A Novel Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3753
HCl solution and 100 mL of saturated NaHCO3 solution, dried
(MgSO4), and filtered. After removal of the solvent under
reduced pressure, the residue was purified by flash chroma-
tography to give 3.15 g of 15: 1H NMR (CDCl3) δ 2.86 (m, 2
H), 2.91 (s, 3 H), 3.02 (s, 3 H), 3.42 (s, 2 H), 3.60 (m, 2 H), 3.62
was stirred at room temperature for 1 h, 1.0 g (2.8 mmol) of
21 in 10 mL of THF was added, and stirring was continued
for 12 h. The reaction mixture was poured into 100 mL of 1
N HCl solution and extracted with EtOAc (3 × 25 mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Purifica-
tion by flash chromatography (2:1 hexane:EtOAc) gave 0.99 g
(80%) of the ethyl ester of 22b. 1H NMR (CDCl3) δ 1.24 (dt, 3
H), 1.97 (dd, 3 H), 2.82 (m, 2 H), 2.92 and 3.02 (dd, 3 H), 3.45
and 3.72 (s, 2 H), 3.61 (m, 2 H), 4.12 (dq, 2 H), 6.98-7.40 (m,
13 H), 7.52 (d, 1 H).
The ester obtained above (0.99 g, 2.24 mmol) in 10 mL of
THF and 1 mL of H2O was treated with 0.47 g (11.21 mmol)
of lithium hydroxide, and the solution was stirred at room
temperature for 12 h. The reaction mixture was then poured
into water and acidified to pH 1 using concentrated HCl. The
aqueous layer was extracted with EtOAc (3 × 25 mL), and
the combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Recrystallization from Et2O yielded 0.6 g (64%) of 22b: mp
130-132 °C. 1H NMR (CDCl3) δ 1.97 (d, 3 H), 2.81 (m, 2 H),
2.89 and 3.01 (d, 3 H), 3.60 (m, 2 H), 3.46 and 3.75 (s, 2 H),
7.05-7.40 (m, 13 H), 7.61 (d, 1 H), 10.32 (bs, 1 H). Anal.
(C26H25NO3) C, H, N.
3-[5-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-2-p h e-
n ylp h en yl]p r op en oic Acid (22a ). This compound was
synthesized according to the procedure described above, except
triethyl phosphonoacetate was used.
6-(Br om om eth yl)cou m a r in (23). A mixture of 6-meth-
ylcoumarin (20 g, 124.87 mmol) and NBS (22.23 g, 124.87
mmol) in 700 mL of CCl4 was refluxed under a sun lamp for
4.5 h. After filtration, the filtrate was concentrated under
reduced pressure. The residue was triturated with EtOAc, and
the resulting solid was collected on a filter to yield 16.0 g (54%)
of crude 23. 23 thus obtained was used for the next reaction
without further purification.
6-(Cya n om eth yl)cou m a r in (24). A solution of 23 (8.43
g, 35.27 mmol) and NaCN (1.73 g, 35.27 mmol) in 60 mL of
DMSO was stirred at room temperature for 2 h. The reaction
mixture was poured into 700 mL of H2O and extracted with
EtOAc (3 × 200 mL). The combined extracts were washed
with water (2 × 150 mL) and brine (150 mL), dried, filtered,
and concentrated under reduced pressure. Purification of the
residue by flash chromatography (1:1 EtOAc:hexane) gave 2.58
g (40%) of 24 as an oil.
6-(Ca r bom eth oxym eth yl)cou m a r in (25). A stream of
dry HCl gas was bubbled into a solution of 24 (2.58 g, 13.95
mmol) in 70 mL of CH3OH at 0 °C for 10 min, and the reaction
mixture was then stirred at room temperature for an ad-
ditional 12 h. After concentration under reduced pressure, the
residue was dissolved in 100 mL of EtOAc, and the solution
was washed with H2O (2 × 50 mL), and brine (1 × 50 mL),
dried with MgSO4, filtered, and concentrated in vacuo to yield
2.88 g (95%) of 25.
Meth yl (Z)-2-(Ben zyloxy)-5-(ca r bom eth oxym eth yl)cin -
n a m a te (27). A solution of 25 (2.63 g, 12.06 mmol) in 20 mL
of EtOH was treated with an aqueous NaOH solution (pre-
pared from 5.0 g, 200 mmol, of NaOH and 10 mL of H2O). After
the mixture was heated under reflux for 12 h, 2.85 mL (24
mmol) of benzyl bromide was added to the reaction mixture,
and refluxing was continued for an additional 3 h. The
reaction mixture was concentrated in vacuo, and the residue
was taken up in H2O, washed with EtOAc (2 × 20 mL), and
acidified to pH 3 with concentrated HCl. The precipitated solid
(26), collected on a filter (2.42 g, 64% yield), was converted to
the diester without further purification.
A stream of dry HCl gas was bubbled into a solution of 26
(1.82 g, 5.82 mmol) in 70 mL of MeOH for 10 min, and then
the mixture was stirred at room temperature for 3 h. After
concentration under reduced pressure, the residue was dis-
solved in 70 mL of EtOAc, and the organic solution was washed
with NaHCO3, H2O, and brine, dried over anhydrous MgSO4,
and concentrated to yield 1.86 g (94%) of 27.
(s, 3 H), 3.74 (s, 2 H), 7.15-7.70 (m, 13 H). Anal. (C25H25
NO3) C, H, N.
-
5-[2-[Met h yl(2-p h en et h yl)a m in o]-2-oxoet h yl]-2-p h e-
n ylben zoic Acid (16). A solution of 15 (250 mg, 0.65 mmol)
in 10 mL of THF:H2O (4:1) and LiOH‚H2O (135.4 mg, 3.23
mmol) was stirred for 48 h. The mixture was poured into 50
mL of H2O, acidified with aqueous HCl solution, and then
extracted with EtOAc. The organic solution was dried and
removed under reduced pressure. Trituation with ether gave
144 mg (59%) of 16 as white solid: mp 123-124 °C; 1H NMR
(CDCl3) δ 2.84 (m, 2 H), 2.92 (s, 3 H), 3.02 (s, 3 H), 3.42 (s, 2
H), 3.61 (m, 2 H), 3.74 (s, 2 H), 7.13-7.81 (m, 13 H). Anal.
(C24H23NO3‚0.25H2O) C, H, N.
2-P h en yl-5-vin ylben zyl Alcoh ol (17). A solution of 12
(1.8 g, 7.55 mmol) in 15 mL of dry CH2Cl2 at -78 °C under
argon was treated with 18.9 mL of DIBAL-H (1 M, 18.8 mmol)
via syringe. The reaction mixture was stirred at -78 °C for 2
h and then slowly warmed to room temperature, and stirring
was continued for 4 h. After the reaction was quenched with
1 mL of CH3OH and 4 mL of H2O, the mixture was stirred for
30 min then poured into 50 mL of 1 N NaOH solution. The
aqueous solution was extracted with CH2Cl2 (3 × 25 mL), the
combined organic layers were dried over anhydrous NaSO4 and
filtered, and the solvent was removed under reduced pressure.
The crude 17 thus obtained was used for the next reaction
without purification.
2-P h en yl-5-vin ylben zyl ter t-Bu tyld ip h en ylsilyl Eth er
(18). A solution of 17 (1.59 g, 7.55 mmol), imidazole (1.29 g,
18.88 mmol), and tert-butyldiphenylsilyl chloride (3.11 g, 11.33
mmol) in 25 mL of DMF was stirred at room temperature for
12 h. The reaction mixture was poured into 100 mL of H2O,
and the aqueous solution was extracted with 1:1 Et2O:hexane
(3 × 60 mL). The combined organic solution were dried and
filtered, and the solvent was removed under reduced pressure.
Purification by flash chromatography (2% Et2O:hexane) gave
2.7 g (80%) of 18: 1H NMR (CDCl3) δ 1.05 (s, 9 H), 4.64 (s, 2
H), 5.27 (d, 1 H), 5.79 (d, 1 H), 6.77 (dd, 1 H), 6.72-7.67 (m,
18 H).
5-[2-[Met h yl(2-p h en et h yl)a m in o]-2-oxoet h yl]-2-p h e-
n ylben zyl ter t-Bu tyld ip h en ylsilyl Eth er (19). 18 was
converted to 19 through a sequence of reactions: (a) hydrobo-
ration, (b) J ones oxidation, and (c) amide formation similar to
the conversion of 12 to 15 described above: 1H NMR (CDCl3)
δ 1.10 (s, 9H), 2.85 (m, 2 H), 2.88 and 3.01 (s, 3 H), 3.62 (m, 2
H), 3.55 and 3.77 (s, 2 H), 4.79 (s, 2 H), 7.10-7.90 (m, 23 H).
5-[2-[Met h yl(2-p h en et h yl)a m in o]-2-oxoet h yl]-2-p h e-
n ylben zyl Alcoh ol (20). To a solution of 19 (2.0 g, 5.02
mmol) in 10 mL of THF was added 5.02 mL (1.0 M, 5.02 mmol)
of tetrabutylammonium fluoride solution, and then the mix-
ture was stirred for 12 h. The reaction mixture was poured
into 50 mL of H2O and extracted with EtOAc (3 × 25 mL).
The combined organic solutions were dried over anhydrous
MgSO4 and filtered, and the filtrate was evaporated under
reduced pressure. Purification by flash chromatography (2:1
hexane:EtOAc) gave 1.54 g (85.6%) of 20: 1H NMR (CDCl3) δ
1.07 (bs, 1 H), 2.84 (m, 2 H), 2.94 (s, 3 H), 3.01 (s, 3 H), 3.46
(s, 2 H), 3.61 (m, 2 H), 3.73 (s, 2 H), 4.57 (s, 2 H), 4.61 (s, 2 H),
7.12-7.42 (m, 8 H). Anal. (C14H25NO2‚0.25H2O) C, H, N.
5-[2-[Met h yl(2-p h en et h yl)a m in o]-2-oxoet h yl]-2-p h e-
n ylben za ld eh yd e (21). To a stirred solution of 20 (1.54 g,
4.28 mmol) in 20 mL of CH2Cl2 was added 1.86 g (21.42 mmol)
of activated MnO2, and the resulting slurry was stirred for 48
h at room temperature. The reaction mixture was filtered
through Celite, and the solvent was removed under reduced
pressure to give 1.45 g (95%) of 21, which was used without
further purification.
2-Meth yl-3-[5-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoet-
h yl]-2-p h en ylp h en yl]p r op en oic Acid (22b). To a solution
of 0.73 g (0.7 mL, 3.08 mmol) of triethyl 2-phosphonopropionate
in 20 mL of dry THF was added 0.092 g(3.08 mmol) of 80%
sodium hydride oil dispersion under argon. After the mixture
Meth yl (Z)-2-(Ben zyloxy)-5-(ca r boxym eth yl)cin n a m a -
te (28). A mixture of 27 (1.86 g, 5.49 mmol) and 230 mg (5.49
mmol) of LiOH‚H2O in 50 mL of a 1:1:1 MeOH:THF:H2O