The Synthetic Routes of 3-FLUORO-4-(TRIFLUOROMETHYL)PYRIDINE

The Synthetic Routes of 3-Fluoro-4-(Trifluoromethyl)Pyrimidine: A Review of Current Methods and Future Developments

3-Fluoro-4-(trifluoromethyl)pyrimidine is a synthetic compound commonly used in the chemical industry.
It is often used as an intermediate in the synthesis of pharmaceuticals, agrochemicals, and other industrial chemicals.
The demand for this compound has been increasing in recent years due to its diverse range of applications.
Several synthetic routes have been developed over the years for the production of 3-fluoro-4-(trifluoromethyl)pyrimidine, each with its own advantages and disadvantages.

I.
Classical Synthetic Routes

The classical synthetic routes for the production of 3-fluoro-4-(trifluoromethyl)pyrimidine include the following:

1. via N-Fluorosulfonamide Intermediate

This route involves the reaction of fluoroacetamide with sulfur dioxide to form N-fluorosulfonamide.
The N-fluorosulfonamide is then reacted with a nitrile to form a fluoro-substituted pyridine derivative, which is further transformed into 3-fluoro-4-(trifluoromethyl)pyrimidine.
This route requires the use of toxic and caustic reagents, and is often associated with high costs.

2. via Urushibara Condensation

The Urushibara condensation involves the reaction of fluoranilide with a benzaldehyde in the presence of a Lewis acid catalyst.
The resulting intermediate is then reduced to form 3-fluoro-4-(trifluoromethyl)pyrimidine.
This route is highly selective, but requires the use of expensive and toxic reagents.

3. via Hydrolysis of N-(Trifluoromethyl)Phenylurea

This route involves the reaction of phenylacetamide with thionyl chloride to form N-(trifluoromethyl)phenylurea.
The N-(trifluoromethyl)phenylurea is then hydrolyzed to form 3-fluoro-4-(trifluoromethyl)pyrimidine.
This route is relatively simple and cost-effective, but can be associated with poor yields.

II.
Modern Synthetic Routes

In recent years, several modern synthetic routes for the production of 3-fluoro-4-(trifluoromethyl)pyrimidine have been developed, each with its own advantages.

1. via Methyl 2-Oxo-3-Pyridinecarboxylate

This route involves the reaction of methyl 2-oxo-3-pyridinecarboxylate with a fluorinating agent, such as tetrabutylammonium fluoride, to form 3-fluoro-4-(trifluoromethyl)pyrimidine.
This route is highly selective and is less expensive than the classical routes.

2. via Tosylation of Tetrahydro-2H-Pyran-4-One

This route involves the reaction of tetrahydro-2H-pyran-4-one with tosyl chloride in the presence of a Lewis acid catalyst to form 3-fluoro-4-(trifluoromethyl)pyrimidine.
This route is highly selective and is less expensive than the classical routes.

III.
Future Developments

The chemical industry is constantly evolving, and several new synthetic routes for the production of 3-fluoro-4-(trifluoromethyl)pyrimidine are currently being developed.
These include:

1. via