H. Engelhardt et al. / European Journal of Medicinal Chemistry 54 (2012) 660e668
667
carboxylic acid ethyl ester. The ester was dissolved in 17 ml ethanol
and 5 ml water. To this solution lithium hydroxide (120 mg,
5.00 mmol) was added. After 16 h the pH value of the reaction
mixture was adjusted to pH 4 and the solvent is evaporated in
vacuum. The crude product was purified using an acid ion exchanger
(Strata-X-C, Phenomenex), yielding of 155 mg (82%) of the title
compound. Purity by method A1: >95%; MS (ESI) m/z 163 (M þ H)þ;
dissolved in 20 ml methanol and 10 mg rany nickel was added. The
reactor was charged with hydrogen gas and the reaction mixture
was stirred for 2 h. The pressure in the reactor was always around
5 bar. Afterwards the catalyst was filtered of and washed three
times with methanol. The solvent was evaporated under reduced
pressure and the crude product was purified using method P2,
yielding 68 mg (96%) of the title compound. Purity by method A1:
>95%; MS (ESI) m/z 293/295 (M þ H)þ, Cl distribution; 1H NMR
1H NMR (DMSO)
d
(ppm) 13.34 (br, 1H), 8.77 (d, J ¼ 5.3 Hz, 1H), 8.53
(d, J ¼ 8.3 Hz, 1H), 7.73 (dd, J ¼ 5.4 Hz, J ¼ 8.3 Hz, 1H), 7.33 (br, 1H);
13C NMR (500 MHz, DMSO)
(ppm) 161.4 (s), 138.0 (s), 136.1 (s),
(500 MHz, DMSO)
d
(ppm) 11.40 (br, 1H), 6.83 (d, J ¼ 1.7 Hz, 1H),
d
6.68 (d, J ¼ 1.9 Hz, 1H), 6.37 (d, J ¼ 1.7 Hz, 1H), 5.66 (br, 2H), 3.75 (br,
135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s).
4H), 2.34 (t, J ¼ 5.1 Hz, 4H), 2.19 (s, 3H); 13C NMR (500 MHz, DMSO)
d
(ppm) 162.4, 135.6, 130.2, 126.5, 123.4, 121.5, 120.0, 118.7, 104.0,
4.2.2.2. Acids 5g and 5h. Pyrrolopyridine carboxylic acid 5g and
Indole carboxylic acid 5h are synthesized in a similar manner to 5f.
45.8, 17.1.
4.2.5.2. Further anilines. Anilines 22, 29, 35 and 41 are synthesized
in a similar manner to 51 e analytic data are given in the
supplementary.
4.2.3. General method C e amide coupling
4.2.3.1. (5-Chloro-7-fluoro-1H-indole-2-yl)-(4-methyl-piperazine-1-
yl)-methanone (49). (5-Chloro-7-fluoro-1H-indole-2-yl)-carbox-
ylic acid (5a) (50 mg, 0.23 mmol), N,N-diisopropylethylamine
4.2.6. 5-Chloro-7-nitro-1H-indole-2-carboxylic acid (5c)
(82
tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol)
were dissolved in 550 l N,N-dimethylformamide. After stirring for
10 min 4-methyl-piperazin 6a (26 l, 0.23 mmol) was added and
m
l, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-
(4-Chloro-2-nitro-phenyl)hydrazine 4c (3.55 g, 18.94 mmol),
ethyl pyruvate 8 (2.10 ml, 18.94 mmol) and toluene-4-sulfonic acid
monohydrate (84 mg, 0.44 mmol) were dissolved in 230 ml toluene
and stirred for 1 h under reflux conditions and the resulting water
was seperated through a water separator. The reaction mixture was
cooled down to 20 ꢁC and diluted with 300 ml ethyl acetate and
treated with 100 ml of a half saturated aqueous sodium hydro-
gencarbonat solution. The organic layer was dried with sodium
sulfate, the solvent was evaporated under reduced pressure,
yielding 5.25 g (18.42 mmol) of 2-[(4-chloro-2-nitro-phenyl)-
hydrazono]-propionic acid ethyl ester. The hydrazone (1.00 g,
3.50 mmol) was suspended in 10 g of polyphosphor acid at 100 ꢁC.
The reaction vessel with the suspension was put in pre heated oil
bath at 195 ꢁC for 5 min. The reaction mixture was cooled down to
50 ꢁC and poured on 200 ml water and than treaded with sodium
carbonate until pH 8 was reached. The mixture was 6 times
extracted with 100 ml dichloromethane. The organic layer was
dried with sodium sulfate, the solvent was evaporated under
reduced pressure and the crude product was purified using chro-
matography method P2, yielding 390 mg (1.46 mmol) of 5-Chloro-
7-nitro-1H-indole-2-carboxylic acid ethyl ester. The ester was dis-
solved in 10 ml ethanol and 10 ml water. To this solution lithium
hydroxide (240 mg, 10.00 mmol) was added. After 16 h the pH
value of the reaction mixture was adjusted to pH 4 and ethyl acetate
was added. The organic layer was separated and dried with sodium
sulfate. The solvent was evaporated under reduced pressure,
yielding of 330 mg (95%) of the title compound. Purity by method
m
m
the reaction mixture was stirred for 16 h at 20 ꢁC. The solvent was
evaporated under reduced pressure and the crude product was
purified using chromatography method P1, yielding 37 mg (53%) of
the title compound. Purity by method A1: >95%; MS (ESI) m/z 296/
298 (M þ H)þ, Cl distribution; 1H NMR (500 MHz, DMSO)
d (ppm)
12.32 (br, 1H), 7.55 (d, J ¼ 1.9 Hz, 1H), 7.19 (dd, J ¼ 1.9 Hz,
JHF ¼ 11.02 Hz, 1H), 6.82 (d, J ¼ 3.1 Hz, 1H), 3.68 (t, J ¼ 4.7 Hz, 4H),
2.34 (t, J ¼ 4.7 Hz, 4H), 2.21 (s, 3H); 13C NMR (500 MHz, DMSO)
d
(ppm) 161.2 (s), 148.7 (d, JCF ¼ 249.1 Hz), 133.1 (s), 130.7 (d,
JCF ¼ 6.4 Hz), 123.3 (d, JCF ¼ 8.5 Hz), 122.7 (d, JCF ¼ 13.1 Hz), 116.6 (d,
JCF ¼ 3.6 Hz), 108.5 (d, JCF ¼ 20.2 Hz), 103.8 (s), 54.6 (s), 46.6 (s).
4.2.3.2. Further amides. Amides 1, 2a, 10e19, 21, 23, 26, 28, 30e32,
34, 36, 38, 39, 40, 42, 43a, 44a, 45a, 46e48, 50, 77, 52a, 53a, 54a,
55e63, 64a, 65a, 66a, 67, 68a, 69e71, 72a, 73a, 74a, 75, 76 and 77
are synthesized in a similar manner to 49 e analytic data are given
in the supplementary.
4.2.4. General method D e deprotection of boc group
4.2.4.1. (7-Methyl-1H-indole-2-yl)-piperazine-1-yl-methanone
(43). 4-(7-Methyl-1H-indole-2-carbonyl)-piperazine-1-carboxylic
acid tert-butyl ester (43a) (106 mg; 0.31 mmol) was dissolved in
2 ml dioxane and treated with a solution of HCl in dioxane (2 ml;
8 mmol). After the reaction mixture was stirred for 3 h at 20 ꢁC, the
solvent was evaporated in vacuum and the crude product was
purified using method P2, yielding 39 mg (52%) of the title
compound. Purity by method A1: >95%; MS (ESI) m/z 244
A1: >95%; MS (ESI) m/z 163 (M þ H)þ; 1H NMR (DMSO)
d (ppm)
13.34 (br, 1H), 8.77 (d, J ¼ 5.3 Hz, 1H), 8.53 (d, J ¼ 8.3 Hz, 1H), 7.73
(dd, J ¼ 5.4 Hz, J ¼ 8.3 Hz, 1H), 7.33 (br, 1H); 13C NMR (500 MHz,
DMSO) d (ppm) 161.8 (s),134.0 (s), 133.5 (s), 132.1 (s), 129.6 (s),127.8
(M þ H)þ; 1H NMR (500 MHz, DMSO)
d
(ppm) 11.39 (br, 1H), 7.42
(s), 123.7 (s), 120.8 (s), 107.9 (s).
(dd, J ¼ 1.9 Hz, J ¼ 6.7 Hz, 1H), 6.99e6.95 (m, 2H), 6.71 (d, J ¼ 1.9 Hz,
1H), 3.68 (t, J ¼ 4.8 Hz, 4H), 2.78 (t, J ¼ 4.8 Hz, 4H), 2.49 (s, 3H); 13C
4.2.7. General method F e ether cleavage
NMR (500 MHz, DMSO)
d
(ppm) 162.4, 135.6, 130.2, 126.5, 123.4,
4.2.7.1. (4-Hydroxy-1H-indole-2-yl)-(4-methyl-piperazine-1-yl)-met
hanone (20). (4-Methoxy-1H-indole-2-yl)-(4-methyl-piperazine-
1-yl)-methanone (19) (50 mg, 0.18 mmol) was dissolved in 1.5 ml
dichloromethane and treated with a boron-tribromide solution
(0.65 ml, 0.65 mmol). The resulting yellow suspension was stirred
for 4 h. Afterwards the solvent was evaporated under reduced
pressure and the crude product was purified using method P3,
yielding 11 mg (23%) of the title compound. Purity by method A1:
>95%; MS (ESI) m/z 260 (M þ H)þ; 1H NMR (500 MHz, DMSO)
121.5, 120.0, 118.7, 104.0, 45.8, 17.1.
4.2.4.2. Further secondary amines. Free secondary amines 2, 43, 44,
45, 52, 53, 54, 64, 65, 66, 68, 72, 73 and 74 are synthesized in
a
similar manner to 43
e analytic data are given in the
supplementary.
4.2.5. General method E e reduction of a nitro group
4.2.5.1. 1(7-Amino-5-Chloro-1H-indole-2-yl)-(4-methyl-piperazine-
d
(ppm) 11.44 (br, 1H), 9.58 (s, 1H), 7.01 (dd, J ¼ 7.9 Hz, J ¼ 8.3 Hz,
1-yl)-methanone
(51). (5-Chloro-7-nitro-1H-indole-2-yl)-(4-
1H), 6.90 (d, J ¼ 8.3 Hz, 1H), 6.86 (d, J ¼ 1.7 Hz, 1H), 6.41 (d,
methyl-piperazine-1-yl)methanone (75) (78 mg; 0.24 mmol) was
J ¼ 7.8 Hz, 1H), 3.79 (br, 4H), 2.39 (t, J ¼ 4.9 Hz, 4H), 2.24 (s, 3H); 13C