Journal of Medicinal Chemistry
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4.4 Hz, 3H), 3.86 (q, J = 7.0 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.49
(dd, J = 2.1, 8.8 Hz, 1H), 7.86 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 8.17
(d, J = 8.1 Hz, 1H), 8.25 (q, J = 4.0 Hz, 2H), 8.27 (d, J = 2.1 Hz, 1H);
MS (ES, m/z) C17H15ClN2O3 requires 330, found 331 [M + H]+.
2-(9-(Butylcarbamoyl)-6-chloro-9H-carbazol-2-yl)propanoic Acid
(10c). Following general procedure B, hydrolysis of ester 9b (80 mg,
0.20 mmol) in the presence of LiOH (24 mg, 1 mmol), followed by
purification by preparative HPLC, furnished acid 10c (45 mg, 60%) as
1.84−1.91 (m, 2H), 3.61 (s, 3H), 4.02 (q, J = 7.0 Hz, 1H), 4.52 (t, J =
6.5 Hz, 2H), 7.37 (dd, J = 8.0, 1.5 Hz, 1H), 7.56 (dd, J = 8.9, 2.2 Hz,
1H), 8.20−8.25 (m, 3H), 8.31 (d, J = 2.1 Hz, 1H); MS (ES, m/z)
C23H26ClNO4 requires 415, found 433 [M + NH4]+.
2-(6-Chloro-9-((hexyloxy)carbonyl)-9H-carbazol-2-yl)propanoic
Acid (12). To a solution of ester 11 (87 mg, 0.21 mmol) in THF (2.5
mL) was added a solution of 6 M HCl (2.5 mL). The solution was
stirred for 5 days at room temperature. EtOAc (10 mL) and H2O (5
mL) were then added. After separation, the organic phase was dried
over MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography (Cy/EtOAc) to furnish acid 12 (46 mg,
1
a white solid: H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J = 7.3 Hz,
3H), 1.47 (m, 5H), 1.66 (p, J = 7.2 Hz, 2H), 3.39 (dd, J = 13.3, 6.4 Hz,
2H), 3.86 (q, J = 7.0 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.51 (dd, J =
8.8, 2.0 Hz, 1H), 7.85−7.87 (m, 2H), 8.18 (d, J = 8.1 Hz, 1H), 8.28 (d,
J = 1.9 Hz, 1H), 8.39 (t, J = 5.4 Hz, 1H), 12.34 (s, 1H); MS (ES, m/z)
C20H21ClN2O3 requires 372, found 371 [M − H]−.
1
55%) as a white solid: H NMR (400 MHz, DMSO-d6) δ 0.89 (t, J =
6.9 Hz, 3H), 1.31−139 (m, 4H), 1.46 (d, J = 7.1 Hz, 3H), 1.49−1.54
(m, 2H), 1.84−1.91 (m, 2H), 3.88 (q, J = 7.1 Hz, 1H), 4.52 (t, J = 6.5
Hz, 2H), 7.38 (dd, J = 8.1, 1.5 Hz, 1H), 7.55 (dd, J = 8.9, 2.2 Hz, 1H),
8.19 (d, J = 8.1 Hz, 1H), 8.22−8.24 (m, 2H), 8.30 (d, J = 2.2 Hz, 1H),
12.38 (s, 1H); MS (ES, m/z) C22H24ClNO4 requires 401, found 400
[M − H]−, 356 [M − H − CO2]−.
2-(6-Chloro-9-(octylcarbamoyl)-9H-carbazol-2-yl)propanoic Acid
(10d). Following general procedure B, hydrolysis of ester 9c (120 mg,
0.27 mmol) in the presence of LiOH (26 mg, 1.08 mmol), followed by
trituration with Et2O, furnished acid 10d (62 mg, 53%) as a white
solid: H NMR (400 MHz, DMSO-d6) δ 0.87 (t, J = 6.7 Hz, 3H),
Benzyl 2-(6-Chloro-9H-carbazol-2-yl)propanoate (13).43 To a
solution of 1 (773 mg, 2.82 mmol, 1 equiv) in DMF (10 mL) was
added K2CO3 (1.17 g, 8.47 mmol, 3 equiv). The mixture was stirred at
room temperature for 30 min, and then BnBr (0.37 mL, 3.10 mmol,
1.1 equiv) was added. After 3 h at room temperature, EtOAc was
added (20 mL), and the mixture was washed with a saturated aqueous
NH4Cl solution (5 mL) and with H2O (5 mL). The organic phase was
then dried over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography (Cy/EtOAc) to yield the
1
1.28−1.44 (m, 10H), 1.46 (d, J = 7.1 Hz, 3H), 1.66 (p, J = 7.0 Hz,
2H), 3.34−3.40 (m, 2H), 3.86 (q, J = 7.0 Hz, 1H), 7.29 (dd, J = 8.1,
1.7 Hz, 1H), 7.50 (dd, J = 8.8, 2.2 Hz, 1H), 7.84−7.87 (m, 2H), 8.18
(d, J = 8.0 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.40 (t, J = 5.5 Hz, 1H),
12.31 (s, 1H); MS (ES, m/z) C24H29ClN2O3 requires 428, found 429
[M + H]+, 447 [M + NH4]+.
2-(6-Chloro-9-((4-chlorophenyl)carbamoyl)-9H-carbazol-2-yl)-
propanoic Acid (10e). To a solution of ester 9d (140 mg, 0.32 mmol)
in THF (5 mL) was added a solution of 6 M HCl (5 mL). The
solution was stirred for 5 days at room temperature. EtOAc (10 mL)
and H2O (5 mL) were then added. After separation, the organic phase
was dried over MgSO4 and concentrated in vacuo. The residue was
triturated with Et2O/pentane to furnish acid 10e (105 mg, 80%) as a
1
corresponding benzyl ester 13 (860 mg, 84%): H NMR (400 MHz,
CDCl3) δ 1.61 (d, J = 7.2 Hz, 3H), 3.94 (q, J = 7.1 Hz, 1H), 5.13 (q, J
= 12.5 Hz, 2H), 7.19 (dd, J = 8.1, 1.3 Hz, 1H), 7.23−7.25 (m, 2H),
7.28−7.36 (m, 6H), 7.94 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H),
8.03 (s, 1H); MS (ES, m/z) C22H18ClNO2 requires 363, found 362
[M − H]−.
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white solid: H NMR (400 MHz, DMSO-d6) δ 1.46 (d, J = 7.1 Hz,
3H), 3.90 (q, J = 7.0 Hz, 1H), 7.35 (dd, J = 8.1, 1.2 Hz, 1H), 7.50 (d, J
= 8.9 Hz, 2H), 7.55 (m, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.88 (s, 1H),
7.92 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.34 (s, 1H), 10.74
(s, 1H); MS (ES, m/z) C22H16Cl2N2O3 requires 426, found 427, 429
[M + H]+, 444, 446 [M + NH4]+.
2-(6-Chloro-9-(hexylmethylcarbamoyl)carbazol-2-yl)propanoic
Acid (10f). Following general procedure B, hydrolysis of ester 9f (60
mg, 0.14 mmol) in the presence of LiOH (8 mg, 0.35 mmol), followed
by trituration with DCM/MeOH, furnished acid 10f (45 mg, 77%) as
a colorless oil: 1H NMR (400 MHz, DMSO-d6) δ 0.71 - 0.79 (m, 2H),
1.16 (m, 6H), 1.44 (dd, J = 2.8, 7.1 Hz, 3H), 1.60 (t, J = 7.1 Hz, 2H),
3.00 (d, J = 1.7 Hz, 3H), 3.41 (h, J = 7.2 Hz, 2H), 3.87 (q, J = 7.1 Hz,
1H), 5.75 (s, 1H), 7.28 (dt, J = 1.6, 8.2 Hz, 1H), 7.43 (d, J = 1.3 Hz,
1H), 7.46 - 7.53 (m, 2H), 8.18 (d, J = 8.1 Hz, 1H), 8.29 (dd, J = 0.9,
1.8 Hz, 1H), 12.36 (s, 1H); MS (ES, m/z) C23H27ClN2O3 requires
414, found 415 [M + H]+.
General Procedure C. To a solution of 13 (or 3 in the case of
14j) in MeCN (5 mL) were successively added the acyl chloride (3
equiv, either obtained from a commercial source or freshly prepared
from the corresponding acid), DMAP (3 equiv), and Et3N (3 equiv).
The mixture was stirred at room temperature for 2 h, and then a
saturated aqueous NH4Cl solution and H2O were added. After
separation, the organic phase was dried over MgSO4 and concentrated
in vacuo. The residue was purified by column chromatography (Cy/
EtOAc).
Benzyl 2-(9-Acetyl-6-chloro-9H-carbazol-2-yl)propanoate (14a).
Following general procedure C, acylation of 13 (185 mg, 0.51 mmol)
in the presence of AcCl (0.11 mL, 1.52 mmol), DMAP (186 mg, 1.52
mmol), and Et3N (0.21 mL, 1.52 mmol) furnished the acetyl derivative
1
14a (200 mg, 97%) as a white solid: H NMR (400 MHz, CDCl3) δ
1.64 (d, J = 7.2 Hz, 3H), 2.82 (s, 3H), 3.98 (q, J = 7.2 Hz, 1H), 5.12−
5.19 (m, 2H), 7.25−7.32 (m, 5H), 7.37 (dd, J = 8.0, 1.3 Hz, 1H), 7.44
(dd, J = 8.9, 2.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 2.1 Hz,
1H), 8.08 (s, 1H), 8.24 (d, J = 8.9 Hz, 1H); MS (ES, m/z)
2-(6-Chloro-9-(cyclohexylcarbamoyl)carbazol-2-yl)propanoic
Acid (10g). Following general procedure B, hydrolysis of ester 9g (60
mg, 0.14 mmol) in the presence of LiOH (8 mg, 0.35 mmol), followed
by trituration with Et2O, furnished acid 10g (51 mg, 89%) as a white
+
C24H20ClNO3 requires 405, found 406 [M + H+], 423 [M + NH4 ].
Benzyl 2-(9-Benzoyl-6-chloro-9H-carbazol-2-yl)propanoate
(14b). Following general procedure C, acylation of 13 (105 mg,
0.29 mmol) in the presence of benzoyl chloride (0.10 mL, 0.87 mmol),
DMAP (106 mg, 0.87 mmol), and Et3N (0.12 mL, 0.87 mmol)
furnished the benzoyl derivative 14b (123 mg, 91%) as a white solid:
1H NMR (400 MHz, CDCl3) δ 1.47 (d, J = 7.2 Hz, 3H), 3.81 (q, J =
1
solid: H NMR (400 MHz, DMSO-d6) δ 1.17−1.31 (m, 2H), 1.43
(dd, J = 9.1, 16.1 Hz, 6H), 1.63 (d, J = 12.8 Hz, 1H), 1.72 - 1.84 (m,
2H), 2.02 (d, J = 9.6 Hz, 2H), 3.68−3.81 (m, 1H), 3.85 (q, J = 7.1 Hz,
1H), 7.27 (dd, J = 1.3, 8.1 Hz, 1H), 7.49 (dd, J = 2.2, 8.8 Hz, 1H),
7.79−7.87 (m, 2H), 8.16 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H),
8.35 (d, J = 7.5 Hz, 1H), 12.34 (s, 1H); MS (ES, m/z) C22H23ClN2O3
requires 398, found 399 [M + H]+.
7.1 Hz, 1H), 5.06−5.14 (m, 2H), 7.23−7.26 (m, 2H), 7.29−7.34 (m,
5H), 7.38 (s, 1H), 7.50−7.54 (m, 3H), 7.65−7.70 (m, 3H), 7.91 (d, J
= 8.0 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H); MS (ES, m/z) C29H22ClNO3
Hexyl 6-Chloro-2-(1-methoxy-1-oxoprop-2-yl)-9H-carbazole-9-
carboxylate (11). To a solution of 3 (140 mg, 0.49 mmol, 1 equiv)
in THF (5 mL) were successively added hexyl chloroformate (freshly
prepared, 215 mg, 1.47 mmol, 3 equiv), DMAP (179 mg, 1.47 mml, 3
equiv), and Et3N (0.20 mL, 1.47 mmol, 3 equiv). The mixture was
heated in the microwave at 100 °C for 3 h. The reaction mixture was
then filtrated and concentrated in vacuo. The residue was purified by
column chromatography (Cy/EtOAc) to furnish the carbamate 11
+
requires 467, found 468 [M + H+], 485 [M + NH4 ].
Benzyl 2-(6-Chloro-9-(4-chlorobenzoyl)-9H-carbazol-2-yl)-
propanoate (14c). Following general procedure C, acylation of 13
(98 mg, 0.27 mmol) in the presence of 4-chlorobenzoyl chloride (0.10
mL, 0.80 mmol), DMAP (98 mg, 0.80 mmol), and Et3N (0.11 mL,
0.80 mmol) furnished the 4-chlorobenzoyl derivative 14c (119 mg,
88%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.47 (d, J = 7.2
Hz, 3H), 3.81 (q, J = 7.2 Hz, 1H), 5.06−5.13 (m, 2H), 7.21−7.24 (m,
2H), 7.28−7.33 (m, 5H), 7.40 (s, 1H), 7.47 (dd, J = 8.6, 5.6 Hz, 3H),
1
(173 mg, 85%) as a white solid: H NMR (400 MHz, DMSO-d6) δ
0.89 (t, J = 6.9 Hz, 3H), 1.33−1.37 (m, 4H), 1.48−1.53 (m, 5H),
O
dx.doi.org/10.1021/jm3011146 | J. Med. Chem. XXXX, XXX, XXX−XXX