Synthesis of Sildenafil citrate and process related impurities

Article abstract of DOI:10.2174/157017811799304304

Synthesis of Sildenafil by the O-alkylation of 5-[2-hydroxy-5-(4- methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H- pyrazolo-[4,3-d]pyrimidin-7-one 8 proved difficult because concomitant alkylation of the pyrimidine moity also occurred. The selective O-alkylation was carried by DCC assisted decarboxilative etherification of the carbonate 9.

Full text of DOI:10.2174/157017811799304304

668
Letters in Organic Chemistry, 2011, 8, 668-673
Synthesis of Sildenafil Citrate and Process Related Impurities
Indukuri V.S. Kumar*,a, Gorantla S. Ramanjaneyulua and Vurimindi H. Bindub
aResearch and Development Centre, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet,
Hyderabad-500078, India
bInstitute of Science and Technology, JNTU, Hyderabad-500072, India
Received January 13, 2011: Revised April 15, 2011: Accepted April 15, 2011
Abstract: Synthesis of Sildenafil by the O-alkylation of 5-[2-hydroxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-
methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one 8 proved difficult because concomitant alkylation of
the pyrimidine moity also occurred. The selective O-alkylation was carried by DCC assisted decarboxilative etherification
of the carbonate 9.
Keywords: Decarboxilative etherification, sildenafil citrate, process impurities.
INTRODUCTION
1H-pyrazolo-5-carboxamide 7. Base induced cyclization of 7
afforded the desired 5-[2-hydroxy-5-(4-methylpiperazin-1-
ylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-
Sildenafil Citrate 1, designated chemically as 1-[[3-(6,7-
dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo-[4,3-d]pyrim-
idin-5-yl)-4-ethoxy phenyl]sulphonyl]-4-methyl piperazine
citrate or 5-[2-ethoxy-5-(4-methylpiperazinyl sulphonyl)
phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one citrate salt is a selective inhibitor of cyclic
guanosine monophosphate (cGMP), specific phosphodie-
sterase type-5 (PDE5). Sildenafil and its preparation were
originally disclosed by Pfizer Inc [1] and it was found useful
for the treatment of certain cardiovascular disorders, such as
angina, hypertension, heart failure, atherosclerosis, etc. Later
it was found that the compound is particularly useful in the
treatment of male erectile dysfunction [2], and an improved
process for the synthesis of Sildenafil citrate was published
(Scheme 1) [3, 4]. In view of its commercial importance
numerous alternate syntheses are described [5, 6], but the
synthesis reported by Pfizer [3] is the most efficient and
commercially viable. One of the critical steps, during
commercial scale manufacturing of 1, is the cyclization
reaction of the immediate precursor to Sildenafil 5. The
ethoxy moiety is doubly activated by the sulphonamide and
the amide groups and it is prone to nucleophilic
substitutions. To circumvent this problem we have recently
published an alternate route for the synthesis of Sildenafil
Citrate 1, where the O-alkylation is carried out after the ring-
closure reaction (Scheme 2) [7].
pyrazolo-[4,3-d]pyrimidin-7-one
8 in 73% yield. The
required O-alkylation was carried, via 9, in a two step
process to afford Sildenafil, which was further converted
into its citrate salt 1.
Initially selective O-alkylation of phenol 8 was tried. In
literature, O-alkylation of phenol 8 with allyl bromide is
reported, but with only 10% yield after purification by
column chromatography [1, 8]. A number of examples for
the O-alkylation of 4-hydroxybenzene sulphonamides, in
moderate to high yield, are reported [9]. When O-alkylation
of 8 with diethylsulphate was tried, in addition to the desired
product Sildenafil 10 formation of three by-products was
observed (Scheme 3, Table 1).
All efforts to improve the selectivity by varying the
alkylating agents and the reaction conditions proved futile.
For the identification and characterization, the byproducts
were separated by silica gel column chromatography.
Compound 11 displayed a molecular ion peak at m/z 502,
indicating the addition of two alkyl residues. When its 13C
NMR spectrum was compared with Sildenafil 10, an
additional methylene moiety was present at 40.1 ppm,
indicating the presence of -NCH2- group. The structure was
confirmed by the 2D and DEPT NMR studies. Compound 12
also displayed a molecular ion peak at m/z 502 and two
methylenes at 62.8 and 64.4 ppm in its 13C NMR spectrum,
suggesting the presence of two -OCH2- groups. Compound
13 displayed a molecular ion peak at m/z 474 and a
methylene at 63.6 ppm in its 13C NMR spectrum, indicating
the assigned constitution. Compound 13, upon alkylation
with diethyl sulphate, afforded the expected dialkylated
product 12.
RESULTS AND DISCUSSION
Our route of synthesis of Sildenafil Citrate 1 is shown in
Scheme 2 [7]. The process involved carbodiimide catalyzed
condensation of 2-hydroxy-5-(4-methyl piperazin-1-ylsul-
phonyl)benzoic acid 6 with 4-amino-1-methyl-3-n-propyl-
pyrazole-5-carboxamide 4 to give 4-[2-hydroxy-5-(4-methyl-
piperazin-1-ylsulphonyl)benzamido)-1-methyl-3-n-propyl-
Since, selective O-alkylation of phenol 8 proved to be
difficult than anticipated, we protected the phenolic hydroxyl
with ethylchloroformate, to obtain 9 (Scheme 2). The
decarboxilative etherification of alkylarylcarbonates to the
corresponding O-alkyl phenols is catalyzed by Pd [10], Rh
*Address correspondence to this author at the Research and Development
Centre, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally,
Shameerpet, Hyderabad-500078, India; Tel: +91 40 23480480;
Fax: 91 40 23480481; E-mail: sunil.indukuri@aptuitlaurus.com
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

Synthesis of Sildenafil Citrate and Process Related Impurities
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
669
O
O
i) ClSO3H
O
ii) N-Methyl
piperazine
O
O
OH
N
N
H2N
+
OH
N
O2S
H2N
N
4
2
3
CDI, EtOAc
O
N
NH2
O
O
N
HN
O
O
i) KOtBu, tBuOH
ii) Citric acid
N
N
N
N
H
O2S
O2S
N
N
Citric acid
N
N
1
5
Scheme 1. Sildenafil Citrate 1 and its route of synthesis.
O
NH2
O
OH
O
N
O
OH
OH HN
N
N
4, DCC,
HOBt, CH2Cl2
NaOH,
diethylene glycol
OH
N
N
H
N
N
O2S
N
O2S
O2S
N
N
N
N
8
6
7
ClCO2Et,
Et3N
O
N
O
OEt
N
N
O
HN
O
HN
O
N
N
Citric acid
DCC, EtOH
N
N
1
O2S
O2S
N
N
N
9
10
Scheme 2. Synthesis of Sildenafil Citrate 1 obtained by decarboxilative etherification of 9.
[10c], Ru [11, 12], Ni [10c] or Fe [13] in the presence of
phosphine ligands. N,N,N’,N’,N”,N”-hexamethylphosphoric
triamide [14] and 4-alkyl-1,1,3,3-tetrabutylguanidine [15]
can also be used for such transformation, albeit at higher
temperature, ca 135-140 °C. We were keen to avoid the
usage of noble metals late in the synthesis. It was observed

670 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Kumar et al.
8
Alkylation
O
O
O
N
N
O
N
N
N
N
O
N
OH
N
N
N
N
N
N
10
+
+
+
O
S
N
O
S
O
S
O
N
N
O
O
N
N
11 (O,N'-diethyl)
Scheme 3. Products formed during O-alkylation of compound 8.
12 (O,O'-diethyl)
13 (O'-ethyl)
Table 1. Ratio of Products (HPLC) Formed During O-Alkylation of Compound 8
HPLC (%)
11
Alkylating Agent
13
S.no
Base (Mol Equivalents)
Solvent
Temp (°C)
12
(Mol Equivalents)
10
8
(O’-
(O,N’-diethyl)
(O,O’-diethyl)
ethyl)
1
2
3
4
5
6
7
8
Diethyl sulphate (1.5)
Diethyl sulphate (2.0)
EtI (1.5)
K2CO3 (1.5)
Acetone
Acetone
THF
reflux
reflux
reflux
70-75
reflux
70-75
32-35
reflux
27
36
29
43
35
49
30
37
51
-
2
7
7
8
3
4
2
3
4
10
14
7
9
25
18
12
4
K2CO3 (1.5)
NaH (1.5)
5
EtI (1.5)
Cs2CO3 (1.5)
Et3N (2.0)
DMF
12
42
34
51
32
EtBr (1.2)
CH2Cl2
Toluene
CH2Cl2
MiBK
3
EtBr (1.2)
Et3N (2.0)
3
4
EtBr (1.2)
4N aq NaOH (1.5) + TBAB
Na2CO3 (1.5)
2
2
EtBr (1.2)
2
3
that the decarboxilative etherification of 9 can be carried
with DCC in ethanol [16], at high temperature (105-110 °C)
and pressure (1.8-4.0 Kg/cm2). After 5-8 hours, the reaction
mixture, when monitored by HPLC, showed a conversion of
61-73% and remaining 18-24% being the de-acylated
compound 8. Usage of other carbodiimide reagents,
prolonged maintenance or variation in temperature and
pressure had no significant improvement on the conversion.
After the work-up procedure, the residue obtained was
slurred in CH2Cl2, the insoluble DCU was filtered off. The
filtrate was diluted by the addition of isopropyl ether, when a
white solid material precipitated out from the solution. Two
crystallizations of the precipitated material from EtOH
afforded pure Sildenafil 10 in 38-44% yield. The CH2Cl2-
isopropyl ether mother liquor, containing phenol 8, was
concentrated and the residue obtained was converted into
carbonate 9 and then again re-subjected to decarboxilative
etherification.
Apart, from the impurities formed during the O-
alkylation of 8, we also identified impurities formed due to
contamination of commercial grade N-methyl piperazine. As
per the guidelines recommended by ICH, the amount of
acceptable level for a known and unknown related
compound (impurity) is less than 0.15 and 0.10%
respectively in an API. In order to quantify and limit the
impurities in the final drug substance, it is mandatory to have
standard for the impurities. It was decided to synthesize
these impurities. Compound 16, the des-methyl impurity of
Sildenafil 10, was prepared by condensing compound 141
with piperazine (Scheme 4).
Compound 18, the N-ethyl impurity of Sildenafil 10, was
synthesized by condensing compound 14 with N-ethyl
piperazine (Scheme 4).
In conclusion, we have synthesized Sildenafil 10 by
carbodiimide mediated decarboxilative etherification of

Synthesis of Sildenafil Citrate and Process Related Impurities
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
671
O
O
N
O
HN
N
HN
O
N
N
N
N
HN
NR
+
O
S
O
S
Cl
N
O
15 R = H
17 R = Et
O
NR
14
16 R = H
18 R = Et
Scheme 4. Products formed during O-alkylation of compound 8.
carbonate 9. The method has been successfully scaled-up to
produce commercial quantities of Sildenafil citrate. Besides
the process related impurities 11, 12, 13, 16 and 18 have
been identified, prepared and characterized.
1099, 1064, 623 cm-1. 13C NMR (DMSO-d6): ꢀ 158.9,
153.4, 149.5, 144.7, 136.1, 131.3, 129.7, 126.7, 125.3, 124.0,
112.9, 64.6, 53.5, 45.8, 45.3, 37.8, 26.9, 21.7, 21.0, 14.2,
1
13.8, 13.6. H NMR (DMSO-d6): ꢀ 7.88 (dd, J 2.4 and 8.8,
1H), 7.82 (d, J 2.3, 1H), 7.42 (d, J 8.9, 1H), 4.26-4.20 (m,
2H), 4.19 (s, 3H), 4.07 (m, 1H), 3.53 (m, 1H), 2.94-2.91 (m,
4H), 2.73 (t, J 7.5, 2H), 2.37-2.34 (m, 4H), 2.14 (s, 3H),
1.72-1.65 (m, 2H), 1.22 (t, J 6.9, 3H), 1.72-1.65 (m, 2H),
1.02 (t, J 7.0, 3H); 0.92 (t, J 7.4, 3H). ESI-MS: m/z 503.3
([MH]+, C24H35N6O4S calcd. 503.3).
EXPERIMENTAL SECTION
General:
1
The H and 13C NMR spectra were recorded on a Bruker
300 MHz Avance FT-NMR spectrometer; the chemical
shifts were reported on ꢀ ppm relative to either internal
standard or tetramethylsilane. The FT-IR spectra were
recorded on Perkin-Elmer 100 FT-IR spectrophotometer and
5-[2-Ethoxy-5-(4-methylpiperazin-1-yl-sulphonyl)phenyl]-
1-methyl-3-n-propyl-1-hydro-7-ethoxy-pyrazolo-[4,3-
d]pyrimidine (12)
only prominent peaks are reported.
The electrospray
It was obtained as a white colored solid material (1.2g).
IR (KBr): 2992, 1603, 1548, 1352, 1175, 1286, 1263, 1066,
624 cm-1. 13C NMR (DMSO-d6): ꢀ 160.2, 155.1, 154.8,
144.7, 143.8, 130.6, 130.1, 128.8, 125.8, 120.4, 113.5, 64.4,
ionization ESI-MS studies were carried on a quadrupole
mass spectrometer Waters Quatro Micro API. All the
reagents used were of LR grade and used as such without
further purification. Silica gel (120-200 mesh) was used for
column chromatograph.
1
62.8, 53.4, 45.7, 45.3, 27.4, 38.3, 21.5, 14.4, 14.1, 13.8. H
NMR (DMSO-d6): ꢀ 7.95 (d, J 2.4, 1H), 7.77 (dd, J 2.5 and
8.7, 1H), 7.37 (d, J 8.8, 1H), 4.63 (q, J 7.1, 2H), 4.20 (q, J
7.0, 2H), 4.17 (s, 3H), 2.91-2.86 (m, 4H), 2.37-2.34 (m, 4H),
2.14 (s, 3H), 1.85-1.77 (m, 2H), 1.47 (t, J 7.1, 3H); 1.31 (t, J
6.9, 3H), 0.95 (t, J 7.4, 3H). ESI-MS: m/z 503.3 ([MH]+,
C24H35N6O4S calcd. 503.3).
O-Alkylation of 5-[2-ethoxy-5-(4-methylpiperazinylsulpho-
nyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo
[4,3-d]pyrimidin-7-one 8
To a stirred mixture of compound 8 ( 27.0g, 0.057 mol),
K2CO3 (11.7g, 0.084 mol) and KI (1.35g, 0.008 mol), in
acetone (135mL) under inert atmosphere, was added diethyl
sulphate (18.3g, 0.118 mol) at ambient temperature. The
temperature of the reaction mass was raised to reflux and
maintained at reflux for 4 hours, when analytical TLC
revealed the absence of 8. The reaction mixture was cooled
to room temperature. The inorganic salts were filtered off
and washing was performed with acetone (10 mL x 3). The
filtrate was concentrated under reduced pressure and the
residue obtained was dissolved in CH2Cl2 (800 mL) and then
was sequentially washed with 5% aq NaHCO3 solution (150
mL) and water (250 mL). The organic layer was dried
(Na2SO4), concentrated under reduced pressure and the
products separated by column chromatography. Elution with
a gradient of MeOH in CH2Cl2 afforded sequentially
compound 10, 11, 12 and 13.
5-[2-Hydroxy-5-(4-methylpiperazin-1-yl-sulphonyl)phenyl]-
1-methyl-3-n-propyl-1-hydro-7-ethoxy-pyrazolo-[4,3-
d]pyrimidine (13)
It was obtained as a off-white colored solid material
(1.1g). IR (KBr): 3437, 1730, 1603, 1556, 1349, 1327, 1259,
1098, 1069, 626 cm-1. 13C NMR (C6d6): ꢀ 164.2, 156.6,
155.8, 144.5, 141.3, 131.3, 130.8, 130.1, 121.4, 119.7, 118.6,
1
63.6, 54.2, 46.4, 45.6, 38.2, 28.1, 22.2, 14.1, 13.9. H NMR
(C6d6): ꢀ 14.65 (brs, 1H), 9.22 (d, J 2.4, 1H), 7.74 (dd, J 2.4
and 8.7, 1H), 7.18 (d, J 8.8, 1H), 4.23-4.20 (m, 2H), 3.59 (s,
3H), 3.12 (m, 4H), 2.91 (t, J 7.4, 2H), 2.11-2.08 (m, 4H),
1.95-1.88 (m, 2H), 1.86 (s, 3H), 1.05 (t, J 7.1, 3H), 0.98 (t, J
7.4, 3H). ESI-MS: m/z 475.2 ([MH]+, C22H31N6O4S calcd.
475.2).
5-[2-Ethoxy-5-(piperazin-1-yl-sulphonyl)phenyl]-1-
methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo-[4,3-
d]pyrimidin-7-one (16)
5-[2-Ethoxy-5-(4-methylpiperazin-1-yl-sulphonyl)phenyl]-
1-methyl-3-n-propyl-1,6-dihydro-6-ethyl-pyrazolo-[4,3-d]
pyrimidin-7-one (11)
To a solution of 5-(5-chlorosulphonyl-2-ethoxyphenyl)-
1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
It was obtained as a off-white colored solid material
(2.5g). IR (KBr): 3034, 1689, 1600, 1561, 1351, 1170, 1287,

672 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Kumar et al.
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was maintained for 3 hours at ambient temperature, when
analytical TLC revealed the completion of the reaction. The
reaction mixture was concentrated under vacuum, the residue
obtained was dissolved in a mixture of CH2Cl2 (450 mL) and
MeOH (25 mL) and washing was performed sequentially
with 5% aq NaHCO3 solution (200 mL) and water (200 mL).
The organic layer was dried (Na2SO4) and then concentrated
under reduced pressure. To the residue obtained was added
MeOH (380 mL) and DMF (20 mL). The suspension mass
was heated to get a homogeneous solution, then allowed to
cool to 0-5 °C and maintained for another 6 hours. The
precipitate was filtered and washed with MeOH (25 mL x 2),
to yield compound 16 as a off-white colored solid material
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1278, 1248, 1027, 611 cm-1. 13C NMR (DMSO-d6): ꢀ 159.8,
153.7, 148.1, 144.9, 137.8, 131.4, 130.0, 126.4, 124.4, 123.6,
113.2, 64.8, 46.7, 44.7, 37.8, 27.1, 21.6, 14.2, 13.8. 1H NMR
(DMSO-d6): ꢀ 7.86-7.77 (m, 2H), 7.38 (d, J 8.7, 1H), 4.22
(dd, J 7.4 and 13.9, 2H), 4.17 (s, 3H), 2.86-2.71 (m, 8H),
2.52-2.49 (m, 2H), 1.81-1.67 (m, 2H), 1.34 (t, J 6.9, 3H),
0.94 (t, J 7.4, 3H). ESI-MS: m/z 461.2 ([MH]+, C21H29N6O4S
calcd. 461.2).
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(400 mL) was added N-ethylpiperazine 17 (33.3g, 0.292
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Seo, J-W.; Han, H.Y.; Kim, T-S.; Jung, I. Pyrrolopyrimidinone
derivatives, process for preparation thereof, and method of using
and composition comprising them. US2005/130983, 2005; (g)
Jolidon, S.; Narquizian, R.; Norcross, R.D.; Pinard, E.
Heterocyclic-substituted phenyl methanones. US2006/178381 A1,
2006; (h) Breitenstein, W.; Hayakawa, K.; Iwasaki, G.; Kanazawa
T.; Kasaoka T.; Koizumi, S.; Matsunaga, S.; Nakajima, M.; Sakaki,
J. Arylsulfonamido-substituted hydroxamic acid derivatives.
US7138432 B1, 2006.
1
13.8, 11.8. H NMR (DMSO-d6): ꢀ 12.22 (brs, 1H), 7.84-
7.81 (m, 2H), 7.38 (d, J 8.7, 1H), 4.21 (q, J 6.9, 2H), 4.16 (s,
3H), 2.89 (brs, 4H), 2.77 (t, J 7.4, 2H), 2.40 (brs, 4H), 2.28
(q, J 7.1, 2H), 1.77-1.69 (m, 2H), 1.33 (t, J 6.9, 3H), 0.95-
0.89 (m, 6H). ESI-MS: m/z 489.3 ([MH]+, C23H33N6O4S
calcd. 489.3).
ACKNOWLEDGEMENT
The authors wish to thank Aptuit Laurus Pvt. Limited for
supporting this work.
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