The Synthetic Routes of 5-(((2S,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

The Synthetic Routes of 5-(((2S,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one: A Comprehensive Review

In the chemical industry, the synthesis of new compounds is a constant endeavor to discover new drugs, materials, and chemicals.
One such compound that has garnered significant attention is 5-(((2S,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, which is commonly referred to as TFT-15.
TFT-15 is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, and has shown promising results in phase 2b clinical trials.

The synthesis of TFT-15 involves several steps, which can be broadly classified into two categories: synthetic routes and chemical reactions.
In this article, we will provide a comprehensive review of the synthetic routes of TFT-15, including the chemical reactions involved in each route.

Synthetic Routes

There are several synthetic routes that have been reported for the synthesis of TFT-15.
Some of the commonly used routes are outlined below:

Route 1: Induction of the Hydroxylamine/Nitrite Pathway with Trifluoromethylphenyl Ether (TFME)

This route involves the use of TFME as a reagent to induce the hydroxylamine/nitrite pathway to synthesize TFT-15.
The synthesis involves several steps, including the protection of the morpholine group with a tert-butyldimethylsilyl (TBDMS) protecting group, the formation of a sulfonate intermediate, and the deprotection of the TBDMS group to obtain the final product.

Route 2: Perrone-Koehler and Stereocontrolled Perrone-Koehler Reactions

This route involves the use of the Perrone-Koehler reaction, which is a venerable aldol reaction, to synthesize TFT-15.
The stereocontrolled Perrone-Koehler reaction is used to obtain the desired stereochemistry of the Morpholine moiety.
The synthesis involves several steps, including the protection of the alcohol group with a benzyl group, the formation of the aldehyde intermediate, the Perrone-Koehler reaction, and the debenzylation step to obtain the final product.

Route 3: Aldehyde-Morpholine Interaction

This route involves the use of an aldehyde and a morpholine derivative to synthesize TFT-15.
The synthesis involves the interaction of the aldehyde with the morpholine derivative, followed by the removal of the morpholine protecting group to obtain the final product.

Chemical Reactions

The synthetic routes of TFT-15 involve several chemical reactions, which are crucial for the synthesis of the compound.
Some of the important chemical reactions involved in the synthesis of TFT-15 are outlined below:

• Induction of the Hydroxylamine/Nitrite Pathway with TFME: This reaction involves the use of TFME to induce the hydroxylamine/nitrite pathway to synthesize TFT-15.
  The reaction involves the initiation of the pathway with TFME, followed by the addition of hydroxylamine, nitrite, and sodium hydroxide to obtain the desired product.
  
• Perrone-Koehler and Stereocontrolled Perrone-