Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3331
(d, J ) 9 Hz, 4 H), 7.08 (d, J ) 9 Hz, 4 H), 7.64 (m, 4 H), 7.78
(m, 2 H), 8.00 (m, 4 H), 8.40 (d, J ) 8 Hz, 2 H); MS (FAB+)
m/z 591 (M + H)+, (FAB-) 589 (M - H)-. Anal. Calcd for
product was extracted with EtOAc and the extracts were
concentrated in vacuo and purified by chromatography (silica
gel, 4:1 CH2Cl2-EtOAc) to afford 4,4-bis(4-(2-quinolylmeth-
oxy)phenyl)-4-hydroxy-2-butynoic acid methyl ester (63) (730
mg, 63%).
C
37H31N2O4Na‚0.25H2O: C, 74.67; H, 5.34; N, 4.71. Found: C,
74.57; H, 5.32; N, 4.52..
A mixture of 1 N NaOH (2 mL) and 63 (730 mg, 0.12 mmol)
in dioxane (25 mL) and methanol (10 mL) was stirred at
ambient temperature for 10 h. The mixture was concentrated
in vacuo, the residue was diluted with water and acidified to
pH 3 with 1 N HCl. The solids were collected by filtration,
washed with water, dried in vacuo and triturated with Et2O-
EtOAc (8:1) to provide 64 (380 mg, 56%): mp 169-172 °C; 1H
NMR (300 MHz, DMSO-d6) δ 5.35 (s, 4 H), 7.04 (d, J ) 9 Hz,
4 H), 7.37 (d, J ) 9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.00
(m, 4 H), 8.40 (d, J ) 8 Hz, 2 H), 13.75 (bs, 1 H); MS (DCI-
NH3) m/z 567 (M + H)+. Anal. Calcd for C36H26N2O4‚0.5 H2O:
C, 75.12; H, 4.73; N, 4.89. Found: C, 75.19; H, 4.80; N, 4.60.
Bis(4-(2-qu in olylm eth oxy)p h en yl)m eth a n ol (65). To a
solution of 6 (640 mg, 1.3 mmol) in THF-MeOH (1:1, 30 mL)
was added NaBH4 (190 mg, 5.2 mmol) and the mixture was
refluxed for 3 h. The mixture was concentrated in vacuo, the
residue was diluted with water and acidified with 10% citric
acid and the precipitated product was collected by filtration,
washed with water and dried in vacuo. Recrystallization from
Et2O-hexanes provided 65 (580 mg, 90%): mp 176-178 °C;
1H NMR (300 MHz, DMSO-d6) δ 5.32 (s, 4 H), 5.58 (s, 1 H),
5.67 (broad s, 1 H), 6.96 (d, J ) 9 Hz, 4 H), 7.24 (d, J ) 9 Hz,
4 H), 7.61 (m, 4 H), 7.78 (m, 2 H), 7.98 (t, J ) 9 Hz, 4 H), 8.39
(d, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z 499 (M + H)+.
Rep r esen ta tive P r oced u r es for Sch em e 4. 4,4-Bis(4-
(2-qu in olylm eth oxy)p h en yl)p en ta n ol (52). To a mixture
of 39 (1.75 g, 3 mmol) and NaBH4 (380 mg, 10 mmol) in THF
o
(50 mL) was added dropwise methanol at 50-55 C and the
mixture stirred for the next 30 min. The mixture was then
cooled to room temperature, poured into water (50 mL) and
acidified to pH 4. The resulting mixture was extracted with
EtOAc, dried with MgSO4 and concentrated in vacuo. The
residue was chromatographed (silica gel, 3:1 CH2Cl2-EtOAc)
to afford 52 (1.46 g, 88%): mp 55-58 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.18 (m, 2 H), 1.48 (s, 3 H), 2.00 (m, 2 H), 3.34
(m, 2 H), 4.34 (t, J ) 6 Hz, 1 H), 5.30 (s, 4 H), 6.96 (d, J ) 9
Hz, 4 H), 7.09 (d, J ) 9 Hz, 4 H), 7.64 (m, 4 H), 7.79 (m, 2 H),
8.00 (t, J ) 8 Hz, 4 H), 8.41 (d, J ) 8 Hz. 2 H); MS (DCI-
NH3) m/z 555 (M + H)+. Anal. Calcd for C37H34N2O3‚0.5H2O:
C, 78.84; H, 6.44; N, 4.97. Found: C, 78.67; H, 5.95; N, 4.70.
4,4-Bis(4-(2-qu in olylm eth oxy)ph en yl)-1-pen tyloxyim in o-
2-p r op ion ic Acid (56). According to the procedure for 11,
compound 52 was converted to 56 (0.26 g, 75%): mp 80-82
1
°C; H NMR (300 MHz, DMSO-d6) δ 1.42 (m, 2 H), 1.53 (s, 3
H), 1.90 (s, 3 H), 2.05 (m, 2 H), 4.11 (t, J ) 7 Hz, 2 H), 5.33 (s,
4 H), 6.95 (d, J ) 9 Hz, 4 H), 7.09 (d, J ) 9 Hz, 4 H), 7.64 (m,
4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.41 (d, J ) 8 Hz, 2 H); MS
(DCI-NH3) m/z 640 (M + H)+. Anal. Calcd for C40H37N3O5:
C, 75.10; H, 5.83; N, 6.57. Found: C, 74.86; H, 6.11; N, 6.27.
1,1-Bis(4-(2-qu in olylm eth oxy)p h en yl)eth a n ol (66). To
a solution of 6 (992 mg, 2 mmol) in THF (20 mL) at -78 oC
was added methylmagnesium bromide (3 M solution in Et2O,
0.8 mL, 2.4 mmol) and the resulting mixture was stirred at
room temperature for 12 h. The mixture was quenched with
saturated NH4Cl and extracted with ethyl acetate. The extract
was washed with water and brine, dried with MgSO4 and
concentrated in vacuo. The residue was chromatographed
(silica gel, 4:1 CH2Cl2-EtOAc) to afford 66 (920 mg, 90%): mp
3,3-Bis(4-(2-qu in olylm eth oxy)p h en yl)-2,2-d im eth yl-1-
p r op ylid en ea m in ooxya cetic Acid Sod iu m Sa lt (61‚Na ).
To a stirred THF (50 mL) solution of 35 (1.33 g, 2.28 mmol) at
room temperature was added LiAlH4 (0.09 g, 2.5 mmol) and
the mixture was stirred 3 h. Water (0.1 mL) was added
followed by the addition of 1 N NaOH (0.1 mL) and water (0.5
mL). The mixture was then concentrated to dryness and
partitioned between water and ethyl acetate. The organic layer
was washed with brine, dried over MgSO4, concentrated in
vacuo and purified by column chromatography (silica gel, 3:2
EtOAc-hexanes) to afford 50 (1.01 g, 80%).
To a solution of 50 (0.4 g, 0.72 mmol) in dry CH2Cl2 (15 mL)
was added DMSO (0.17 g, 2.17 mmol). The mixture was cooled
to -78 °C and oxalyl chloride (0.14 g, 1.08 mmol) was added.
The mixture was stirred for 0.5 h, triethylamine (0.37 g, 3.6
mmol) was added and the mixture was allowed to warm to
room temperature. The mixture was concentrated in vacuo and
triturated with dry THF. The THF solution was filtered and
the solids were washed with additional THF. The combined
THF solution was concentrated in vacuo to give crude 58 which
was immediately reacted with a mixture of carboxylmethy-
oxyamine hemi-HCl (110 mg, 1 mmol) and AcONa‚3H2O (138
mg, 1 mmol) in 1,4-dioxane (10 mL), MeOH (7 mL) and H2O
(5 mL) at room temperature for 8 h. The mixture was then
concentrated in vacuo, water (10 mL) was added and the
product was filtered, washed with water and dried in vacuo
to provide 61 (315 mg, 77%). According to the procedure for
42‚Na , compound 61 was converted to the sodium salt 61‚
Na : 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 6 H), 3.89 (s, 1
H), 4.06 (s, 2 H), 5.32 (s, 4 H), 6.97 (d, J ) 9 Hz, 4 H), 7.31 (d,
J ) 9 Hz, 4 H), 7.46 (s, 1 H), 7.65 (m, 4 H), 7.78 (m, 2 H), 8.01
(t, J ) 9 Hz, 4 H), 8.40 (d, J ) 9 Hz, 2 H); MS (FAB+) m/z 648
(M + Na)+, 626 (M + H)+.
1
129-131 °C; H NMR (300 MHz, DMSO-d6) δ 1.74 (s, 3 H),
5.32 (s, 4 H), 5.48 (s, 1 H), 6.95 (d, J ) 9 Hz, 4 H), 7.30 (d, J
) 9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.01 (m, 4 H), 8.39
(d, J ) 8 Hz, 2 H); MS (DCI-NH3) m/z 513 (M + H)+. Anal.
Calcd for C34H28N2O3: C, 79.67; H, 5.51; N, 5.46. Found: C,
79.48; H, 5.62; N, 5.25.
Bis(4-(2-qu in olylm eth oxy)ph en yl)m eth ylth ioacetic Acid
(69). To a solution of 65 (0.75 g, 1.51 mmol) in CH2Cl2-CHCl3
(1:1, 8 mL) was added ZnI2 (0.601 g, 1.91 mmol). After stirring
10 min, ethyl 2-mercaptoacetate (0.239 mL, 2.18 mmol) was
added and the mixture was stirred for 14 h at room temper-
ature. Water was added and product was extracted with
CHCl3. The organic layer was washed with water and brine,
dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by chromatography (silica gel, 2:1 hex-
anes-EtOAc) to provide the ethyl ester intermediate (650 mg,
72%).
The ester (0.609 g, 1.01 mmol) was dissolved in a mixture
of EtOH-THF (3:1, 20 mL) at room temperature and 1 N
NaOH (1.27 mL, 1.27 mmol) was added. The reaction mixture
was refluxed for 15 h, H2O (50 mL) was added, followed by
10% aqueous citric acid to pH 3, and the product was extracted
with EtOAc. The organic layer was washed with water and
brine, dried over MgSO4 and concentrated in vacuo. The
residue was triturated with hexane and the solid was collected
by filtration to provide 69 (300 mg, 52%): mp 175-180 °C; 1H
NMR (300 MHz, DMSO-d6) δ 3.02 (s, 2 H), 5.29 (s, 1 H), 5.34
(s, 4 H), 7.03 (d, J ) 9 Hz, 4 H), 7.33 (d, J ) 9 Hz, 4 H), 7.63
(m, 4 H), 7.79 (m, 2 H), 8.00 (m, 4 H), 8.41 (d, J ) 9 Hz, 1 H),
12.51 (br s, 1 H); MS (DCI-NH3) m/z 573 (M + H)+. Anal.
Rep r esen ta tive P r oced u r es for Sch em e 5. 4,4-Bis(4-
(2-qu in olylm eth oxy)p h en yl)-4-h yd r oxy-2-bu tyn oic Acid
(64). To a solution of 6 (980 mg, 2 mmol) and propiolic acid
(0.19 mL, 3 mmol) in THF (40 mL) at -78 °C was added LDA
(1.5 M solution in THF, 4 mL, 6 mmol) and the mixture was
left at room temperature for 24 h. Water was added; the
mixture was acidified to pH 5 and extracted with ethyl acetate.
The extract was dried with MgSO4 and concentrated in vacuo.
The residue was dissolved in DMF (40 mL) and treated with
methyl iodide (2 mL) and NaHCO3 (170 mg, 2 mmol) for 24 h
at room temperature. The mixture was poured into water, the
Calcd for
Found: C, 71.08; H, 5.11; N, 4.41.
C35H28N2O4S‚H2O: C, 70.95; H, 5.14; N, 4.73.
1,1-Bis(4-(2-qu in olylm eth oxy)p h en yl)-1-eth ylth ioa ce-
tic Acid (70). A mixture of 66 (300 mg, 0.6 mmol) and ethyl
2-mercaptoacetate (0.1 mL, 0.7 mmol) in CH2Cl2 (15 mL) at 0
°C was treated with BF3‚Et2O (0.24 mL, 2 mmol) and the