A. Bridoux et al. / Bioorg. Med. Chem. 18 (2010) 3910–3924
3921
benzoyl chloride (67
l
L, 0.6 mmol, 1.0 equiv) and HCl–iPrOH (50
l
L,
1.0 equiv), 3-fluorobenzoyl chloride (416.5
equiv) and HCl–iPrOH (48
eluent (DCM/EtOAc, 60/40). Yield 10%; mp 213 °C (from iPrOH);
light brown crystals; TLC Rf 0.62 (EtOAc/EtOH, 90/10); IR cmꢁ1
l
L, 3.4 mmol, 2.0
0.3 mmol, 1.0 equiv) gave the product. Column eluent (DCM/EtOAc,
90/10). Yield 57%; mp 183 °C (from iPrOH); light brown crystals; TLC
Rf 0.78 (DCM/MeOH, 90/10); IR cmꢁ1: 2956, 1678, 1464; 1H NMR
(CDCl3) d: 1.92 (m, 4H, 2CH2), 2.62 (m, 2H, CH2), 2.99 (s, 3H, CH3),
3.00 (m, 1H, CHH0), 3.25 (m, 3H, CHH0, CH2), 3.47 (m, 4H, 2CH2),
3.70 (m, 1H, CHH0), 3.84 (s, 3H, CH3), 3.90 (m, 1H, CHH0), 4.14 (m,
2H, CH2), 4.15 (m, 1H, CHH0), 4.85 (m, 1H, CHH0), 6.53 (m, 1H, ArH),
6.74 (m, 4H, ArH), 6.91 (d, J = 9.0 Hz, 1H, ArH), 7.56 (t, J = 8.0 Hz,
1H, ArH), 7.63–7.73 (m, 4H, ArH), 13.40 (br, 1H, NH+); Anal. Calcd
for C34H37FN2O5ꢂHClꢂH2O (627.1): C, 65.12; H, 6.43; N, 4.47. Found:
C, 64.99; H, 6.21; N, 4.45; MS (+APCI) m/z 573 (3.6) [M+H]+ (calcd
for C34H38FN2O5 573.6 [M+H]+).
lL, 0.2 mmol) gave the product. Column
:
2954, 1687; 1H NMR (DMSO-d6) d: 1.87 (m, 4H, 2CH2), 2.34 (m,
2H, CH2), 2.85 (m, 1H, CHH0), 2.90 (s, 3H, CH3), 3.08 (m, 1H, CHH0),
3.36 (m, 2H, CH2), 3.67 (m, 1H, CHH0), 3.68 (m, 4H, 2CH2), 3.79 (s,
3H, CH3), 3.87 (m, 1H, CHH0), 4.15 (m, 2H, CH2), 4.33 (m, 1H, CHH0),
4.70 (m, 1H, CHH0), 6.81 (m, 4H, ArH), 7.13 (d, J = 9.0 Hz, 1H, ArH),
7.19 (m, 1H, ArH), 7.56 (m, 4H, ArH), 11.33 (br, 1H, NH+); Anal.
Calcd for C34H36ClF2N2O5ꢂHClꢂ1½H2O (654.1) requires C, 62.37; H,
6.11; N, 4.28; found C, 62.36; H, 6.18; N, 4.09; MS (+APCI) m/z
591 (3.7) [M+H]+ (calcd for C34H37F2N2O5 591.6 [M+H]+).
5.3.16. 5-Benzoyl-2-{3-[3-fluoro-5-(4-methoxytetrahydro-4H-4-
pyranyl)phenoxy]propyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]indole hydrochloride (31)
5.3.19. 5-(4-Fluorobenzoyl)-2-{3-[3-fluoro-5-(4-methoxytet-
rahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (34)
Following general procedure for benzoylation and benzylation,
NaH (15 mg, 0.4 mmol, 1.0 equiv), 2-{3-[3-fluoro-5-(4-methoxy-
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-2,3,4,5-tetrahy-dro-1H-
pyrido[4,3-b]indole (28) (160 mg, 0.4 mmol, 1.0 equiv), benzoyl
Following general procedure for benzoylation and benzylation,
NaH (50 mg, 1.1 mmol, 1.0 equiv), 2-{3-[3-fluoro-5-(4-methoxy-
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-tet-
rahydro-1H-pyrido[4,3-b]indole
1.0 equiv), 4-fluorobenzoyl chloride (128
and HCl–iPrOH (20 L, 0.1 mmol) gave the product. Column eluent
(26)
(500 mg,
1.1 mmol,
chloride (43
lL, 0.4 mmol, 1.0 equiv) and HCl–iPrOH (34
lL,
lL, 1.1 mmol, 1.0 equiv)
0.2 mmol, 1.0 equiv) gave the product. Column eluent (DCM/
EtOAc, 50/50). Yield 48%; mp 174 °C (from DCM/Et2O, 50/50); light
brown crystals; TLC Rf 0.78 (DCM/MeOH, 90/10); IR cmꢁ1: 2976,
1685; 1H NMR (CDCl3) d: 1.92 (m, 4H, 2CH2), 2.64 (m, 2H, CH2),
2.99 (s, 3H, CH3), 3.25 (m, 1H, CHH0), 3.45 (m, 2H, CH2), 3.58 (m,
1H, CHH0), 3.71 (m, 1H, CHH0), 3.82 (m, 4H, 2CH2), 3.86 (m, 1H,
CHH0), 4.14 (m, 2H, CH2), 4.23 (m, 1H, CHH0), 4.82 (m, 1H, CHH0),
6.51 (ddd, J = 10.0 Hz, J = 2.0 Hz, J = 2.0 Hz, 1H, ArH), 6.71 (m, 1H,
ArH), 6.73 (d, J = 2.0 Hz, 1H, ArH), 7.12–7.72 (m, 9H, ArH), 13.35
(br, 1H, NH+); HPLC (Kromasil C18, H2O/MeOH/TFA (26:74:0.1),
k = 220 nm) rt.: 7.6 min (90%); Anal. Calcd for C33H35FN2O3ꢂ
HClꢂ13 4H2O (609.5): C, 64.97; H, 6.19; N, 4.59. Found: C, 64.93;
H, 6.15; N, 4.85 (the degradation of the product was observed dur-
ing the analysis); MS (+APCI) m/z 543 (3.6) [M+H]+ (calcd for
C33H36FN2O4 543.6 [M+H]+).
l
(EtOAc/EtOH, 90/10). Yield 11%; mp 177 °C (from iPrOH); light
brown crystals; TLC Rf 0.69 (AcOEt/EtOH, 90/10); IR cmꢁ1: 2946,
1679; 1H NMR (CDCl3) d: 1.88 (m, 4H, 2CH2), 2.35 (m, 2H, CH2),
2.82 (m, 1H, CHH0), 2.91 (s, 3H, CH3), 3.09 (m, 1H, CHH0), 3.37 (m,
1H, CHH0), 3.44 (m, 2H, CH2), 3.68 (m, 4H, 2CH2), 3.76 (m, 1H,
CHH0), 3.80 (s, 3H, CH3), 4.16 (m, 2H, CH2), 4.33 (m, 1H, CHH0),
4.75 (m, 1H, CHH0), 5.72 (br, 1H, NH+), 6.82 (m, 4H, ArH), 7.18 (d,
J = 9.0 Hz, 1H, ArH), 7.19 (d, J = 2.0 Hz, 1H, ArH), 7.44 (dd,
J = 8.5 Hz, J = 8.5 Hz, 2H, ArH), 7.72 (dd, J = 8.5 Hz, J = 5.0 Hz, 2H,
ArH); Anal. Calcd for C34H36F2N2O5ꢂHClꢂ1/2H2O (636.1): C, 64.23;
H, 5.82; N, 4.41. Found: C, 64.05; H, 6.13; N, 4.51; MS (+APCI) m/
z 591 (3.7) [M+H]+ (calcd for C34H37F2N2O5 591.6 [M+H]+).
5.3.20. 5-(4-Chlorobenzoyl)-2-{3-[3-fluoro-5-(4-methoxytet-
rahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (35)
Following general procedure for benzoylation and benzylation,
NaH (85 mg, 2.1 mmol, 1.0 equiv), 2-{3-[3-fluoro-5-(4-methoxy-
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-tet-
rahydro-1H-pyrido[4,3-b]indole (26) (1.0 g, 2.1 mmol, 1.0 equiv),
5.3.17. 5-(2-Fluorobenzoyl)-2-{3-[3-fluoro-5-(4-methoxy-
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (32)
Following general procedure for benzoylation and benzylation,
NaH (77 mg, 1.7 mmol, 1.0 equiv), 2-{3-[3-fluoro-5-(4-methoxytet-
rahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-tetra-
hydro-1H-pyrido[4,3-b]indole (26) (800 mg, 1.7 mmol, 1.0 equiv),
4-chlorobenzoyl chloride (271
lL, 2.1 mmol, 1.0 equiv) and HCl–
iPrOH (135 L, 0.7 mmol) gave the product. Column eluent
l
2-fluorobenzoyl chloride (205
l
L, 1.7 mmol, 1.0 equiv) and HCl–
(DCM/MeOH, 99/1). Yield 33%; mp 172 °C (from DCM/cyclohexane
50/50); light brown crystals; TLC Rf 0.67 (DCM/MeOH, 90/10); IR
cmꢁ1: 2948, 1681; 1H NMR (CDCl3) d: 1.93 (m, 4H, 2CH2), 2.60
(m, 2H, 2CH2), 2.90 (m, 1H, CHH0), 2.98 (s, 3H, CH3), 3.16 (m, 1H,
CHH0), 3.42 (m, 2H, CH2), 3.60 (m, 1H, CHH0), 3.65 (m, 4H, 2CH2),
3.83 (s, 3H, CH3), 3.90 (m, 1H, CHH0), 4.07 (m, 2H, CH2), 4.20 (m,
1H, CHH0), 4.78 (m, 1H, CHH0), 6.50 (d, J = 9.0 Hz, 1H, ArH), 6.73
(m, 3H, ArH), 6.83 (m, 1H, ArH), 6.92 (d, J = 9.0 Hz, ArH), 7.51 (d,
J = 8.0 Hz, ArH), 7.67 (d, J = 8.0 Hz, ArH), 13.24 (br, 1H, NH+); Anal.
Calcd for C34H36ClFN2O5ꢂHClꢂ1½H2O (670.5): C, 60.84; H, 5.96; N,
4.17. Found: C, 60.95; H, 5.99; N, 4.37; MS (+APCI) m/z 607 (3.8)
[M], 609 (3.8) [M+2] (calcd for C34H36ClFN2O5 607.1 [M]).
iPrOH (136 L, 0.3 mmol) gave the product. Column eluent (DCM/
l
EtOAc, 60/40). Yield 16%; mp >230 °C (from iPrOH); white crystals;
TLC Rf 0.81 (EtOAc/EtOH, 80/20); IR cmꢁ1: 2930, 1676; 1H NMR
(DMSO-d6) d: 1.87 (m, 4H, 2CH2), 2.31 (m, 2H, CH2), (m, 1H, CHH0),
2.90 (s, 3H, CH3), 2.97 (m, 1H, CHH0), 3.42 (m, 2H, CH2), 3.65 (m, 1H,
CHH0), 3.66 (m, 4H, 2CH2), 3.75 (m, 1H, CHH0), 3.79 (s, 3H, CH3), 4.15
(m, 2H, CH2), 4.33 (m, 1H, CHH0), 4.71 (m, 1H, CHH0), 6.82 (m, 3H,
ArH), 6.85 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H, ArH), 7.19 (m, 2H, ArH),
7.46 (m, 2H, ArH), 7.73 (m, 2H, ArH), 10.72 (br, 1H, NH+); Anal. Calcd
for C34H36F2N2O5ꢂHClꢂH2O (645.1): C, 63.03; H, 6.09; N, 4.34. Found:
C, 63.21; H, 6.11; N, 4.32; MS (+APCI) m/z 591 (3.7) [M+H]+ (calcd
for C34H37F2N2O5 591.6 [M+H]+).
5.3.21. 2-{3-[3-Fluoro-5-(4-methoxytetrahydro-4H-4-pyranyl)
phenoxy]propyl}-8-methoxy-5-(2,4,6-trichlorobenzoyl)-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (36)
Following general procedure for benzoylation and benzylation,
NaH (85 mg, 2.1 mmol, 1.0 equiv), 2-{3-[3-fluoro-5-(4-methoxy-
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-tet-
rahydro-1H-pyrido[4,3-b]indole (26) (1.0 g, 2.1 mmol, 1.0 equiv),
5.3.18. 5-(3-Fluorobenzoyl)-2-{3-[3-fluoro-5-(4-methoxy
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (33)
Following general procedure for benzoylation and benzylation,
NaH (70 mg, 1.7 mmol, 1.0 equiv), 2-{3-[3-fluoro-5-(4-methoxy-
tetrahydro-4H-4-pyranyl)phenoxy]propyl}-8-methoxy-2,3,4,5-tet-
rahydro-1H-pyrido[4,3-b]indole
(26)
(800 mg,
1.7 mmol,
2,4,6-trichlorobenzoyl chloride (667 lL, 4.3 mmol, 2.0 equiv) and