Synthesis and Inhibitory Activity
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2703
4-(1′-Cycloh exen yl)m et h yl-3-h yd r oxy-5-m et h oxyb en -
zoic Acid (11). Compound 10 (246 mg, 1 mmol) was added to
a stirred suspension of Ag2O (350 mg, 1.5 mmol) in 5% aqueous
NaOH (8 mL, 1.0 mmol). After being stirred for 16 h, the
suspension was filtered and the solid was washed with H2O.
The filtrate was cooled to 0 °C, acidified with concentrated HCl,
and extracted with ethyl ether (3 × 25 mL). Drying (MgSO4)
and concentration afforded 245 mg (94%) of 11a as a solid:
mp 152-153 °C (ether/acetone); IR (cm-1) 3390, 2930, 1690,
(2 × 50 mL). The combined ether extracts were dried (K2CO3),
concentrated in vacuo, and chromatographed (silica/1% v/v
TEA in toluene) to provide 55 mg (93%) of the free base of 5f
as a light-yellow oil: IR (neat, cm-1) 2935, 2856, 2792, 1623,
1
1430, 1286, 1097, 1002, 917, 761; H NMR δ 1.5-1.42 (br m,
4 H), 1.78-1.66 (br m, 6 H), 2.31 (s, 3 H), 2.35 (m, 2 H), 2.45
(br m, 2 H), 2.89 (s, 2 H), 3.41 (br m, 2 H), 3.78 (br m, 1 H),
3.83 (s, 3 H), 6.43 (d, 1 H, J ) 9.5 Hz), 7.16 (d, 1 H, J ) 9.5
Hz), 7.24 (br m, 1 H); 13C NMR δ 23.15, 25.07, 37.36, 37.86,
46.13, 55.44, 90.47, 103.03, 111.89, 113.33, 125.29, 128.22,
129.03, 129.77, 156.14, 157.75, 167.36; MS (thermospray) m/z
345 (MH+).
1
1585, 1425, 1315, 1100, 775; H NMR (acetone-d6) δ 1.57 (br
m, 4 H), 1.96 (br m, 4 H), 3.31 (br s, 2 H), 3.72 (br s, exc, 1 H),
3.82 (s, 3 H), 5.26 (br s, 1 H), 7.14 (d, J ) 2 Hz, H), 7.26 (d, J
) 2 Hz, 1 H); 13C NMR (acetone-d6) δ 22.1, 22.6, 25.2, 28.0,
32.2, 56.0, 102.1, 112.3, 120.8, 1233.7, 136.0, 136.1, 156.6,
158.8, 191.9. Anal. (C15H18O4) C, H.
4-Meth oxysp ir o[ben zofu r a n -2(3H)-cycloh exa n e]-6-ca r -
boxylic Acid (5a ). Amberlyst 15 (1.0 g) was added in one
portion to a solution of 11a (70 mg, 0.27 mmol) in benzene (10
mL), and the mixture was stirred at room temperature until
no starting material was observed in TLC. The suspension was
filtered, and the filtrate was concentrated to afford 64 mg
(91%) of 5a as off-white crystals: mp 203-205 °C (ether/
acetone); IR (cm-1) 2930, 1675, 1600, 1425, 1330, 1275, 1220,
1125, 1035, 950, 780, 735; 1H NMR (acetone-d6) δ 1.63 (br m,
10 H), 2.91 (s, 2 H), 3.87 (s, 3 H), 7.00 (s, 1 H), 7.13 (s, 1 H);
13C NMR (acetone-d6) δ 23.6, 25.7, 37.8, 39.1, 55.9, 90.5, 104.8,
105.0, 119.8, 132.8, 157.3, 160.9, 167.7; HRMS, exact mass for
Hyd r och lor id e. The free base of 5j (530 mg, 1.54 mmol)
was dissolved in dry ether (10 mL) and acidified with an
ethanolic solution of HCl to pH 3.0, after which the precipitate
was filtrated, washed with ether, and dried in vacuo to afford
456 mg of 5j as a colorless solid: mp 255-256 °C (EtOH/ether).
Anal. (C20H28N2O3‚HCl) C, H, N, Cl.
4-Meth oxysp ir o[ben zofu r a n -2(3H)-cycloh exa n e]-7-h y-
d r oxa m ic Acid (5k ). The acid chloride was prepared from
5c (1.31 g, 5 mmol) in dry CHCl3 (15 mL) and SOCl2 (2 mL,
27.4 mmol) as above, and the mixture was stirred at 50-55
°C for 2.5 h. The mixture was concentrated in vacuo, and the
crude acid chloride (ca. 1.4 g) was dissolved in dry toluene (12
mL). The mixture was added dropwise to a stirred and cooled
(to 0 °C) solution prepared from NH2OH‚H2SO4 (2.0 g, 12.2
mmol) and 85% KOH (2.5 g, 38 mmol) at 0-5 °C. The reaction
mixture was stirred at room temperature for 1 h, poured onto
a mixture of ice/water (40 mL), and extracted with ether (2 ×
20 mL). Drying (MgSO4) and concentration in vacuo afforded
0.8 g of the crude product, which was purified by chromatog-
raphy to provide 210 mg (15.1%) of 5k as a light-pink solid:
mp 165-167 °C (95% EtOH); IR (cm-1) 3370, 3118, 2929, 2858,
C
15H18O4, calcd m/z 262.1205, obsd m/z 262.1205. Anal.
(C15H18O4) C, H.
4-Meth oxysp ir o[ben zofu r a n -2(3H)-cycloh exa n e]-6-ca r -
boxa ld eh yd e (12). Intermediate 10 (50 mg, 0.2 mmol) was
cyclized using the above procedure for 5a to afford 48 mg (96%)
of 12 as a solid: mp 88-89 °C (ether/hexanes); IR (cm-1) 2940,
1
1
2850, 1690, 1600, 1325, 1220, 1130, 1110, 1035, 835, 685; H
1648, 1463, 1284, 1093, 1043, 917, 765; H NMR δ 1.95-1.4
NMR δ 1.70 (br m, 10 H), 2.82 (s, 2 H), 3.88 (s, 3 H), 6.89 (s,
1 H), 6.93 (s, 1 H), 9.87 (s, 1 H); 13C NMR δ 23.0, 25.1, 37.2,
38.5, 55.6, 90.4, 102.8, 105.6, 121.3, 138.2, 156.9, 160.5, 191.8.
Anal. (C15H18O3) C, H.
(br m, 10 H), 2.91 (s, 2H), 3.85 (s, 3 H), 6.49 (d, 1 H, J ) 9.5
Hz), 7.86 (d, 1 H, J ) 9.5 Hz), 9.93 (br s, ex 1 H); 13C NMR δ
23.22, 24.88, 37.18, 37.76, 55.57, 92.90, 103.66, 106.19, 113.54,
130.50, 157.29, 159.48, 163.74; MS (thermospray) m/z 278
(MH+), Anal. (C15H19NO4) C, H, N.
4-Hyd r oxysp ir o[ben zofu r a n -2(3H)-cycloh exa n e]-6-ca r -
boxa ld eh yd e (13). Compound 12 was demethylated as de-
scribed for 9. Thus, t-BuSH (0.28 mL, 2.5 mmol) in HMPA (2
mL), 2.4 M n-BuLi (1 mL, 2.4 mmol), and 12 (201 mg, 0.82
mmol) in HMPA (5 mL) were reacted to give a crude product
that was purified by column chromatography to afford 165 mg
(87%) of 13 as fine needles: mp 115-116 °C (ether/hexanes);
IR (cm-1) 3250, 2930, 1665, 1585, 1305, 1280, 1250, 1205, 1175,
4-(1′-Cycloh exen yl)m eth yl-3,5-d im eth oxyben zyl Alco-
h ol (14). The procedure used for coupling was as described
for 9. Thus, 2.2 M n-BuLi (32 mL, 70.4 mmol) was added to a
cooled solution of 6 (5.0 g, 29.7 mmol) and TMEDA (10.5 mL,
69.7 mmol) in dry THF (300 mL) at 0 °C. After 2 h of stirring
at room temperature, the mixture was cooled to -78 °C, CuI
(7.0 g, 36.7 mmol) was added, and the suspension was warmed
to -45 °C and stirred at that temperature over a 90 min
period. The reaction mixture was recooled again to -78 °C,
and 8 (6.8 g, 38.8 mmol) was added. The mixture was stirred
at room temperature for 24 h. The mixture was worked up as
for 9, and the crude product was purified by chromatography
to give 6.0 g (77%) of 14 as white needles: mp 61-63 °C
(hexanes); IR (cm-1) 3290, 2930, 1590, 1460, 1425, 1210, 1140,
1120; 1H NMR δ 1.56 (br m, 4 H), 1.93 (br m, 4 H), 2.62 (br s,
1 H, exc), 3.26 (br s, 2 H), 3.79 (s, 6 H), 4.59 (s, 2 H), 5.20 (br
s, 1 H), 6.54 (s, 2 H); 13C NMR δ 22.5, 23.1, 25.3, 28.8, 30.6,
55.8, 65.7, 102.5, 116.6, 119.9, 136.3, 139.8, 158.5. Anal.
(C16H22O3) C, H.
1
840, 805, 740; H NMR δ 1.3-1.9 (br m, 10 H), 2.97 (s, 2 H),
6.85 (s, 1 H), 6.90 (s, 1 H), 9.80 (s, 1 H); 13C NMR δ 23.0, 25.0,
37.2, 38.1, 90.4, 104.3, 108.6, 120.3, 138.0, 153.2, 161.2, 192.2;
HRMS, exact mass for C14H16O3, calcd m/z 232.1099, obsd m/z
232.1010.
4-Hyd r oxysp ir o[ben zofu r a n -2(3H)-cycloh exa n e]-6-ca r -
boxylic Acid (5b). Compound 13 was oxidized as described
for 10. Thus, 13 (48 mg, 0.21 mmol) was oxidized in a
suspension of Ag2O (120 mg, 0.52 mmol) in 5% aqueous NaOH
to afford 49 mg (96%) of 5b as a light-brown powder: mp 223-
225 °C (acetone/ether); IR (cm-1) 3300, 2940, 1720, 1610, 1435,
1
1225, 1200, 1060, 965; H NMR (acetone-d6) δ 1.75 (br m, 10
H), 2.94 (s, 2 H), 3.73 (br s, exc, 1 H), 6.87 (s, 1 H), 7.08 (s, 1
H); 13C NMR (acetone-d6) δ 23.6, 25.7, 37.8, 39.0, 90.1, 103.0,
109.9, 118.6, 132.4, 154.9, 161.3, 167.9; HRMS, exact mass for
6-(1′-Cycloh exen yl)m eth yl-5,7-dim eth oxy-1(3H)-isoben -
zofu r a n on e (15). A solution of 2.0 M n-BuLi in hexanes (4.2
mL, 8.4 mmol) was added to a stirred solution of 14 (1.0 g,
3.82 mmol) and TMEDA (0.69 mL, 4.58 mmol) in hexanes (50
mL) at 0 °C under a nitrogen stream. The reaction mixture
was warmed slowly to room temperature, stirred for an
additional 1.5 h, and recooled to -78 °C, after which dry carbon
dioxide was bubbled for 1 h at -78 °C and over 1 h at room
temperature. A solution of 2 N NaOH (25 mL) was added, the
unreacted material was extracted with ether (50 mL), the
aqueous phase was acidified with 6 N HCl, and the reaction
product was extracted with ether (4 × 50 mL). Drying (MgSO4)
and concentration of the organic phase afforded 727 mg (66%)
C
14H16O4, calcd m/z 248.1049, obsd m/z 248.1050. Anal.
(C14H16O4) C, H.
4-Meth oxy-7-(N-m eth yl-N′-p ip er a zin yl)ca r boxysp ir o-
[ben zofu r a n -2(3H)-cycloh exa n e] Hyd r och lor id e (5j). To
a solution of 5c (450 mg, 1.72 mmol) in dry CHCl3 (7 mL),
SOCl2 (1 mL, 13.7 mmol) was added, and the reaction mixture
was stirred at 50-55 °C for 2.5 h. The mixture was concen-
trated in vacuo, the crude acid chloride (ca. 480 mg) was
dissolved in dry toluene (10 mL) and stirred at room temper-
ature, and N-methylpiperazine (1 mL, 9 mmol) was added in
one portion. The reaction mixture was stirred for an additional
1.5 h and concentrated in vacuo, and the residue was shaken
with 25% aqueous K2CO3 (15 mL) and extracted with ether
of 15 as a solid: mp 103-104 °C (hexanes/ether); IR (cm-1
)
3000-2820, 1740, 1600, 1460, 1420, 1340, 1240, 1200, 1090,
1
1015 and 940; H NMR δ 1.48-2.00 (m, 8 H), 3.30 (s, 2 H),