Benazepril Synthesis by Dr Anthony Crasto

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 ACE Inhibitors are medications that belong in
the class of medications known as
antihypertensive medications.
 ACE Inhibitors work on the Renin-
Angiotensin-Aldosterone System

 Benazepril, brand name Lotensin (Novartis), is
a medication used to treat high blood
pressure (hypertension), congestive heart
failure, and chronic renal failure. Upon
cleavage of its ester group by the liver,
benazepril is converted into its active form
benazeprilat, a non-sulfhydryl angiotensin-
converting enzyme (ACE) inhibitor.

 ACE Inhibitors work in the lungs to inhibit
Angiotensin Converting Enzyme from turning
Angiotensin I into Angiotensin II.
 These medications cause an increase of
bradykinin, which inhibits kinase II, another
name for Angiotensin Converting Enzyme.
(Lehne, 2007, pg. 464)
 Blood Pressure is decreased due to a decrease in
blood volume, peripheral resistance, and cardiac
load.
 ACE Inhibitors, inhibit vasoconstriction and
release of aldosterone which inhibits the
retention of sodium and water.

Generic Name Trade Name
 benazepril
 captopril
 enalapril
 enalaprilat
 fosinopril
 lisinopril
 moexipril
 perinodopril
 quinapril
 ramipril
 Lotensin
 Capoten
 Vasotec
 Vasotec IV
 Monopril
 Prinivil, Zestril
 Univasc
 Aceon
 Accupril
 Altace

 is also known as (3S)-3-(((1S)-1-Carboxy-3-
phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-
benzazepine-1-acetic acid, 3-ethyl ester, monohydrochloride;
Benazepril HCl; Cibacen; Cibacen CHF; Labopol.
 It belongs to the product categories of Intermediates & Fine
Chemicals; Pharmaceuticals; Amines; Aromatics; Heterocycles.
 This chemical’s molecular formula is C24H29ClN2O5 and molecular
weight is 460.96. What’s more, its IUPAC name 2-[(3S)-3-[[(2S)-
1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-
dihydro-3H-1-benzazepin-1-yl]acetic acid hydrochloride. In
addition, Benazepril hydrochloride (CAS 86541-74-4) is
crystalline solid which is soluble in DMSO.
 It is used in high blood pressure and congestive heart
failure. When you are using this chemical, you should not
breathe dust and avoid contact with skin and eyes.

Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin
1-Carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-1-
benzazepin-2-one monohydrochloride; 3(S)-[1(S)-Ethoxycarbonyl-3-phenylpropylamino]-2-oxo-
2,3,4,5-tetrahydro-1-benzazepine-1-acetic acid monohydrochloride
【CAS】 86541-74-4, 86541-75-5 (free base)
MF C24-H28-N2-O5.Cl-H
MW 460.9551rot–[Alpha] 20 D -141.0 °. (C = 0.9, ethanol)
Cardiovascular Drugs, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE)
Inhibitors
Launched-1990
Novartis (Originator), Pierre Fabre (Licensee), Andrx (Generic), Eon Labs (Generic), KV Pharmaceutical
(Generic), Mylan (Generic)

 EARLIER Preparation of Benazepril
hydrochloride (CAS 86541-74-4): The
reaction of 2(R)-hydroxy-4-phenyl butyric
acid ethyl ester (I) with
trifluoromethanesulfonic anhydride in
dichloromethane gives the corresponding
triflate (II), which is then condensed with the
amino benzazepinone (III) by means of NMM
in the same solvent to provide the target
benazepril.

 Benazepril (CAS REGISTRY No. 86541-75-5) first disclosed inUS
4,410,520 is one of the well-known ACE inhibitors and is used
for the treatment of hypertension.
 Chemically, Benazepril, is (3S)-1-(carboxymethyl-[[(1(S)-1-
(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one.
 Benazepril is administered orally in the form of hydrochloride
salt (CAS REGISTRY No. 86541-74-4) represented by formula (I).
 The preparation of benazepril disclosed in US 4,410,520 , J. Med.
Chem. 1985, 28, 1511-1516, and Helvetica Chimica Acta (1988)
71, 337-342, as given in scheme 1, NEXT SLIDE involves
reductive amination of ethyl 2-oxo-4-phenyl butyrate (IV) with
sodium salt of (3S)-3-amino-1-carboxymethyl-2,3,4,5-
tetrahydro-1 H-benzazepin-2-one (III).

 In example 12 of US 4,410,520 , the crude benazepril (II)
obtained in a diastereomeric ratio of SS: SR=70:30 was
dissolved in dichloromethane and treated with HCl gas to
obtain benazepril hydrochloride. The benazepril
hydrochloride of formula (I) obtained as a foam was
crystallized from methyl ethyl ketone to obtain in a SS:
SR=95:5 diastereomeric ratio. Benazepril hydrochloride
was further purified by recrystallization from a mixture of
3-pentanone/methanol (10:1), melting point: 188-190 °C.
 Alternatively, in example 27 of US 4,410,520 , benazepril
hydrochloride was purified by refluxing in
chloroform, filtering, and washing first with chloroform
and then with diethyl ether. The melting point of
benazepril hydrochloride obtained as per this example is
184-186 °C.

 An alternative process disclosed in US 4,785,089 involves
nucleophilic substitution of (3S)-3-amino-1-t-
butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-
benzazepine-2-one (V), using the chiral substrate ethyl
(2R)-2-(4-nitrobenzenesulfonyl)-4-phenyl butyrate (VI) in
presence of N-methylmorpholine (scheme 2). NEXT SLIDE
 The benazepril t-butyl ester (IIa) obtained in a
diastereomeric ratio of SS: SR=96:4 was hydrolyzed to
benazepril (II) and converted to hydrochloride salt by
treating with HCl gas in ethyl acetate.
 The crystalline suspension of benazepril hydrochloride in
ethyl acetate was diluted with acetone and filtered to
obtain in a diastereomeric ratio of SS: SR=99.1:0.9.
Further purification by refluxing in ethyl acetate afforded
benazepril hydrochloride in a diastereomeric ratio of SS:
SR=99.7:0.3, melting point of 181 °C.

 The Merck Index., 12th edition reports benazepril
hydrochloride crystals obtained from 3-
pentanone+methanol (10:1), melting point 188-190 °C
 The crystallization methods taught in the prior art does
not consistently produce a constant diastereomeric
composition of SS:SR diastereomer. This is evident from
the variation in the melting points of the benazepril
hydrochloride reported in three different working
examples, which varies between 181 to 190°C.
 The variation in diastereomeric composition of a
pharmaceutical substance is not desirable as it would
affect its efficacy. Hence there is a need for a
crystallization process that consistently produce a
constant diastereomeric composition of SS diastereomer in
greater than 99.8%.

 Coming to the crystalline form, it is well known in the
art that the solid form of a pharmaceutical substance
affect the dissolution rate, solubility and
bioavailability. The solid form may be controlled by
process employed for the manufacture of the
pharmaceutical substance. In particular the process
of purification of the solid substance by
crystallization is used to control the solid form
(Organic Process Research & Development, 2003, 7,
958-1027).
 It has been found that the crystalline form of
benazepril hydrochloride obtained from processes of
prior art documents is designated as crystalline Form
A as evident from the following documents.

 In a monograph published by Al-badar et al in Profiles of Drug
Substances, Excipients, and Related Methodology, Vol. 31, 2004,
p117-161; benazepril hydrochloride prepared by the process
disclosed in US 4,410,520 , and J. Med. Chem. 1985, 28, 1511-
1516, has been characterized by powder X-ray diffraction
pattern having 2θ peaks at 6.6, 9.9, 11.9, 13.7, 14.0, 14.9, 15.3,
16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 22.2, 25.2, 25.5, 26.4,
26.6, 27.1, 27.9, 29.8, 30.4, 31.0, 32.6, 33.3, 33.8, 34.4, 35.5,
38.2, 39.9, 43.9, 48.9.
 The major peaks are at 6.6, 9.9, 11.9, 13.7, 14.9, 16.4, 17.3,
18.9, 19.6, 20.2, 20.9, 21.5, 25.2, 25.5, 26.4, 26.6, 27.9, 31.0,
and 32.6.
 WO 2004/013105 A1 also discloses that by following the
processes of the prior art mentioned above, crystalline
benazepril hydrochloride is isolated in a form designated as
Form A having a powder X-ray diffraction pattern with 2θ values
at 6.7, 10.1, 12.0, 13.8, 15.1, 16.4, 17.4, 19.0, 19.6, 20.2, 20.9,
21.0, 25.3, 25.5, 26.4, 26.6, 27.6, 28.0, 31.0, 32.7.

 WO 2004/013105 A1 discloses that benazepril
hydrochloride Form A may be prepared from a
concentrated solution of the benazepril hydrochloride in a
solvent selected from C1-C10 alcohol, N,N-
dimethylformamide, N-methylpyrrolidone by adding an
anti-solvent selected from C4-C12 alkane or C1-
C10 acetate, preferably, hexane or ethyl acetate.
 WO 2004/013105 A1 in Example 5 describes a process of
making crystalline form A of benazepril hydrochloride by
passing HCl gas into a solution of benazepril free base in
diethyl ether and filtering the resulting suspension.
 Similarly, in Example 6, the benazepril hydrochloride was
dissolved in water free ethanol and the resulting solution
was added to heptane at 20° C to obtain the crystalline
Form A.

 Further, WO 2004/013105 A1 , mentions a list of
solvents and anti-solvents that can be used to
make benazepril hydrochloride crystalline Form
A. However, there is no enabling disclosure and
the document is silent on the diastereomeric
purity of the crystalline form A obtainable by the
process disclosed.
 The processes of crystallization and/or
recrystallization disclosed in the prior art do not
consistently produce benazepril hydrochloride
with constant diasteromeric content as evident
from the variation in the melting point of the
crystalline benazepril hydrochloride obtained
from crystallization from various solvents.

Benzazepin-2-ones, process for their preparation,
pharmaceutical preparations containing these compounds
and the compounds for therapeutical use
Watthey, J.W.H. (Novartis AG)
EP 0072352; GB 2103614; JP 8338260
SYNTHETIC SCHEMES

 The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I)
with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-
1H-(1)benzazepin-2-one (II), which is treated with sodium
acetate and reduced with H2 over Pd/C in acetic acid yielding 3-
chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The
reaction of (III) with sodium azide in DMSO affords 3-azido-
2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is
condensed with benzyl bromoacetate (V) by means of NaH in
DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-
tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI)
with Raney-Ni in ethanol-water yields 3-amino-1-
(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-
(1)benzazepin-2-one (VII), which is debenzylated by
hydrogenation with H2 over Pd/C in ethanol affording 3-amino-
1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one
(VIII). Finally, this compound is condensed with ethyl 3-
benzylpyruvate (IX) by means of sodium cyanoborohydride in
methanol acetic acid.

Process for the
preparation of
benazepril
Kumar, Y.; De, S.;
Thaper, R.K.;
Kumar, D.S.M.
(Ranbaxy
Laboratories Ltd.)
WO 0276375

 The reaction of 2(R)-hydroxy-4-phenyl butyric acid
ethyl ester (I) with trifluoromethanesulfonic
anhydride in dichloromethane gives the
corresponding triflate (II), which is then condensed
with the amino benzazepinone (III) by means of
NMM in the same solvent to provide the target
benazepril.

Synthesis of 14C-labeled 3-([1-
ethoxycarbonyl-3-phenyl-(1S)-
propyl]amino)-2,3,4,5-tetrahydro-2-
oxo-1H-1-(3S)-benzazepine-1-
acetic acid hydrochloride ([14C]CGS
14824A)
Chaudhuri, N.K.; Patera, R.; Markus,
B.; Sung, M.-S.
J Label Compd Radiopharm
1987,24(10),1177-84

 A new synthesis of CGS-14824A is given: The reaction of 3-
bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile
(II), which is hydrolyzed to the corresponding butyric acid (III).
The cyclization of (III) with polyphosphoric acid affords 1-
tetralone (IV), which is brominated to 2-bromo-1-tetralone (V)
and treated with hydroxylamine to give the oxime (VI). The
Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-
tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with
sodium azide to afford the azide derivative (VIII).
 The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means
of KOH and tetrabutylammonium bromide in THF gives the N-
alkylated azide (X), which is reduced by catalytic hydrogenation
to the corresponding amine (XI). The hydrolysis of the ester
group of (XI) with NaOH yields the free acetic acid derivative (XII),
which is finally reductocondensed with ethyl 2-oxo-4-
phenylbutyrate (XIII) by means of sodium cyanoborohydride.

 see translated version————-First, 2,3,4,5 – tetrahydro-1H-[1] azepin-2 phenyl – one (2)
Preparation of
the dry reaction flask, add α- tetralone 20g (0.137mol), stacked acid 7.36g (0.171mol) and
chloroform 140ml, was stirred at 40 ℃ in 1h concentrated sulfuric acid was slowly added
dropwise 36ml, acid layer was separated and poured into 900ml water to give a creamy
solid. Recrystallization with hot water to give white crystals (2) 15.5g (70%), mp141 ℃. (Acidic
filtrate and after a small amount of product can be obtained.)
Second, 3,3 – dichloro-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (3) of the
prepared
in a dry reaction flask, (2) 48.3g (0.3mol) and xylene solution of 1300ml, phosphorus
pentachloride 188g (0.9mol), stirred and gradually heated to at 0.5h 90 ℃, (Caution! When
phosphorus pentachloride dissolved hydrogen chloride gas had severe.) 90 ℃ the reaction was
continued for 0.5h, filtered to remove a small amount of suspended solids, solvent recovery
under reduced pressure, to the residue was added saturated sodium bicarbonate solution,
100ml, stirred until a solid precipitate complete, filtered and the cake washed with ethanol
(100ml × 2), diethyl ether (50ml) and dried to give (3) 69.0g (90%), mp185 ~ 187 ℃.
III.3 – chloro-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (4) Preparation of
the reaction flask (3) 10g (0.087mol), Sodium acetate 77g (0.11mol), acetic acid 460ml and 5%
Pd-C 0.86g, under atmospheric pressure at room temperature to a hydrogen-absorbing up
total of 950ml (about 0.5h). Filtration, recycling the catalyst recovered solvent, the residue was
dried under reduced pressure, and then added 900ml of 10% sodium bicarbonate solution and
dichloromethane 300ml, stirring, standing, the organic layer was separated and the aqueous
layer extracted with dichloromethane (300ml × 3) extracted organic layers were combined,
dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure. Diethyl
ether was added to the cured 350ml, and mashed, filtered and dried to give (4) 8.19g (95%),
mp163 ~ 167 ℃.

 4 (3) – azido-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (5)
Preparation of
the dry reaction flask (4) 15.9g ( 0.08mol), sodium azide 6.4g (0.10mol)
and 320ml solution of dimethyl sulfate, the reaction was stirred at 80 ℃
3h, cooled to room temperature, poured into ice-water (1L) to
precipitate a pale yellow solid , filtered and dried under reduced
pressure at 75 ℃ to give (5) 14.7g (90%), mp142 ~ 145 ℃.
V.3 – azido-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 –
acetate (6) Preparation of
the dry reaction flask, (5) 3.0g (0.015mol), tetrabutylammonium
bromide, 0.5g (0.0015 mol), powdered potassium hydroxide 1.1g
(0.016mol) and 30ml of tetrahydrofuran solution of ethyl bromoacetate
was added 1.9ml ( 0.016mol), stirred rapidly at room temperature for
1.5h (nitrogen). Water was added: dichloromethane (50:100 ml), stirred,
allowed to stand, the organic layer separated. Washed with water, dried
over anhydrous sodium sulfate, the solvent recovered under reduced
pressure to give a pale yellow oil (6) 4.1g (96%) (can be used directly in
the next step).

 VI.3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 –
acetate (7) Preparation of
the dry reaction flask, (6 ) 20.0g (0.070mol), ethanol 100ml, 10% Pd-C
1.0g stirring, at room temperature, 303.9kPa hydrogenated under a
hydrogen pressure 1.5h, intermittent deflated to remove the generated
nitrogen gas, after the reaction was collected by filtration Pd / C,
recovery of solvents under reduced pressure to give a yellow oil, add
ether l00ml, mashed, filtered and dried to give a white solid (7) 17.0g
(93%) mp101 ~ 102 ℃.
Seven, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 –
one-1 – acetate (8) Preparation of
the reaction flask, adding (7) 25.1g (0.096mol), L – tartaric acid 14.4g
(0.096mol) and hot ethanol 200ml, stirring to dissolve, cooled at room
temperature overnight, filtered and dried under reduced pressure to give
a white powder 30.7g, with ethanol Recrystallization twice (each 200ml),
to give (8) tartaric acid salt of 13.6g (34%), mp168 ~ 169 ℃, with 10%
ammonium hydroxide, to give a white solid (8) 8.0g (95%) mp104 ~ 106
℃.
Eight, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 –
one-1 – acetate (9)

 Preparation of
the reaction flask, (8) 4.0g (0.056mol) and 150ml of methanol solution
of sodium hydroxide 2.1g (0.056moI) and a solution of 5ml of water,
stirred at room temperature for 2h, the solvent recovered under reduced
pressure, the residue was dried and diethyl ether was added 100ml,
trace broken, filtered, and dried to give (9) 12.9g (89%) (used directly in
the next step).
IX benazepril (1) Synthesis of
the reaction flask (9) 12.9g (0.050mol), 2 – oxo-4 – phenylbutyrate
31.0g (0.15mol), acetic acid and 100ml methanol 75ml, the reaction was
stirred at room temperature for 1h (nitrogen). Of sodium borohydride
cyanide was slowly added dropwise 3.8g (0.062mol) and 30ml of
methanol solution of (4h was completed within), stirred overnight,
heat. Concentrated hydrochloric acid 10ml, 1h stirring at room
temperature, the solvent was recovered under reduced pressure, water
was added to the residue and diethyl ether 400ml l00ml, dissolved with
concentrated ammonium hydroxide and the pH adjusted to 9.3, the
organic layer was separated and the aqueous layer acidified with
concentrated hydrochloric to pH 4.3, extracted with ethyl acetate (100ml
× 3) extracted organic layers were combined,

 dried over anhydrous magnesium sulfate, the solvent recovered under reduced
pressure, to the residue was added methylene chloride (150ml) to dissolve. And
pass into dry hydrogen chloride after 5min recovered solvent under reduced
pressure, to the residue was added hot ethyl ketone 100ml, stirring to dissolve,
cooled and precipitated solid was filtered to give crude product (1). A 3 – amyl
ketone / methanol (volume ratio 10:1) (110ml) was recrystallized (1) 5.8 g, mp
188 ~ 190 ℃, [alpha] D
20 -141.0 (C = 0.9, C 2 H 5 OH )
[Spectral Data] (free base) [2]
MS: m / Z (%) 424 (M + , 2), 351 (100), 190 (22), 91 (65)
] [other synthetic routes
described in the reference literature.
 [References]
[1] Briggs LH et al. J Chem Soc, 1937, 456
[2] Watthey WH et al. J Med Clmm, 1985, 28:1511
[3] EP 1986, 206933 (CA, 1987, 107: 77434e)
[4] EP 1983, 72352 (CA, 1983, 99:53621 d)
[5] package insert: Lotensin
[6] property protection case I: Lotensin
[7] property protection case II: Lotensin
[8] Drug Monograph information: BENAZEPRIL


 more info
 Benazepril M.p. 148.5°.
 Proprietary names. Briem; Cibace; Cibacen; Cibacene; Labopal; Lotensin;
Tensanil; Zinandril.
 C24H28N2O5,HCl=461.0
 CAS—86541–74–4
 A white to off–white crystalline powder. It is soluble in water, ethanol
and methanol.
 Partition Coefficient.
 Log P(octanol/water), 3.50.
 Gas Chromatography.
 System GP—RI 3030 (benazepril-ME); RI 2985 (M (benazeprilate)-ME3).
 Column: 3% OV-101 on Gaschrom Q, 80–100 mesh (Ciba-Geigy), pyrex
glass (1.5 m × 2 mm i.d.). Column and injector port temperature: 275°.
Carrier gas: helium, flow rate 30 mL/min. MS detection (EI, SIM).
Retention times: benazepril (methyl ester derivative) 2.55 min;
benazeprilat (derivative) 2.3 min. [G. Kaiser et al.,J.
Chromatogr.,1987, 419, 123–133].

 High Performance Liquid Chromatography.
 System HAA—retention time 17.0 min.
 Column: C18 (RP-BDS, 5 μm packing, 250 × 3 mm i.d.).
Mobile phase: sodium dihydrogen phosphate (0.025 M, pH
4.8):acetonitrile (55:45). 0.4 mL/min flow rate. UV
detection (λ=250 nm). Retention time:
benazepril hydrochloride, 4.95 min. [I. E. Panderi and M.
Parissi-Polou,J. Pharm. Biomed. Anal.,1999, 21, 1017–
1024].
 Column: Hypersil ODS (5 μm, 250 × 4.5 mm). Mobile
phase: sodium heptanesulfonate (20 mM, pH
2.5):acetonitrile (5% THF) (52:48 v/v), 1.0 mL/min flow
rate. UV detection (λ=215 nm). Retention time: 15 min. [D.
Bonazzi et al.,J. Pharm. Biomed. Anal.,1997, 16, 431–438].

 Ultraviolet Spectrum.
 Aqueous acid (0.2 M NH2SO4)—237 nm; basic—
241 nm; aqueous acid (0.1 M hydrochloric acid)—
237.2 nm (hydrochloride salt).
 Reference(s):
Clarke’s Analysis of Drugs and Poisons
Watthey, J.W.H. et al.: J. Med. Chem. (JMCMAR)
28, 1511 (1985).
US 4 410 520 (Ciba-Geigy; 18.10.1983; prior.
11.8.1981, 9.11.1981, 19.7.1982).
EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA-
prior. 11.8.1981, 9.11.1981).

DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MOBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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