Overview of Sildenafil Synthesis
Sildenafil, also known as compound UK-92,480, is a medication synthesized by a team of pharmaceutical chemists led by Simon Campbell working at Pfizer's Sandwich, Kent, research facilities. Its synthesis is a meticulous process that yields an effective compound for treating erectile dysfunction, hypertension (high blood pressure), and angina pectoris (a form of cardiovascular disease).
Detailed Process of Sildenafil Synthesis:
The synthesis of sildenafil begins with the reaction of a diketoester and hydrazine to produce the pyrazole ring. It's important to note that this reaction needs to be regioselective for N-methylation of the pyrazole.
Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
In the next phase, 3-propylpyrazole-5-carboxylic acid ethyl ester undergoes methylation with hot dimethyl sulfate. This process is integral to forming the core structure of the sildenafil molecule.
Hydrolysis with aqueous sodium hydroxide (NaOH)
Following methylation, the product is subjected to hydrolysis using aqueous sodium hydroxide (NaOH). This step frees the acid group, preparing it for further modifications.
Nitration with oleum/fuming nitric acid
The intermediate product is then nitrated using oleum/fuming nitric acid. This chemical reaction introduces a nitro group to the compound, which plays a crucial role in the subsequent synthesis steps.
Chlorosulfonation of the pyrimidinone derivative
One of the key steps in sildenafil synthesis involves chlorosulfonation of the 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, a pyrimidinone derivative.
This results in the formation of 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7.
Coupling with N-methylpiperazine
The penultimate step involves coupling with N-methylpiperazine. This step is integral to forming the final sildenafil structure.
Sildenafil Citrate: The Final Product and Its First Report in Bioorganic & Medicinal Chemistry Letters
The product of this synthesis process, sildenafil citrate, was first reported in Bioorganic & Medicinal Chemistry Letters. This compound, also known as Viagra, was designed to treat angina and hypertension by blocking the enzyme phosphodiesterase-5, which hydrolyzes cyclic guanosine monophosphate (cGMP), a vasodilator that facilitates increased blood flow.
Discussion of the Reaction Scheme
In the synthesis scheme of sildenafil, the pyrimidone heterocycle ring is formed by adding potassium t-butoxide in t-butanol to minimize the formation of side products. The synthesis scheme further includes the conversion of sildenafil (4) from the compound 5a and N-phenylethylenediamine with a yield of 92%.
Explanation of the Use of Compound 6 in Coupling Reaction with Compound 4
The solution of compound 6, formed during the synthesis process, can be used directly after filtration in the coupling reaction with compound 4. This step is essential to obtaining the final sildenafil structure.
The Cyclization of Compound 7 to Give Sildenafil
The cyclization of compound 7, a crucial step in the synthesis process, provides sildenafil. This process has been reported to achieve yields of up to 95%.
Efficiency of the Process: Achieving Yields Up to 95%
The synthesis of sildenafil is highly efficient, with the potential to achieve yields as high as 95%. This remarkable yield underscores the robustness and precision of the synthetic process.
Mechanism of Action and Use of Sildenafil
Sildenafil, available in tablets (20 mg), oral suspension (10 mg/mL), and injectable (10 mg/12.5 mL) forms, functions as a phosphodiesterase inhibitor, predominantly for the treatment of erectile dysfunction. Its mechanism of action involves inhibiting the breakdown of cyclic guanosine monophosphate (cGMP) by blocking the enzyme phosphodiesterase type 5 (PDE5). By preserving cGMP levels, sildenafil aids in enhancing blood flow, thereby alleviating erectile dysfunction and contributing to the treatment of pulmonary arterial hypertension (PAH). The recommended dosage for tablet and oral suspension formulations is 5 mg or 20 mg three times daily, taken 4 to 6 hours apart.