The Synthetic Routes of 4-Morpholinecarboxamide, N-(2-aminoethyl)-, ethanedioate (Landiolol)

4-Morpholinecarboxamide, N-(2-aminoethyl)-, ethanedioate, commonly referred to as Landiolol, is a drug used in the treatment of hypertension and angina pectoris.
The synthesis of Landiolol involves several synthetic routes, which can be broadly classified into two categories: conventional synthesis and synthesis using novel methods.

Conventional Synthesis of Landiolol:

The conventional synthesis of Landiolol involves several steps, which include the preparation of the basic structure of the drug and its subsequent modification to introduce the required functional groups.
The basic structure of Landiolol is a 4-morpholinecarboxamide, which is synthesized by the reaction of morpholine with carbon dioxide in the presence of an acid catalyst.
The resulting morpholine carboxylic acid is then converted into the required amide by reaction with an appropriate amine.

One of the commonly used synthetic routes for Landiolol involves the following steps:

Step 1: Preparation of morpholine carboxylic acid
Morpholine is reacted with carbon dioxide in the presence of a strong acid catalyst such as sulfuric acid or phosphoric acid.
The reaction is exothermic and requires careful handling.
The resultant morpholine carboxylic acid is then dissolved in a suitable solvent such as water or ethanol.

Step 2: Preparation of N-(2-aminoethyl)amide
N-(2-Aminoethyl)amide, also known as Diisopropylamine, is reacted with morpholine carboxylic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or hydrochloric acid.
The reaction is exothermic and requires careful handling.
The resultant N-(2-aminoethyl)amide is then purified by precipitation with a suitable solvent such as diethyl ether.

Step 3: Preparation of Landiolol
The N-(2-aminoethyl)amide prepared in step 2 is then reacted with ethanedioic acid in the presence of a condensing agent such as DCC or hydrochloric acid.
The reaction is exothermic and requires careful handling.
The resultant Landiolol is then purified by crystallization or chromatography.

Novel Synthesis of Landiolol:

In recent years, several novel synthetic routes for Landiolol have been developed, which offer advantages over conventional synthesis.
These include increased efficiency, reduced costs, and reduced use of hazardous reagents.
Some of these novel synthetic routes are discussed below:

1. Microwave-assisted synthesis:
   One of the recent developments in the synthesis of Landiolol is the use of microwave irradiation to accelerate the reaction.
   In this method, the morpholine carboxylic acid is first prepared by the reaction of morpholine with carbon dioxide, and then reacted with N-(2-aminoethyl)amine in the presence of a condensing agent such as DCC or hydrochloric acid.
   The resultant N-(2-aminoethyl)amide is then reacted with ethanedioic acid in the presence of a catalytic amount of palladium on barium sulfate.
   The reaction is carried out in a microwave reactor, which ensures rapid heating and cooling of the reaction mixture, leading to increased efficiency and reduced reaction times.
   
2. Aqueous phase synthesis:
   Another novel synthetic route for Landiolol involves the use of water as the reaction medium.
   In this method, morpholine carboxylic acid is first prepared by the reaction of morpholine with carbon dioxide in water, and then reacted with N-(2-amino