treated with chloroform, and the insoluble portion was removed by
filtration. The filtrate was evaporated to dryness. The residue was
poured into ice water and extracted with chloroform. The organic
layer was washed with brine and dried. The solvent was evaporated
off, giving a residue which was purified by silica gel column
chromatography [chloroform–ethyl acetate (10 : 1)] to give (E)-
17c (0.28 g, 29.2%) as yellow needles (found: C, 66.16; H, 6.30; N,
6.23. C25H28N2O6 requires C, 66.36; H, 6.24; N, 6.19%); mp 176.4–
177.7 ◦C; dH (500 MHz; CDCl3; Me4Si) 2.51 (3H, s, COCH3), 2.60
and 2.0, 6-H), 8.08 (1H, d, J 2.2, 4-H); m/z (EI) 517 (M + 2,
30.34), 515 (M+, 30.23), 72 (100.00).
Compound (22a) was prepared from 20e according to the
procedure described for 22b.
(E)-7-[2-[2-(3,4-Dimethoxyphenyl)ethylcarbamoyl]-1-methylvinyl]-
2-ethoxycarbonylpropionyl-3-phenylbenzo[b]furan (27b)
General procedure for 27a, 27d, 31a, 31b. A mixture of
8c (0.43 g, 1.1 mmol), (E)-N-[2-(3,4-dimethoxyphenyl)ethyl]-
2-butenamide (0.40 g, 1.6 mmol), palladium acetate (12 mg,
0.052 mmol), tri-o-tolylphosphine (32 mg, 0.11 mmol) and
triethylamine (8.0 ml) was heated at 90–100 ◦C for 16 h. The
mixture was treated with CHCl3, and the insoluble portion was
removed by filtration. The filtrate was evaporated to dryness. The
residue was poured into water, and extracted with chloroform.
The organic layer was washed with brine and dried. The solvent
was evaporated off. The residue was purified by silica gel column
chromatography [chloroform–ethyl acetate (5 : 2)] to give a yellow
solid. This solid was recrystallized from methanol to give 27b
(0.18 g, 29.5%) as yellow needles (found: C, 71.27; H, 6.22; N,
2.48. C34H35NO7·1/4H2O requires C, 71.13; H, 6.23; N, 2.44%);
mp 145.6–147.4 ◦C; dH (500 MHz; CDCl3; Me4Si) 1.23 (3H, m,
OCH2CH3), 2.69 (2H, t, J 6.8, CH2CH2), 2.75 (3H, d, J 0.9,
=
(3H, d, J 1.4, CH CCH3), 2.81 (2H, t, J 6.8, NCH2CH2), 3.60
(2H, m, NCH2CH2), 3.86 (3H, s, OCH3), 3.87 (3H, s, OCH3),
4.01 (3H, s, OCH3), 5.55 (1H, brt, J 5.6, NHCH2CH2), 5.72 (2H,
ꢀ
=
brs, NH2), 5.74 (1H, q, J 1.4, CH CCH3), 6.73–6.75 (2H, m, 2 -,
6ꢀ-H), 6.81 (1H, d, J 8.7, 5ꢀ-H), 6.91 (1H, d, J 8.3, 6-H), 6.97 (1H,
d, J 8.3, 5-H); m/z (EI) 452 (M+, 17.77), 244 (100.00).
In a similar manner to that described above, 16a gave 17a, 17b,
16b gave 17d–17f, 18a gave 19a, 19b, 18b gave 19c, 18c gave 19d–
19f, 18d gave 19g.
2-Acetyl-3-acetylamino-4-bromo-7-methoxybenzo[b]furan (18a)
General procedure for 18b–18d, 19h, 30c. A mixture of 16a
(1.0 g, 3.5 mmol) and acetyl chloride (0.37 g, 5.3 mmol) in
tetrahydrofuran (50 ml) was heated at 60 ◦C for 8.5 h. The reaction
mixture was poured into ice water, and the resulting precipitate was
collected by filtration, then recrystallized from ethyl acetate to give
18a (0.84 g, 73.0%) as pale yellow needles (found: C, 47.86; H, 3.70;
N, 4.26. C13H12BrNO4 requires C, 47.87; H, 3.71; N, 4.29%); mp
235.3–237.4 ◦C; dH (60 MHz; CDCl3; Me4Si) 2.25 (3H, s, COCH3),
2.59 (3H, s, COCH3), 4.02 (3H, s, OCH3), 6.88 (1H, d, J 8.4, 6-H),
7.37 (1H, d, J 8.5, 5-H), 8.49 (1H, brs, NH); m/z (EI) 327 (M +
2, 20.51%), 325 (M+, 20.88), 283 (100.00).
=
CH CCH3), 2.87 (2H, t, J 7.3, NCH2CH2), 3.25 (2H, t, J 6.9,
CH2CH2), 3.62–3.66 (2H, m, NCH2CH2), 3.86 (3H, s, OCH3),
3.87 (3H, s, OCH3), 4.12 (2H, q, J 7.3, OCH2CH3), 5.92 (1H, t,
=
J 5.5, NH), 6.51 (1H, d, J 0.9, CH CCH3), 6.77–6.84 (3H, m,
2ꢀ-, 5ꢀ-, 6ꢀ-H), 7.31 (1H, t, J 7.8, 5-H), 7.44–7.60 (7H, m, 4-, 6-H,
phenyl H); m/z (EI) 569 (M+, 5.82%), 164 (100.00).
In a similar manner to that described above, 8c gave 27a, 27d,
30b gave 31b, 30c gave 31a. 27c and 27e were obtained in the usual
manner from 27b and 27d, respectively.
In a similar manner to that described above, 16a gave 18b–18d,
17a gave 19h, 30a gave 30c.
Measurement of calcium mobilization in CHO cells
Evaluation for BLT1 and BLT2 receptor inhibitory activity was
carried out according to a procedure reported previously.17,18
5-Bromo-3-[4-(diethoxyphosphoryl)-4-diethylcarbamoylbutyryl]-
2-methylbenzo[b]furan (22b)
To a suspension of NaH (60% in oil, 69 mg, 1.7 mmol) in THF
(10 ml) was added dropwise a solution of ethyl diethylphospho-
noacetamide (0.39 g, 1.6 mmol) in THF (10 ml) under a N2
atmosphere at −10 ◦C with stirring. The solution was stirred until
it became clear. A solution of 20e (0.30 ml, 0.87 mmol) in THF
(20 ml) was added dropwise to the clear solution at 27 ◦C, and the
mixture was stirred at the same temperature for 5 h. The mixture
was then quenched with saturated NH4Cl solution and extracted
with ethyl acetate. The organic layer was washed with brine and
dried. The solvent was evaporated off, giving a residue which
was purified by silica gel column chromatography [chloroform–
ethyl acetate (20 : 1)] to give (E)-22b (0.13 g, 63.8%) as pale
yellow needles (found: C, 50.96; H, 6.09; N, 2.68. C22H31BrNO6P
requires C, 51.17; H, 6.05; N, 2.71%); mp 92.7–95.6 ◦C; dH
(400 MHz; CDCl3; Me4Si) 1.13 (3H, t, J 7.2, NCH2CH3), 1.19
(3H, t, J 7.2, NCH2CH3), 1.32 (3H, t, J 6.8, OCH2CH3), 1.34
(3H, t, J 7.0, OCH2CH3), 2.32–2.51 (2H, m, COCH2CH2), 2.76
(3H, s, CH3), 2.83–2.93 (1H, m, COCH2CH2), 3.06–3.14 (1H, m,
COCH2CH2), 3.22–3.38 (2H, m, NCH2CH3), 3.45–3.55 (2H, m,
NCH2CH3, CH), 3.61–3.70 (1H, m, NCH2CH3), 4.11–4.22 (4H,
m, OCH2CH3 × 2), 7.30 (1H, d, J 8.8, 7-H), 7.39 (1H, dd, J 8.6
Acknowledgements
This work was supported in part by a grant from the Ministry
of Education, Culture, Sports, Science and Technology of Japan
for a ‘‘University–Industry Joint Research” Project (2004–2008).
The authors thank the staff of the Instrument Analysis Center
of Mukogawa Women’s University for the 1H-NMR and MS
measurements and element analyses.
References
1 C. Brink, S. Dahle´n, J. Drazen, J. F. Evans, D. W. P. Hay, S. Nicosia,
C. N. Serhan, T. Shimizu and T. Yokomizo, Pharmacol. Rev., 2003, 55,
195–227.
2 T. Yokomizo, T. Izumi, K. Chang, Y. Takuwa and T. Shimizu, Nature,
1997, 387, 620–624.
3 T. Yokomizo, K. Masuda, K. Toda, T. Izumi and T. Shimizu,
Am. J. Respir. Crit. Care Med., 2000, 161, S51–55.
4 T. Yokomizo, K. Kato, K. Terawaki, T. Izumi and T. Shimizu, J. Exp.
Med., 2000, 192, 421–431.
5 A. Toba, T. Yokomizo and T. Shimizu, Prostaglandins & Other Lipid
Mediators, 2002, 68/69, 575–585.
6 T. Yokomizo, T. Izumi and T. Shimizu, Arch. Biochem. Biophys., 2001,
385, 231–241.
306 | Org. Biomol. Chem., 2008, 6, 296–307
This journal is
The Royal Society of Chemistry 2008
©