Arch. Pharm. Pharm. Med. Chem. 2002, 335, 547–555
SAR of 3-Dodecanoylindole-2-carboxylic Acids 553
stirred for 24 h at room temperature.The reaction mixture was
diluted with H2O, acidified with 2 N HCl, and extracted with
Et2O. The organic layer was dried (Na2SO4), filtered, and con-
centrated.The residue was purified by chromatography (petro-
leum ether/ethyl acetate, 9:1) to yield the diethyl ester of 16
(150 mg, 54 %). An aliquot of this compound (130 mg,
0.23 mmol) was saponified with KOH by a method similar to
that described for the synthesis of 7. Recrystallization from
methanol gave 16 (25 mg, 21 %) as a solid;mp 212–213 °C.1H-
NMR (DMSO-d6):δ = 0.84 (t, J = 7 Hz, 3 H, CH3), 1.20–1.34 (m,
16 H, (CH2)8), 1.63 (quint, J = 7 Hz, 2 H, CH2CH2CO), 2.90 (t,
J = 7 Hz, 2 H, CH2CO), 5.20–5.22 (m, 2 H, NCH2), 6.48–6.59
(m, 2 H, CH=CH), 7.28 (t, J = 8 Hz, 1 H, aromat. H), 7.36 (t, J =
8 Hz, 1 H, aromat.H), 7.47 (d, J = 8 Hz, 2 H, aromat.H), 7.70 (d,
J = 8 Hz, 1 H, aromat.H), 7.85 (d, J = 8 Hz, 2 H, aromat.H), 7.96
(d, J = 8 Hz, 1 H, aromat. H). Anal. (C31H37NO5) C, H, N.
4.20–4.41 (m, 6 H, 3 × CH2), 6.90 (d, J = 9 Hz, 2 H, aromat. H),
7.43 (d, J = 9 Hz, 2 H, aromat. H), 7.67 (s, 1 H, CH).
Diethyl 2-{4-[2-(2-carboxy-3-dodecanoylindol-1-yl)ethoxy]-
benzylidene}malonate (12)
To the mixture of 6 (241 mg, 0.65 mmol), powdered KOH (85 %)
(43 mg, 0.65 mmol) and 18-crown-6 ether (0.1 mmol, 26 mg)
was added dry benzene (10 mL). After removing about half of
the volume of the benzene by evaporation, the mixture was re-
fluxed for 30 min. Subsequently, the solution of 11 (290 mg,
0.78 mmol) in dry benzene (5 mL) was added and heating at re-
flux was continued for 6 h. The cooled solution was chromato-
graphed using petroleum ether/ethyl acetate (8:2) as eluent to
yield 12 (267 mg, 62 %) as oil. 1H-NMR (CDCl3): δ (ppm) = 0.88
(t, J = 7 Hz, 3 H, CH3), 1.18–1.44 (m, 25 H, (CH2)8) and 3 ×
OCH2CH3), 1.75 (quint, J = 7 Hz, 2 H, CH2CH2CO), 2.90 (t, J =
7 Hz, 2 H, CH2CO), 4.23–4.50 (m, 8 H, 4 × CH2), 4.80 (t, J = 5
Hz, 2 H, CH2), 6.79 (d, J = 2 Hz, 2 H, aromat. H), 7.27–7.63 (m,
6 H, aromat. H and CH), 7.86 (d, J = 8 Hz, 2 H, aromat. H).
1-[(6-Carboxynaphthalen-2-yl)methyl]-3-dodecanoylindole-
2-carboxylic acid (17)
The compound was prepared from 6 and methyl 6-bromometh-
ylnaphthalene-2-carboxylate [23] by a method similar to that
described for 7. It was purified by chromatography (Et2O/acetic
acid, 100:1) and precipitated from Et2O/petroleum ether (yield:
2-{4-[2-(2-Carboxy-3-dodecanoylindol-1-yl)ethoxy]benzyl}
malonic acid (13)
A mixture of 12 (257 mg, 0.39 mmol) and Pd/C (10 %) (20 mg)
in THF (15 mL) was stirred under a balloon filled with hydrogen
for 3 h at room temperature. After the addition of kieselguhr the
mixture was filtered and the filtrate evaporated. The residue
was purified by chromatography (petroleum ether/ethyl ace-
tate, 9:1).To the obtained ester intermediate was added EtOH
(18 mL) and 10 % aqueous KOH (6 mL) and the resulting mix-
ture was refluxed for 1 h, cooled, diluted with water, acidified
with dilute HCl, and extracted with Et2O. The organic phase
was washed with dilute HCl, dried over Na2SO4, and the solvent
was evaporated. The product was precipitated from THF/
petroleum ether to give 13 (20 mg, 11 %) as a solid; mp 97 °C
(decomposition). 1H-NMR (CDCl3): δ (ppm) = 0.88 (t, J = 7 Hz,
3 H, CH3), 1.20–1.41 (m, 14 H, (CH2)7), 1.47 (quint, J = 7 Hz,
2 H, CH2CH2CH2CO), 1.86 (quint, J = 7 Hz, 2 H, CH2CH2CO),
3.17 (d, J = 7 Hz, 2 H, CH2CH(COOH)2), 3.28 (t, J = 7 Hz, 2 H,
CH2CO), 3.65 (t, J = 7 Hz, 1 H, CH2CH(COOH)2), 4.43 (t, J =
5 Hz, 2 H, OCH2CH2N), 5.14 (broad, 2 H, OCH2CH2N), 6.70 (d,
J = 8 Hz, 2 H, aromat.H), 7.05 (d, J = 8 Hz, 2H, aromat.H), 7.44
(t, J = 8 Hz, 1H, aromat. H), 7.52 (t, J = 8 Hz, 1H, aromat. H),
7.82 (d, J = 8 Hz, 1H, aromat. H), 7.99 (d, J = 8 Hz, 1H, aromat.
H).
1
43 %); mp 219–220 °C. H-NMR (DMSO-d6): δ = 0.84 (t, J =
7 Hz, 3 H, CH3), 1.20–1.32 (m, 16 H, (CH2)8), 1.65 (quint, J =
7 Hz, 2 H, CH2CH2CO), 2.91 (t, J = 7 Hz, 2 H, CH2CO), 5.83 (s,
2 H, NCH2), 7.23–7.29 (m, 2 H, aromat. H), 7.36 (d, J = 9 Hz,
1 H, aromat. H), 7.60 (d, J = 9 Hz, 1 H, aromat. H), 7.70 (s, 1 H,
aromat. H), 7.87 (d, J = 9 Hz, 1 H, aromat. H), 7.91–7.98 (m,
2 H, aromat. H), 8.04 (d, J = 9 Hz, 1 H, aromat. H), 8.53 (s, 1 H,
aromat. H).
1-[2-(4-Carboxyphenyl)benzyl]-3-dodecanoylindole-2-
carboxylic acid (18)
The mixture of 6 (234 mg, 0.63 mmol), t-BuOK (71 mg,
0.63 mmol), and dry DMSO (5 mL) was heated at 110–120 °C
for 5 min. After addition of ethyl 4-(2-bromomethylphenyl)ben-
zoate [24, 25] (200 mg, 0.63 mmol) heating was continued for
an additional 15 min at the same temperature.The cooled reac-
tion mixture was diluted with brine and extracted with Et2O.The
organic layer was dried over Na2SO4 and the solvent was evap-
orated. The residue was chromatographed with petroleum
ether/ethyl acetate (9:1) to yield the diethyl ester of 18 (196 mg,
51 %). An aliquot of this compound (160 mg, 0.26 mmol) was
saponified with KOH by a method similar to that described for
the synthesis of 7.Precipitation fromTHF/petroleum ether gave
18 (102 mg, 71 %) as a solid;mp 182–183 °C.1H-NMR (DMSO-
d6):δ = 0.84 (t, J = 7 Hz, 3 H, CH3), 1.21–1.25 (m, 16 H, (CH2)8),
1.61 (quint, J = 7 Hz, 2 H, CH2CH2CO), 2.87 (t, J = 7 Hz, 2 H,
CH2CO), 5.56 (s, 2 H, NCH2), 6.46 (d, J = 8 Hz, 1 H, aromat.H),
7.20–7.36 (m, 6 H, aromat. H), 7.65 (d, J = 8 Hz, 2 H, aromat.
H), 7.93 (d, J = 8 Hz, 1 H, aromat. H), 8.07 (d, J = 8 Hz, 2 H,
aromat. H). Anal. (C35H39NO5) C, H, N.
Ethyl 1-[3-bromo-3-(4-ethoxycarbonylphenyl)propyl]-3-do-
decanoylindole-2-carboxylate (15)
The mixture of ethyl 3-dodecanoyl-1-{3-[4-(ethoxycarbonyl)-
phenyl]propyl}indole-2-carboxylate [20] (14) (950 mg,
1.69 mmol), N-bromosuccinimide (301 mg, 1.69 mmol), and
α,αЈ-azobisisobutyronitrile (20 mg) in dry CCl4 (10 mL) was re-
fluxed for 4 h. After cooling the mixture was filtered and evapo-
rated to dryness to yield 15 (1.34 g, 81 %) as waxy solid. MS
(CI): m/z (%) = 642 [M+ + 1]. 1H-NMR (CDCl3): δ = 0.88 (t, J =
7 Hz, 3 H, CH3), 1.22–1.41 (m, 16 H, (CH2)8), 1.38 (t, J = 7 Hz,
3 H, OCH2CH3), 1.39 (t, J = 7 Hz, 3 H, OCH2CH3), 1.74 (quint,
J = 7 Hz, 2 H, CH2CH2CO), 2.63–2.78 (m, 2 H, CH2CHBr), 2.89
(t, J = 7 Hz, 2 H, CH2CO), 4.38 (q, J = 7 Hz, 2 H, OCH2CH3), 4.43
(q, J = 7 Hz, 2 H, OCH2CH3), 4.44–4.65 (m, 2 H, NCH2), 4.99–
5.02 (m, 1 H, CH2CHBr), 7.26–7.45 (m, 5 H, aromat.H), 7.87 (d,
J = 8 Hz, 1 H, aromat. H), 8.01 (d, J = 8 Hz, 2 H, aromat. H).
1-[3-(4-Carboxyphenyl)benzyl]-3-dodecanoylindole-2-carb-
oxylic acid (19)
Preparation started from 6 and ethyl 4-(3-bromomethylphenyl)-
benzoate [24, 25] using a procedure similar to that described
for the synthesis of 18. Yield: 45 %; mp. 183–185 °C. 1H-NMR
(DMSO-d6):δ = 0.84 (t, J = 7 Hz, 3 H, CH3), 1.22–1.24 (m, 16 H,
(CH2)8), 1.64 (quint, J = 7 Hz, 2 H, CH2CH2CO), 2.91 (t, J = 7 Hz,
2 H, CH2CO), 5.71 (s, 2 H, NCH2), 7.09 (d, J = 8 Hz, 1 H, aromat.
H), 7.23–7.42 (m, 3 H, aromat. H), 7.56–7.66 (m, 3 H, aromat.
H), 7.71 (d, J = 8 Hz, 2 H, aromat. H), 7.95 (t, J = 8 Hz, 1 H,
aromat.H), 8.00 (d, J = 8 Hz, 2 H, aromat.H).Anal.(C35H39NO5)
C, H, N.
(E)-1-[3-(4-Carboxyphenyl)prop-2-en-1-yl]-3-dodecanoyl-
indole-2-carboxylic acid (16)
The mixture of 15 (320 mg, 0.5 mmol) and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (0.15 mL, 1 mmol) in dry THF (5 mL) was