The Synthetic Routes of Temozolomide

Temozolomide is an anti-cancer drug that belongs to a class of drugs called alkylating agents.
It is primarily used to treat brain tumors, specifically glioblastoma multiforme, which is a highly malignant brain cancer.
The synthetic route of temozolomide has undergone several modifications over the years, each aimed at improving the efficiency and yield of the synthesis.

The original synthetic route for temozolomide was first described by Scheinberg and co-workers in 1984.
The synthesis involved a series of steps that included the preparation of a substituted salicylic acid derivative, which was then transformed into a substituted nitrosobenzene derivative.
The nitrosobenzene derivative was then reacted with a halogenated alkane to form a substituted alkane derivative, which was finally alkylated with a substituted xanthene derivative.

However, this synthesis was found to be cumbersome and had several disadvantages, such as low yield, high cost, and the use of hazardous reagents.
As a result, several alternative synthetic routes for temozolomide have been developed over the years.

One of the most commonly used synthetic routes for temozolomide is the route developed by Bally and co-workers in 1991.
This synthesis involves the preparation of a substituted salicylate derivative, which is then treated with sodium nitrite to form a substituted nitrosobenzene derivative.
The nitrosobenzene derivative is then transformed into a substituted alkane derivative using a Suzuki reaction.
The final step involves the alkylation of the alkane derivative with a substituted xanthene derivative.

Another route for temozolomide synthesis was developed by Helvig and co-workers in 1996.
This synthesis involves the preparation of a substituted benzaldehyde derivative, which is then treated with a substituted hydrazine derivative to form a substituted hydrazone derivative.
The hydrazone derivative is then transformed into a substituted nitro compound using a nitrosonium salt.
The final step involves the alkylation of the nitro compound with a substituted xanthene derivative.

Recently, a new synthetic route for temozolomide has been developed by Xu and co-workers in 2017.
This synthesis involves the preparation of a substituted phenol derivative, which is then transformed into a substituted quinone derivative using a Husar-Lewis reaction.
The quinone derivative is then reduced to form a substituted ketone derivative, which is finally alkylated with a substituted xanthene derivative.

Each of these synthetic routes for temozolomide has its own advantages and disadvantages.
For example, the route developed by Bally and co-workers is more efficient and less expensive than the original synthesis, while the route developed by Helvig and co-workers is more environmentally friendly as it avoids the use of hazardous reagents such as sodium nitrite.

Overall, the development of new and improved synthetic routes for temozolomide is an active area of research in the chemical industry.
However, the cost and environmental impact of these syntheses must be carefully considered to ensure that the final product is both effective and economically viable.