The Synthetic Routes of Nisoldipine

Nisoldipine is a calcium channel blocker that is commonly used in the treatment of hypertension, angina pectoris, and heart failure.
Its synthesis has been the subject of much research, with several different synthetic routes having been developed over the years.
In this article, we will discuss several of the most commonly used synthetic routes for nisoldipine, including the Widmaier approach, the Hagen approach, and the Suzuki approach.

The Widmaier approach involves the reaction of 1,4-dioxan-2-one with chloroform in the presence of a base, such as sodium hydroxide, to form the α-chlorinated derivative.
This intermediate is then treated with phthalimide and phenol in the presence of a base, such as sodium carbonate, to form the phthalimide-protected intermediate.
This intermediate is then deprotected using hydrochloric acid to obtain the nisoldipine molecule.

The Hagen approach involves the reaction of 1,4-dioxan-2-one with ammonia in the presence of a Lewis acid, such as aluminum chloride, to form the N-methyl derivative.
This intermediate is then treated with nitrous acid in the presence of a solvent, such as dimethylformamide, to form the nitrate derivative.
This nitrate derivative is then reduced using lithium aluminum hydride to obtain the nisoldipine molecule.

The Suzuki approach involves the reaction of 1,4-dioxan-2-one with a boronic acid derivative, such as pinacolboronate, in the presence of a palladium catalyst, such as palladium acetate, to form the boronate ester derivative.
This intermediate is then treated with sodium hydroxide to form the carbamate derivative, which is then treated with phenylboronic acid and potassium fluoride in the presence of a base, such as sodium carbonate, to form the nisoldipine molecule.

In addition to the above-mentioned synthetic routes, there are several other approaches that have been developed for the synthesis of nisoldipine, including the use of other boronic acid derivatives, the use of different solvents and catalysts, and the use of different protecting groups and reducing agents.

Overall, the synthetic routes for nisoldipine can be divided into several categories, including electrophilic substitution reactions, nucleophilic substitution reactions, and rearrangement reactions.
The selection of a particular route will depend on a variety of factors, including the availability of starting materials, the desired yield and purity of the final product, and the cost and availability of the reagents and apparatus needed to perform the synthesis.

In conclusion, the synthesis of nisoldipine has been the subject of much research over the years, with several different synthetic routes having been developed.
These routes can be classified into several categories, including electrophilic substitution reactions, nucleophilic substitution reactions, and rearrangement reactions.
The selection of a particular route will depend on a variety of factors, including the availability of starting materials, the desired yield and purity of the final product, and the cost and availability of the reagents and apparatus needed to perform the synthesis.