J =
1.52 and 2.0 Hz).
Isosorbide-2-aspirinate-5-(3-methylbenzoate) (5k). 5b (0.2 g,
0.65 mmol) was reacted with 3-toluic acid (0.09 g, 0.72 mmol)
according to GP1 to yield crude product as a clear oil. Purifica-
tion by flash chromatography using hexane and EtOAc (3:2) as
eluent yielded compound 5k as white crystals (0.12 g, 43.2%);
mp 96-98 °C. HRMS: C23H22O8, [M þ Na]þ requires 449.1212;
found 449.1234. Anal. C23H22O8 requires C 64.78, H 5.20; found
C 64.67, H 5.28. 1H NMR δ (CDCl3): 2.36 (3H, s), 2.43 (3H, s),
4.09 (4H, m), 4.65 (1H, d, J = 5.0 Hz), 5.04 (1H, t, J = 5.04 and
5.0 Hz), 5.43 (2H, m), 7.12 (1H, d, J = 8.0 Hz), 7.35 (3H, m),
7.58 (1H, q, J = 1.0, 6.56, and 1.48 Hz), 8.01 (1H, dd, J = 1.0
and 1.52 Hz).