What is benzene sulphonic acid used for drug synthesis？

Benzene sulphonic acid uses are majorly in pharmaceutical applications including as a buffering agent, pH modifier, stabilizing agent as well as an intermediate in the preparation of API.

Benzene sulfonic acid and its derivatives have multiple roles in drug synthesis, including as salt-forming groups of active pharmaceutical ingredients (APIs), organic synthesis catalysts, drug intermediates and prodrug modification groups. The following is an explanation based on specific drug cases and application scenarios:

1. As a drug salt-forming group (improving solubility and stability)

Benzenesulfonic acid converts alkaline drugs into water-soluble salts through salt-forming reactions to improve bioavailability:

Antiallergic drug: Bepotastine besylate

Synthesis key: 2-pyridinecarboxylic acid and chlorobenzene react in 9 steps to generate a racemic intermediate, and then obtain an optically pure (S)-isomer (>99% ee) through D-DBTA chiral separation, and finally salt with benzenesulfonic acid.

Advantages: Benzenesulfonate improves drug solubility and is suitable for oral preparations.

Antihypertensive drug: Amlodipine besylate

Synthesis route: Using phthalic anhydride and ethanolamine as raw materials, the four-step reaction of condensation, Hantzsch cyclization, reduction and salt formation has a total yield of 31.3%.

Process optimization: p-toluenesulfonic acid is used instead of concentrated sulfuric acid to catalyze esterification and reduce oxidation by-products.

Neuralgia treatment drug: Milobarline besylate

Key steps: The racemic intermediate is subjected to Horner-Wadsworth-Emmons reaction to construct a carbon skeleton, and D-mandelic acid is split and then salted with benzenesulfonic acid, with a total yield of 15.67%.

Industrial value: The chiral splitting process reduces the dependence on expensive SFC technology.

2. As an acid catalyst (replacing traditional inorganic acids)

Benzenesulfonic acid derivatives (such as p-toluenesulfonic acid) are widely used in catalysis due to their mild acidity and low oxidizing properties:

Esterification and dehydration reactions

Replacing concentrated sulfuric acid to catalyze the esterification of oleic acid and methanol, with a conversion rate of 62.4% at 80°C, avoiding carbonization side reactions.

Dehydration of secondary/tertiary alcohols to olefins: For example, 3-hydroxysteroids are catalyzed by p-toluenesulfonic acid in benzene solvent to generate Δ²-olefins (yield 85-98%).

Removal of Boc protecting group

Solid acid catalyst (TsOH-Si) replaces trifluoroacetic acid, and efficiently removes the Boc group at 100°C for 5 minutes. The product is released by NH₃/MeOH, with a purity of >90%.

Heterocyclic synthesis

toluenesulfonic acid is used to catalyze the synthesis of 1,2,4,5-tetraarylimidazole and oxane fragrances, with mild conditions and high yields.

As a drug intermediate or prodrug modification group

Sulfonic acid group enhances drug performance through structural modification:

Prodrug design: Quercetin benzene sulfonate

Converting quercetin hydroxyl group into sulfonate, lipid solubility increased by 57600 times (in ethyl acetate), Log P optimized to 1.67-2.02, significantly improving oral absorption.

Antitumor prodrug: Soy isoflavone sulfonate

Sulfonate derivatives were synthesized by microwave method, and HPLC verified that their water solubility was improved and the theoretical polar surface area (TPSA) was reduced, indicating better membrane penetration ability.

Herbicide synthesis: Bensulfuron

O-methoxycarbonylbenzenesulfonamide was condensed with methyl chloroformate to avoid the use of highly toxic phosgene, with a total yield of 81.3%.

4. Process optimization and safety precautions

Green substitution

Solid acid catalysts (such as silica-loaded benzenesulfonic acid) gradually replaced liquid acids to reduce equipment corrosion and wastewater pollution.

Safety risks

Benzenesulfonic acid is highly corrosive and needs to be stored in a moisture-proof and light-proof environment; HCl produced during synthesis needs to be effectively treated (such as vacuum debenzenization).

 

Summary and application trends

The core value of benzenesulfonic acid in drug synthesis lies in:

Salt formation optimization: solving the solubility problem of alkaline drugs;

Catalytic innovation: promoting green processes (such as immobilized acid catalysts);

Prodrug innovation: improving pharmacokinetic properties through sulfonate modification.

Future directions include the development of chiral sulfonic acid catalysts (such as BINOL derivatives) and smart responsive sulfonic acid prodrugs (such as pH-sensitive release systems).