An improved synthesis of a b-blocker celiprolol hydrochloride

Article abstract of DOI:10.3184/174751911X13192995267028

Celiprolol hydrochloride, a β-blocker drug, has been synthesised from 4-chloronitrobenzene. The route involved hydrolysis of the chloride and acetylation of the phenol, reduction of the nitro group, and acylation of theamine. This was followed by Fries rearrangement of the acetyl group, Williamson etherification with epichlorohydrin, followed by opening of the epoxide ring and salt formation. The overall yield of celipropol was 39.1% on the basis of 4-chloronitrobenzene. The Fries rearrangement was substantially improved. The process is suitable for industrial application because of its convenient and environmentally friendly reaction conditions.

Full text of DOI:10.3184/174751911X13192995267028

640 RESEARCH PAPER
NOVEMBER, 640–643
JOURNAL OF CHEMICAL RESEARCH 2011
An improved synthesis of a b-blocker celiprolol hydrochloride
Li Jia, Xiao-yuan Maob, Chao Qiana,* and Xin-zhi Chena
aDepartment of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, P. R. China
bCollege of Chemical Engineering and Materials Science, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
Celiprolol hydrochloride, a β-blocker drug, has been synthesised from 4-chloronitrobenzene. The route involved
hydrolysis of the chloride and acetylation of the phenol, reduction of the nitro group, and acylation of theamine.
This was followed by Fries rearrangement of the acetyl group, Williamson etherification with epichlorohydrin,
followed by opening of the epoxide ring and salt formation. The overall yield of celipropol was 39.1% on the basis of
4-chloronitrobenzene. The Fries rearrangement was substantially improved. The process is suitable for industrial
application because of its convenient and environmentally friendly reaction conditions.
Keywords: celiprolol hydrochloride, 4-chloronitrobenzene, fries rearrangement, co-solvent, epichlorohydrin, β-blockers
Aryloxypropanolamine (1) drugs are useful β-blockers, β-
adrenergic receptor blocking drugs, which have been pre-
scribed for treating cardiovascular disorders such as cardiac
arrhythmia or ischaemic heart disease and hypertension since
the 1980s.1–2 A large number of β-blockers related to 1 have
been marketed including propranolol, nodolol, practolol,
metaprolol, 4-hydroxypropranolol, and celiprolol.3 Celiprolol
hydrochloride (2) is a long-acting cardioselective β-adrenergic
receptor blocking agent which also possesses α2-receptor
blocking properties.4
solvent, is poisonous and it complicated the separation of
rearrangement product which was isolated by steam distilla-
tion or by extracting with aqueous alkali. The Fries rearrange-
ment can be considered to be the ‘bottleneck’ of the whole of
Joshi’s route.
Here we report our effort aimed at a novel approach of
celiprolol base (7) starting from 4-chloronitrobenzene (14),
which is less expensive than the starting materials.
Results and discussion
The current synthesis5 of celiprolol (2) starts from 4-ethoxy
aniline (3) (Scheme 1). This is treated with diethyl carbamoyl
chloride in the presence of potassium bicarbonate to give 3-
(4-ethoxyphenyl)-1,1-diethylurea (4). Friedel-Crafts acylation
with acetyl chloride catalysed by aluminum chloride gives
an acetophenone derivative. Reaction of the acetophenone
derivative 5 with epichlorohydrin followed by treatment
with hydrobromic acid gives the bromohydrin (6). Celiprolol
base (7) is obtained by reaction of the bromohydrin (6) with
tert-butylamine, in the presence of triethylamine, and this is
converted to the hydrochloride salt. This starts from an expen-
sive reactant and the preparation of bromohydrin (6) with
hydrobromic acid is unnecessary.
Celiprolol hydrochloride was prepared (Scheme 3) by hydro-
lysis of the chlorine, esterification, reduction of the nitro
group and acylation of amine. This was followed by Fries rear-
rangement of the phenolic ester and Williamson etherification
with epichlorohydrin. Opening of the epoxide ring and salt
formation gave celiprolol hydrochloride.
The key intermediate in the synthetic sequence was the
urea derivative 17. Its retrosynthesis is given in Scheme 4.
Disconnection 17a would require an acylation with diethyl
carbamoyl chloride (DECC) of an aniline derivative 19, which
could be prepared from 15 by Fries rearrangement or from
10 by reduction of the nitro group. The amino group must
be protected in advance since it is more nucleophilic than
the hydroxyl group in the acetylation of 20 to prepare 15.
In the other plan involving 4-nitrophenyl acetate (9), the
nitro group was the major barrier to improving the yield of the
Fries rearrangement7 which was similar with Joshi’s route.
Finally, we chose the disconnection 17b in which the Fries
rearrangement was carried out with a relatively weak electron
donating substituent on the benzene ring. The acetyl group was
An improved process reported by Joshi et al.6 started from
4-nitrophenol. The nitro group was not reduced until interme-
diate 12 was obtained as shown in Scheme 2. Although the
presence of nitro group in the aromatic ring simplified the
purification of the intermediates, this strong electron-with-
drawing group meant that the Fries rearrangement proceeded
in a low yield. Moreover, nitrobenzene which was chosen as
Scheme 1 Zolss’s route.
* Correspondent. E-mail: chemtec@163.com

JOURNAL OF CHEMICAL RESEARCH 2011 641
Scheme 2 Joshi’s improved route.
Scheme 3 An improved route of celiprolol.

642 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 4 The retrosynthesis of 17.
Table 2 Yield of 18 with different amounts of epichlorohydrin
in the O-alkylation
introduced before reduction of the nitro of 4-nitrophenol which
was prepared from 4-chloronitrobenzene (14).
The preparation of 4-nitrophenyl acetate (9) from 4-
chloronitrobenzene (14) has been studied in our previous
work.8 The product of hydrolysis, sodium 4-nitrophenolate
was acetylated successfully with acetic anhydride and without
any catalyst.
The reaction temperature for the Fries rearrangement is
usually higher than 100 °C, and the solvents which are used
are always high boiling point liquids such as chlorobenzene
or nitrobenzene, which are both poisonous and explosive7,9.
Initially, it was found that the mixture of anhydrous aluminum
chloride and the reactant 16 gave a tarry viscous product under
solvent-free conditions. Three alkali or alkaline-earth metal
salts were added respectively, and it was found that sodium
chloride and potassium chloride were good co-solvents in the
proportions as shown in Table 1. In addition, the subsequent
treatment of the product was much simpler than other processes
mentioned above.
O-Alkylation of intermediate 17 with an excess of epichlo-
rohydrin in the presence of sodium hydroxide and a catalytic
amount of DMSO was also studied. The proper molar ratio
of epichlorohydrin and 17 was 2.0 to give 18 in 82.3% yield
(Table 2). DMSO was employed as a co-solvent and played an
important role in the O-alkylation as shown in Table 3.
The synthesis of celiprolol base (7), required the ring-
opening of epoxide 18, with tert-butylamine. This afforded the
Entry
Epichlorohydrin/mola
Yield /%b
1
2
3
4
5
0.10
0.15
0.20
0.25
0.30
61.2
73.5
82.3
83.9
83.7
a Condition: 0.1mol reactant 17, 50 °C, 12 h.
b Isolated yield.
Table 3 Conversion of 17 with different amounts of DMSO in
the O-alkylation
Entry
DMSO/mLa
Reaction time/h Conversionb
1
2
3
4
5
0
1
24
Partial
24
Complete
Complete
Complete
Complete
3
17.5
12
11
5
10
a Reactants and condition: reactant 17 (37.5 g, 0.15 mol), epichlo-
rohydrin (47.1 g, 0.30 mol), sodium hydroxide (8 g, 0.20 mol) ,
50 °C.
b Monitored by TLC (EtOAc/hexanes = 1:1, V/V).
solid product without treatment the intermediate 18 with
hydrobromic acid to give a bromohydrin. Different solvents or
solvent-free conditions were employed. Water unfortunately
was not a good candidate but the reaction in ethanol gave 7 in
92.3% yield (Table 4).
Celiprolol base (7) was converted to celiprolol hydrochlo-
ride (2) by treatment with moisture-free hydrogen chloride in
acetone in 81.3% yield.
In conclusion, the new improved process for celiprolol
overcomes the disadvantages of Zolss’s and Joshi’s processes.
Every step gives fulfilling satisfactory yield and the overall
yield is 39.1% on the basis of 4-chloronitrobenzene, which is
higher than Zolss’s (35.9%) and Joshi’s (33.3%) processes.
Table 1 The effect of different salts and molar ratios on the
reaction mixture
Entry
Composition
Molar ratio a Appearance
1
2
3
4
5
6
AlCl3 + 16
1: 1
Darkened
Paste
Paste
Paste
Liquid
Liquid
AlCl3 + CaCl2 + 16
AlCl3 + NaCl + 16
AlCl3 + NaCl + 16
AlCl3 + NaCl + 16
AlCl3 + KCl + 16
3: 3: 1
1: 1: 1
2: 2: 1
3: 3: 1
3: 3: 1
a On the basis of reactant 16.

JOURNAL OF CHEMICAL RESEARCH 2011 643
Table 4 Different solvents employed in the synthesis of
celiprolol base (7)
washed with ice water until the washings were acid-free. The product
was dried in the air, giving a white crystalline powder (21.2 g, 84.7%).
The intermediate 17 was recrystallised from diisopropyl ether
Entry
Solventa
Reaction time/h Yield/%b
1
and ethyl acetate (5:1), m.p. 105.3–107.5 °C. H NMR (400 MHz,
CDCl3): δ 12.04 (bs, 1 H), 8.01 (d, J = 2.0 Hz, 1 H), 7.26 (dd,
J = 2.0 Hz, J = 7.5 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 6.40 (bs, 1H),
3.38 (q, J = 10.0 Hz, 4 H), 2.61 (s, 3H), 1.22 (t, J = 10.0 Hz, 6H).
Anal. Calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C,
62.35; H, 7.31; N, 11.17%.
1
2
3
4
5
Water
24
8
71.3
92.3
79.5
75.2
68.9
Ethanol
Acetone
Dichloromethane
Neat
8
8
8
Celiprolol base (7): The intermediate 17 (37.5 g, 0.15 mol), epi-
chlorohydrin (47.1 g, 0.30 mol), sodium hydroxide (8.0 g, 0.20 mol),
and DMSO (5 mL) were cplaced in a reaction vessel. The solution
was stirred for 12 h at 50 °C, cooled to room temperature, and filtered.
The excess epichlorohydrin was recovered from the filtrate by con-
centration under vacuum. Toluene (200 mL) was added to the residue
to extract the product. The organic layer was washed with dilute
sodium hydroxide (200 mL, 8%), then saturated sodium chloride
solution (200 mL). The toluene was removed by water bath under
reduced pressure. Ethanol (200 mL) and tert-butylamine (109.5 g,
1.5 mol) were poured into the residue, which was then refluxed for 8 h
to allow the reaction to proceed to completion. Acetone (100 mL) was
added to the mixture, which had been concentrated under vacuum, to
precipitate the product. The mixture was filtered off and washed with
acetone and water. The product was dried in the air, giving a white
crystalline powder 7 (43.0 g ,76%), m.p. 116.4–118.0 °C, lit.5 117–
118 °C, TLC: homogeneous with authentic specimen. Anal. Calcd for
C20H33N3O4: C, 63.30; H, 8.76; N, 11.07. Found: C, 63.25; H, 8.80; N,
11.04%.
Celiprolol hydrochloride (2): Celiprolol base 7 (38 g, 0.1 mol) was
dissolved in 170 mL acetone and cooled to room temperature.
Moisture-free hydrogen chloride dried with concentrated sulfuric acid
was injected into the reaction vessel continuously until the pH was
5.5–6.0 ensuring the product was completely precipitated. The sepa-
rated solid was filtered and washed with acetone, and dried in air to
give the title compound 2 (37.0 g, 81.3%), m.p. 197.8–198.4 °C, lit.6
197–198 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.0 Hz, 1 H),
7.59 (dd, J = 2.0, 9.0 Hz, 1 H), 6.86 (d, J = 9.0 Hz, 1 H), 6.36 (bs, 1
H), 4.15–4.20 (m, 1 H), 3.85–4.05 (m, 2 H), 3.40 (q, J = 10.0 Hz, 4
H), 2.96–3.10 (m, 2 H), 2.60 (s, 3 H), 2.55 (bs, 2 H), 2.20 (bs, 1 H),
1.47 (s, 9 H), 1.20 (t, J = 10.0 Hz, 6 H).
a Condition: tert-butylamine (109.5 g, 1.5 mol) and 200 mL
solvent, reflux, 8h.
b Isolated yield.
Experimental
All reagents were obtained commercially and were used without
further purification. Melting points were determined on a WSR-2
1
capillary melting point apparatus and are uncorrected. H NMR data
were recorded on a Bruker 400 MHz spectrometer operating at
400 (1H) MHz in CDCl3 solutions and TMS as internal standard.
Elemental analyses were recorded on a Vario E1 III elementary
analyser.
4-Nitrophenyl acetate (9): 4-Nitrochlorobenzene (14) (15.8 g,
0.10 mol) was taken up in 15% aqueous sodium hydroxide (66.7 g,
0.25 mol) in a 400-mL autoclave. The mixture was heated at 140 °C
for 10 h, after which time the starting material had been consumed as
shown by TLC (developing solvent, EtOAc/hexane = 1:4, V/V), the
pressure during reaction was 0.3 MPa). The mixture was then cooled
to room temperature, and the resulting orange solid was filtered and
washed with EtOAc (10 mL). The crude product and acetic anhydride
(20.4 g, 0.2 mol) were stirred in a flask and heated to 80 °C for 30 min
and then cooled. Water was added to precipitate the product. The
precipitated product was filtered off, washed with water and dried in
the air, giving a pale yellow crystalline powder (16.4 g, 90.5%), m.p.
1
77.2–78.1 °C, lit.10 77–78 °C. H NMR (400 MHz, CDCl3): δ 8.28
(d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 2.36 (s, 3H).
4-Aminophenyl acetate (15): 4-Nitrophenyl acetate (9) (18.0 g,
0.1 mol) in ethyl acetate (100 mL) was hydrogenated at 0.5 MPa
with 5% Pd/C (1.0 g) at 65 °C. The reaction was monitored by
TLC (developing solvent, EtOAc/hexanes = 1:4, V/V). After complete
reduction (6.5 h), the catalyst was filtered, and the filtrate was
concentrated under vacuum to afford the amino compound (15)
We thank the National Natural Science Foundation of China
(20776127), the National Key Technology R&D Program
(2007BAI34B07), the Natural Science Foundation of the
Zhejiang Province (Y4090045, R4090358).
1
(13.9 g, 92%), m.p. 72.4–74.2 °C, lit.11 73 °C. H NMR (400 MHz,
CDCl3): δ 6.82 (d, J = 8.8 Hz, 2 H), 6.59 (d, J = 8.8 Hz, 2 H), 3.62 (bs,
2 H), 2.22 (s, 3 H).
4-(3,3-Diethylureido) phenyl acetate (16): The acetate (15) (49.0 g,
0.33 mol), sodium bicarbonate (56.0 g, 0.67 mol) and acetone (80 mL)
were combined and stirred. DECC (50 mL, 0.37 mol) was added
dropwise with a cooling bath maintaining the temperature below
30 °C. After the addition was complete, the temperature of the mixture
was kept at 30 °C for 12 h. Then the mixture was refluxed for 5 h,
after which time the starting material 15 had been consumed as shown
by TLC (developing solvent, EtOAc/hexanes = 1:1, V/V). A saturated
solution of sodium bicarbonate (200 mL) was added to the mixture,
which was stirred for a further 5 min. The oily layer was separated
from the mixture, and its pH was adjusted to 6.0 by the addition of
concentrated hydrochloric acid. The precipitated product was filtered
off and washed with water. The product was dried in the air, giving
a white solid (74.0 g, 90.8%), m.p. 133.2–134.7 °C. 1H NMR
(400 MHz, CDCl3): δ 8.10 (s, 1 H), 7.17 (d, J = 7.8 Hz, 2H), 6.63
(d, J = 7.8 Hz, 2H), 3.33(q, J = 10.0 Hz, 4H), 2.20 (s, 3 H), 1.08
(t, J = 10.0 Hz, 6H). Anal. Calcd for C13H18N2O3: C, 62.38; H, 7.25; N,
11.19. Found: C, 62.32; H, 7.35; N, 11.14%.
Received 8 October 2011; accepted 20 October 2011
Paper 1100920 doi: 10.3184/174751911X13192995267028
Published online: 22 November 2011
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