| Identification | More | [Name]
Sildenafil citrate | [CAS]
171599-83-0 | [Synonyms]
1-[[3-(4,7-DIHYDRO-1-METHYL-7-OXO-3-PROPYL-1H-PYRAZOLO[4,3-D]PYRIMIDIN-5-YL)-4-ETHOXYPHENYL]SULFONYL]-4-METHYLPIPERAZINE, CITRATE
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1h-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate
SILDENAFIL CITRATE
VIAGRA
din-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methyl-,2-hydroxy-1,2,3-propanetricarbo
piperazine,1-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1h-pyrazolo(4,3-d)pyrimi
piperazine,1-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1h-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methyl-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)
uk92480-10
SILDANAFIL CITRATE (BULK)
SildenafilBaseC28H38N6O11S
SildenafilCitrate/SildenafilBaseC28H38N6O11S
1-[[3-(4,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine, Citrate
SILDENAFIL CITRATE(RG)
5(2-ETHOXY-5(4-METHYLPIPERAZINE)SULPHONYLPHENYL)-1
1-[[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate | [EINECS(EC#)]
200-659-6 | [Molecular Formula]
C28H38N6O11S | [MDL Number]
MFCD02102122 | [Molecular Weight]
666.7 | [MOL File]
171599-83-0.mol |
| Chemical Properties | Back Directory | [Appearance]
White Solid | [Melting point ]
187-189°C | [storage temp. ]
2-8°C | [solubility ]
DMSO: >20mg/mL | [form ]
white powder | [color ]
White | [Water Solubility ]
3.488g/L(temperature not stated) | [Usage]
An orally active selective type 5 cGMP phosphodiesterase inhibitor | [Merck ]
14,8489 | [BCS Class]
1 | [Stability:]
Store in Freezer | [InChIKey]
DEIYFTQMQPDXOT-UHFFFAOYSA-N | [SMILES]
C1(=CC(=CC=C1OCC)S(=O)(=O)N1CCN(C)CC1)C1=NC(C2N(N=C(CCC)C=2N1)C)=O.C(O)(C(=O)O)(CC(=O)O)CC(=O)O | [CAS DataBase Reference]
171599-83-0(CAS DataBase Reference) |
| Safety Data | Back Directory | [Hazard Codes ]
Xi | [Risk Statements ]
R36/37/38:Irritating to eyes, respiratory system and skin . | [Safety Statements ]
36 | [WGK Germany ]
3 | [RTECS ]
TL4284390 | [HS Code ]
2933595960 | [Safety Profile]
A poison by ingestion. Human systemic effects. When heated to decomposition it emits toxic vapors of NOx and SOx. |
| Hazard Information | Back Directory | [Description]
Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE5) with IC50 values of 3.6 and 3 nM for PDE5 activity in isolated rabbit platelets and human corpus cavernosum, respectively.1 It is selective for PDE5 over PDE1 and PDE3 (IC50s = 0.26 and 65 μM, respectively). Sildenafil reverses glucose-induced decreases in angiopoietin 1 (ANG1) expression and reduction of capillary-like tube formation by mouse dermal endothelial cells in vitro and increases the number of functional blood vessels and regional blood flow in the sciatic nerve in a db/db mouse model of diabetic peripheral neuropathy.2 It increases the ratio of maximum intracavernosal pressure to mean arterial blood pressure (ICP/MAP), a measure of erectile function, in castrated rats when administered at a dose of 20 mg/kg per day.3 Sildenafil (0.5 mg/kg) also reduces cardiac arrest and resuscitation-induced increases in angiotensin II (Item No. 17150), angiotensin converting enzyme (ACE), ACE2, and various angiotensin receptors and increases survival in a porcine model of ischemia/reperfusion injury.4 Formulations containing sildenafil have been used in the treatment of erectile dysfunction, pulmonary arterial hypertension, and high-altitude pulmonary edema associated with altitude sickness. | [Chemical Properties]
White Solid | [Originator]
Alsigra,Alembic Ltd.,India | [Uses]
agent | [Uses]
An orally active selective type 5 cGMP phosphodiesterase inhibitor | [Uses]
Enzyme inhibitor | [Definition]
ChEBI: The citrate salt of sildenafil. | [Manufacturing Process]
A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester (24.1 g, 0.132
mol) (prepared by the method of Chem. Pharm. Bull., 1984, 32, 1568) and
dimethyl sulfate (16.8 g, 0.133 mol) were heated to 90°C for 2.5 h. The
mixture was dissolved in dichloromethane and the solution washed with
sodium carbonate solution. The organic phase was separated, dried (MgSO4)
and evaporated under vacuum to give a solid. Chromatography on silica gel
(300 g), eluting with dichloromethane gave the 1-methyl-3-n-propylpyrazole-
5-carboxylic acid ethyl ester as a colourless oil (20.4 g, 79%).
1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol)
was suspended in 6 N aqueous sodium hydroxide solution (50 ml, 0.30 mol).
The mixture was heated to 80°C for 2 h then diluted with water (50 ml) and
acidified with concentrated hydrochloric acid (25 ml). Filtration gave the 1-
methyl-3-n-propylpyrazole-5-carboxylic acid as pale brown crystals (12.3 g,
71%), melting point 150°-154°C.
1-Methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added
portionwise to a mixture of oleum (13 ml) and fuming nitric acid (11 ml),
keeping the temperature below 60°C. After the addition, the mixture was
heated at 60°C overnight and then cooled to room temperature before being
poured onto ice. Filtration of the precipitate gave the 1-methyl-4-nitro-3-npropylpyrazole-
5-carboxylic acid as a white solid (11.5 g, 75%), melting point
124°-127°C.
1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) was
added to thionyl chloride (50 ml) and the resulting mixture heated under
reflux for 3 h. The reaction mixture was then cooled and excess thionyl
chloride removed by evaporation under vacuum. The oily residue was
dissolved in acetone (50 ml) and the solution cautiously added to a mixture of
ice (50 g) and concentrated aqueous ammonium hydroxide solution (50 ml).
The precipitate was collected by filtration to provide the 1-methyl-4-nitro-3-npropylpyrazole-
5-carboxamide as a pale yellow solid (8.77 g, 78%), melting
point 141°-143°C.
1-Methyl-4-nito-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and
stannous chloride dihydrate (18.4 g, 81 mmol) were suspended in ethanol and
the mixture heated under reflux for 2 h. The resulting solution was cooled to
room temperature, basified to pH 9 by the addition of 2 N aqueous sodium
hydroxide solution and extracted with dichloromethane (3 x 150 ml). The
organic extracts were combined, dried (MgSO4) and evaporated under
vacuum. Trituration of the residue with ether gave the 4-amino-1-methyl-3-npropylpyrazole-
5-carboxamide as an off-white solid (2.77 g, 94%), melting
point 98°-101°C.
A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane
(50 ml) was added to a stirred solution of 4-amino-1-methyl-3-npropylpyrazole-
5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine
(0.02 g, 0.1 64 mmol) and triethylamine (3.34 g, 33.0 mmol) in
dichloromethane (50 ml) at 0°C. The resulting mixture was allowed to warm
to room temperature and stirred for a further 2 h. The solvent was evaporated
under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane
and methanol (250 ml), and then the solution washed with 1 N hydrochloric
acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude
material was chromatographed on silica gel (200 g), eluting with a 97:3
mixture of dichloromethane and methanol, to give a pink solid; crystallisation
from ethyl acetate-hexane gave the 4-(2-ethoxybenzamido)-1-methyl-3-npropylpyrazole-
5-carboxamide as a pale pink solid (2.2 g, 40%), melting point
153°-155°C.
4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g,
0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g,
1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml).
Ethanol (700 ml) was added and the resulting mixture heated under reflux for
2.5 h, cooled, then evaporated under vacuum. The resulting solid was treated
with 2 N hydrochloric acid (380 ml), with external cooling, and the mixture
was extracted with dichloromethane (1 x 700 ml, 3 x 200 ml). The combined
organic extracts were washed successively with saturated aqueous sodium
carbonate solution (3 x 400 ml) and brine (300 ml), then dried (Na2SO4) and
evaporated under vacuum. Chromatography of the residue on silica gel (1000
g), using a methanol in dichloromethane elution gradient (0-1%), followed by
trituration of the crude product with ether (300 ml), gave the 5-(2-
ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-one as a colourless solid (152.2 g, 72%), melting point 143°-146°C.
5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to
chlorosulfonic acid (20 ml) at 0°C under a nitrogen atmosphere. After being
stirred overnight, the reaction solution was cautiously added to ice-water (150ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane
and methanol (4 x 100 ml). The combined extracts were dried (Na2SO4) and
evaporated under vacuum to give the required 5-(5-chlorosulphonyl-2-
ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-one as a white solid (12.8 g, 97%), melting point 179°-181°C.
4-Methylpiperidine was added to a stirred suspension of 5-(5-chlorosulphonyl-
2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one in ethanol at room temperature. The resulting mixture was
stirred for 4 days before removing the solvent by evaporation under vacuum.
The residue was dissolved in a 9:1 mixture of dichloromethane and methanol
and the solution washed with saturated aqueous sodium carbonate solution.
The aqueous phase was further extracted with dichloromethane-methanol
mixtures (3 x 100 ml) and all the organic fractions were combined, dried
(MgSO4) and evaporated under vacuum to give a solid. Crystallisation from a
mixture of methanol-dimethylformamide gave the 5-[2-ethoxy-5-(4-
methylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[
4,3-d]-pyrimidin-7-one as an off-white solid, melting point 187°-
189°C.
After addition of citric acid to the 5-[2-ethoxy-5-(4-
methylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[
4,3-d]-pyrimidin-7-one (sildenafil) the it's salt is obtained, namely
sildenafil citrate. | [Brand name]
Viagra (Pfizer). | [Therapeutic Function]
Vasodilator | [General Description]
Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards | [Biological Activity]
Orally active, potent inhibitor of phosphodiesterase 5 (PDE5) (IC 50 = 4 nM). Enhances nitric oxide-dependent relaxation of human corpus cavernosum in vitro . | [Biochem/physiol Actions]
Sildenafil is a potent, selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5). Sildenafil is used to treat erectile dysfunction and pulmonary arterial hypertension. NO activates guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation. Sildenafil enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP. | [Pharmacokinetics]
Analysis of Middle Eastern data (mean ± SD) revealed Cmax = 398.9 ± 107.7 ng/ml; Tmax = 1.84 ± 0.22 h; t1/2 = 2.66 ± 0.97 h; AUC0–24 = 1475 ± 515.3 ng.h/ml; AUC0-∞ = 1556 ± 567.58 ng.h/ml. | [Side effects]
The more common side effects of sildenafil citrate include: headache, skin flushing, indigestion, abnormal vision, nasal congestion, back pain, nausea, dizziness, rash, etc. | [Synthesis]
The synthesis of sildenafil citrate was first reported in the Bioorganic & Medicinal Chemistry Letters, Vol 6, pp. 1819, 1824, 1996. The reaction scheme is reproduced below. Sildenafil was reported in this journal as "a potent and selective inhibitor of type 5 PDE with utility for the treatment of male erectile dysfunction".
The first step of the synthesis is the reaction of a diketoester (1) and hydrazine to give the pyrazole ring. The regioselective N-methylation of the pyrazole and hydrolysis gives a carboxylic acid (3). Compound (3) is then reacted with HNO3 and H2SO4 to give a nitrated product.
This is then followed by a carboxamide formation and the reduction of the nitro group. The compound (4) is then acylated under basic conditions and this produces the pyrazolopyrimidinone (6). (6) is then chlorosulphonylated selectively on the 5'-position of the phenyl ring. This can then couple with an amine to give sildenafil (7).
www.ch.ic.ac.uk/local/projects/p_hazel/synthesis2.html | [Veterinary Drugs and Treatments]
Sildenafil may be of benefit in the adjunctive treatment of pulmonary
hypertension in small animals.
In humans, sildenafil is indicated for erectile dysfunction or pulmonary
hypertension. | [storage]
Desiccate at RT | [structure and hydrogen bonding]
Sildenafil citrate (SC) has been widely used for the treatment of erectile disorder. A detailed study concerning solid-state structure of this compound is very important for understanding enzyme (PDE5)-inhibitor (sildenafil) interaction. It is also of interest to determine sildenafil’s protonation sites, as they may be responsible for its binding to the phosphodiesterase acidic amino acids.
Sildenafil citrate (Viagra) and sildenafil base in pure form were characterized by 1H, 13C, 15N NMR spectroscopy in solution, solid-state, and pharmaceutical dosage forms.42 The analysis of chemical shifts showed that: (i) N6-H forms intramolecular hydrogen bonds, (ii) N25 is protonated in the salt, and (iii) intermolecular OH. . .N hydrogen bonds involving N2 and N4 are present in the solid sildenafil citrate. The 13C CPMAS spectra of the tablets containing different amounts of sildenafil citrate were recorded and showed that chemical shifts of sildenafil citrate in pure form and in pharmaceutical dosage forms are the same. SC is easily detected in the pharmaceutical dosage forms since only two of its carbon resonances (OCH2 and quaternary carbon of the citrate anion) fall into carbohydrate-type region of the excipient.
Solid-state 13C and 15N MAS NMR have recently been used to investigate how water interacts with SC.43 When the humidity is altered, the water concentration in the solid compound changes but does not reach a stoichiometric (e.g., 1:1) ratio to form a true hydrate. Only one set of 15N and 13C signals was observed for each humidity level indicating that water incorporated into the crystal lattice of SC is very mobile and exchanges rapidly between various sites. The 13C data showed the formation of a hydrogen bond between water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the conformation of the propyl group. Additionally, 15N dipolar dephasing (DD) experiments confirmed that the sildenafil molecule is only protonated in the piperazine ring. | [References]
1) Terrett?et al.?(1996),?Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction; Bioorg. Med. Chem. Lett.,?6?1819
2) Ballard?et al.?(1998),?Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes; J. Urol.,?159?2164
3) Turko?et al.?(1999),?Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds; Mol. Pharmacol.,?56?124
4) Teixeira?et al.?(2006),?Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta; J. Pharmacol. Exp. Therap.,?316?654
5) Ghofrani?et al.?(2006),?Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond; Nat. Rev. Drug Discov.,?5?689 |
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