The Synthetic Routes of Levocetirizine dihydrochloride

Levocetirizine dihydrochloride is an antihistamine drug used to treat allergy symptoms such as sneezing, runny nose, and itching eyes.
It is commonly sold under the brand name of Zyrtec.
The synthesis of Levocetirizine dihydrochloride can be achieved through various synthetic routes, which can be broadly classified into two categories: chemical synthesis and biotechnological synthesis.
In this article, we will discuss the synthetic routes of Levocetirizine dihydrochloride through chemical synthesis.

Chemical Synthesis of Levocetirizine Dihydrochloride:

Route 1: Hydrolysis of N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]acetamide with Lithium Hydroxide

This route involves the hydrolysis of N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]acetamide with lithium hydroxide to form Levocetirizine dihydrochloride.
The starting material N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]acetamide is first synthesized by reacting N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]-N-(tetrahydro-2H-pyran-2-yl)acetamide with N,N-dimethylformamide in the presence of a base such as sodium hydroxide.
The reaction mixture is then treated with lithium hydroxide, and the product is extracted with a solvent such as ethyl acetate.
The resulting organic phase is dried and concentrated to obtain Levocetirizine dihydrochloride.

Route 2: Reduction of N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]-N-(tetrahydro-2H-pyran-2-yl)acetamide with Lithium Aluminum Hydroxide

This route involves the reduction of N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]-N-(tetrahydro-2H-pyran-2-yl)acetamide with lithium aluminum hydroxide to form Levocetirizine dihydrochloride.
The starting material N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]-N-(tetrahydro-2H-pyran-2-yl)acetamide is first synthesized by reacting N-[(1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl]acetamide with N-(tetrahydro-2H-pyran-2-yl)acetamide in the presence of a solvent such as DMF.
The resulting mixture is then treated with lithium aluminum hydroxide, and the product is extracted with a solvent such as ethyl acetate.
The resulting organic phase is dried and concentrated to obtain Levocetirizine dihydrochloride.

Route 3: Reductive Amination of N-(2-(4-chlorophenyl)ethyl)acetamide with N-((1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl)acetamide

This route involves the reductive amination of N-(2-(4-chlorophenyl)ethyl)acetamide with N-((1S)-1-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl)acetamide to form Levocetiriz