The Synthetic Routes of 6-Mercapto-3(2H)-pyridazinethione

Introduction:

6-Mercapto-3(2H)-pyridazinethione, also known as Captisol, is a widely used ligand in various chemical reactions, especially in the production of APIs (Active Pharmaceutical Ingredients).
The use of Captisol as a chelating agent has gained much attention because of its high stability and selectivity towards transition metals.

In the chemical industry, the synthetic routes of Captisol have been a topic of much research and experimentation.
The reason for this is that the traditional methods of synthesizing Captisol have been found to be expensive and time-consuming.
Therefore, researchers have been exploring alternate methods to synthesize Captisol with improved efficiency and cost-effectiveness.

Synthetic Routes of Captisol:

1. Hydrochlorination of 2-mercaptobenzamide:

2-Mercaptobenzamide is a readily available starting material for the synthesis of Captisol.
The hydrochlorination of 2-mercaptobenzamide in the presence of a Lewis acid catalyst, such as aluminum chloride, results in the formation of Captisol.
The reaction proceeds through the following steps:

C6H12N2S2 + 2 HCl → C6H12N2S2Cl2 + H2O

2. Reduction of N-chlorosuccinimide:

N-Chlorosuccinimide is another starting material that can be used for the synthesis of Captisol.
The reduction of N-chlorosuccinimide using a reducing agent such as sodium borohydride results in the formation of Captisol.
The reaction proceeds through the following steps:

C6H12N2S2Cl + 2 NaBH4 → C6H12N2S2 + 2 NaBCl4

3. Direct synthesis from 2-thiopyridine:

2-Thiopyridine is a simple starting material that can be used for the direct synthesis of Captisol.
The synthesis of Captisol from 2-thiopyridine involves the reaction of the thiopyridine with chloroform and sodium hydroxide under proper conditions, resulting in the formation of Captisol.
The reaction proceeds through the following steps:

C6H4N2S + Cl2 + 2 NaOH → C6H12N2S2 + 2 NaCl + H2O

4. Mannich reaction:

The Mannich reaction is another method for the synthesis of Captisol.
The reaction involves the reaction of 2-mercaptobenzaldehyde with formaldehyde and ammonia in the presence of a base, such as sodium hydroxide.
The reaction proceeds through the following steps:

C6H12N2S + CH2O + 2NH3 + NaOH → C6H12N2S + 2CH3OH + NaCl

Advantages of the synthetic routes for Captisol:

The above-mentioned synthetic routes for Captisol have their own advantages and disadvantages.
For example, the hydrochlorination method is a cost-effective method, but it requires the use of a strong acid catalyst.
On the other hand, the Mannich reaction method is a mild reaction conditions but it requires the use of toxic reagents such as formaldehyde and ammonia.

Conclusion:

The synthetic routes of Captisol are many and varied, and each method has its own advantages and disadvantages.
The best method for the synthesis of Captisol depends on the availability of starting materials, the desired yield, and the cost and safety of the reaction conditions.
However, the most commonly used method for the synthesis of Captisol is the hydrochlorination of 2-mercaptobenzamide.