The Synthetic Routes of Ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

The synthesis of ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is a complex and challenging process that requires a thorough understanding of synthetic routes and methodologies.
This article provides a comprehensive overview of the synthetic routes available for the preparation of ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, highlighting the advantages and disadvantages of each route, and providing a critical evaluation of the literature.

1. Route 1: via 6,7,8-Trifluoro-4-oxoquinoline-2-carboxylic acid

The first reported synthetic route to ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate involves the conversion of 6,7,8-trifluoro-4-oxoquinoline-2-carboxylic acid (1) to the target compound through a sequence of chemical reactions.

Step 1: Preparation of 6,7,8-Trifluoro-4-oxoquinoline-2-carboxylic acid

The synthesis of 6,7,8-trifluoro-4-oxoquinoline-2-carboxylic acid represents the starting point for the synthesis of ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Several synthetic routes have been reported for the preparation of 6,7,8-trifluoro-4-oxoquinoline-2-carboxylic acid, including the following:

• From 2,3-Dihydro-4-oxo-1,2,3-benzotriazine via 2,3-Dihydro-4-oxo-1,2,3-benzotriazin-1-ium iodide (Scheme 1A) [1].
  
• From 2,3-Dihydro-5-oxo-1,2,3-benzotriazine via 2,3-Dihydro-5-oxo-1,2,3-benzotriazin-1-ium chloride (Scheme 1B) [2].
  

In both cases, the intermediate 2,3-Dihydro-4-oxo-1,2,3-benzotriazine is prepared from salicylic aldehyde and sodium hydroxide, followed by treatment with iodide or chloride.
The subsequent treatment with ammonia and sodium hydroxide leads to the formation of the corresponding 2,3-Dihydro-4-oxo-1,2,3-benzotriazine.
The subsequent condensation with 3-fluorophenylboronic acid followed by a boron trifluoride etherate and hydrolysis leads to the synthesis of 6,7,8-trifluoro-4-oxoquinoline-2-carboxylic acid.

Step 2: Condensation of 6,7,8-Trifluoro-4-oxoquinoline-2-carboxylic acid with Ethyl Bromide

The synthesis of the target compound ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate involves the condensation of 6,7,8-trifluoro-4-oxoquinoline-2-carboxylic acid with ethyl bromide.
This reaction can be carried out using a variety of reagents and conditions, such as the following:

• Heating a mixture of 6,7,