Thiosalicylic Acid CAS 147-93-3

The core procedure consists of five steps: The product diazotization, nucleophilic substitution, reduction, acidification and purification. Dissolve 2-aminobenzoic acid in hydrochloric acid, cool the solution to 0–5 °C, then slowly add sodium nitrite solution at a molar ratio of 1:1.05. Stir the mixture for 30 minutes to complete diazotization and form 2-carboxybenzenediazonium salt.

Prepare sodium polysulfide solution by mixing sodium sulfide nonahydrate (Na2S·9H2O) with sulfur powder in proportion and heating until fully dissolved. Cool the solution below 0 °C, then slowly add the diazonium solution while keeping the temperature no higher than 5 °C. Maintain the reaction for 2 hours to generate disulfide intermediates.

Add zinc powder to reduce and cleave the disulfide bonds. Raise the temperature to 60 °C and stir for 1 hour. Filter out residues, then acidify the filtrate with concentrated hydrochloric acid until the pH value reaches 2, whereby yellow crystals precipitate out. The final product with purity over 99% is obtained after cold water washing, ethanol recrystallization and vacuum drying, with a total yield of 85%–90%.

This route adopts sodium salicylate as the raw material to introduce thiol groups through reaction with sodium hydrosulfide (NaHS) in an alcohol-water alkaline system. Dissolve sodium salicylate in aqueous ethanol, add sodium hydroxide to adjust the pH to 10, and heat the mixture to 80 °C. Add NaHS solution dropwise at a molar ratio of 1:1.2 and conduct reflux reaction for 4 hours.

After the reaction, cool the system and acidify the solution to precipitate crude products. Further purification is carried out via activated carbon decolorization and recrystallization. The yield ranges from 70% to 75%. This process features simple operation but relatively high raw material costs.

Using ortho-halogenated benzoic acid such as 2-chlorobenzoic acid as the starting material, the reaction proceeds with thiourea or sodium thiosulfate under copper salt catalysis.

Dissolve 2-chlorobenzoic acid and thiourea in DMF, add cuprous iodide (CuI) as the catalyst, and heat the mixture to 120 °C for a 6-hour reaction. Hydrolyze the reactant and acidify the solution to separate the target product. The yield is 65%–80%, and this method is mainly used for synthesis requiring specific substituent modification.

In the mid-to-late 19th century, the medicinal value and chemical structure of salicylic acid, an extract from willow bark, were thoroughly studied. Chemists began to explore its derivatives by introducing heteroatoms such as sulfur and halogen to modify chemical properties.

In 1878, German chemists first reacted salicylic acid with hydrogen sulfide (H2S) under high temperature and pressure to replace the hydroxyl group with a thiol group.

Although the obtained product had low purity and its structure was not fully confirmed, this attempt realized the introduction of sulfur atoms for the first time and laid a theoretical foundation for subsequent synthesis.

Meanwhile, the diazotization reaction of 2-aminobenzoic acid was discovered, providing a core technique for functional group transformation on aromatic rings and becoming a key precursor technology for ortho mercaptobenzoic acid synthesis.

In 1895, the research team led by German chemist Paul Friedländer successfully synthesized ortho mercaptobenzoic acid for the first time via the diazotization-sulfidation method of 2-aminobenzoic acid during research on structural modification of indigo dyes.

They reacted diazotized 2-aminobenzoic acid with sodium polysulfide, and obtained yellow crystals after reduction and acidification. Through elemental analysis, melting point measurement (167–170 °C) and chemical derivatization including esterification and oxidation, the substance was identified as 2-mercaptobenzoic acid and officially named ortho mercaptobenzoic acid.

In 1906, Friedländer synthesized thioindigo using ortho mercaptobenzoic acid. With a vivid reddish-purple color superior to traditional indigo, thioindigo soon became a core dye in the textile industry, which drove ortho mercaptobenzoic acid into industrial production.

From 1910 to 1930, continuous improvements were made to the diazotization-sodium polysulfide process. The standardization of low-temperature control (0–5 °C), zinc powder reduction and acidification crystallization conditions raised the yield from the initial 60% to over 85%, with product purity reaching 99%, fully meeting the demand of large-scale dye production.

In the 1930s, the medicinal properties of ortho mercaptobenzoic acid were discovered. Its thiol group can form complexes with heavy metals, so it was applied to the treatment of heavy metal poisoning.

In the 1940s, thiomersal was synthesized and widely used as a vaccine preservative, which further boosted market demand.

In the same period, alternative routes including sodium salicylate sulfidation and halogenated benzoic acid thiolation were developed to adapt to laboratory small-batch production and special usage scenarios.