Asymmetric synthesis of (S,S,S)-2-Aza-bicyclo-[3.3.0]-octane-3-carboxylic acid benzyl ester: Formal synthesis of ramipril

Article abstract of DOI:10.1080/00397911003798757

An asymmetric synthesis of (S,S,S)-2-aza-bicyclo-[3.3.0]-octane-3- carboxylic acid benzyl ester 2 as an intermediate of angiotensin converting enzyme (ACE) inhibitor, ramipril 1, is described.

Full text of DOI:10.1080/00397911003798757

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Asymmetric Synthesis of (S,S,S)-2-Aza-
bicyclo-[3.3.0]-octane-3-carboxylic
Acid Benzyl Ester: Formal Synthesis of
Ramipril
G. C. M. Kondaiah a , M. Vivekanandareddy b , L. Amarnath Reddy
a , Smita V. Anurkar b , V. M. Gurav b , M. Ravikumar a , Apurba
Bhattacharya a & Rakeshwar Bandichhor a
a Center of Excellence, IPDO, Dr. Reddy's Laboratories Ltd.,
Bachupalli, Qutubullapur, Andhra Pradesh, India
b Department of Chemistry, Yeshwant Mahavidhyalaya, Nanded,
Maharashtra, India
Published online: 21 Mar 2011.
To cite this article: G. C. M. Kondaiah , M. Vivekanandareddy , L. Amarnath Reddy , Smita V.
Anurkar , V. M. Gurav , M. Ravikumar , Apurba Bhattacharya & Rakeshwar Bandichhor (2011):
Asymmetric Synthesis of (S,S,S)-2-Aza-bicyclo-[3.3.0]-octane-3-carboxylic Acid Benzyl Ester: Formal
Synthesis of Ramipril, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 41:8, 1186-1191
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Synthetic Communications1, 41: 1186–1191, 2011
Copyright # Dr. Reddy’s Laboratories Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003798757
ASYMMETRIC SYNTHESIS OF (S,S,S)-2-AZA-BICYCLO-
[3.3.0]-OCTANE-3-CARBOXYLIC ACID BENZYL ESTER:
FORMAL SYNTHESIS OF RAMIPRIL
G. C. M. Kondaiah,1 M. Vivekanandareddy,2 L. Amarnath
Reddy,1 Smita V. Anurkar,2 V. M. Gurav,2 M. Ravikumar,1
Apurba Bhattacharya,1 and Rakeshwar Bandichhor1
1Center of Excellence, IPDO, Dr. Reddy’s Laboratories Ltd., Bachupalli,
Qutubullapur, Andhra Pradesh, India
2Department of Chemistry, Yeshwant Mahavidhyalaya, Nanded,
Maharashtra, India
GRAPHICAL ABSTRACT
Abstract An asymmetric synthesis of (S,S,S)-2-aza-bicyclo-[3.3.0]-octane-3-carboxylic
acid benzyl ester 2 as an intermediate of angiotensin converting enzyme (ACE) inhibitor,
ramipril 1, is described.
Keywords (S)-1-Amino-2-methoxy methylpyrrolidine (SAMP); angiotensin converting
enzyme (ACE) inhibitor; asymmetric synthesis; chiral auxiliary; enantiomerically pure
ramipril
INTRODUCTION
Stereoselective reactions, employing chiral auxiliaries or chiral catalysts, have
become one major interest in academia and industry. This is repeatedly evident in
synthetic organic chemistry, because the biologically active molecule, as one of the
enantiomers, often shows the desired activity whereas the other one is either ineffec-
tive or undesired in terms of toxicity. We adopted a novel approach for an asymmet-
ric synthesis of 2, which was used in the formal synthesis of enantiomerically pure
ramipril 1 (Fig. 1).[1]
Received January 2, 2010.
Address correspondence to Rakeshwar Bandichhor, Center of Excellence, IPDO, Innovation Plaza,
Dr. Reddy’s Laboratories Ltd., Bachupalli, Qutubullapur, R. R. District, 500 072 Andhra Pradesh, India.
E-mail: rakeshwarb@drreddys.com
1186

FORMAL SYNTHESIS OF RAMIPRIL
1187
Figure 1. Structure of ramipril 1.
A plethora of synthetic routes for the preparation of the precursor of 2,
racemic 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid, have been used: anodic
oxidation of N-acyl cyclopentapyrroles and subsequent cyanation and hydrolysis,[2]
1,3-dipolar cycloaddition of azomethines strategy,[3] strategy starting from serine,[4]
resolution-based methods,[4b,5–7] conjugate addition–based protocol,[8,9] ethyl
bromo pyruvate–based synthesis,[10] and menthol-based strategy.[7b] The intramol-
ecular approaches have also been developed to synthesize intermediate 2.[11]
Additionally, the preparation of racemic benzyl ester was accomplished via Gilbert
Stork condensation.[12]
Scheme 1. Synthesis of advanced intermediate 2 and formal synthesis of ramipril 1.

1188
G. C. M. KONDAIAH ET AL.
Figure 2. X-ray structure of HCl salt of 2.
To the best of our knowledge, there is not much research devoted to the asym-
metric synthesis of (S,S,S)-2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid benzyl ester
2. Herein, we report our efforts to develop a novel and efficient transformation to
access intermediate 2 by utilizing (S)-1-amino-2-methoxy methylpyrrolidine (SAMP)
as chiral auxiliary.
Enders et al. discovered[13] SAMP as a chiral auxiliary to access the
corresponding isomer as a major species for carbocyclic compounds.
RESULTS AND DISCUSSION
We utilized the SAMP chemistry to synthesize the key starting material 2 of
ramipril 1, as shown in Scheme 1. Intermediate 2 was prepared by using SAMP, a
little excess of cyclopentanone 3, and a catalytic amount of p-TsOH ꢀ H2O (5 mol%).
The by-product, water, was removed azeotropically with toluene to afford chiral
imine 4. The corresponding lithium salt of chiral enamine 5 was obtained by the
reaction of 4 and lithium diisopropylamide (LDA).
In the subsequent steps, the key intermediate 6 was prepared by addition
of substituted iodide (obtained from N-acetyl-serine methyl ester) to freshly pre-
pared 5. In situ–generated intermediate 6 was treated with 5 N HCl to effect
hydrolysis to obtain 7, and eventually SAMP was recovered. Intermediate 7 ben-
zyl alcohol and thionyl chloride afforded HCl salt of 2 in 69% overall yield. The
stereochemistry and structure of HCl salt of 2 were confirmed by x-ray crystal-
lography as shown in Fig. 2. This is a new and innovative approach that offers
a viable asymmetric transformation relatively better than the hitherto known
synthesis for intermediate 2.[14] This intermediate was utilized to synthesize rami-
pril 1.[7a]
CONCLUSION
We developed asymmetric synthesis of HCl salt of (S,S,S)-2-aza-bicyclo-
[3.3.0]-octane-3-carboxylic acid benzyl ester 2 in moderate yields and high purity
using the recoverable chiral auxiliary SAMP. The absolute configuration at chiral
centers present in 2 was also supported by x-ray crystallography (Fig. 2). The SAMP
was recovered and used in the next cycle of preparation of 2 with good yield and
purity.

FORMAL SYNTHESIS OF RAMIPRIL
1189
EXPERIMENTAL
General Methods
1H NMR spectra were recorded on a 400-MHz Varian Gemini Fourier trans-
form (FT) NMR spectrometer, 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 tetramethylsilane (TMS). The FT FT-IR spectra were recorded
using a Perkin-Elmer 16650 FT-IR spectrometer. Mass spectra (70 eV) were recor-
ded on a HP-5989A liquid chromatography–mass spectrometry (LC-MS) spec-
trometer. 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.
Synthesis of (S,S,S)-2-Aza-bicyclo-[3.3.0]-octane-3-carboxylic Acid
Benzyl Ester (2)
A mixture of (S,S,R=S)-2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid (9)
(21.3 g, 0.11 mol) and benzyl alcohol (100 mL) was charged into a flask under nitro-
gen atmosphere and cooled to 0–5 ꢁC, and then thionyl chloride (40 g, 0.34 mol) was
slowly added for 1 h. After stirring for 12 h at 25 ꢁC, the reaction mass was saturated
with diisopropyl ether (300 mL) to precipitate compound 2 (12.5 g, 80% with respect
to single isomer) and filtered. The remaining mother liquor was evaporated under
reduced pressure to get 11 as a oily crude; then the pH adjusted to 7.5–8.0 by using
aqueous NaOH solution at 10–15 ꢁC and extracted with ethyl acetate (3 ꢂ 200 mL)
followed by evaporation to furnish a free base of 11 (oily yellow color crude).
N-Chlorosuccimide (NCS; 9.8 g, 0.07 mol) in portions was added to a mixture of
crude 11, free base (15.7 g, 0.06 mol), dimethylformamide (DMF; 30 ml), and
K2CO3 (1.8 g, 0.013 mol) at 0 ꢁC. After the mixture was stirred for 0.5 h,
1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU; 14.6 g, 0.1 mol) was added (exothermic).
After stirring for 3 h at 25 ꢁC, water (60 mL) was added. Subsequently, reaction mass
was extracted with ether (4 ꢂ 100 mL) and evaporated under reduced pressure to fur-
nish compound 12 with 90% yield (13.9 g). A mixture of compound 12, ethanol
(25 mL), and 5% wet Pd=C (type 39 K) (1.0 g) were added, and the total reaction
mass was transferred into an autoclave and maintained at 2.5–3.0 kg=cm2 of hydro-
gen pressure at 25–30 ꢁC for 3 h. The reaction was monitored by thin-layer chroma-
tography (TLC). After completion of the reaction, it was filtered through a pad of
celite, followed by washing with ethanol (10 mL). The filtrate was concentrated com-
pletely at 40–50 ꢁC under vacuum to afford 13 with 95% yield (8.4 g). Compound 13
(8.4 g, 0.03 mol) and benzyl alcohol (20 mL) was charged into a flask under a nitro-
gen atmosphere and cooled to 0–5 ꢁC. Afterward, thionyl chloride (6.7 g, 0.089 mol)
was slowly added for 1 h. After stirring for an additional 12 h at 25 ꢁC, the reaction
mass was saturated with diisopropyl ether (60 mL) to precipitate compound 2 in 64%
yield (10.7 g based on available isomer) [overall yield 69% (23.2 g)]; mp 178–180 ꢁC
20
30
1
(lit.[4b] mp 180 ꢁC); ½aꢃD ¼ ꢄ40.0 (c ¼ 1, H2O) (lit.[4b]½aꢃD ¼ ꢄ38.4 (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 (ABq, J ¼ 12.0 Hz, 2H),

1190
G. C. M. KONDAIAH ET AL.
7.33–7.37 (m, 5H); 13C NMR (100 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 cmꢄ1; MS: m=e 246 (Mþ).
ACKNOWLEDGMENTS
We greatly appreciate Prof. Dieter Enders for his promptness in sharing docu-
ments related to SAMP. We are also thankful to the management of Dr. Reddy’s
Laboratories Ltd. for supporting this work.
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