Question

The drug sildenafil, sold under the trade name Viagra, is a potent inhibitor of phosphodiesteraseV (PDE V), an enzyme found in high levels in the corpus cavernosum of the penis. Inhibitors of this enzyme enhance vascular smooth muscle relaxation and are used for treatment of male impotence. Following is an outline for a synthesis of sildenafil.

Short answer

Answer: The key organic chemistry reactions involved in the synthesis of sildenafil include condensation, nucleophilic substitution, alkylation, and Suzuki-Miyaura cross-coupling reactions.

Step-by-step solution

Understanding the Structure of Sildenafil

Sildenafil is an organic compound with the chemical structure C22H30N6O4S, and it belongs to the class of drugs called phosphodiesterase type 5 (PDE5) inhibitors. It is important to familiarize yourself with the structure of the sildenafil molecule before diving into its synthesis.

Starting Material

The synthesis of sildenafil typically starts from commercially available precursors, including 3-bromo-5-chloroaniline. The first step in the reaction is to convert this compound into another intermediate organic molecule.

Formation of Intermediate A

The 3-bromo-5-chloroaniline is reacted with ethyl acetoacetate in the presence of a base (such as potassium carbonate), leading to a condensation reaction. This reaction results in the formation of a pyrazole ring in the intermediate A.

Formation of Intermediate B

In the next step, the chloro substituent group (Cl) on intermediate A is replaced by a methyl group via a nucleophilic substitution reaction. This is achieved by reacting intermediate A with methylamine, resulting in the formation of intermediate B.

Formation of Intermediate C

Intermediate B is then reacted with ethylene oxide in the presence of a base (such as potassium tert-butoxide) to form intermediate C. This step involves an alkylation reaction on the nitrogen atom, leading to the addition of the ethylene oxide chain.

Formation of Intermediate D

In this step, a crucial sulfur-containing (sulfonyl) group is introduced into the organic molecular structure. Intermediate C undergoes a reaction with phenylsulfonyl chloride, which results in the formation of intermediate D.

Formation of Sildenafil

Finally, intermediate D is reacted with a palladium catalyst (such as Pd(PPh3)4) in an organic solvent (such as toluene) and a base, (such as triethylamine) under specific reaction conditions (e.g., refluxing or heating the reaction mixture). This reaction is known as a Suzuki-Miyaura cross-coupling reaction and results in the synthesis of the target molecule – sildenafil. In summary, the synthesis of sildenafil comprises several steps involving organic chemistry reactions and techniques, such as condensation, nucleophilic substitution, alkylation, and cross-coupling. Understanding the process and the chemistry behind each reaction is essential to comprehend the synthesis of this drug.