C. Comoy et al. / Bioorg. Med. Chem. 8 (2000) 483±495
493
2.70±2.82 (m, 1H, ArCH2), 3.10±3.33 (m, 4H, CH2N),
3.77 (t, 2H, CH2NCO,J=7.0 Hz), 3.84 (dd, 1H, OCH2,
J=8.1, 11.0 Hz), 4.16 (d, 1H, OCH2, J=11.0 Hz), 5.46
(br s, 1H, OH), 6.36 (d, 1H, Harom, J=8.1 Hz), 6.41 (d,
1H, Harom, J=8.1 Hz), 6.94 (t, 1H, Harom,J=8.1 Hz);
anal. C28H40N2O6: (C, H, N).
with CH2Cl2 and puri®ed by a column chromatography
(eluent: CH2Cl2:MeOH, 99:1) to give the desired bro-
mide as an oil (0.720 g) in 82% yield, IR (®lm) n (cm 1):
1
1650 (NCO), 1240 (COC); H NMR (CDCl3) d: 1.39±
1.74 (m, 21H, CH2, CH3), 2.24±2.40 (m, 4H, CHCH2N,
ArCH2, CH2), 2.58 (s, 4H, NCOCH2), 2.67±2.81 (m,
1H, ArCH2), 3.16±3.30 (m, 4H, CH2N), 3.60 (t, 2H,
BrCH2, J=6.4 Hz), 3.77 (t, 2H, CH2NCO, J=6.8 Hz),
3.82 (dd, 1H, OCH2, J=8.5, 10.4 Hz), 4.10 (t, 2H,
CH2O, J=5.6 Hz), 4.13±4.20 (m, 1H, OCH2), 6.41 (d,
1H, Harom, J=8.2 Hz), 6.47 (d, 1H, Harom,J=8.2 Hz),
7.05 (t, 1H, Harom, J=8.2 Hz).
8-{4-[N-(5-(2-(4-(4-Fluorobenzoyl)piperidine)ethyloxy)-
3,4-dihydro-2H-1-benzopyran-3-ylmethyl]amino]butyl}-8-
azaspiro[4.5]decane-7,9-dione (2b). The 8-{4-[N-(5-(2-(4-
(4-¯uorobenzoyl)piperidine)ethyloxy)-3,4-dihydro-2H-
1-benzopyran-3-ylmethyl]-N-(t-butyloxycarbonyl)amino]-
butyl}-8-azaspiro[4.5]decane-7,9-dione was prepared
according to the method used for 1d from the phenol 11
(0.650 g, 1.30 mmol) in DMF (8 mL), potassium car-
bonate (0.540 g, 3.90 mmol), 1-(2-chloroethyl)-4-(4-
¯uorobenzoyl)piperidine 7 (0.525 g, 1.95 mmol) and a
catalytic amount of potassium iodide. The expected
product was obtained after a column chromatography
(eluent: CH2Cl2:MeOH, 95:5) as an oil (0.780 g) in 82%
yield, IR (®lm) n (cm 1): 1650 (NCO, CO), 1240 (COC);
1H NMR (CDCl3) d: 1.37±1.72 (m, 21H, CH2, CH3),
1.81±1.90 (m, 4H, CH2), 2.24±2.37 (m, 3H, CHCH2N,
ArCH2, CHCO), 2.56 (s, 4H, NCOCH2), 2.70±2.81 (m,
1H, ArCH2), 2.86 (t, 2H, NCH2, J=5.9 Hz), 3.05±3.28
(m, 8H, CH2N), 3.71±3.85 (m, 3H, OCH2, CH2NCO),
A solution of the bromide described above (0.700 g, 1.13
mmol) in DMF (5 mL), diisopropylethylamine (0.583 g,
4.51 mmol), 2-aminoindane hydrochloride (0.287 g, 1.69
mmol) in DMF (5 mL) and a catalytic amount of
potassium iodide was stirred 72 h at 60 ꢁC. After eva-
poration of solvent and addition of water, the crude
product was extracted with CH2Cl2 and puri®ed by a
column chromatography (eluent: CH2Cl2:MeOH, 99:1)
to aord the expected compound as an amorphous solid
(0.260 g) in 34% yield, IR (KBr) n (cm 1): 3560±3160
(NH), 1640 (NCO), 1220 (COC); 1H NMR (CDCl3,
D2O) d: 1.37±1.74 (m, 21H, CH2, CH3), 2.10±2.37 (m,
4H, CHCH2N, ArCH2), 2.53 (s, 4H, NCOCH2), 2.64±
2.77 (m, 1H, ArCH2), 2.95±3.34 (m, 10H, CH2, CH2N,
CH2N(Boc)CH2), 3.73 (t, 2H, CH2NCO, J=6.9 Hz),
3.78±3.86 (m, 2H, OCH2, NHCH), 4.06 (t, 2H, OCH2,
J=5.9 Hz), 4.09±4.18 (m, 1H, OCH2), 6.39 (d, 1H,
Harom, J=8.1 Hz), 6.47 (d, 1H, Harom, J=8.1 Hz), 7.01
(t, 1H, Harom, J=8.1 Hz), 7.12±7.23 (m, 4H, Harom).
4.08±4.19 (m, 3H, OCH2, CH2O), 6.41 (d, 1H, Harom
,
J=8.2 Hz), 6.48 (d, 1H, Harom, J=8.2 Hz), 7.02 (t, 1H,
Harom,J=8.2 Hz), 7.13 (t, 2H, Harom, J=8.6 Hz), 7.98
(dd, 2H, Harom, J=5.6, 8.6 Hz).
To a solution of the N-t-butyloxycarbonylamine descri-
bed above (0.780 g, 1.06 mmol) in CH2Cl2 (10 mL) was
added dropwise tri¯uoroacetic acid (1.23 mL, 15.96
mmol). The mixture was stirred for 16 h at room tempera-
ture and, then, a saturated sodium hydrogenocarbonate
solution was added. The compound was chromato-
graphied (eluent: CH2Cl2:MeOH, 95:5) to aord the
expected derivative 2b as an oil (0.550 g) in 82% yield,
IR (®lm) n (cm 1): 3640±3100 (NH), 1650 (NCO, CO),
To a solution of the N-t-butyloxycarbonylamine descri-
bed above (0.380 g, 0.56 mmol) in CH2Cl2 (8 mL) was
added dropwise tri¯uoroacetic acid (0.90 mL, 11.30
mmol). The reaction mixture was stirred at room tem-
perature for 16 h, then the solution was hydrolyzed with
a saturated sodium hydrogenocarbonate solution. The
product, extracted with CH2Cl2, was puri®ed by a col-
umn chromatography (eluent: CH2Cl2:MeOH, 9:1) to
aord the expected compound 2c as an oil (0.250 g) in
77% yield, IR (®lm) n (cm 1): 3620-3100 (NH), 1640
1
1230 (COC); H NMR (CDCl3, D2O) d: 1.44±1.76 (m,
12H, CH2), 1.85±1.98 (m, 4H, CH2), 2.22±2.46 (m, 3H,
CHCH2N, ArCH2, CHCO), 2.59 (s, 4H, NCOCH2),
2.66±2.78 (m, 4H, CH2N), 2.85 (dd, 1H, ArCH2, J=5.5,
17.2 Hz), 2.90 (t, 2H, NCH2, J=5.7 Hz), 3.08±3.43 (m,
4H, CH2N), 3.72±3.80 (m, 2H, CH2NCO), 3.88 (dd, 1H,
OCH2, J=7.5, 10.7 Hz), 4.07±4.17 (m, 2H, OCH2),
4.20±4.28 (m, 1H, OCH2), 6.40 (d, 1H, Harom, J=8.2
1
(NCO), 1230 (COC); H NMR (CDCl3, D2O) d: 1.40±
1.85 (m, 12H, CH2), 2.01±2.12 (m, 2H, CH2), 2.19±2.40
(m, 2H, CHCH2N, ArCH2), 2.57 (s, 4H, NCOCH2),
2.60±2.98 (m, 9H, ArCH2, CH2N, CH2), 3.16±3.27 (m,
2H, CH2), 3.68±3.86 (m, 4H, OCH2, CH2NCO, NCH),
3.98±4.07 (m, 2H, CH2O), 4.19±4.26 (m, 1H, OCH2),
Hz), 6.46 (d, 1H, Harom, J=8.2 Hz), 7.02 (t, 1H, Harom
,
J=8.2 Hz), 7.13 (t, 2H, Harom, J=8.6 Hz), 7.97 (dd, 2H,
Harom,J=5.6, 8.6 Hz); MS (CI/NH3) m/z 634 (M+1);
anal. C37H48N3O5F: (C, H, N, F).
6.38 (d, 1H, Harom, J=7.9 Hz), 6.45 (d, 1H, Harom,
J=7.9 Hz), 7.01 (t, 1H, Harom, J=7.9 Hz), 7.10±7.23
(m, 4H, Harom); MS (EI) m/z 573 (M+); anal.
C35H47N3O4, C2H2O4: (C, H, N).
8-{4-[N-[5-(3-(2-Aminoindane)propyloxy)-3,4-dihyro-2H-
1-benzopyran-3-ylmethyl]amino]butyl}-8-azaspiro[4.5]de-
cane-7,9-dione (2c). A mixture of phenol 11 (0.710 g,
1.42 mmol) in toluene (10 mL) and carbonate potassium
(1.960 g, 14.20 mmol) was re¯uxed for 30 min. Then,
1,3-dibromopropane (0.860 g, 4.26 mmol) and n-tetra-
butylammonium bromide (0.092 g, 0.28 mmol) were
added. The reactional solution was heated to re¯ux for
12 h. After ®ltration on Celite, evaporation of toluene
and addition of water, the crude product was extracted
1-N-n-Propyl-4-[2-(4-(4-¯uorobenzoyl)piperidine)ethoxy]-
50-methoxy-30,40-dihydrospiro[piperazin-2,30(20H)-benzo-
pyran] (4c). A mixture of chroman 1254 (0.290 g, 1.05
mmol) in dry acetonitrile (CH3CN) (5 mL), potassium
carbonate (0.435 g, 3.15 mmol), chloro derivative 7
(0.425 g, 1.58 mmol) and potassium iodide (catalytic
amount) were re¯uxed. After total consumption of the
starting material, the mixture was hydrolyzed and the
crude product was extracted with CH2Cl2 (15 mL).