The Synthetic Routes of 3-AMINO-5-CHLORO-2-FLUOROPYRIDINE

The synthesis of 3-amino-5-chloro-2-fluoropyridine is a critical step in the production of various pharmaceuticals, agrochemicals, and other chemical products.
There are several synthetic routes available for the preparation of this compound, each with its own advantages and disadvantages.
In this article, we will discuss three widely used synthetic routes for the synthesis of 3-amino-5-chloro-2-fluoropyridine and their underlying mechanisms.

Route 1: via α-aminopyridine-N-oxide

The first synthetic route for the synthesis of 3-amino-5-chloro-2-fluoropyridine involves the formation of α-aminopyridine-N-oxide, followed by nitration to produce the desired fluorine-substituted compound.
The reaction mechanism is as follows:

(1) N-Methyl-D-alanine → α-Aminopyridine-N-oxide

α-Aminopyridine-N-oxide is generated by the oxidation of N-methyl-D-alanine with sodium hydroxide in the presence of a catalytic amount of hydrogen peroxide.

(2) α-Aminopyridine-N-oxide + HNO3 → 3-Amino-5-chloro-2-fluoropyridine

The nitration of α-aminopyridine-N-oxide with nitric acid produces 3-amino-5-chloro-2-fluoropyridine.

(3) H2O2 + HNO3 → HNO2 + H2O

Hydrogen peroxide is used as a catalyst to generate the hydrogen nitrate ion, which then reacts with α-aminopyridine-N-oxide to form the desired product.

Route 2: via 2-fluoro-5-nitroso-N-methylpyridine

The second synthetic route for the synthesis of 3-amino-5-chloro-2-fluoropyridine involves the formation of 2-fluoro-5-nitroso-N-methylpyridine, followed by reduction to produce the desired product.
The reaction mechanism is as follows:

(1) C5H10N2O2 + HNO2 + K2CO3 → 2-Fluoro-5-nitroso-N-methylpyridine

2-Chloromethyl nitrate is treated with sodium hydroxide in the presence of carbonate to generate 2-fluoro-5-nitroso-N-methylpyridine.

(2) 2-Fluoro-5-nitroso-N-methylpyridine + 4NH4Cl → 3-Amino-5-chloro-2-fluoropyridine

2-Fluoro-5-nitroso-N-methylpyridine is reduced to 3-amino-5-chloro-2-fluoropyridine by treatment with ammonium chloride in the presence of water.

Route 3: via 3-amino-5-chloro-2-fluoro-N-methylpyridine

The third synthetic route for the synthesis of 3-amino-5-chloro-2-fluoropyridine involves the formation of 3-amino-5-chloro-2-fluoro-N-methylpyridine, followed by dehydrogenation to produce the desired product.
The reaction mechanism is as follows:

(1) C5H10N2O2 + HNO2 → 3-Amino-5-chloro-2