Formal synthesis of the ACE inhibitor benazepril·HCl via an asymmetric aza-Michael reaction

Article abstract of DOI:10.3390/11080641

A formal enantioselective synthesis of benazepril·HCl (4), an antihypertensive drug, is reported. Our synthesis employed an asymmetric aza-Michael addition of L-homophenylalanine ethyl ester (LHPE, 1) to 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl est

Full text of DOI:10.3390/11080641

Molecules 2006, 11, 641-648
molecules
ISSN 1420-3049
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Full Paper
Formal Synthesis of the ACE Inhibitor Benazepril·HCl via an
Asymmetric Aza-Michael Reaction
Luo-Ting Yu 1,2,5, Ji-Ling Huang 1, Ching-Yao Chang 3,4 and Teng-Kuei Yang 3,5,*
1 Laboratory of Organometallic Chemistry, East China University of Science & Technology, Shanghai,
200237, P.R. China
2
Department of Pharmaceutical and Biochemical Engineering, Sichuan University, Sichuan, 610065,
P.R. China
3
Department of Chemistry, National Chung-Hsing University, Taichung, 402, Taiwan
4
Department of Biotechnology and Bioinformatics, Asia University, Wufeng, Taichung, 413, Taiwan
5
Wisdom Pharmaceutical Co. Ltd., Haimen, Jiangsu, 226100, P.R. China
*Author to whom correspondence should be addressed; e-mail: tk@wisdompharma.com.
Received: 26 June 2006; in revised form: 20 July 2006 / Accepted: 23 August 2006 / Published: 23
August 2006
Abstract: A formal enantioselective synthesis of benazepril·HCl (4), an anti-
hypertensive drug, is reported. Our synthesis employed an asymmetric aza-Michael
addition of L-homophenylalanine ethyl ester (LHPE, 1) to 4-(2-nitrophenyl)-4-oxo-
but-2-enoic acid methyl ester (6) as the key step to prepare (2S,3’S)-2-(2-oxo-2,3,4,5-
tetrahydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric acid ethyl ester (8), which
is the key intermediate leading to benazepril·HCl (4).
Keywords: Asymmetric Aza-Michael reaction, L-homophenylalanine ethyl ester,
benazepril·HCl, ACE inhibitor.
Introduction
Angiotensin converting enzyme (ACE) inhibitors [1] constitute a major class of anti-hypertensive
drugs that has been widely studied and developed over the past few decades. Among the familiar ACE
inhibitors that have come to the market or to the clinic, most contain an unnatural chiral amino ethyl

Molecules 2006, 11
642
ester, L-homophenylalanine ethyl ester (LHPE, 1), in their framework, such as enalapril (2) [2],
lisinopril (3) [3], and benazepril·HCl (4) [4] (Figure 1).
Figure 1. LHPE and related ACE inhibitors.
O
H
NH2
CO2Et
N
N
CH3 CO2Et
CO2H
Enalapril 2
LHPE 1
O
H
N
H
N
N
CO2Et
CO2H
CO2Et
N
HCl
O
CO2H
H2N
Benazepril⋅HCl 4
Lisinopril 3
Among them, benazepril·HCl (4) is the most potent one, having less side-effects and better stability
due to its unique skeleton, different from that of the others. Compound 4 has been a quite popular
subject over the years in both academic and industrial sectors, but only a few papers have been
published concerning its synthesis. Both Watthey [4] and Boyer [5] used α-tetralone as starting
material to prepare benazepril·HCl (4), and both their synthesis went through rather tedious resolution
processes. Herein, we describe a convergent pathway in which compound 8, a key chiral intermediate
to benazepril·HCl (4), was prepared through an asymmetric aza-Michael reaction.
The asymmetric aza-Michael addition reaction of chiral amines to α,β-unsaturated carbonyl
compounds is a very useful method to prepare optical active amino acids [6] because of its mild
reaction conditions and good chemical yields. In our strategy, commercially available LHPE 1 was
employed as nucleophilic reagent toward 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl ester (6) to
set up the second chiral center via an asymmetric 1,4-addition reaction. The nitro group of the coupled
ethyl ester 7 was then reduced by Pd/C catalyzed hydrogenation, and the resulting amino group reacted
in situ intramolecularly with the ester group to give the cyclized (2S,3’
S
)-caprolactam 8 (Scheme 1).
-benzo[ ]azepin-3-
From the compound 8, (2 ,3' )-2-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1
S
S
H
b
ylamino)-4-phenylbutyric acid ethyl ester hydrochloride (benazepril·HCl, 4) could be then prepared
efficiently [7].

Molecules 2006, 11
643
Scheme 1.
EtO
HN
O
O
NH2
OCH3
O
CH2Cl2, r.t
CO2Et
OCH3
+
O
NO2
O
aza-Michael reaction
NO2
LHPE 1
7
6
1) 150psi H2, Pd-C, 40 oC,
THF(1N HCl)
2) HOAc/ Toluene, 90 oC
H
H
N
ref. 7
N
CO2Et
N
CO2Et
N
O
HCl
O
H
CO2H
(2S, 3'S)-8
Benazepril HCl 4
Results and Discussion
First, we used commercially 40% aqueous glyoxylic acid and o-nitroacetophenone (5) as starting
materials to prepare 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl ester (6) via an aldol
condensation reaction [8] (Scheme 2). A large coupling constant (15.6 Hz) for the olefinic protons,
which appeared at
δ
7.3 and 6.4, suggested a trans geometry for the double bond.
Scheme 2.
O
O
OCH3
HO2CCHO
O
CH3OH/ H2SO4/ Toluene
NO2
NO2
5
6
With an optically active amine as the chiral nucleophile, the aza-Michael addition to α,β-unsaturated
carbonyl compounds should proceed in an asymmetric fashion, and thus one diastereomer should be
generated predominately. However, equal amount of the two diastereomers would be produced
through the equilibrium of a reversible addition-elimination process. To resolve this problem, we have
tested the following two ways: 1) selecting suitable aza-Michael reaction conditions to achieve
dynamic resolution, in which solvent would be the main factor. The differences in solubility or solvent
effect between the two diastereoisomers can be employed to improve the diastereoselectivity through
the equilibrium of the reversible aza-Michael reaction [6]. In addition, the reaction stoichiometry,
temperature, reaction time, and acidity may also exert certain influences on the diastereoselectivity. 2)
introducing metallic counterions to affect the reversibility of the aza-Michael reaction through metallic
chelation, or formation of amino-metal complex to modify the nucleophilicity of the amino group [9].
The results are discussed in detail below:

Molecules 2006, 11
644
Table 1. Solvent Effect of Asymmetric Aza-Michael Reaction.
Entrya
Solvent
Reaction
time (hr)
17
Diastereomeric ratio of 7
Conversion
(%)c,d
96.0
b
(
S, S) : (R, S
4.20 : 1
3.75 : 1
2.15 : 1
1.91 : 1
1.88 : 1
1.87 : 1
1.86 : 1
1.83 : 1
1.81 : 1
1.80 : 1
1.69 : 1
1.68 : 1
1.67 : 1
1.60 : 1
1.53 : 1
)
1
2
Dichloromethane
Acetonitrile
Ethanol
26
99.0
3
18
98.0
4
Isopropanol
Xylene
16
98.8
5
16
99.3
6
Pyridine
33
98.2
7
Ether
25
98.2
8
Benzene
16
98.6
9
Acetonitrile/H2O
Isobutanol
tert-Butanol
DME
35
99.2
10
11
12
13
14
33
96.9
18
96.7
25
97.5
Ethyl acetate
Toluene
18
95.2
16
99.1
15
THF
16
98.6
a.
All reactions were carried out under room temperature. And the ratio of unsaturated ester 6 to
LHPE 1 was 1.00:1.05
b.
c.
1
Diastereomeric ratios were taken directly from H-NMR by comparison of the characteristic
peaks of the two diastereomers at δ3.74 for (S,S)-form and δ3.71 for (R,S)-form.
The conversions were determined from the characteristic 1H-NMR peak of the unsaturated ester
6 at δ3.80.
d. The isolated yields of ester 7 were around 90% for most of the reactions listed in Table 1.
According to our results (Table 1), higher diastereomeric ratios of the compound 7 were observed
in polar aprotic solvents such as dichloromethane (4.20:1) and acetonitrile (3.73:1), while all of the
other solvents gave poor diastereomeric ratios (2.15:1~1.53:1) for this asymmetric addition process.
The stoichiometric ratio of unsaturated ester 6 to LHPE 1 could be adjusted from 2.00 to 0.50, but
some excess LHPE 1 accelerated the reaction rate, so the best ratio of ester 6 to LHPE 1 was 1.00:1.10
(Table 2, entry 5), which lead to the highest observed diastereomeric selectivity of 4.50:1. In addition,
the suitable reaction concentrations of unsaturated ester 6 were 1%~20% (w/w), as lower
concentrations resulted in lower conversion yields and higher concentrations resulted in lower
diastereomeric ratios (Table 2, entries 21~22).
The optimum reaction temperature range was 20~40°C. Lower temperatures prolonged the reaction
times, which might lower the diastereomeric ratios, while higher reaction temperatures would enhance
the reversibility of the aza-Michael reaction, which likewise might also lower the diastereomeric ratio
(Table 2, entries 7~9). Consequently, we did most reactions at a temperature of 20°C.
Reaction times of 15~35 hours are suitable for this asymmetric aza-Michael reaction (Table 2,
entries 3, 10~16), because shorter times would result in lower conversion and prolonged times would
lower the diastereomeric ratios. This may due to the fact that the aza-Michael reaction is a kinetically

Molecules 2006, 11
645
controlled process at the beginning and then becomes a thermodynamic equilibrium. Noteworthy,
although a high diastereselectivity was achieved in CH2Cl2 in short time, decreasing diastereomeric
ratios of product 7 and significant amounts of the starting reactants were observed after a long time.
This phenomenon may be accounted for by the occurrence of the retro-Michael process [10]. We also
found that alkaline additives such as NEt3 could accelerated the aza-Michael reaction but could not
improve the diastereoselectivity (Table 2, entries 23~25).
Table 2. The Variation of Reaction Conditions on the Aza-Michael Reaction.
Entry Solvent a
/addictive
LHPE
Reaction
time (hr)
Reaction
Proportion of
diastereomers
Conversionb
（%）
(equiv.)
temperature
(°C)
20
(S, S) : (R, S)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/Et3N
C2H5OH
C2H5OH/Et3N
0.50
0.90
1.05
1.10
1.50
2.00
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.10
1.10
0.95
0.95
0.95
0.95
1.05c
1.05d
1.15
1.15
1.15
53
53
16
16
16
16
35
16
16
10
26
35
40
53
120
168
10
26
35
40
24
24
12
18
12
2.89 : 1
3.10 : 1
4.15 : 1
4.50 : 1
3.85 : 1
3.07 : 1
2.70 : 1
3.75 : 1
2.20 : 1
3.36 : 1
3.68 : 1
3.76 : 1
3.60 : 1
3.29 : 1
0.62 : 1
0.54 : 1
3.82 : 1
3.87 : 1
3.79 : 1
3.56 : 1
2.56 : 1
-
86.7
92.5
96.0
96.0
98.0
97.5
90.8
96.2
98.0
90.5
95.3
96.2
96.0
94.4
[b]
2
20
3
20
4
20
5
20
6
20
7
0
8
40
9
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
20
20
20
20
20
20
20
[b]
20
88.7
88.5
91.3
91.6
98.0
-
20
20
20
20
20
20
1.59 : 1
2.15 : 1
2.11 : 1
99.0
98.3
100.0
20
20
a.
The amount of solvent was based on the concentration 1~10% of unsaturated ester 6.
For diastereomeric ratios, conversions, and isolated yields, please see Table 1.
The starting materials were separated out.
b.
b.
c.
d.
The concentration of unsaturated ester 6 was >30%.
The concentration of unsaturated ester 6 was <0.1% and the addition product was non-detectable over a
long reaction time.

Molecules 2006, 11
646
On the other hand, we had also studied the effects of introducing metallic counterions in the aza-
Michael reaction. We originally wished to cause a “metal chelate effect” in which the metal ion
becomes chelated with the heteroatoms of compound 7 to form a rather stable conformation that mayn
decrease the reversibility of the aza-Michael reaction. However, the current results indicated that we
did not observe any significant change in diastereselectivity with or without the additive metallic
compounds. In fact, some transition metal salts even blocked the aza-Michael reaction [11].
After the aza-Michael reaction, a 4:1 mixture of the two diastereomers was obtained. The mixture
was reduced by Pd/C catalyzed hydrogenation, and then the resulting amino functionality reacted in
situ with the ester group intramolecularly to give the cyclized (2S,3’S)-caprolactam 8 (Scheme 1) and
according to the literature [7], benazepril·HCl 4 could be easily obtained from compound 8.
Conclusions
This report has offered a novel strategy for the asymmetric synthesis of the ACE inhibitor
benazepril·HCl (4). Through an asymmetric aza-Michael reaction, we kinetically synthesized
(2S,3’S)-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric acid ethyl ester
(8), a known key intermediate for the preparation of compound 4. Our results indicated that the
diastereoselectivity of this 1,4-addition reaction was greatly influenced by solvent effects, but was not
so sensitive to other influencing factors, such as stoichiometry, reaction temperatures, and counterion
effects. Thus, this report not only offers an ecomomical synthesis to benazepril·HCl (4), but also offers
useful knowledge for the preparation of chiral β-keto-aminoesters in general.
Experimental
General
Starting materials were obtained from commercial suppliers and used without further purification
unless otherwise stated. Flash column chromatography was carried out using Merck silica gel 60
(0.063-0.200 mm). Melting points are uncorrected. Optical rotations were measured on a Perkin Elmer
241 polarimeter. Infrared spectra were recorded on a Hitachi 270-30 Infrared Spectrophotometer.
NMR spectra were recorded for CDCl3 solutions on a Varian Mercury 400 instrument operating at 400
MHz (for 1H) and 10 MHz (for 13C), respectively. The chemical shifts are reported as δ values in ppm
relative to TMS in CDCl3 (δ=0), used as internal standard for 1H-NMR spectra and the center peak of
CDCl3 (δ=77.0 ppm) used as the internal standard in the 13C-NMR spectra. FAB-mass were collected
on a JMS-700 Double Focusing Mass Spectrometer. Elemental analyses were run on a Foss Heraeus
CHN-O-RAPID Elemental Analyzer.
Preparation of 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl ester (6)
An aqueous solution of glyoxylic acid (72 g, 40%) was concentrated to 2/3 volume under reduced
pressure, and then concentrated sulfuric acid (0.8 g), methanol (120 mL), and toluene (90 mL) were
added. The mixture was refluxed for 5 hours. The methanol was distilled off and then
o-nitro-
acetophenone (22.3 g, 135 mmol) in toluene (90 mL) was added. The reaction mixture was heated to

Molecules 2006, 11
647
110~130 °C for 36 hours to remove water by azeotropic distillation. After cooling, the toluene phase
was collected and washed with saturated sodium bicarbonate (20 mL x 2) and water (20 mL x 2). The
organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude
product was recrystallized in ether (120 mL) to give 20.67 g of a yellowish solid (20.67 g, 65%); mp
55-56 °C; IR (neat): 1730, 1682, 1529, 1348, 1309 cm-1; 1H-NMR:
7.77(m, 1H,CH), 7.72-7.68(m, 1H, CH), 7.47(d, = 8 Hz, 1H, CH), 7.31(d,
6.39(d, 191.7, 165.2, 146.2, 139.4, 135.0, 134.5,
= 15.6 Hz, 1H, CH), 3.80(s, 3H, CH3); 13C- NMR:
δ
8.21 (d,
J
= 8 Hz, 1H, CH), 7.81-
J = 15.6 Hz, 1H, CH),
J
J
δ
132.2, 131.3, 128.6, 124.5, 52.4; MS (EI): m/z 235 (M+ ), 204, 189, 150, 134 (100%), 113, 104, 76, 59;
HRMS (EI): Calcd. for C11H9NO5 M+ 235.0581, Found M+ 235.0477; Anal. Calcd for C11H9NO5: C,
56.17; H, 3.86; N, 5.96; Found: C, 56.16; H, 3.94; N, 6.06.
General procedure for Aza-Michael addition reactions
A 50 mL flask was charged with 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl ester (6, 2.35 g,
10 mmol) and L-homophenylalanine ethyl ester (2.28 g, 11 mmol) in the desired solvent (20 mL) and
the mixture was stirred at ambient temperature (or another suitable temperature) for the given reaction
times. The reaction mixture was concentrated to give a crude product that was purified by
chromatography to afford (2S,2’S)-2-(1-(methoxycarbonyl)-3-(2-nitrophenyl)-3-oxopropylamino)-4-
phenylbutyric acid ethyl ester (7) as a mixture of two diastereomers. The diastereoselectivities and
1
yields obtained are shown in Table 1. Mixture of compound 7: H-NMR:
δ 8.11 (d, 1H, Ph), 7.75-
7.50 (m, 3H, Ph), 7.30-7.15 (m, 5H, Ph), 4.25-4.15 (m, 2H, OCH2), 3.90-3.85 (m, 1H, NHCH), 3.74 &
3.71 (s, 3H, OCH3), 3.45-3.15 (m, 3H, NHCHCH2), 2.80-2.65 (m, 2H, CH2), 2.10-1.80 (m, 2H, CH2),
1.35-1.25 (m, 3H, OCH2CH3).
Preparation of (2S,3’S)-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric
acid ethyl ester (8).
To a solution of methyl 4-oxo-4-nitrophenyl-2-aminobutanoate 7 (1.46 g, 1.0 mmol) in THF (20
mL) was added Pd-C (5%, 0.14 g) in a pressure vessel. The reaction mixture was hydrogenated at 40
°C under 150 psi of H2 for 24 hours, then HCl (1 N, 6 mL) was added to the reaction mixture and
hydrogenated at 40 °C under 150 psi of H2 for another 16 hours. The reaction mixture was filtered and
basified with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl
acetate (50 mL x 2). The combined organic layer was dried with MgSO4 and purified by flash column
chromatography to obtain the (S,S)-diastereomer (0.69 g). It was then refluxed in 10% acetic acid-
toluene solution for 24 hours. The reaction mixture was concentrated to give the crude product (0.55 g).
The crude product was purified chromatography to afford the title compound 8 as a pale yellow solid
(0.15 g, 40%); [α]D -168.1 (c 1.09, CHCl3); mp 110-111 °C; IR (neat): 3224, 2948, 1734, 1676, 1494,
1
1160 cm-1; H-NMR:
δ 7.76 (br, 1H, CONH), 7.29-7.13 (m, 8H, CH), 6.99 (d, J = 8.0 Hz, 1H, CH),
4.12-4.03 (m, 2H, CO2CH2CH3), 3.33-3.26 (m, 2H, CHNH), 2.91-2.84 (m, 1H, CH2), 2.75-2.61 (m,
3H, CH2), 2.55-2.42 (m, 1H, CH2), 2.10-1.88 (m, 3H, CH2), 1.15 (t, = 7.2 Hz, 3H, CO2CH2CH3);
13C-NMR:
175.3, 174.2, 141.3, 136.6, 134.3, 129.6, 128.3, 128.2, 127.5, 125.9, 125.8, 122.0, 60.5,
J
δ
60.0, 56.6, 37.8, 35.0, 32.1, 28.9, 14.1; MS (FAB): m/z 367 (MH+, 100%), 293, 206, 154, 91, 77, 51;
Anal. Calcd. for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.88; H, 7.36; N, 7.63.

Molecules 2006, 11
648
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Sample availability: Samples of compounds 1 and 4 are available on request from the authors.
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