B. Di Giacomo et al. / Il Farmaco 54 (1999) 600–610
605
brine (200 ml) and dried (Na2SO4). Evaporation of the
solvent yielded a residue (14 g) which was submitted to
flash chromatography: elution with light petroleum–
ether (8:2) afforded a product (10, 9.8 g, 63.5%) which
1.60 (6H, s, 2×Me), 1.85 (2H, m, ClCH2CH2), 2.00
(2H, m, ClCH2CH2CH2), 3.50 (2H, t, ClCH2), 3.70–
4.00 (4H, 2×m, ꢀOCH2CH2Oꢀ), 7.35 (4H, m, Ar),
10.08 (1H, br s, CO2H).
1
contained traces of isomers; H NMR (CDCl3) l 1.40
(6H, s, 2×Me), 2.00 (3H, s, MeCO), 2.20 (2H, m,
ClCH2CH2), 3.20 (2H, t, CH2CO), 3.70 (2H, t, ClCH2),
4.20 (2H, s, CH2OAc), 7.70 (4H, 2×d, J=8.5 Hz,
Ar).
5.8. Methyl 2-[4-(1-ethylendioxo-4-chlorobutyl)-
phenyl]-isobutyrate (14)
An ethereal solution of diazomethane (150 ml, from
21 g of Diazald®) was added dropwise (10 min) to a
cold (0°C) solution of 13 (13.0 g, 39 mmol) in anhy-
drous ether (100 ml). The resulting yellow solution was
carefully evaporated to dryness to give 14 (12.5 g,
5.5. 2-[4-(1-Ethylendioxo-4-chlorobutyl)-phenyl]-
isobutyl acetate (11)
1
Ethylene glycol (5.56 g, 89.6 mmol) and p-toluene-
sulfonic acid monohydrate (0.40 g, 2.1 mmol) were
added to a solution of 10 (18.0 g, 60.6 mmol) in
anhydrous benzene (700 ml) and the resulting mixture
was refluxed 24 h in a argon atmosphere taking care of
removing the reaction water by a Dean–Stark trap.
After cooling and evaporation of the solvent, the
residue was diluted with AcOEt (350 ml), washed with
water (4×200 ml), brine (200 ml) and dried (Na2SO4).
Evaporation of the solvent gave a residue which was
submitted to flash chromatography: elution with light
petroleum–ether (8:2) afforded 11 (14.0 g, 68%); 1H
NMR (CDCl3) l 1.40 (6H, s, 2×Me), 1.85 (2H, m,
ClCH2CH2), 1.95 (2H, m, ClCH2CH2CH2), 2.00 (3H, s,
MeCO), 3.50 (2H, m, ClCH2), 3.70–4.00 (4H, 2×m,
ꢀOCH2CH2Oꢀ), 4.10 (2H, s, CH2OAc), 7.35 (4H,
m, Ar).
92%); H NMR (CDCl3) l 1.55 (6H, s, 2×Me), 1.85
(2H, m, ClCH2CH2), 2.00 (2H, m, ClCH2CH2CH2),
3.50 (2H, t, ClCH2), 3.65 (3H, s, OMe), 3.70–4.00 (4H,
2×m, ꢀOCH2CH2Oꢀ), 7.35 (4H, m, Ar).
5.9. Methyl 2-[4-(4-chlorobutyryl)-phenyl]-isobutyrate
(15)
A 2 N HCl solution in THF (76 ml) was added to a
solution of 14 (12.0 g, 36.7 mmol) in THF (74 ml) and
the resulting mixture was magnetically stirred for 15 h
at room temperature. The reaction mixture was then
diluted with water (100 ml) and extracted with AcOEt
(3×50 ml). The combined organic phases were washed
with water (50 ml), brine (50 ml) and dried over anhy-
drous Na2SO4. After evaporation of the solvent, the
residue (10 g) was submitted to flash chromatography:
elution with light petroleum–ether (8:2) yielded 15
5.6. 2-[4-(1-Ethylendioxo-4-chlorobutyl)-phenyl]-
isobutanol (12)
1
(9.26 g, 89%); H NMR (CDCl3) l 1.60 (6H, s, 2×
Me), 2.20 (2H, m, ClCH2CH2), 3.15 (2H, t, CH2CO),
3.68 (2H, t, ClCH2), 3.70 (3H, s, OMe), 7.45 and 7.95
(4H, 2×d, J=8.5 Hz, Ar); 13C NMR (CDCl3) l
26.34, 26.80, 35.20, 44.53, 46.82, 52.26, 126.00, 128.17,
135.28, 150.11, 176.46, 198.35.
A solution of 11 (14.0 g, 41.1 mmol) in 2% methano-
lic NaOH (300 ml) was stirred at room temperature for
30 min. The reaction mixture was then diluted with
water (200 ml) and extracted with AcOEt (3×300 ml).
The combined organic phases were washed with brine
(200 ml) and dried (Na2SO4). Evaporation of the sol-
5.10. Methyl 2-[4-(1-hydroxy-4-chlorobutyl)-phenyl]-
isobutyrate (16)
1
vent afforded 12 (12.2 g, 99%); H NMR (CDCl3) l
1.35 (6H, s, 2×Me), 1.85 (2H, m, ClCH2CH2), 2.00
(2H, m, ClCH2CH2CH2), 3.50 (2H, t, ClCH2), 3.60
(2H, s, CH2OH), 3.70–4.00 (4H, 2×m, ꢀOCH2-
CH2Oꢀ), 7.35 (4H, m, Ar).
A suspension of NaBH4 (5.0 g, 133 mmol) in MeOH
(300 ml) was added to a cold (0°C), magnetically
stirred solution of 15 (9.26 g, 32.7 mmol) in THF (600
ml). Stirring was continued at 0°C for 30 min after
which pH was adjusted to 7 (3 N HCl) and the solvent
evaporated off. The residue was taken up in AcOEt (80
ml), washed with water (2×20 ml), brine (20 ml) and
dried over anhydrous Na2SO4. Evaporation of the sol-
vent and flash chromatography of the residue (light
5.7. 2-[4-(1-Ethylendioxo-4-chlorobutyl)-phenyl]-
isobutyric acid (13)
Jones reagent (30 ml) was added dropwise in 15 min
to a solution of 12 (14.0 g, 46.8 mmol) in acetone
(1000 ml) kept under stirring at 0°C. The reaction
mixture was then filtered the filtrate was diluted with
AcOEt (1000 ml), washed with water (5×300 ml),
brine (300 ml) and dried (Na2SO4). Evaporation of the
1
petroleum–AcOEt, 8:2) afforded 16 (8.9 g, 95%); H
NMR (CDCl3) l 1.55 (6H, s, 2×Me), 1.85 (4H, m,
CH2CH2CHOH), 2.45 (1H, br s, OH), 3.50 (2H, m,
ClCH2), 3.60 (3H, s, OMe), 4.65 (1H, t, CHOH), 7.30
(4H, m, Ar).
1
solvent yielded 13 (13.0 g, 89%); H NMR (CDCl3) d