1428
Vol. 49, No. 11
was stirred under atmospheric pressure of hydrogen at room temperature for vacuo. After addition of H2O to the residue, resulting precipitates were col-
1 h. The catalyst was removed by filtration on Celite, and the filtrate was lected and washed with H2O to give 28 (1.91 g, 5.40 mmol, quant.) as a col-
concentrated to give 18 (1.51 g, 6.11 mmol, quant.) as a yellow powder,
orless powder, which was used for the next reaction without further purifica-
1
which was used for the next reaction without further purification. H-NMR tion. 1H-NMR (DMSO-d6) d: 3.03 (2H, t, Jϭ8.4 Hz), 3.53 (2H, s), 4.07 (2H,
(CDCl3) d: 1.30 (3H, t, Jϭ7.1 Hz), 3.08 (2H, t, Jϭ8.2 Hz), 3.52 (2H, s), t, Jϭ8.4 Hz), 4.27 (2H, d, Jϭ5.7 Hz), 6.47 (1H, t, Jϭ6.0 Hz), 7.05 (1H, d.
3.66 (2H, br), 4.06 (2H, t, Jϭ8.2 Hz), 4.24 (2H, q, Jϭ7.1 Hz), 6.37 (1H, dd, Jϭ8.1 Hz), 7.22—7.35 (6H, m), 8.01 (1H, s), 8.59 (1H, s), 12.76 (1H, br).
Jϭ8.2, 2.1 Hz), 6.94 (1H, d, Jϭ8.2 Hz), 7.67 (1H, d, Jϭ2.1 Hz). FAB-MS FAB-MS m/z: 354 [(MϩϩH)ϩ].
m/z: 249 [(MϩϩH)ϩ].
Compounds 29—32 were prepared in a manner similar to that described
Compounds 19—22 were prepared in a manner similar to that described for 28 from compound 24—27, and these compounds were used for the next
for 18 from compounds 14—17, and these compounds were used for the reaction without further purification.
next reaction without further purification.
3-[7-(3-Benzylureido)-1,2,3,4-tetrahydroquinolin-1-yl]-3-oxopropanoic
Ethyl 3-(7-Amino-1,2,3,4-tetrahydroquinolin-1-yl)-3-oxopropanoate (19):
Acid (29): Colorless powder. Yield: 68%. 1H-NMR (DMSO-d6) d: 1.86 (2H,
1
Pale yellow oil. Yield: quant. H-NMR (CDCl3) d: 1.26 (3H, t, Jϭ7.1 Hz), quint., Jϭ6.3 Hz), 2.62 (2H, t, Jϭ6.3 Hz), 3.57 (2H, br), 3.65 (2H, t,
1.94 (2H, quint, Jϭ6.6 Hz), 2.62 (2H, t, Jϭ6.6 Hz), 3.62 (2H, s), 3.78 (2H,
Jϭ6.3 Hz), 4.29 (2H, d, Jϭ5.8 Hz), 6.56 (1H, br), 7.03 (1H, d. Jϭ8.3 Hz),
br t, Jϭ6.6 Hz), 4.16 (2H, q, Jϭ7.1 Hz), 6.49 (1H, dd, Jϭ8.2, 2.4 Hz), 6.52 7.17—7.48 (7H, m), 8.51 (1H, s), 12.55 (1H, s). FAB-MS m/z: 368
(1H, br), 6.93 (1H, d, Jϭ8.2 Hz). FAB-MS m/z: 263 [(MϩϩH)ϩ].
[(MϩϩH)ϩ].
Ethyl 3-(8-Nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)-3-oxopropanoate
3-[8-(3-Benzylureido)-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl]-3-oxo-
1
(20): Ivory powder. Yield: quant. 1H-NMR (CDCl3) d: 1.23 (3H, t, propanoic Acid (30): Colorless powder. Yield: 83%. H-NMR (DMSO-d6)
Jϭ7.2 Hz), 1.28—1.34 (1H, m), 1.74—2.00 (3H, m), 2.53—2.78 (3H, m), d: 1.24 (1H, br), 1.72 (2H, br), 1.84—1.92 (1H, m), 2.53—2.78 (3H, m),
3.26 (2H, Abq, Jϭ15.3 Hz), 3.68 (2H, br), 4.13 (2H, q, Jϭ7.2 Hz), 4.63— 3.11 (2H, s), 4.29 (2H, br), 4.47 (1H, br d, Jϭ13.2 Hz), 6.67 (1H, t,
4.70 (1H, m), 6.51—6.57 (3H, m), 7.00 (1H, d, Jϭ8.1 Hz). FAB-MS m/z: Jϭ6.0 Hz), 7.14 (1H, d, Jϭ8.4 Hz), 7.22—7.34 (7H, m), 8.62 (1H, s), 12.44
277 [(MϩϩH)ϩ].
(1H, s). FAB-MS m/z: 382 [(MϩϩH)ϩ].
Ethyl 3-(6-Aminoindolin-1-yl)-2-methyl-3-oxopropanoate (21): Colorless
(R,S)-3-[6-(3-Benzylureido)indolin-1-yl]-2-methyl-3-oxopropanoic Acid
1
powder. Yield: 75%. H-NMR (DMSO-d6) d: 1.17 (3H, t, Jϭ6.8 Hz), 1.30 (31): Ivory powder. Yield: 93%. 1H-NMR (DMSO-d6) d: 1.28 (3H, d,
(3H, d, Jϭ6.9 Hz), 2.96 (2H, t, Jϭ8.3 Hz), 3.86 (1H, q, Jϭ6.9 Hz), 4.10— Jϭ7.3 Hz), 3.06 (2H, t, Jϭ8.3 Hz), 3.78—3.81 (1H, m), 3.82—4.12 (1H,
4.17 (4H, m), 4.97 (2H, br), 6.24 (1H, dd, Jϭ7.8, 2.1 Hz), 6.86 (1H, d,
Jϭ7.8 Hz), 7.44 (1H, d, Jϭ2.1 Hz). FAB-MS m/z: 263 [(MϩϩH)ϩ].
m), 4.14—4.22 (1H, m), 4.28 (2H, d, Jϭ5.9 Hz), 6.49 (1H, t, Jϭ5.9 Hz),
7.07 (1H, d, Jϭ7.8 Hz), 7.22—7.35 (6H, m), 8.09 (1H, d, Jϭ1.9 Hz), 8.55
Ethyl 3-(6-Aminoindolin-1-yl)-2,2-dimethyl-3-oxopropanoate (22): Col- (1H, s), 12.71 (1H, br). FAB-MS m/z: 368 [(MϩϩH)ϩ].
orless powder. Yield: 95%. 1H-NMR (DMSO-d6) d: 1.18 (3H, t, Jϭ6.9 Hz),
3-[6-(3-Benzylureido)indolin-1-yl]-2,2-dimethyl-3-oxopropanoic
Acid
1.40 (6H, s), 2.89 (2H, t, Jϭ7.8 Hz), 3.74 (2H, t, Jϭ7.8 Hz), 4.17 (2H, q, (32): Pale yellow powder. Yield: 99%. 1H-NMR (DMSO-d6) d: 1.39 (6H, s),
Jϭ6.9 Hz), 4.96 (2H, br), 6.24 (1H, dd, Jϭ7.8, 2.0 Hz), 6.85 (1H, d, 3.01 (2H, t, Jϭ8.3 Hz), 3.91 (2H, t, Jϭ8.3 Hz), 4.29 (2H, d, Jϭ5.9 Hz), 6.48
Jϭ7.8 Hz), 7.46 (1H, d, Jϭ2.0 Hz). FAB-MS m/z: 277 [(MϩϩH)ϩ].
Ethyl 3-[6-(3-Benzylureido)indolin-1-yl]-3-oxopropanoate (23) To the
solution of 18 (1.51 g, 6.11 mmol) in acetonitrile (30 ml) was added benzyl
(1H, t, Jϭ5.9 Hz), 7.07 (1H, d, Jϭ7.8 Hz), 7.20—7.35 (6H, m), 8.13 (1H, d,
Jϭ1.9 Hz), 8.54 (1H, s), 13.03 (1H, br). FAB-MS m/z: 380 [(MϩϪH)ϩ].
Method A. (R,S)-Ethyl 3-{3-[6-(3-Benzylureido)indolin-1-yl]-3-oxo-
isocyanate (900 mg, 6.76 mmol) at room temperature. The reaction mixture propanoylamino}-3-(pyridin-3-yl)propanoate (38a) A mixture of 28
was stirred at room temperature for 12 h, then the solvent was removed in (1.30 g, 3.70 mmol), CDI (0.72 g, 4.40 mmol), and DMF (20 ml) was stirred
vacuo and the residue was washed with 2-propanol and diethylether to give at 0 °C for 1 h. To the mixture was added a solution of 5 (1.20 g, 4.40 mmol)
23 (2.15 g, 5.64 mmol, 92%) as a colorless solid, which was used for the
next reaction without further purification. 1H-NMR (DMSO-d6) d: 1.21 (3H, ture for 4 h. The reaction mixture was then diluted with H2O (100 ml), and
t, Jϭ7.2 Hz), 3.04 (2H, t, Jϭ8.1 Hz), 3.65 (2H, s), 4.03—4.18 (4H, m), 4.28 resulting precipitates were collected and washed with H2O to give 38a
(2H, d, Jϭ5.7 Hz), 6.45 (1H, t, Jϭ5.7 Hz), 7.07 (1H, d. Jϭ8.1 Hz), 7.20— (1.40 g, 2.64 mmol, 71%) as an ivory solid, which was used for the next re-
7.36 (6H, m), 8.03 (1H, s), 8.57 (1H, s). FAB-MS m/z: 382 [(MϩϩH)ϩ].
in DMF (10 ml) and Et3N (1.11 g, 11 .0 mmol) and stirred at room tempera-
action without further purification. 1H-NMR (DMSO-d6) d: 1.11 (3H, t,
Compounds 24—27 were prepared in a manner similar to that described Jϭ7.1 Hz), 2.87 (2H, d, Jϭ7.9 Hz), 3.01 (2H, br t, Jϭ8.3 Hz), 3.43 (2H, s),
for 23 from compounds 19—22, and these compounds were used for the 3.98—4.11 (4H, m), 4.27 (2H, d, Jϭ5.9 Hz), 5.23—5.29 (1H, m), 6.43 (1H,
next reaction without further purification.
br t, Jϭ5.9 Hz), 7.06 (1H, d, Jϭ8.3 Hz), 7.21—7.39 (7H, m), 7.78 (1H, br d,
Jϭ8.3 Hz), 7.98 (1H, d, Jϭ1.4 Hz), 8.46 (1H, dd, Jϭ3.9, 1.0 Hz), 8.59 (2H,
s), 8.76 (1H, d, Jϭ7.8 Hz). FAB-MS m/z: 530 [(MϩϩH)ϩ].
Compound 38c and 39 were prepared following a procedure similar to
Method A, and were used for the next reaction without further purification.
(R,S)-Ethyl 3-{3-[6-(3-Benzylureido)indolin-1-yl]-3-oxopropanoylamino}-
3-methylpropanoate (38c): This compound was prepared from 28c and 34 as
Ethyl 3-[(3-Benzylureido)-1,2,3,4-tetrahydroquinolin-1-yl]-3-oxopropanoate
(24): Colorless powder. Yield: quant. 1H-NMR (DMSO-d6) d: 1.14 (3H, br t,
Jϭ6.3 Hz), 1.85 (2H, quint., Jϭ6.3 Hz), 2.62 (2H, t, Jϭ6.3 Hz), 3.64—3.67
(4H, m), 4.04 (2H, br), 4.29 (2H, d, Jϭ5.8 Hz), 6.58 (1H, br), 7.03 (1H, d.
Jϭ8.3 Hz), 7.14—7.52 (7H, m), 8.53 (1H, s). FAB-MS m/z: 396
[(MϩϩH)ϩ].
Ethyl 3-[8-(3-Benzylureido)-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl]-3-ox- an ivory powder. Yield 57%. 1H-NMR (DMSO-d6) d: 1.11 (3H, d,
opropanoate (25): Colorless powder. Yield: 84%. H-NMR (CDCl3) d: 1.14 Jϭ6.8 Hz), 1.17 (3H, t, Jϭ6.8 Hz), 2.38 (1H, dd, Jϭ15.1, 7.3 Hz), 2.52 (1H,
1
(3H, t, Jϭ7.2 Hz), 1.25—1.33 (1H, m), 1.74—2.00 (3H, m), 2.56—2.77 dd, Jϭ15.1, 6.4 Hz), 3.03 (2H, br t, Jϭ8.3 Hz), 3.35 (2H, s), 4.02—4.24 (5H,
(3H, m), 3.25 (2H, Abq, Jϭ15.6 Hz), 4.00 (2H, q, Jϭ7.2 Hz), 4.23 (2H, d, m), 4.27 (2H, d, Jϭ6.0 Hz), 6.45 (1H, br t, Jϭ6.0 Hz), 7.06 (1H, d,
Jϭ5.7 Hz), 4.54—4.61 (1H, m), 5.80 (1H, t, Jϭ5.7 Hz), 7.00 (1H, d, Jϭ7.8 Hz), 7.21—7.36 (6H, m), 8.01 (1H, d, Jϭ1.8 Hz), 8.02 (1H, d,
Jϭ2.1 Hz), 7.11 (1H, d, Jϭ8.7 Hz), 7.23—7.35 (5H, m), 7.52 (1H, dd,
Jϭ7.8 Hz), 8.56 (1H, s). FAB-MS m/z: 467 [(MϩϩH)ϩ].
(R,S)-Ethyl 3-{3-[7-(3-Benzylureido)-1,2,3,4-tetrahydroquinolin-1-yl]-3-
oxopropanoylamino}-3-(pyridin-3-yl)propanoate (39): This compound was
prepared from 29 and 5 as a colorless powder. Yield: 97%. 1H-NMR
Jϭ8.4, 2.4 Hz). FAB-MS m/z: 410 [(MϩϩH)ϩ].
Ethyl 3-[6-(3-Benzylureido)indolin-1-yl]-2-methyl-3-oxopropanoate (26):
Amorphous powder. Yield: 93%. 1H-NMR (DMSO-d6) d: 1.17 (3H, t,
Jϭ6.8 Hz), 1.31 (3H, d, Jϭ7.3 Hz), 3.06 (2H, t, Jϭ8.3 Hz), 3.89 (1H, q, (CDCl3) d: 1.14 (3H, t, Jϭ7.2 Hz), 1.88 (2H, quint., Jϭ6.6 Hz), 2.61 (2H, t,
Jϭ7.3 Hz), 4.02—4.24 (4H, m), 4.28 (2H, d, Jϭ5.8 Hz), 6.47 (1H, t, Jϭ6.6 Hz), 2.72 (1H, dd, Jϭ15.9, 6.6 Hz), 2.83 (1H, dd, Jϭ15.9, 6.6 Hz),
Jϭ5.8 Hz), 7.22—7.35 (6H, m), 8.09 (1H, d, Jϭ2.0 Hz), 8.55 (1H, s). FAB- 3.50 (1H, d, Jϭ15.9 Hz), 3.57 (1H, d, Jϭ15.9 Hz), 3.70—3.75 (2H, m), 4.03
MS m/z: 396 [(MϩϩH)ϩ].
(2H, q, Jϭ7.2 Hz), 4.40 (2H, d, Jϭ5.4 Hz), 5.26—5.33 (1H, m), 5.94 (1H,
Ethyl 3-[6-(3-Benzylureido)indolin-1-yl]-2,2-dimethyl-3-oxopropanoate br), 6.91 (1H, br), 6.97 (1H, d, Jϭ8.1 Hz), 7.16—7.30 (7H, m), 7.42 (1H,
1
(27): Colorless powder. Yield: 99%. H-NMR (DMSO-d6) d: 1.18 (3H, t,
Jϭ6.8 Hz), 1.41 (6H, s), 3.00 (2H, t, Jϭ7.8 Hz), 3.81 (2H, t, Jϭ7.8 Hz),
4.18 (2H, q, Jϭ6.8 Hz), 4.28 (2H, d, Jϭ5.9 Hz), 6.49 (1H, t, Jϭ5.9 Hz), 7.07
(1H, d, Jϭ8.3 Hz), 7.19—7.35 (6H, m), 8.14 (1H, d, Jϭ2.0 Hz), 8.54 (1H,
s). FAB-MS m/z: 410 [(MϩϩH)ϩ].
br), 7.58 (1H, d, Jϭ8.1 Hz), 8.19 (1H, br), 8.44 (1H, dd, Jϭ4.8, 1.5 Hz),
8.52 (1H, s). FAB-MS m/z: 544 [(MϩϩH)ϩ].
(R,S)-Ethyl 3-Amino-3-(naphthalen-2-yl)propanoate (36) To a mix-
ture of napthalene-2-aldehyde (3.12 g, 20.0 mmol), ammoniun acetate
(3.86 g, 50.0 mmol) in 2-propanol (20 ml) was added malonic acid (2.08 g,
3-[6-(3-Benzylureido)indolin-1-yl]-3-oxopropanoic Acid (28) A mix- 20.0 mmol) and heated at reflux for 4 h. The resulting precipitates were fil-
ture of the urea 23 (2.06 g, 5.40 mmol), 1 M NaOH (18.9 ml) and methanol tered off, and the filtrate was concentrated in vacuo. The residue was diluted
(60 ml) and THF (60 ml) was stirred at room temperature for 2 h, then the re- with ethanol (30 ml) and SOCl2 (2.2 ml) was added dropwise to the mixture
action mixture was acidified with 1 M HCl (20 ml) and concentrated in at Ϫ20 °C. The reaction mixture was warmed to room temperature, then