Improved, gram-scale synthesis of sildenafil in water using arylacetic acid as the acyl source in the pyrazolo[4,3-d]pyrimidin-7-one ring formation

Article abstract of DOI:10.1039/d0nj01236j

An improved, gram-scale synthesis of the blockbuster drug sildenafil, used for the treatment of male erectile dysfunction, has been developed. Unlike the previous literature, the current method demonstrates the use of arylacetic acid as an acyl source, a cheap oxidant K₂S₂O₈, and water as the reaction medium in the key step of pyrrazolo[4,3-d]pyrimidin-7-one ring formation. As well as being a green and benign approach, the current method reduces the cost by half compared to our previous strategy. In addition, the general relevance of the method has been demonstrated in the synthesis of a variety of quinazolinone and benzothiazole derivatives with excellent functional group tolerance.

Full text of DOI:10.1039/d0nj01236j

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Improved, gram-scale synthesis of sildenafil in water using
arylacetic acid as the acyl source in the pyrazolo[4,3-d]pyrimidin-
7-one ring formation
Received 00th January 20xx,
Accepted 00th January 20xx
Joydev K. Laha,*a Upma Gulati,a Saima,a Anjali Guptaa and Harish Kumar Indurthia
DOI: 10.1039/x0xx00000x
An improved, gram-scale synthesis of the blockbuster drug sildenafil, used for the treatment of male erectile dysfunction,
has been developed. Unlike the previous literature, the current method demonstrates the use of arylacetic acid as an acyl
source, a cheap oxidant K2S2O8, and water as reaction media in the key step of pyrrazolo[4,3-d]pyrimidin-7-one ring
formation. Beside a green and benign approach, the current method reduces the cost by half compared to our previous
strategy. In addition, the general relevance of the method has been demonstrated in the synthesis of a variety of
quinazolinone
and
benzothiazole
derivatives
with
excellent
functional
group
tolerance.
pulmonary hypertension.5 The global erectile drugs market
valued approximately USD 4.82 billion in 2017 of which Viagra
dominated the market with more than 27% of the market
share, fetching over USD 2.4 billion revenue.6 The commercial
method developed by Pfizer for the large scale production of
sildenafil is shown in Scheme 1.
Introduction
India’s overwhelming dependence on China for generic active
pharmaceutical ingredients (APIs) to the extent over 65
percent of the requirement is a serious concern in the
production of affordable medicines used in current health care
in India.1 While many Indian pharmaceutical companies
produce generic APIs, the similar research activities in
academia are rarely postulated.2 Evolution of innovative, cost-
effective processes for generic API synthesis and
manufacturing in academic-industry joint venture could
advance production of generic APIs in India. C-H/N-H
functionalization via oxidative coupling is an emerging
research area in organic chemistry promoting various C-C and
C-X bond formation expediently, often under green
conditions.3a Despite its potential, its application in generic API
synthesis3b has rarely been demonstrated.
Sildenafil,
a selective phosphodiesterase type 5 (PDE-5)
inhibitor, developed by Pfizer for the treatment of male
erectile dysfunction (MED) is a highly profitable drug currently
sold in the market under the brand name ViagraTM.4 While the
cyclic guanosine-3,5-monophosphate (cGMP), an important
messenger that controls many physiological processes, is
produced by cyclase enzymes, PDE-5 reduces the intracellular
level of cGMP. The inhibition of the activities of PDE-5 by
sildenafil leads to higher levels of cGMP, which is used in a
therapeutic strategy for MED and for the treatment of
Scheme 1: Commercial method for sildenafil synthesis
a.Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062, India.
In Pfizer’s manufacturing process, the coupling between
aromatic acid 1a and pyrazole amine
upon intramolecular cyclization gives sildenafil 4 4a
pyrazolo[4,3-d]pyrimidin-7-one ring formation in involving
2
gives amide
3, which
.
The
Email: jlaha@niper.ac.in
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
4
two steps, amide coupling and intramolecular cyclization, is
the key to the successive development of the manufacturing
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process. While the current manufacturing route is well previous chemistry features certain advantages including one-
developed and robust, the significant limitations including the step synthesis of the , K2S2O8 as the cheap and exclusive
5
use of over stoichiometric amount of amide coupling agent reagent, and mild reaction conditions, the limitations may
1,1՚-carbonyldiimidazole (CDI) and a strong hygroscopic base include the preparation of arylglyoxylic acid requiring selenium
Kt-OBu for intramolecular cyclization, and production of dioxide, use of Kt-OBu to prepare the salt of arylglyoxylic acid,
equimolar quantities of wastes leaves the scope for further organic solvent CH3CN, and inability to scale up. Looking at the
environmental safe development. Therefore, any eco-friendly current demand and commercial market of sildenafil, we were
development to the scalable synthesis of sildenafil while encouraged to overcome the limitations of our previous
obviating the use of any coupling agent and strong base, synthesis. Although the use of arylacetic acids as an acyl
however involving the use of a cheap reagent, and most source has already been explored,14 however its annulation
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importantly, using water as the reaction media is desirable.
reactions with ortho-substituted anilines in water for the
Subsequent to the development of Pfizer’s method, a number synthesis of heterocycles remains elusive. Herein, we describe
of synthetic methods involving a variety of substrates served an improved synthesis of sildenafil demonstrated in gram
as an acyl source, such as 2-ethoxybenzaldehyde,7 2- scale. The current synthesis uses arylacetic acid as an acyl
ethoxybenzoic
acid,8
2-ethoxybenzoyl
chloride,9
2- component, which does not involve any use of selenium
ethoxybenzamides,10 2-ethoxystyrene,11 and 2-ethoxybenzyl dioxide, neither involves the use of its salt obviating the use of
amine12 have been developed for the synthesis of sildenafil Kt-OBu. Perhaps most importantly, organic solvent used in our
(Scheme 2). Although these reports potentially could be previous method13 is replaced with water in the current
translated to the scale up synthesis of sildenafil, several of method. Implementation of these parameters in the synthesis
them suffer from the limitations, such as requiring the use of not only satisfies principles of green chemistry, but also makes
metals and expensive ligands, a high temperature, expensive the synthesis sustainable, environmental friendly, users safe,
reagents, and organic solvents for coupling of the two starting and cost effective. The operational simplicity together with
materials. More importantly, the focus of these reports was scalability and ready to transfer the technology could be
not improvement in the synthesis of sildenafil. Consequently, especially attractive for commercialization.
the challenges in the original Pfizer method have rarely been
addressed in these reports.
Results and Discussion
Our investigation started with the reaction of commercially
available both
2 (Sigma-Aldrich price INR 18,922 for 5 grams)
and phenylacetic acid 6a for the synthesis of pyrazolo[4,3-
d]pyrimidin-7-one using water as the primary reaction
medium. Heating a mixture of
2 and phenylacetic acid 6a in
the presence of K2S2O8 (1 equiv) in water at 80 ˚C largely
produced benzaldehyde together with a trace of the desired
pyrazolo[4,3-d]pyrimidin-7-one
7 (Table 1, entry 1). As 2
appears to be expensive for the subsequent optimization, we
carried out further investigation using a structurally similar
substrate, 2-aminobenzamide
presence of K2S2O8 (1 equiv) in water at 80 ˚C resulted in
similar observation with a trace of quinazolinone in this case
(entry 2). Increasing the stoichiometry of persulfate to 2 equiv
delivered in ca. 20% yield (entry 3). When the stoichiometry
8. Reaction of 6a and 8 in the
9
9
of persulfate was increased to 3 equiv, the yield of
improved significantly (72% yield, entry 4).
9 was
Table 1: Optimization of the reactiona
Scheme 2: Different approaches for the synthesis of intermediate 5
Previously, we developed the annulations of 2-
aminobenzamides and arylglyoxylates to the synthesis of
quinazolinones using a cheap oxidant K2S2O8 enabling two
steps to occur sequentially.13 Utilizing the chemistry, we were
able to prepare the core skeleton of sildenafil, pyrazolo[4,3-
d]pyrimidin-7-one
5 and ultimately demonstrated to the
synthesis of sildenafil. While the sildenafil synthesis with our
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7
8
9
CHO
COOH
persulfate
operationally simple and commercially applicable. In contrast
to our previous synthetic methodology, the current approach
+
7 / 9
2 / 8
+
H2O, 80 °C
6a
Yield
(%)
Persulfate
(equiv)
Entry
1.
Substrate
focuses on
a greener method of improved process
development involving the use of water as the only solvent
and avoiding the use of organic solvents. Also, limiting the
number of steps towards sildenafil synthesis by utilising easily
available acyl source and avoiding the use of toxic reagents
such as SeO2 makes the process more viable. All these factors
collectively add to the merits of the process and ultimately
reduce the cost of production to almost half the previous
amount (Figure 1).
K2S2O8
(1)
tracesb
tracesc
48d
2
8
O
O
K
2S2O8
(1)
2.
3.
N
H2N
NH2
NH2
N
K2S2O8
(2)
H2N
8
8
Pr
8
2
K2S2O8
(3)
4.
5.
72c
O
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O
K2S2O8
(4)
70c
46c
8
8
8
2
N
HN
NH
N
N
Na2S2O8
(3)
N
6.
7.
8.
Pr
9
7
60c
59b
(NH4)2S2O8
(3)
Current Method
K
2S2O8
(3)
Our Previous Approach
Comparison
a Reagents and conditions: 6a (0.25 mmol), 2/8 (0.25mmol), persulfate (0.75mmol) unless otherwise stated, H2O (1 mL), 80
°C, 4-12 h; b isolated yield of 7; c isolated yield of 9; d isolated yield of benzaldehyde.
O
O
N
N
COOK
OEt
COOH
OEt
HN
oxidant
water
O
oxidant
N
N
S
organic
solvent
N
Further increase in the persulfate concentration did not prove
effective in improving the yield (entry 5). Replacing K2S2O8 with
other persulfate, such as sodium persulfate or ammonium
persulfate did not bring any significant change in the yield
(entry 6-7). The optimized condition entailed the reaction of
phenylacetic acid 6a and 2-aminobenzamide
of K2S2O8 (3 equiv) in water at 80 ˚C yielding
yield. Under the optimized condition, reaction of
resulted in in 59% yield (entry 8). Although the obtained
O
Pr
OEt
Acyl
Phenylaceticacid
Comparativelyless
K salt of phenylglyoxylicacid
Comparativelymore
Source
No. of
Steps
8
9
in the presence
in 72% isolated
Water as reactionmedium
Approx.INR 5,300/g
Organicsolvents
2 and 6a
Solvent
Cost
7
yield of pyrazolo[4,3-d]pyrimidin-7-one is only good,
annulation reactions of arylacetic acid with 2-substituted
anilines and similar motifs in water have been developed for
the first time. It should be noted here that in addition to the
Approx.INR 10,000/g
Figure 1: Improvements in the process for sildenafil synthesis
desired products
7 and 9
, the formation of aniline polymers15
Also a comparison using common green chemistry metrics
indicates that the present methodology is analogous to the
already available literature procedures. Atom economy of the
present method is quite comparable to that of the commercial
process and is quite better than our previous approach. Also
the yield of the current process is comparable to our previous
approach and quite better than the reported commercial
procedure (Figure 2).
could account for the respective mass balances.
With the optimized condition in hand, we were focused on the
improved synthesis of sildenafil. 2-Ethoxyphenylacetic acid
(
10) and
water at 80 ˚C to obtain the corresponding product
yield. Chlorosulfonation of followed by reaction with N-
methylpiperazine gave sildenafil ( ) with an overall 62% yield
2
were reacted in the presence of K2S2O8 (3 equiv) in
5
in 67%
5
4
(Scheme 3). Importantly, we were able to prepare sildenafil in
more than a gram quantity utilizing the procedure. Thus, the
current synthesis is promising towards further scale up of
sildenafil under green condition.
Process Comparison using Green Chemistry Metrics
90
80
70
60
50
40
30
20
10
0
O
O
N
HN
N
K2S2O8 (3 equiv.)
H2O, 80 °C, 12 h
COOH H2 N
+
N
N
N
OEt
H2N
Pr
Pr
OEt
5 (67% yield)
10
2
O
N
N
1. ClSO3 H, 0 °C
2. N-methylpiperazine
HN
O
N
N
S
N
Atom
Yield
O
Pr
OEt
Economy
Sildenafil(4)
(62% yield)
Scale upto1g
Commercial
method
83.8
47.8
Scheme 3: Synthesis of Sildenafil
Previous Approach
Present Method
75.11
81.86
65
62
The developed method upgrades sildenafil synthesis in terms
of sustainability and cost as only water is used as the solvent
along with easily available arylacetic acid making the process
Figure 2: Process comparison using green chemistry metrics
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To demonstrate the general applicability of the protocol, we
then investigated the reaction of arylacetic acids with o-
substituted anilines for the synthesis of N-heterocycles.
Interestingly,
a
variety of quinazolin-4-ones16 could be
successfully synthesised utilizing the reactions of various
arylacetic acids (6a-6j) and substituted 2-aminobenzamides (8,
8a) under the optimized condition. The substrates containing
both electron-donating and electron-withdrawing groups
worked well and the corresponding quinazolin-4-ones (9, 9a-
9j) could be synthesised in moderate to good yields (Scheme
4). The report demonstrates, for the first time, use of readily
available arylacetic acids as an alternate acyl source inthe
synthesis of quinazolin-4-ones featuring sildenafil synthesis in
water in moderate to good yields. The scope was further
investigated using indole-3-acetic acid, 1-naphthylacetic acid
and pyridine-3-acetic acid. In case of indole-3-acetic acid, the
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Scheme 5: Synthesis of various 2-arylbenzo[d]thiazoles
desired
product
(2-(1H-indol-3-yl)quinazolin-4(3H)-one)
After developing the substrate scope, we then switched over
to the understanding of reaction mechanism wherein a few
control experiments were performed (Scheme 6). Heating
phenylacetic acid 6a alone in the presence of K2S2O8 in water
at 80 ˚C for 1 h gave benzaldehyde as the only product (eq. 1).
formation was observed in less in 10% yield whereas, in the
other two cases no product formation was observed.
Similarly, reaction of diphenylacetic acid (1l) with
8 under the
optimized conditions did not yield any annulated product. Only
benzophenone (13) was obtained in this reaction (eq. 2). These
experiments suggest that a carbonyl compound could be an
intermediate in the reaction. Reaction of phenylacetic acid 6a
and 2-aminobenzamide
8 under the standard conditions in the
presence of TEMPO or BHT radical quenchers did not give any
product suggesting the involvement of a free radical pathway
(eq. 3 and 4).
Scheme 4: Synthesis of various quinazolin-4-ones
A
variety of 2-arylbenzo[d]thiazoles17
(12a-h) were also
synthesised successfully using the protocol (Scheme 5). When
different arylacetic acids were exposed to o-aminothiophenol
(11) under the optimized condition, benzothiazoles were
obtained in moderate to good yields. A couple of reports are
available for the synthesis of 2-arylbenzo[d]thiazoles, however
none of them utilizes water as the solvent, thereby making this
protocol a greener method for synthesis of these heterocycles.
Scheme 6: Control Experiments
Also the reaction of benzaldehyde and 2-aminobenzamide
8
under the standard conditions gave indicating the route of
9
reaction via benzaldehyde formation (eq. 5). Further, reaction
of benzamide and 6a under the optimized conditions gave only
benzaldehyde as the exclusive product together with
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unreacted benzamide (eq. 6). This experiment reveals that overcomes some of the limitations of our previous sildenafil
imine formation could occur with the arylamine rather than synthesis in terms avoiding a toxic reagent SeO2, organic
amide functionality. Subsequently, the imine could undergo solvent CH3CN, and reduced number of steps. In addition, the
oxidation followed by intramolecular cyclization or direct method also provides a straightforward and concise pathway
cyclization to form the product. During time oriented HRMS to synthesise a variety of quinazolinone and benzothiazole
studies a peak at m/z [M]+ = 240.0836 was observed which derivatives with excellent functional group tolerance. The
could correspond to the intermediate 20 with a calculated m/z development of a greener approach using water as the
[M]+ = 240.0899.
solvent, utilizing easily available cheap reagents, and reduced
cost of production are some of the important features of this
work.
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Based on these observations and already available reports of
arylacetic acids14 and radical reactions in water,18 a plausible
mechanism for an intermolecular imine formation followed by
an intramolecular cyclization to the synthesis of N-heterocycle
synthesis is proposed (Scheme 7). Phenylacetic acid 6a could
undergo decarboxylation by reaction with sulfate radical
anion, generated by homolytic cleavage of K2S2O8 under
thermal conditions, and generate benzyl radical (14) which
could undergo three competitive pathways; Path A [reaction
with a hydroxyl radical and generation of benzyl alcohol (15)],
Path B [loss of an electron from benzyl radical to generate the
corresponding benzyl carbocation (16)], or Path C [involving a
reaction between benzyl radical and aniline radical cation
thereby generating an intermediate 18]. Further, the
generated benzyl carbocation (16) can also undergo two
competitive pathways; Path D (nucleophilic attack of water
and formation of benzyl alcohol) or Path E (nucleophilic attack
of aniline derivative and formation of intermediate 18). The
intermediates, so generated, can undergo subsequent
reactions for product formation as show in Scheme 7. There is
a possibility of any of these pathways being followed during
the course of reaction. Also, the probability of multiple
pathways being followed simultaneously is not ruled out.
Experimental
Typical procedure for the synthesis of 1-methyl-5-phenyl-3-
propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4a):
In an oven-dried screw-cap sealed tube equipped with a
magnetic stir bar was charged with 4-amino-1-methyl-3-
propyl-1H-pyrazole-5-carboxamide (0.5 mmol), phenylacetic
acid (1 equiv) and K2S2O8 (3 equiv). Water (2 mL) was then
added in the sealed tube. The tube was sealed and the mixture
was allowed to stir at 80 ˚C for 12 h. The reaction mixture was
cooled to room temperature and then extracted with EtOAc.
The organic layer was dried over Na2SO4, concentrated under
reduced pressure and purified by using column
chromatography (100-200 # silica, EtOAc – Hexane = 3:7) to
give the desired cyclised product. Compound 4a: 1-methyl-5-
phenyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-
one (4a)12: White solid (59%); 1H NMR (400 MHz, CDCl3): δ
12.41 (s, 1H), 8.07-8.06 (m, 2H), 7.60-7.51 (m, 3H), 4.15 (s, 3H),
2.80 (t, J = 7.3 Hz, 2H), 1.76 (sx, J = 7.0 Hz, 2H), 0.96 (t, J = 7.3
Hz, 3H).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from NIPER, S.A.S. Nagar and CSIR, New Delhi
is greatly acknowledged.
Notes and references
1
(a) M. Baumann and I. R. Baxendale, Beilstein J. Org. Chem.,
2013, 2265–2319; (b) BioSpectrum,
9
,
https://www.biospectrumindia.com/views/17/9425/overco
ming-dependency-on-china-.html (accessed August, 2019).
A. Studer, D. P. Curran, Angew. Chem. Int. Ed., 2016, 55, 58-
102.
(a) NIH Consensus Development Panel on Impotence.
Impotence. JAMA, 1993, 270, 83-90; (b) P. Gupta and A.
Mahajan, RSC Adv., 2015, 5, 26686-26705.
2
3
Scheme 7: Plausible mechanism
Conclusion
4
5
(a) D. J. Dale, P. J. Dunn, C. Golightly, M. L. Hughes, P. C.
Levett, A. K. Pearce, P. M. Searle, G. Ward and A. S. Wood,
In conclusion, we have demonstrated a green and benign
approach for the sustainable synthesis of sildenafil with an
improved yield. The process unveils, for the first time, the use
of arylacetic acids in sildenafil synthesis. The current method
Org. Process Res. Dev., 2000,
4
, 17-22; (b) P. J. Dunn, S.
Galvin and K. Hettenbach, Green Chem., 2004,
6, 43-48.
H. Wilkens, A. Guth, J. Konig, N. Forestier, B. Cremers, B.
Hennen, M. Bohm and G. W. Sybrecht, Circulation, 2001,
104, 1218-1222.
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A. S. Bell, D. Brown and N. K. Terrett EP0463756A1, 1992.
(a) O. Achmatowicz, R. Balicki, U. Chmielowiec, A. Zaworska,
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Page 7 of 7
New Journal of Chemistry
View Article Online
DOI: 10.1039/D0NJ01236J
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Improved, gram-scale synthesis of sildenafil in water using arylacetic acid as the acyl
source in the pyrazolo[4,3-d]pyrimidin-7-one ring formation
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Joydev K. Laha,*a Upma Gulati,a Saima,a Anjali Guptaa and Harish Kumar Indurthia
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N
H2N
X
R
Alternative acyl source
K2S2O8
H2O
COOH
+
Only Oxidant
X
R
X= CONH2, SH
Water as the solvent
Single step
Variety of quinazolinones
and benzothiazoles
O
N
NH
O
O
Drug synthesis in water
N
S
N
N
Pr
N
EtO
Sildenafil