Expeditious synthesis of ramipril: An angiotensin converting enzyme (ACE) inhibitor

Article abstract of DOI:10.1080/00397910801989238

We document an efficient and cost-effective synthesis of ramipril 1 utilizing (i) an environmentally benign process for the esterification of racemic 2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid hydrochloride 2 using boric acid as a catalyst and (ii) a robust resolution process for the synthesis of 3a by means of inexpensive and recyclable L-(+)-mandelic acid as key steps. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801989238

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Expeditious Synthesis of Ramipril: An
Angiotensin Converting Enzyme (ACE)
Inhibitor
Golla China Malakondaiah a b , V. M. Gurav a , Lekkala Amarnath Reddy b ,
Karrothu Srihari Babu b , Bolugoddu Vijaya Bhaskar b , Padi Pratap Reddy b ,
Apurba Bhattacharya b & Ramasamy Vijaya Anand b
a Department of Chemistry , Yeshwant Mahavidhyalaya , Maharashtra, India
b Center of Excellence, Integrated Product Development Organization
(IPDO), Dr. Reddy's Laboratories Ltd. , Bachupalli, Qutubullapur, R. R. Dist.,
Andhra Pradesh, India
Published online: 09 May 2008.
To cite this article: Golla China Malakondaiah , V. M. Gurav , Lekkala Amarnath Reddy , Karrothu Srihari
Babu , Bolugoddu Vijaya Bhaskar , Padi Pratap Reddy , Apurba Bhattacharya & Ramasamy Vijaya Anand
(2008) Expeditious Synthesis of Ramipril: An Angiotensin Converting Enzyme (ACE) Inhibitor , Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:11,
1737-1744, DOI: 10.1080/00397910801989238
To link to this article: http://dx.doi.org/10.1080/00397910801989238
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Synthetic Communicationsw, 38: 1737–1744, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801989238
Expeditious Synthesis of Ramipril: An
Angiotensin Converting Enzyme (ACE)
Inhibitor
Golla China Malakondaiah,1,2 V. M. Gurav,1
Lekkala Amarnath Reddy,2 Karrothu Srihari Babu,2
Bolugoddu Vijaya Bhaskar,2 Padi Pratap Reddy,2
Apurba Bhattacharya,2 and Ramasamy Vijaya Anand2
1Department of Chemistry, Yeshwant Mahavidhyalaya, Maharashtra,
India
2Center of Excellence, Integrated Product Development Organization
(IPDO), Dr. Reddy’s Laboratories Ltd., Bachupalli, Andhra Pradesh, India
Abstract: We document an efficient and cost-effective synthesis of ramipril 1 utilizing
(i) an environmentally benign process for the esterification of racemic 2-aza-bicyclo-
[3.3.0]-octane-3-carboxylic acid hydrochloride 2 using boric acid as a catalyst and
(ii) a robust resolution process for the synthesis of 3a by means of inexpensive and
recyclable L-(þ)-mandelic acid as key steps.
Keywords: Boric acid, esterification, L-(þ)-mandelic acid, ramipril, resolution
INTRODUCTION
Ramipril 1[1] (Fig. 1), a 2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid
derivative, belongs to a class of angiotensin converting enzyme (ACE) inhibi-
tors,[2] which are used for treating high blood pressure and congestive heart
failure and also for preventing kidney failure due to high blood pressure
Received October 12, 2007
DRL-IPD Communication No. IPDO-IPM-00086.
Address correspondence to Ramasamy Vijaya Anand, Center of Excellence,
Integrated Product Development Organization (IPDO)-Innovation Plaza, Dr. Reddy’s
Laboratories Ltd., Bachupalli, Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh,
India. E-mail: vijayaanandr@drreddys.com
1737

1738
G. C. Malakondaiah et al.
Figure 1. Molecular framework of ramipril 1.
and diabetes. It is a prodrug that gets hydrolyzed in the liver after absorption
from the gastrointestinal tract to form the active ACE inhibitor ramiprilate.[3]
Ramiprilate lowers the conversion of angiotensin I to angiotensin II (which
is responsible for tightening the blood vessels), which results in dilation
of peripheral vessels and reduction in vascular resistance. Ramipril is
available in the market under the brand name Altacew as capsules for oral
administration.
Structurally, ramipril 1 features five chiral centers, all are having the
S configuration, three of which are on a 2-aza-bicyclo-[3.3.0]-octane-3-carboxylic
acid core and two from the N-substituted alanine derivative. These two fragments
are connected through an amide tether. Few literature precedents are available for
the synthesis of ramipril 1[4]; unfortunately all of them involve purification
techniques such as column chromatography and repeated recrystallization at
least in one of the stages, which made them industrially less attractive. Herein,
we divulge our efforts to synthesize optically pure ramipril 1 utilizing the
following key steps: (a) environmentally benign process for the esterification of
2 using boric acid as a catalyst and (b) resolution of the bicyclic amino ester
intermediate 3 with inexpensive and recyclable L(þ)-mandelic acid.[5]
RESULTS AND DISCUSSION
Our approach to the synthesis of ramipril 1 starts with readily available
racemic 2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid 2.[6] While
exploring the concept of green chemistry in industrial processes,[7] we discov-
ered that boric acid[8] efficiently catalyzed the esterification of 2 with 2 equiva-
lents of benzyl alcohol in toluene under reflux conditions to provide the ester 3
in 83% yield (Scheme 1). In contrast to this, the hitherto known routes for the
synthesis of 3 invole benzylation of 2 with a large excess of benzyl alcohol and
thionyl chloride, and the product 3 was precipitated by the addition of 15
volumes of diisopropyl ether with respect to benzyl alcohol, which made
the workup process combersome and not ecofriendly. The synthesis of 3 by
our method is an environmentally benign process because no effluents are
generated and no additional solvents are required to precipitate the product.
The resolution of racemic 2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid
benzyl ester 3 was carried out by means of commercially available and

Expeditious Synthesis of Ramipril
1739
Scheme 1. Synthesis of ramipril 1. Conditions: (i) H3BO3 (cat.), BnOH, phme,
D, 83%; (ii) NaOH then L(þ)-mandelic acid, EtOAc, 0–5 8C, aq. HCl, 90%, 2 steps
(with respect to single isomer); (iii) 4, Et3N, CH2Cl2, 0–5 8C, 94%; (iv) Pd-C/H2,
EtOH, 0–10 8C, 95%.
inexpensive L(þ)-mandelic acid to furnish (S,S,S)-2-aza-bicyclo-[3.3.0]-
octane-3-carboxylic acid benzyl ester 3a in 45% yield (90% with respect to
a single isomer).[5] Apart from L(þ)-mandelic acid, various other resolving
agents such as L-(þ)-tartaric acid, (þ)-dibenzyl tartaric acid, (þ)-di-p-
toluoyl tartaric acid, (þ)-camphorsulfonic acid, (þ)-naproxen, and (þ)-
ibuprofen were screened but gave unsatisfactory results. The L(þ)-mandelic
acid used for the resolution process was recycled and reused several times
without affecting the yield and chiral purity of 3a (Table 1).
The (S,S,S)-2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid benzyl ester
3a thus obtained was coupled with benzyl N-(2S-carbethoxy-3-phenyl
propyl)-S-alanine acid chloride 4, which in turn was prepared by the
reaction of PCl5 with the corresponding acid (commercially available from
Aarthi Drugs Pvt. Ltd., Mumbai) in the presence of triethylamine to furnish
ramipril benzyl ester 5 in 94% yield. The reaction was very efficient, and
no other side products or impurities were detected. We also carried out the
condensation reaction between 3a and 4 in the presence of a catalytic
Table 1. Resolution of 3 using recycled L(þ)-mandelic acid
Number of
cycles
Yield of 3a
(%)a
Chiral purity
of 3a (%)b
S. no.
1
2
3
1
2
3
90
90
91
99.85
99.66
99.70
aWith respect to single isomer.
bDetermined by HPLC.

1740
G. C. Malakondaiah et al.
amount of boric acid under reflux conditions in toluene, but the desired
product 5 was formed only in 20% yield; this might be due to the instability
of 4 under thermal conditions. Finally, hydrogenolysis of ramipril benzyl
ester 5 provided optically pure ramipril 1 in 95% yield (Scheme 1).[5]
CONCLUSION
A simple, commercially viable process for the synthesis of ramipril 1 was
accomplished through esterification of racemic 2-aza-bicyclo-[3.3.0]-
octane-3-carboxylic acid 2, in an environmentally benign manner, using
boric acid as a catalyst and a robust resolution process for the synthesis of
3a by means of inexpensive and recyclable L-(þ)-mandelic acid. This
process addressed all the manufacturing concerns with respect to environ-
mental safety and quality. Upon practicing the disclosed process, a significant
cost reduction in the synthesis of ramipril 1 was realized.
EXPERIMENTAL SECTION
General Methods
1H NMR spectra were recorded on a 400-MHz Varian Gemini FT NMR spec-
trometer, and 13C NMR spectra were recorded using a 200-MHz Varian Gemini
FT NMR spectrometer. The chemical shifts are reported in d ppm relative to
TMS. The Fourier transform infra red (FT-IR) spectra were recorded using a
Perkin-Elmer 16650 FT-IR spectrometer. Mass spectra (70 eV) were recorded
on a HP-5989A LC-MS spectrometer. The melting points were determined
using the capillary method on a Polmon (model MP-96) melting-point
apparatus and are uncorrected. The solvents and reagents were used without
further purification.
Preparation of Racemic 2-Azabicyclo-[3.3.0]-octane-3-carboxylic
Acid Benzyl Ester Hydrochloride (3)
A mixture of racemic 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid (10.0 g,
0.065 mol), boric acid (0.30 g, 0.0048 mol), benzyl alcohol (40.6 g,
0.195 mol), and toluene (100 mL) was charged in a Dean-Stark container
and refluxed (105–110 8C) for 10 h. During the reaction, water was
removed azeotropically. After the reaction was complete (monitored by
thin-layer chromatography, TLC), the reaction mass was cooled to room
temperature. Boric acid was filtered off, and the filtrate was concentrated
under reduced pressure to yield the crude product. Dry HCl was passed
through the crude product in DCM (50 mL) to precipitate the title
compound 3[6c] as a white powder. Yield 15 g (83%); mp 180 8C (lit.[6c] mp

Expeditious Synthesis of Ramipril
1741
185 8C); 1H NMR (400 MHz, CDCl3) d 1.36–1.42 (m, 1H), 1.58–1.75
(m, 2H), 1.82–2.01 (m, 3H), 2.32–2.37 (m, 1H), 2.58 (dt, J ¼ 13.2, 8.4 Hz,
1H), 2.83–2.88 (m, 1H), 4.31 (td, J ¼ 8.0, 3.6 Hz, 1H), 4.43 (t, J ¼ 8.4 Hz,
1H), 5.20 (AB q, J ¼ 12.0 Hz, 2H), 7.33–7.37 (m, 5H); 13C NMR
(50 MHz, DMSO) d 24.12, 29.59, 31.04, 33.45, 41.35, 60.07, 63.77, 66.95,
128.12, 128.26, 128.42, 135.17, 167.30; FT IR (KBr disc) 1761 cm21; MS:
m/e 246 (Mþ).
Preparation of (S,S,S)-2-Azabicyclo-[3.3.0]-octane-3-carboxylic
Acid Benzyl Ester Hydrochloride (3a)
A suspension of racemic 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid
benzyl ester hydrochloride (100.0 g, 0.36 mol) in EtOAc (400 mL) was
treated with 20% aqueous sodium hydroxide solution (130 mL, 0.65 mol)
and stirred for an hour at 0–5 8C. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (2 ꢀ 250 mL). The combined
organic layer was then concentrated under reduced pressure to yield the free
base (87.0 g, 0.36 mol). A solution of L-(þ)-mandelic acid (54.0 g,
0.36 mol) in EtOAc (350 mL) was added to this crude product, and the
resulting reaction mixture was stirred for 2 h at 0–5 8C. The reaction
mixture was filtered, and the salt was washed with chilled EtOAc (100 mL)
and dried at 60–65 8C to provide (S,S,S)-2-azabicyclo-[3.3.0]-octane-3-
carboxylic acid benzyl ester mandelate salt as a white powder (67.0 g,
47.5% [95% with respect to single isomer]); mp 116 8C; [a]2D0 ¼ þ14.0
(c ¼ 1, H2O); 1H NMR (400 MHz, DMSO) d 1.36–1.55 (m, 5H),
1.61–1.64 (m, 2H), 2.24–2.31 (m, 1H), 2.55–2.59 (m, 1H), 3.65 (bt,
J ¼ 6.8 Hz, 1H), 3.81 (dd, J ¼ 10.0, 6.8 Hz, 1H), 4.89 (s, 1H), 5.13 (AB q,
J ¼ 12.4 Hz, 2H), 7.22–7.41 (m, 10H); 13C NMR (50 MHz, DMSO) d
23.64, 31.92, 32.45, 36.03, 41.86, 60.45, 63.20, 65.92, 72.75, 126.49,
127.02, 127.79, 127.86, 128.07, 128.42, 135.83, 141.45, 171.15, 174.48; IR
(KBr disc) 1752, 1646, 1584, 1358 cm21; MS: m/e 246 (Mþ).
A suspension of (S,S,S)-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid
benzyl ester mandelate salt (50.0 g, 0.13 mol) in CH2Cl2 (250 mL) was
treated with 25% aqueous sodium hydroxide solution (40.0 mL, 0.25 mol) at
0–5 8C and stirred for 30–40 min. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 ꢀ 50 mL). Conc. HCl (12 mL)
was added to the combined organic layer at 0–5 8C, stirred for an hour, and
filtered. The resultant solid was washed with chilled CH2Cl2 (50 mL) and
dried at 60 8C for 4–5 h under vacuum to provide the title compound 3a as a
white solid. Yield 33.7 g (95%); mp 178–180 8C (lit.[6c] mp 180 8C);
1
[a]2D0 ¼ 240.0 (c ¼ 1, H2O) [lit.[6c] [a]D30 ¼ 238.4 (c ¼ 1, H2O)]; H NMR
(400 MHz, CDCl3) d 1.36–1.42 (m, 1H), 1.58–1.75 (m, 2H), 1.82–2.01
(m, 3H), 2.32–2.37 (m, 1H), 2.58 (dt, J ¼ 13.2, 8.4 Hz, 1H), 2.83–2.88
(m, 1H), 4.31 (td, J ¼ 8.0, 3.6 Hz, 1H), 4.43 (t, J ¼ 8.4 Hz, 1H), 5.20 (AB q,

1742
G. C. Malakondaiah et al.
J ¼ 12.0 Hz, 2H), 7.33–7.37 (m, 5H); 13C NMR (50 MHz, DMSO) d 24.07,
29.60, 31.02, 33.45, 41.37, 60.11, 63.81, 66.99, 128.11, 128.28, 128.43,
135.14, 167.32; FT IR (KBr disc) 1758 cm21; MS: m/e 246 (Mþ).
Preparation of N-(2S-Carbethoxy-3-phenyl Propyl)-S-alanoyl
Chloride Hydrochloride (4)
A
mixture of N-(2S-carbethoxy-3-phenyl propyl)-S-alanine (27.0 g,
0.091 mol), toluene (240 mL), and chloroform (30 mL) was charged into a
clean, dry, round-bottom flask and cooled to 15–20 8C. Dry HCl gas was
passed through it for about 15–20 min. The resultant suspension was
further cooled to 0–5 8C, and PCl5 (25 g, 0.12 mol) to this was added. The
reaction mixture was stirred for an hour at 0–5 8C and at 25–30 8C for 3 h.
It was filtered, and the solid collected was washed with toluene (30 mL)
and petroleum ether (75 mL) to afford N-(2S-carbethoxy-3-phenyl propyl)-
S-alanoyl chloride hydrochloride 4 as a white solid. Yield 30.6 g (95%);
this compound was used as such in the next step.
Preparation of Ramipril Benzyl Ester (5)
A solution of 4 (28.7 g, 0.086 mol) in CH2Cl2 (500 mL) was added in a drop wise
manner to a mixture of (S,S,S)-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid
benzyl ester hydrochloride 3a (18.2 g, 0.065 mol) and Et3N (22.5 g,
0.222 mol) in CH2Cl2 (300 mL) at 0–5 8C, and the resulting solution was
stirred for 3 h. After the reaction was complete (vide TLC), water (500 mL)
was added to the reaction mixture, and the organic layer was separated out. It
was washed with saturated aqueous sodium carbonate solution (275 mL)
followed by brine solution. The organic layer was dried over anhydrous
Na2SO4. Removal of solvent under vacuum at 30–35 8C afforded the ramipril
benzyl ester 5[9] as a viscous paste. Yield 32.1 g (94%); [a]2D4 ¼ 213.5 (c ¼ 1
in 0.1 N methanolic HCl);1H NMR (400 MHz, CDCl3) (2:1 rotamers) d 1.23
(d, J ¼ 7.2 Hz, 3H), 1.28 (t, J ¼ 7.2 Hz, 3H), 1.50–1.63 (m, 1H), 1.71–1.81
(m, 3H), 1.86–2.07 (m, 3H), 2.11–2.22 (m, 1H), 2.29–2.40 (m, 2H),
2.63–2.79 (m, 3H), 3.19 (t, J ¼ 6.8 Hz, 1H), 3.32–3.34 (m, 0.5H), 3.64
(q, J ¼ 6.8 Hz, 1H), 4.17 (q, J ¼ 7.2 Hz, 2H), 4.08–4.31 (m, 1H), 4.43–4.47
(m, 0.5H), 4.68 (dd, J ¼ 8.8, 6.4 Hz, 1H), 5.10 (d, J ¼ 12.4 Hz, 1H), 5.19
(d, J ¼ 12.4 Hz, 1H), 7.15–7.19 (m, 3H), 7.22–7.28 (m, 2H), 7.32–7.35
(m, 5H); FT IR (neat) 1739, 1645 cm21; MS: m/e 529 (Mþþ Na).
Preparation of Ramipril (1)
A mixture of ramipril benzyl ester 5 (32.0 g, 0.063 mol), ethanol (200 mL),
water (20 mL), and wet palladium carbon (6.5 g [10% Pd]) was charged in

Expeditious Synthesis of Ramipril
1743
an autoclave and maintained at 2.5–3.0 kg/cm2 of hydrogen pressure at
0–10 8C. The reaction was monitored by high performance liquid chromato-
graphy (HPLC). After the reaction was complete, the reaction mixture was
filtered through a pad of Celitew followed by washing with acetone
(50 mL). The filtrate was concentrated at 15–20 8C under vacuum to afford
the crude ramipril 1. It was dissolved in a mixture of diisopropyl ether
(65 mL) and diethyl ether (33 mL), cooled to 0–5 8C, and maintained for
45–60 min. The separated solid was filtered and washed with a mixture of
di-isopropyl ether and diethyl ether (33 mL: 17 mL) to provide pure
ramipril 1[4h] as a white solid. Yield 25.0 g (95%); mp 110 8C (lit.[4h] mp
108 8C); [a]2D0
¼
þ38.0 (c ¼ 1 in 0.1 N methanolic HCl) [lit.[10]
[a]2D4 ¼ þ33.2 (c ¼ 1 in 0.1 N ethanolic HCl)]; 1H NMR (400 MHz,
CDCl3) d 1.23 (t, J ¼ 7.2 Hz, 3H), 1.39 (d, J ¼ 6.8 Hz, 3H), 1.58–1.66
(m, 3H), 1.74–1.88 (m, 4H), 2.23–2.33 (m, 1H), 2.37–2.44 (m, 1H), 2.52–
2.79 (m, 4H), 3.98–4.04 (m, 2H), 4.10–4.26 (m, 3H), 4.31 (dd, J ¼ 8.0,
5.6 Hz, 1H), 7.17–7.21 (m, 3H), 7.27–7.31 (m, 2H); FT IR (KBr disc)
3445, 1744, 1653 cm21; MS: m/e 417 (Mþ).
ACKNOWLEDGMENTS
We greatly appreciate the supportive environment encouraged at Dr. Reddy’s
Laboratories Ltd. We are thankful to Intellectual Property Management
(IPM), Nuclear Magnetic Resonance (NMR) group of Dr. Reddy’s Research
Foundation (DRF) and the analytical group of Active Pharmaceutical Ingradi-
ents (API) Unit III for their generous support.
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11. Chiral cell OJ 205 ꢀ 4.6 mm or equivalent, flow rate 0.5 mL/min with a UV
detector at 215nm, 20 mL, run time 40 min. Mobile phase: a mixture of 94
volumes of n-hexane, 6 volumes of ethanol, 2.2 mL of diethyeamine and 0.2 mL
of trifluoroacetic acid.