Gastrointestinal Absorption of Heparin
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1169
solid, mp 94-96 °C. 1H NMR (300 MHz, DMSO-d6): δ 12.73
(1H, s), 11.95 (1H, s), 8.80 (1H, t), 7.83 (1H, m), 7.37 (1H, m),
6.86 (2H, m), 3.26 (2H, m), 2.17 (2H, t), 1.49 (4H, m), 1.26 (8H,
br m).
in methanol (100 mL), and 10% palladium on carbon (0.5 g)
was added. The reaction was stirred overnight at room
temperature under an atmosphere of hydrogen. The resulting
suspension was filtered in an inert amosphere, and the
methanolic filtrate was evaporated under vacuum to give 29
as a tan solid (1.0 g, 73.9%). 1H NMR (300 MHz, DMSO-d6):
δ 8.15 (1H, t), 7.42 (1H, d), 7.1 (1H, t), 6.65 (1H, d), 6.5 (1H,
t), 6.35 (2H, s), 3.2 (2H, q), 2.1 (2H, q), 1.5 (4H, m), 1.25 (6H,
m).
8-(2-Ca r boxyben zoyl)a m in oocta n oic Acid (30). 8-Ami-
nocaprylic acid (5 g, 0.31 mmol) was dissolved in water (50
mL). A solution of phthalic anhydride (4.64 g, 0.31 mmol) in
dioxane (20 mL) was added rapidly via an addition funnel, and
the mixture was stirred overnight at room temperature. The
pH of the reaction mixture was adjusted to ∼1 with concen-
trated hydrochloric acid, and the mixture was extracted with
ethyl acetate (2 × 50 mL). The combined organic extracts were
dried over magnesium sulfate and concentrated under vacuum.
The residue was recrystallized from ethyl acetate to give 30
as a white solid (2.45 g, 25.4%). 1H NMR (300 MHz, DMSO-
d6): δ 12.5 (1H, s), 8.25 (1H, t), 7.7 (1H, dd), 7.5 (2H, m), 7.4
(1H, dd), 3.2 (2H, q), 2.2 (2H, t), 1.5 (4H, m), 1.3 (6H, m).
8-[(2-Hyd r oxyp h en yl)a cetyl]a m in oca p r ylic Acid (67).
2-Coumaranone (4.21 g, 31.4 mmol) was dissolved in acetoni-
trile (75 mL) by stirring under an argon atmosphere. Tri-
ethylamine (3.18 g, 31.4 mmol) and 8-aminocaprylic acid (5.00
g, 31.4 mmol) were added, a tan slurry formed, and the
reaction mixture was heated at reflux overnight. The reaction
was cooled to room temperature and concentrated under
vacuum. The residue was dissolved in methylene chloride, and
the organic phase was washed with aqueous hydrochloric acid
(2 N, 2 × 100 mL). The organic phase was then dried over
anhydrous sodium sulfate and concentrated under vacuum.
The resulting tan solid was dried overnight to give 67 as a
tan solid (8.35 g, 70.4%), mp 93-7 °C. 1H NMR (300 MHz,
DMSO-d6): δ 8.81 (1H, s), 8.66 (1H, t), 7.94 (1H, dd), 7.72 (1H,
td), 7.48 (1H, d), 7.41 (1H, td), 3.29 (2H, q), 2.17 (2H, t), 1.47
(4H, m), 1.27 (6H, m).
1-Am in ou n d ec-10-en e (72). A mixture of 10-undecene-
1-ol (25.00 g, 147 mmol), triphenylphosphine (38.52 g, 147
mmol), and phthalimide (21.64 g, 147 mmol) in dry THF (150
mL) was stirred vigorously under argon. The reaction mixture
was then placed in an ice/water bath. Diisopropyl azodicar-
boxylate (DIAD, 29.71 g, 147 mmol) was dissolved in THF (50
mL) and added dropwise via an addition funnel. Upon
completion of the addition, the reaction was stirred at room
temperature for 4 h. The solvent was evaporated under
vacuum, and ether (150 mL) was added to precipitate the
triphenylphosphine oxide and hydrazine dicarboxylate which
were removed by filtration. The precipitate was rinsed with
ether (2 × 150 mL), and the combined filtrates were evapo-
rated to give a yellow solid. The solid was triturated with
warm hexanes (3 × 200 mL) and filtered. The combined
hexanes were evaporated to give 1-phthalimidylunden-10-ene
as a yellow wax.
The yellow wax was dissolved in ethanol (200 mL). Hydra-
zine monohydrate (7.35 g, 147 mmol) was added. The mixture
was refluxed for 2 h to give a suspension. After the mixture
was cooled to room temperature, concentrated hydrochloric
acid (150 mL) was added, and the solid was filtered through a
sintered glass filter. The residue was washed with water (150
mL), and the combined filtrates were evaporated to give a
yellow solid. The solid was dissolved in sodium hydroxide (1
M, 250 mL) and extracted with ether (2 × 200 mL). The ether
was dried and evaporated to give a yellow oil. The oil was
purified by vacuum distillation (0.1 mmHg, 49-55 °C) to give
72 as a clear, colorless oil (15.52 g, 62.5%). 1H NMR (300 MHz,
DMSO-d6): δ 5.77 (1H, br m). 4.94 (2H, m), 2.48 (2H, m), 1.99
(2H, m), 1.23 (14 H, br m).
1-[O-Acetyl(2-h ydr oxyben zoyl)am in o]u n dec-10-en e (73).
O-Acetylsalicyloyl chloride (18.23 g, 91.8 mmol) in THF (150
mL) was cooled in an ice/water bath. Triethylamine (9.28 g
91.8 mmol), followed by 1-aminoundec-10-ene (15.52 g, 91.8
mmol) in THF (50 mL), was added dropwise via an addition
funnel. The ice/water bath was removed, and the reaction was
stirred overnight at room temperature. The solvent was
removed by evaporation under vacuum, and the residue was
dissolved in ethyl acetate (200 mL). The ethyl acetate was
washed with water (2 × 150 mL). The organic layer was dried
with sodium sulfate, decolorized with activated charcoal, and
evaporated to give 73 as a tan solid (29.85 g, 98%). 1H NMR
(300 MHz, DMSO-d6): δ 8.24 (1H, t), 7.50 (2H, m), 7.30 (1H,
m), 7.15 (1H, m), 5.78 (1H, m), 4.95 (2H, m), 3.15 (2H, q), 2.19
(3H, s), 1.99 (2H, m), 1.47 (2H, m), 1.26 (12H, br s).
8-[N-(3-Cou m a r in ca r bon yl)]a m in oca p r ylic Acid (68).
A mixture of salicylaldehyde (8.8 mL, 82.7 mmol), dimethyl-
malonate (13.8 mL, 90 mmol), piperidine (1.1 mL), and acetic
acid (0.45 mL) in ethanol (50 mL) was heated to reflux for 3
h. Hot water (50 mL) was added to the reaction, and the
resulting mixture was cooled to room temperature. A white
solid formed. The reaction mixture was further cooled in a
ice/water bath for 1 h prior to filtration. The white solid was
collected by filtration, and the isolated solid was recrystallized
from 40% aqueous ethanol v/v to give 3-(methoxycarbonyl)-
1
coumarin as white needles (11.0 g, 61%), mp 111-113 °C. H
NMR (CDCl3): δ 8.58 (1H, s), 7.52-7.88 (2H, m), 7.31-7.42
(2H, m), 3.95 (3H, s).
10-(2-Hyd r oxyben zoyl)a m in od eca n oic Acid (9). Potas-
sium permanganate (42.74 g, 270 mmol) was added to a
mixture of sulfuric acid (9 M, 60 mL) and glacial acetic acid
(30 mL) in water (1500 mL). The mixture was stirred rapidly
with cooling in an ice/water bath. A mixture of 73 (29.85 g,
90 mmol) and Adogen 464 (1.65 g) in methylene chloride (500
mL) was added dropwise over 45 min. After the addition was
complete, the reaction mixture was allowed to come to room
temperature and stirred for 5 h. Sodium bisulfite (40 g) was
added to decolorize the reaction mixture. The organic layer
was separated, and the aqueous layer was washed with
methylene chloride (3 × 200 mL). The combined methylene
chloride layers were dried over sodium sulfate and concen-
trated under vacuum. The resulting tan solid was dissolved
in 50% v/v aqueous methanol, decolorized with activated
carbon, and recrystallized. Upon cooling, a white solid pre-
cipitated and was isolated by filtration. After being dried
overnight in a vacuum oven, 9 was obtained as a tan solid
(13.07 g, 45.5%), mp 85-87 °C. 1H NMR (300 MHz, DMSO-
d6): δ 12.72 (1H, s), 11.95 (1H, s), 8.80 (1H, t), 7.82 (1H, m),
7.37 (1H, m), 6.86 (2H, m), 3.27 (2H, m), 2.17 (2H, t), 1.51 (4H,
m), 1.24 (10H, br m).
Aqueous hydrochloride acid (3 N, 200 mL) was added
portionwise to a hot mixture of 3-(methoxycarbonyl)coumarin
(5.0 g, 22.9 mmol) in ethanol (100 mL). The resulting solution
was heated at 55-60 °C for 2 h. A white solid formed, and
the mixture was cooled to room temperature. The solid was
filtered and recrystallized from ethanol to give 3-coumarin-
carboxylic acid as a white crystalline solid (3.38 g, 78%), mp
187-190 °C. 1H NMR (CDCl3): δ 12.25 (1H, br s), 8.97 (1H,
s), 7.75-7.92 (2H, m), 7.75 (2H, d).
A mixture of 3-coumarincarboxylic acid (1.9 g, 10.0 mmol)
and thionyl chloride (20 mL) was heated to reflux for 3 h. The
excess thionyl chloride was evaporated under vacuum, and
toluene (5 mL) was added to the residual yellow solid. The
toluene was evaporated under vacuum, and the product was
used without further purification.
Aqueous sodium hydroxide (5%, 14 mL, 21.5 mmol) was
added to a mixture of 8-aminocaprylic acid (1.62 g, 10.15 mmol)
in methylene chloride (20 mL). The mixture was cooled in an
ice/water bath, and the acid chloride from the preceding step
was added in a methylene chloride/THF solution (2:5, 28 mL).
The mixture was stirred at 0 °C for 2 h, allowed to come to
room temperature, and stirred for an additional 2 h. The
solvent was evaporated under vacuum, and the residue was
8-(2-Am in oben zoyl)a m in oocta n oic Acid (29). 8-(2-Ni-
trobenzoyl)aminooctanoic acid (1.5 g, 5 mmol) was dissolved