The Synthetic Routes of 2-CHLORO-3-FLUOROPYRIDINE-5-BORONIC ACID

2-Chloro-3-fluoropyridine-5-boronic acid is an important intermediate in the production of various pharmaceuticals, agrochemicals, and other chemical products.
The synthesis of this compound can be achieved through different routes, and in this article, we will discuss some of the most widely used synthetic routes of 2-chloro-3-fluoropyridine-5-boronic acid.

Synthesis Route 1: Via N-Bridgeway Method

This route involves the synthesis of 2-chloro-3-fluoropyridine-5-boronic acid via an N-bridgeway method.
The reaction sequence involves the formation of an imine intermediate, followed by boronation, reduction, and finally, chlorination.

The process typically involves the following steps:

1. Preparation of the imine intermediate: To a solution of 2-fluoro-3-pyridineboronic acid in a suitable solvent, such as toluene or dichloromethane, a suitable amount of N-Bridgeway reagent, such as pyridinium chloride or 2,2'-azobis(2-methylbutyronitrile) (AIBN), is added.
   The reaction mixture is then heated to a specified temperature for a specified duration to form the imine intermediate.
   
2. Boronation: The resulting imine intermediate is then treated with a suitable boron source, such as boron trifluoride diethyl ether (BF3•OEt2), in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium(0) (Pd(PPy3)) or dichloro(bisbenzonato)metal(II) (DCM), to form the boronic acid intermediate.
   
3. Reduction: The boronic acid intermediate is then reduced to form the boronic acid by hydrogenation in the presence of a suitable catalyst, such as palladium on barium sulfate.
   
4. Chlorination: The resulting boronic acid is then chlorinated by treatment with a suitable chlorinating agent, such as thionyl chloride or phosphorus trichloride, to form 2-chloro-3-fluoropyridine-5-boronic acid.
   

Synthesis Route 2: Via Boronate Ether Route

This route involves the synthesis of 2-chloro-3-fluoropyridine-5-boronic acid via a boronate ester intermediate.
The reaction sequence involves the formation of a boronate ester intermediate, followed by hydrolysis, reduction, and finally, chlorination.

The process typically involves the following steps:

1. Preparation of the boronate ester intermediate: To a solution of 2-fluoro-3-pyridineboronic acid in a suitable solvent, such as toluene or dichloromethane, a suitable amount of a boronate ester, such as boronic acid dimethyl ester or boronic acid phenyl ester, is added.
   The reaction mixture is then treated with a suitable base, such as sodium hydroxide, to form the boronate ester intermediate.
   
2. Hydrolysis: The boronate ester intermediate is then hydrolyzed by treatment with water to form the boronic acid intermediate.
   
3. Reduction: The resulting boronic acid is then reduced to form the boronic acid by hydrogenation in the presence of a suitable catalyst, such as palladium on barium sulfate.
   
4. Chlorination: The resulting boronic acid is then chlorinated by treatment with a suitable chlorinating agent, such as phosphorus trichloride, to form 2-chloro-3-fluoropyridine-5-boronic acid.
   

Synthesis Route 3: Via Pall