Application of Ugi three component reaction for the synthesis of quinapril hydrochloride

Article abstract of DOI:10.1080/00397911.2019.1682168

A novel, efficient and concise synthesis of chirally pure quinapril hydrochloride is described. The key step is the formation of α-amino amide backbone in one step using Ugi three component reaction. This method allows short access to α-amino amide chain which is a part of many drugs used for treatment of high blood pressure. A large molecular library can be synthesized by changing the components in Ugi reaction.

Full text of DOI:10.1080/00397911.2019.1682168

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Application of Ugi three component reaction for
the synthesis of quinapril hydrochloride
Bhushan B. Borase, Himanshu M. Godbole, Girij P. Singh, Pritesh R.
Upadhyay, Anurag Trivedi, Varadaraj Bhat & Gautham G. Shenoy
To cite this article: Bhushan B. Borase, Himanshu M. Godbole, Girij P. Singh, Pritesh R.
Upadhyay, Anurag Trivedi, Varadaraj Bhat & Gautham G. Shenoy (2019): Application of Ugi three
component reaction for the synthesis of quinapril hydrochloride, Synthetic Communications, DOI:
10.1080/00397911.2019.1682168
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https://doi.org/10.1080/00397911.2019.1682168
Application of Ugi three component reaction for the
synthesis of quinapril hydrochloride
Bhushan B. Borasea, Himanshu M. Godbolea, Girij P. Singha, Pritesh R. Upadhyaya,
Anurag Trivedia, Varadaraj Bhatb, and Gautham G. Shenoyb
b
aResearch and Development, Lupin Limited, Mulshi, India; Manipal Academy of Higher Education,
Manipal, India
ABSTRACT
ARTICLE HISTORY
Received 23 February 2019
A novel, efficient and concise synthesis of chirally pure quinapril
hydrochloride is described. The key step is the formation of a-amino
amide backbone in one step using Ugi three component reaction.
This method allows short access to a-amino amide chain which is a
part of many drugs used for treatment of high blood pressure. A
large molecular library can be synthesized by changing the compo-
nents in Ugi reaction.
KEYWORDS
a-amino amide; isocyanides;
Ugi reaction
GRAPHICAL ABSTRACT
Introduction
Quinapril hydrochloride is an active pharmaceutical ingredient indicated for the treat-
ment of high blood pressure (hypertension) and as an adjunctive therapy in the man-
agement of heart failure. It may be use for the treatment of hypertension by itself or in
combination with thiazide diuretics and digoxin for heart failure. Phenyl acetamide,
a-amino amide, a-amino acid chemotypes exhibits a wide range of biological activities
and are building blocks to molecules like Etidocaine, Enalapril and Quinapril (Fig. 1).
Multicomponent reactions (MCRs) have become very popular and a powerful strategy
in modern organic synthesis.[1a,b,c] Among them, Ugi reaction provides a facile access to
a-amino amide in one step.[2a,b] Hence, we turned our attention to exploring new syn-
thetic routes for quinapril hydrochloride (ACE inhibitor) by using the U3CR.
CONTACT Himanshu M. Godbole
himanshugodbole@rediffmail.com
Research and Development, Lupin Limited,
Mulshi, Maharashtra, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
B. BORASE ET AL.
Figure 1. Representative examples of biologically active compounds containing a-amino amide and
amino acid backbone.
Results and discussion
We report herein, the first synthesis of quinapril hydrochloride (Fig. 1) using Ugi 3CR
through the intermediacy of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (TIQ). This
method is superior to the prior art synthetic methods because the a-amino amide back-
bone of quinapril is synthesized in one-step. The subsequent steps followed by ring for-
mation gave quinapril hydrochloride in good yield. In 1986, Klutchko et al., reported
first multistep synthesis of quinapril hydrochloride.[3a] Later, few modified synthetic
strategies were developed, which involved use of advance intermediates, acid chloride
and amine approach, use of hazardous chemicals like benzsulfonamide, phosphorous
pentachloride. The disadvantage of above method was handling of these hazardous
chemicals in large scale synthesis faced various difficulties.[3b] Other synthetic methods
involved use of acid amine coupling approach by using DCC and HOBt. Removal of
insoluble DCU byproduct, low solubility of HOBt in water and formation of DKP
impurity[3a] were demerits of this method. Some recent synthetic methods used carbox-
yanhydride prepared from poisonous phosgene.[3b] whereas our synthetic approach
involved cheaper starting materials, cleaner and scalable reactions conditions.

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Table 1. Ugi product 4–8.
Reaction condition (a) Ethyl-2-amino-4-phenylbutanoate (b) Acetaldehyde, (c) Isonitrile (1 mmol each), catalyst TiCl4,
methanol, RT.
Initially, to examine the feasibility of the Ugi three-component reaction (U3CR), we
conducted a model reaction using acetaldehyde, isonitrile of glycine benzyl ester,
L-homophenyl alanine ethyl ester and TiCl4 catalyst. The reaction gave the Ugi product
(4) in good yield (Table 1).
Different Lewis acids like TiCl4, phenyl phosphinic acid borox were screened as cata-
lysts to increase the yield, and lower down reaction time. Among the Lewis acids tested,
TiCl4 gave the best results[4a,b,c,d] (Table 2).
Ugi products (4–8) were synthesized using optimized conditions and characterized by
1H NMR, 13C NMR, HRMS, and IR spectroscopy. A summary of above reactions and
optimized conditions is depicted in Table 2. Yields were significantly higher and reac-
tion times were considerably shorter relative to the un-catalyzed reactions run under
Ugi’s original conditions.[5a,b,c]
Inspired from the U3CR as above, we focused our efforts towards the search for a new
efficient methodology for the synthesis of quinapril hydrochloride. Benzyl-2-isocyano-3-
phenyl propanoate, acetaldehyde and ethyl-2-amino-4-phenylbutanoate were reacted in

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B. BORASE ET AL.
Table 2. Identification of suitable catalyst for Ugi product 8.
Entry
Temp. (h)
Time (5 mol %)
Solvent
Lewis acid
Yield
dr
1
2
3
4
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
48
48
48
24
MeOH
MeOH PPA
MeOH
none
45%
Borox
TiCl4
40%
70:30
50%
70:30
60:40
80:20
MeOH
80%
PPA ¼ phenyl phosphinic acid.
Borox ¼ BINOL þ BH3ꢁSMe2 þ H2O þ 2, 4, 6-trimethylphenol complex.
TiCl4 ¼ Titanium Tetrachloride.
dr ¼ Diastereomeric ratio.
methanol using TICl4 catalyst (Table 2) to obtain mixture of diastereomers (8) and (9)
with diastereomeric ratio 80:20. Diastereomeric mixture (8) and (9) was chromatographi-
cally inseparable. This mixture of diastereomers was further purified by reacting with
1
maleic acid. Diastereomer (8) and (9) were characterized by H NMR, 13C NMR, HRMS,
SOR, IR spectroscopy. Major diastereomer (8) was taken further for the synthesis of qui-
napril HCl (Scheme 1).
Alternatively, above reaction was performed in ethanol with L-homophenyl alanine,
acetaldehyde and benzyl-2-isocyano-3-phenylpropanotae using TiCl4 as a catalyst to
yield mixture of diastereomers (8) and (9) (dr. 80:20) (Yield 40%)[4a,b,c,d] (Scheme 1).
After major diastereomer (8) in hand, it was thought to protect secondary amine
–NH of diastereomer (8) with benzyl bromide. Accordingly, diastereomer (8) was
reacted with benzyl bromide, Na2CO3 in DMF at room temperature to obtain com-
pound (10) (60%) (Scheme 1).
Compound (10) was further subjected to TIQ ring formation using p-toluene sulfonic
acid monohydrate, paraformaldehyde in toluene to furnish compound (11). We have
chosen this method because, p-toluene sulfonic acid monohydrate is mild, easy to han-
dle, shorten reaction time and gave good yield (65–67%) (Scheme 1).
Alternatively, other conditions were tried mainly (HCHO)n/ethanol HCl, (HCHO)n/
TFA, (HCHO)n/AcOH, (HCHO)n/H2SO4, and 1,3 dioxolane/HCl. Above listed meth-
ods gave yield of compound (11) in the range of 50–60%[6a,b,c,d] (Scheme 1).
Debenzylation of compound (11) was achieved by using catalytic hydrogenation (20%
Pd(OH)2/C, conc. HCl) at 60 psi in autoclave to give quinapril hydrochloride
(12)[7a,b,c,d,e,f] (Scheme 1).
1
The quinapril hydrochloride (12) thus obtained was characterized by H NMR, 13C
NMR, HRMS, SOR, IR spectroscopy and data was in accordance with literature.[7a,b,c,d,e,f]
The synthetic method developed is described in Scheme 1.
Experimental details
All reagents were purchase from Sigma Aldrich, S D Fine and used without further
purification. TLC Aluminum sheets Silica gel 60 F254, Merck Life Science Pvt. Ltd. The
NMR spectra recorded on a Bruker 500 MHz AVANCE III HD, Software –Topspin 3.5
at room temperature in CDCl3, DMSO-d6 using TMS as an internal reference. HRMS
data acquired by Waters Xevo G2 QTOF mass spectrometer. Specific optical rotation
recorded on Rudolph Research Analytical, Autopol V plus instrument. I.R. spectra
(FTIR) recorded on Perkin spectrum 400 FTIR spectrometer. Waters HPLC, software
chromeleon 6.80. Quinapril HCl checked on HPLC Diastereoisomers method as per

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Scheme 1. Stepwise conversion of Ugi 3CR product 8 into quinapril (Entry 8–12). (i) Methanol, cata-
lytic TiCl4, (80%) (ii) Purification (iii) Benzyl bromide, DMF, Na2CO3, (60%) (iv) p-TSA.1H2O, (HCHO)n,
toluene, reflux, (67%) (v) Pd (OH)2/C, Ethanol. H2 (g) 60 psi. Conc HCl. (85%).
European Pharmacopeia 9.0 page no. 3459-3461. Ugi reaction monitored on
chiral method, mobile phase (80:20) ratio of n-Hexane: Ethanol, column used
CHIRALPAK-AD-H, particle size 5 mm, dimensions 4.6 mm/ ꢂ 250 mmL flow rate
1 mL minꢃ1, UV ¼ 205 nm, Column Oven Temperature 25 ꢀC, sampler tempera-
ture 15 ꢀC.
General procedure for the ugi reaction: (Ugi products 4, 5, 6, 7, 8)
Procedure for ethyl-(benzyloxy)-1-oxo-3-phenylpropan-2-yl) amino)-1-oxopropan-2-yl)
amino)-4-phenylbutanoate (8)
A solution of ethyl-2-amino 4-phenyl butanoate (1 g. 4.8 mmol), acetaldehyde (0.2 g,
4.8 mmol) in methanol was stirred for 20–30 min. To this solution, a solution benzyl-
2-isocyno-3-phenyl propionate (1.27 g, 4.8 mmol) in methanol (5 mL) was added
followed by TiCl4 (5 mol %) (0.045 g). The reaction mixture was stirred for 24 h. The
progress of the reaction was monitored by TLC (ethyl acetate: hexane, 1:1). After

6
B. BORASE ET AL.
completion of reaction, the reaction mixture was evaporated under reduced pressure at
45 ꢀC. Residue was extracted with ethyl acetate (10 mL) and washed with brine. The
organic layer was separated and dried over sodium sulfate. The organic layer was con-
centrated under reduced pressure at 40–45 ꢀC to get mixture diastereomers (8) and (9)
as thick oil (80%). The mixture of diastereomers was chromatographically inseparable.
The mixture of diastereomers (8) and (9) was filtered through silica gel bed to remove
other impurities[1–3] (Table 1).
The mixture of diastereomers (8) and (9) was dissolved in ethyl acetate (5 vol) and a
solution of maleic acid (1 mmol) in ethyl acetate (5 vol) was added. The reaction mix-
ture was stirred till solid formation observed. The solid obtained was filtered and
washed with cold ethyl acetate to get maleate salt of diastereomer (8).
A mixture of maleate salt of diastereomer (8) and aqueous saturated NaHCO3 (5 vol)
in ethyl acetate (5 vol) was stirred for 5–10 min. at room temperature. Organic layer was
separated and dried over anhydrous Na2SO4. It was evaporated to get diastereomer (8)
as thick yellow oil.
Ethyl-(benzyloxy)-1-oxo-3-phenylpropan-2-yl) amino)-1-oxopropan-2-yl) amino)-4-
phenylbutanoate (8)
25
Yield 60%, 1.2 g. thick yellow oil. [a]D – 19.8 (c 0.5, MeOH). IR (KBr) Vmax 699, 1182,
1247, 1505, 1604, 1682, 1732, 2928 cmꢃ1 1H NMR (500 MHz, CDCl3), d (ppm)
.
1.26–1.29 (m, 6 H), 1.66–1.74 (m. 2 H), 1.79–1.85 (m, 1 H), 2.42–2.60 (m, 2 H), 3.05 (q,
J ¼ 7 Hz, 1 H), 3.12–3.22 (m, 3 H), 4.11–4.20 (m, 2 H), 4.93–4.97 (m, 1 H), 5.15 (d,
J ¼ 12 Hz, 1 H), 5.19 (d, J ¼ 12 Hz, 1 H), 7.03–7.05 (m, 2 H), 7.07–7.16 (m, 3 H),
7.19–7.22 (m, 3 H), 7.27–7.39 (m, 7 H), 7.68 (d, J ¼ 9 Hz, 1 H, Amide). 13C NMR
(125 MHz) d: 14.2, 20.2, 31.9, 35.5, 37.8, 52.2, 57.5, 60.4, 61.0, 67.2, 125.9, 127.1, 128.3,
128.3, 128.4, 128.5, 128.6, 128.6, 129.3, 135.1, 135.6, 141.4, 171.2, 174.4, 175.0. HRMS
calculated (m/z) [M þ H]þ: 517.2624; Found; 517.2623. Chiral HPLC ¼ 100%.
Conclusion
In conclusion, we have demonstrated the effectiveness of TiCl4 catalyzed Ugi three com-
ponent reactions for the synthesis of quinapril HCl. A highly efficient, and atom econ-
omy methodology for the chirally pure quinapril hydrochloride (ACE inhibitor)
synthesis has been established. Hence, these efficient procedures regarded as a new and
time saving future method for the preparation of pharmaceutically relevant phenylaceti-
midamide, phenylacetamide, and a-amino acid derivatives (Fig. 1).
General experimental details, characterization of Ugi products 3 to 12 are available in
Supporting information.
Acknowledgments
The authors acknowledge Lupin Research Park and Manipal Academy of Higher Education for
providing the opportunity to take up this research work. Thankful to Lupin Research Park, R&D,
Analytical team for supporting the analysis.

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