Z. Yu et al.
After stirring for further 0.5 h, the reaction mixture was cooled to
ambient temperature, filtered and filtercake was washed with
carbon tetrachloride (3 Â 5 mL). The filtrate was washed with
saturated sodium bicarbonate solution, dried over MgSO4 and
evaporated to afford compound (4) as a brown solid (4.35 g,
90%). The compound (4) was used directly without further
purification.
Methyl-2,2-dimethyl-2-phenyl acetate (8)
Methanol (25 mL), 2,2-dimethyl-2-phenyl-aceic acid (5.03 g,
30.6 mmol) and concentrated sulphuric acid (98%, 1 mL) were
charged to a flask at ambient temperature. The temperature was
raised to reflux at 701C and maintained for 12 h. After
completion, the mixture was cooled to ambient temperature,
neutralized with aqueous ammonia and extracted with dichlor-
omethane (3 Â 50 mL). The combined dichloromethane layers
were dried over MgSO4 and concentrated to obtain compound
(8) as a colorless liquid (5.12 g, 94%).
1-[4-(1,1-dimethylethyl)phenyl]-4-[4-hydroxy-1-piperidi-
neyl]-butanone (5)
To a suspension of anhydrous Na2CO3 (2.68 g, 25.2 mmol) and KI
(4.25 g, 25.6 mmol) in acetone (50 mL) was added 4-chloro-1-[4-
(1,1-dimethylethyl)phenyl]-1-butanone (5.97 g, 25.0 mmol) and
4-hydropiperidine (5.06 g, 50.1 mmol). The reaction mixture was
refluxed at 701C overnight. After completion, the mixture was
cooled to ambient temperature and filtered. The filter cake
was washed with acetone (3 Â 5 mL) and the filtrate was
evaporated to afford a brown sticky liquid. The crude product
was purified by chromatography on silica gel (120 g) column,
eluted with 0–5% MeOH in dichloromethane. The title
compound was obtained as a pale yellow solid (4.57 g, 60%).
1HNMR (CDCl3): d 1.34 (s, 9H), d 1.55–1.65 (m, 2H), d 1.93–2.02
(m, 4H), d 2.27 (t, J = 12.0 Hz, 2H), d 2.49 (t, J = 9.0 Hz, 2H),
d 2.81–2.88 (m, 2H), d 3.00 (t, J = 6.0 Hz, 2H), d 3.71-3.76 (m, 1H),
d 7.46 (d, J = 9.0 Hz, 2H), d 7. 89 (d, J = 9.0 Hz, 2H).
1H-NMR (CDCl3): d 1.58 (s, 6H), d 3.65 (s, 3H), d 7.21–7.26
(m, 2H), d 7.33 (d, J = 3.0 Hz, 3H).
2-methyl-2-phenyl propanol (9)
To a chilled solution of compound (8) (5.12 g, 28.7 mmol) in dry
THF (20 mL) was added sodium borohydride (1.06 g, 28.0 mmol)
in portions within 0.5 h. The mixture was stirred at ambient
temperature for 3 h. After completion, the PH was adjusted to
3–4 with 10% HCl and the mixture was filtered. The filtrate
was extracted with dichloromethane (3 Â 50 mL) and the
combined extracts were dried over MgSO4, concentrated under
reduced pressure to obtain compound (9) as a colorless liquid
(3.95 g, 92%).
2-methyl-2-phenylpropyl acetate (10)
[2H5]-ebastine (6)
To a chilled solution of compound (9) (3.95 g, 26.3 mmol) in
pyridine (20 mL) was added acetic anhydride (5.31 g, 52.1 mmol)
slowly. The mixture was stirred for 2 h at 10–201C, then ethyl
acetate (50 mL) and chilled water (25 mL) were added to quench
the reaction. After stirring for further 0.5 h, 10% chilled HCl
(50 mL) was added to the mixture. The organic layer was
separated and washed with saturated sodium bicarbonate
solution until PH of 7–8 was obtained. The separated organic
layer was dried over MgSO4 and concentrated under reduced
pressure to obtain 2-methyl-2-phenylpropyl acetate (10) as a
pale green liquid (4.45 g, 88%).
To a suspension of anhydrous Na2CO3 (1.23 g, 11.6 mmol) in
toluene (10 mL) was added [2H5]-bromodiphenylmethane (4)
(0.91 g, 3.6 mmol) and compound (5) (1.12 g, 3.7 mmol). The
reaction mixture was refluxed at 1251C for 6 h and then cooled
to amibent temperature. The precipitate were filtered and
filtercake was washed with toluene (3 Â 2 mL). The solvent
was removed under reduced pressure to give the product as a
dark brown sticky liquid. The crude product was purified by
chromatography on silica gel (60 g) column, eluted
with 0–40% EtOAc in hexane to afford (6) as a white solid
(1.10 g, 65%).
1HNMR (CDCl3): d 1.34 (s, 9H), d 1.67–1.73 (m, 2H), d 1.87–1.97
(m, 4H),d 2.12 (s, 2H), d 2.38 (t, J = 9.0, 2H), d 2.76 (t, J = 6.0, 2H),
d 2.97 (t, J = 9.0, 2H), d 3.41–3.43 (m, 2H), d 5.51 (s, 1H), d 7.21–7.35
(m, 5H), d 7.45 (d, J = 9.0 Hz, 2H), d 7. 89 (d, J = 9.0 Hz, 2H).
Ethyl-2-[4-(4-chloro-butyryl)phenyl]-2-methyl propanoate (11)
Dry Dichloromethane (30 mL) and aluminium chloride (4.61 g,
34.6 mmol) were charged to a flask and chilled to À101C
in a ice–salt bath. Compound (10) (4.45 g, 23.1 mmol) was
stripped with toluene (2 Â 10 mL), dissolved in dry dichloro-
methane (10 mL) and added slowly. The mixture was stirred
for 0.5 h at À101C under N2 atmosphere. 4-chloro butyryl
chloride (3.90 g, 27.7 mmol) was dissolved in dry dichloro-
methane (10 mL) and added slowly to the reaction mixture.
The mixture was stirred for additional 2 h at 01C. After
completion, the mixture was quenched slowly with 10% HCl
at 10–201C. The dichloromethane layer was separated and the
aqueous layer was extracted with dichloromethane (2 Â 80 mL).
The combined dichloromethane layers were dried over MgSO4
and concentrated under vacuum to obtain crude product as a
brown sticky liquid. The crude product was purified by
chromatography on silica gel (120 g) column, eluted with
EtOAc/Hexanes (1:10) to obtain (11) as a pale brown liquid
(4.78 g, 70%).
[2H5]-ebastine fumarate(7)
[2H5]-ebastine (6) (1.10 g, 2.3 mmol) was dissolved in ethanol
(2 mL) and stirred at amibent temperature. Fumaric acid (0.26 g,
2.3 mmol) was dissolved in ethanol (4 mL) and added to
the reaction flask drop wise. The reaction mixture was stirred
for 20 min. Some white precipitate started to form. The
precipitate was filtered and washed with ethanol (2 Â 1 mL).
The solid was dried under vacuum to afford (7) as a white solid
(1.26 g, 92%).
1HNMR (DMSO-d6): d 1.29 (s, 9H), d 1.54–1.62 (m, 2H), d
1.80–1.84 (m, 4H), d 2.34 (s, 2 H), d 2.50 (t, J = 3.0 Hz, 2H), d 2.84
(t, J = 9.0 Hz, 2H), d 3.00 (t, J = 6.0 Hz, 2H), d 3.39 (s, 1H), d 5.51
(s, 1H), d 6.57 (s, 2H), d 7.29–7.38 (m, 5H), d 7.51 (d, J = 9.0 Hz, 2H),
d 7.87 (d, J = 9.0 Hz, 2H). MS-EI (m/z): 474.2 (5), 475.2 (M1, 100),
476.2 (40), 477.2 (10), 487.2 (2). HPLC (XDB-C18, CH3OH/
10mmol/L CH3COONH4 10.05% TEA = 90/10, 1.0 mL/min):
tR 6.1 min (499.5%).
1H-NMR (CDCl3): d 1.39 (s, 6H), d 2.00 (s, 3H), d 2.19–2.28
(m, 2H), d 3.18 (t, J = 9.0 Hz, 2H), d 3.70 (t, J = 3.0 Hz, 2H), d 4.16
(s, 2H), d 7.46 (d, J = 6.0 Hz, 2H), d 7.93 (d, J = 9.0 Hz, 2H).
J. Label Compd. Radiopharm 2011, 54 352–356
Copyright r 2011 John Wiley & Sons, Ltd.