δ 2.73 (s, 3H, Ac), 7.04 (d, J ) 9.0, Hz, 1 H, Ar), 8.34 (dd,
J ) 2.0, 9.0 Hz, 1 H, Ar), 8.69 (d, J ) 2.0 Hz, 1H, Ar),
was filtered, and the filtrate was concentrated under vacuum
to afford the amino compound (13) (25 g, 92%).
1
1
2.84 (s, 1H, OH).
-[(2′,3′-Epoxy)-propoxyl-5-nitro-acetophenone (11). A
mixture of 10 (60 g, 0.33 mol), K CO (92 g, 0.66 mol),
HNMR (200 MHz, CDCl ) δ 1.15 (s, 9H, t-Bu), 2.50-
3
2
2.75 (m, 5H, Ac, NCH and OH), 2.86 (m, 1H, NCH), 3.60
2
3
(
(
2
m, 1H, CHO), 4.0 (m, 2H, OCH ), 4.85 (bs, 1H, NH), 6.80
bs, 2H, Ar), 7.05 (s, 1H, Ar).
benzyltriethylammonium chloride (4.0 g, 0.017 mol), and
epichlorohydrin (700 mL) were heated at 75 °C with stirring
for 10 h, cooled to room temperature, and filtered. The filtrate
To the amine (13) (20 g, 0.071 mole) in THF (100 mL)
containing Et N (25 mL, 0.18 mol) and maintained at 40
C, was added DECC (15 mL), and the reaction progress
3
was concentrated under vacuum to afford 11 (75 g, 96%)
°
1
(
500 mL of epichlorohydrin is recovered). H NMR (200
was monitored by HPLC. After 48 h the reaction mixture
was concentrated, extracted with ethyl acetate (2 × 100 mL),
dried over anhydrous sodium sulfate, and concentrated. The
residue was dissolved in acetone (200 mL) and filtered
through a short bed of neutral alumina. The filtrate was
concentrated under vacuum to afford celiprolol base (6) (24.3
g, 90%) and crystallized from acetone, mp 116-118 °C lit.4
MHz, CDCl
H), 3.46 (m, 1H), 4.08 (dd, J ) 7.4, 13.7 Hz, 1 H), 4.58
dd, J ) 3.1, 13.7 Hz, 1 H), 7.08 (d, J ) 9.0 Hz, 1 H, Ar),
3
) δ 2.67 (s, 3H, Ac), 2.80 (m, 1H), 2.99 (m,
1
(
8
.31 (dd, J ) 2.0, 9.0 Hz, 1 H, Ar), 8.58 (d, J ) 2.0 Hz, 1
+
H, Ar). Mass: 237(M ).
2-(3′-tert-Butylamino-2′-hydroxy-propoxy)-5-nitro-ace-
tophenone (12). Glycidyl ether (11) (75 g, 0.316 mole), tert-
butylamine (100 mL, 0.95 mol) and water (300 mL) were
combined and stirred at room temperature for 12 h. Excess
of tert-butylamine was removed under reduced pressure, and
the resulting residue was extracted with ethyl acetate (2 ×
(
117-118 °C), TLC: homogeneous with authentic specimen;
1
H NMR (200 MHz, CDCl
8.0 Hz, 6 H, 2 x CH ), 2.20 (bs, 1 H, OH), 2.55-2.70
m, 4H, Ac and NCH), 2.85 (dd, J ) 4.0, 13.5 Hz, 1H,
NCH), 3.34 (q, J ) 8.0 Hz, 4H, 2 x CH ), 3.85-4.05 (m,
H, OCH and CHO), 6.36 (s, 1H, NH), 6.86 (d, J ) 9.0
3
) δ 1.07 (s, 9H, t-Bu), 1.20 (t, J
)
(
3
3
300 mL). The organic layer was dried with anhydrous sodium
3
2
sulfate and concentrated to give 12 (84 g, 86%). The
intermediate 12 was recrystallized from diisopropyl ether and
Hz, 1H, Ar), 7.44 (d, J ) 2.0 Hz, 1H, Ar), 7.75 (dd, J )
2.0, 9.0 Hz, 1H, Ar).
1
ethyl acetate (5:1), mp 105-107 °C. H NMR (200 MHz,
Celiprolol Hydrochloride (2). Celiprolol base 6 (24 g,
CDCl
3
) δ 1.10 (s, 9 H, t-Bu), 2.30 (bs, 1H, OH), 2.70 (m,
H, Ac and NCH), 2.90 (dd, J ) 4.0, 13.5 Hz, 1H, NCH),
.0 (m, 1H, CHO), 4.20 (m, 2H, OCH ), 7.06 (d, J ) 9.0
0
.0615 mol) was dissolved in 100 mL acetone and cooled
to 20 °C. 4 N HCl (20 mL) was added until the pH is 5.5-
.0 and stirred for 90 min. The separated salt was filtered
and washed with acetone and dried to give the title compound
4
4
2
6
Hz, 1H, Ar), 8.30 (dd, J ) 2.0, 9.0 Hz, 1H, Ar), 8.58 (d, J
2.0 Hz, 1H, Ar). Analysis. Calcd. For C15 : C,
8.06; H, 7.09. Found: C, 57.83; H, 7.21.
Celiprolol Base (6). Compound 12 (30, 0.096 mol) in
)
22 5 2
H O N
2
,3
5
2 (21 g, 80%), mp 197-198 °C, lit. mp 197-200 °C.
methanol (180 mL) was hydrogenated at 20 psi with 10%
Pd/C (3 g) at room temperature. The reaction was monitored
by HPLC. After complete reduction (5-6 h), the catalyst
Received for review September 23, 2000.
OP000297L
178
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development