B. Biasotti et al. / Bioorg. Med. Chem. 11 (2003) 2247–2254
2253
100%) of 20, mp 152–154 ꢁC, NMR (DMSO-d6) d 1.33
(t, J=6.9 Hz, Me), 4.01 (q, J=6.9 Hz, CH2), 5.79 (br s,
2H exch. with D2O), 6.12 (dd, J=8.5, 2.2 Hz, ArH),
6.20 (d, J=2.2 Hz, ArH), 7.48 (d, J=8.5 Hz, ArH),
11.98 (br s, 1H exch. with D2O). ). Anal. calcd for
C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.48;
H, 6.05; N, 7.65.
filtered, washed with water and dried under vacuum at
50 ꢁC to give 16.5 g of the title compound as a light
brown powder (yield 82.6%), mp >250 ꢁC, NMR
(DMSO-d6) d 1.45 (t, J=6.9 Hz, Me), 4.43 (q, J=6.9
Hz, CH2), 7.55 (dd, J=8.2, 0.3 Hz, ArH), 7.79 (d,
J=0.3 Hz, ArH), 7.91 (s, ArH benzimidazole), 8.36 (d,
J=8.2 Hz, ArH), 11.62 (s, 1H). Anal. calcd for
C16H11Cl2N3O: C, 57.85; H, 3.34, N, 12.65. Found: C,
57.87; H, 3.26; N, 12.58.
2-Ethoxy-4-cyanobenzoic acid (21). CuCN (12 g, 134
mmol) was suspended in 100 mL of distilled water.
NaCN (18.3 g, 373 mmol) was added with vigorous
stirring and the internal temperature was kept below
40 ꢁC until all the CuCN went into solution. A suspen-
sion of 2-ethoxy-4-aminobenzoic acid (20 g, 110 mmol),
in water (200 mL) and concentrated HCl (33 mL) was
stirred and cooled in an ice bath. When the temperature
reached 5 ꢁC, a solution of NaNO2 (9.7 g, 140 mmol) in
water (30 mL) was added dropwise at such a rate as to
maintain the temperature below 5 ꢁC. When all the
NaNO2 was added, the solution was slowly introduced
through an ice-cooled dropping funnel into the reactor
containing the NaCN/CuCN solution. A reaction took
place with the vigorous formation of N2. A few drops of
1-octanol were added to keep the foaming under con-
trol. Stirring was continued for 4 h. The resulting sus-
pension was then extracted with ethyl acetate (3ꢃ100
mL) and the organic phase dried over MgSO4 and eva-
porated under vacuum obtaining 15 g of the title com-
pound (yield 71.1%) as a light brown powder, mp 170–
172 ꢁC. NMR (DMSO-d6) d 1.60 (t, J=6.9 Hz, Me), 4.37
(q, J=6.9 Hz, CH2), 7.30 (d, J=0.9 Hz, ArH), 7.41 (dd,
J=8.2, 0.9 Hz, ArH), 8.27 (d, J=8.2 Hz, ArH), 10.42 (s
br, 1H exch. with D2O). ). Anal. calcd for C10H9NO3: C,
62.82; H, 4.74, N, 7.33. Found: C, 62.93; H, 4.82; N, 7.22.
5,6-Dichloro-2-(4-carboxy-2-ethoxyphenyl)benzimidazole
hydrochloride (24). A mixture of 5,6-dichloro-2-(4-
cyano-2-ethoxyphenyl)benzimidazole
hydrochloride
(16.3 g, 44.2 mmol) and 32% NaOH (40 mL) in ethanol
(100 mL) was refluxed for 8 h. After cooling to room
temperature the organic solvent was removed under
vacuum and the aqueous phase was acidified with
37% HCl, and stirred for 1 h. The solid was filtered,
washed with water (100 mL) and dried at 50 ꢁC
under vacuum to give 12 g as a light brown powder
(yield 70%), mp >250 ꢁC, NMR (DMSO-d6) d 8.70
(s br, 3H, exch. with D2O); 1.45 (t, J=6.9 Hz, Me),
4.44 (q, J=6.9 Hz, CH2), 7.69 (dd, J=8.2, 0.2 Hz,
ArH), 7.71 (d, J=0.2 Hz, ArH), 8.02 (s, ArH benzi-
midazole), 8.29 (d, J=8.2 Hz, ArH). Anal. calcd for
C16H13Cl3N2O3: C, 49.57; H, 3.38; N, 7.23. Found:
C, 49.77; H, 3.20; N, 7.38.
4-(5,6-Dichlorobenzimidazol-2-yl)-N-(2,2,6,6-tetrame-
thylpiperidin-4-yl)-3-ethoxybenzamide (25). A mixture of
5,6-dichloro-2-(4-carboxy-2-ethoxyphenyl)benzimidazole
hydrochloride (1 g, 2.58 mmol) and of thionyl chloride
(8 mL) in dichloromethane (20 mL) was refluxed for 3 h.
After cooling to room temperature the solvent was
removed under vacuum and the crude residue was used
in the following reaction without further purification.
The acid chloride was added portionwise to a solution
of 4-amino-2,2,6,6-tetramethylpiperidine (0.612 g, 3.87
mmol), triethylamine (5 mL, 36 mmol) in dichloro-
methane (50 mL). Stirring was continued at room tem-
perature for 2 h. The solvent was removed under
vacuum and the residue was suspended in water (50 mL)
and filtered. The solid was dried at 50 ꢁC under vacuum
and then crystallised with ethanol to give 0.6 g of the
title compꢁound as a light brown powder (yield 47.5%),
2-Ethoxy-4-cyanobenzoyl chloride (22). 2-Ethoxy-4-cya-
nobenzoic acid (10 g, 52.3 mmol) and thionyl chloride
(50 mL) were refluxed in CH2Cl2 (80 mL) for 5 h. Sol-
vent was removed under vacuum to leave 10.9 g of an
off white solid (52 mmol, yield 99%) that was used
without further purification.
5,6-Dichloro-2-(4-cyano-2-ethoxyphenyl)benzimidazole
hydrochloride (23). A solution of 2-ethoxy-4-cyano-
benzoyl chloride (10.9 g, 52 mmol) in dichloromethane
(109 mL) was added dropwise in 5 h to a solution of 4,5-
dichlorophenylenediamine (18.5 g, 104.5 mmol) and
triethylamine (53 g=72.6 mL, 523 mmol) in dichloro-
methane (550 mL). Stirring was continued for addi-
tional 2 h. The solvent was removed under vacuum and
the residue was triturated with water (100 mL), filtered
and dried at 50ꢁC under vacuum. The solid was sus-
pended in diethyl ether (200 mL), stirred for 1 h, filtered
and dried under vacuum to give 19 g of N-(2-amino-4,5-
dichlorophenyl)-2-ethoxy-4-cyanobenzamide (yield 51%),
mp 195–198 ꢁC. A suspension of N-(2-amino-4,5-
dichlorophenyl)-2-ethoxy-4-cyanobenzamide (19 g, 54.2
mmol) and P2O5 (19 g, 134 mmol) in xylene (380 mL)
was refluxed for 24 h. Additional P2O5 (9.5 g, 67 mmol)
was added and the mixture was refluxed for 48 h. Sol-
vent was removed under reduced pressure. The residue
was treated with 30% NaOH (80 mL) and water (100
mL) and then acidified with 37% HCl. The solid was
1
mp >280 C, H NMR (DMSO-d6) d 1.05 (s, 6H), 1.20
(dd, 2H), 1.05 (s, 6H), 1.20 (s, 6H), 1.50 (t, 3H), 1.73 (d,
2H), 4.35–4.22 (m, 1H), 4.40 (q, 2H), 7.59 (d, 1H), 7.64
(s, 1H), 7.90 (s, 2H), 8.30 (m, 2H), 12.20 (s br, 1H), m/z
488 (MH+); 473; 124. Anal. calcd for C25H30Cl2N4O2:
C, 61.35; H, 6.18; N, 11.45. Found: C, 61.22; H, 6.27; N,
11.58.
N-4-Phenylmethylpiperidinamide of 3-ethoxy-4-(5,6-di-
chlorobenzimidazol-2-yl)benzoic acid (26). Prepared fol-
lowing the general procedure described above, for
example, for 25. Obtained in 63% yield after tri-
turation with abs. EtOH. Mp 295 ꢁC, NMR d 1.48
(t, CH3), 1.54–1.69 (CH2), 1.80 (CH2), 2.03 (CH2),
2.84 (CH2), 3.48 (s, ArylCH2N), 3.87–3.82 (m,
CHNH), 4.28 (q, 2H, OCH2), 6.12 (d, NHCO),
7.2–8.0 (11H arom), 8.12 (s, 1H), 8.59 (d, 1H,
J=8), 11.63 (1H, NH). m/z 522 (MH+). Anal.