Tolvaptan

Tolvaptan is a selective vasopressin V2 receptor antagonist approved for the treatment of euvolemic and hypervolemic hyponatremia and for slowing the progression of autosomal dominant polycystic kidney disease (ADPKD) . Tolvaptan works by blocking vasopressin binding to V2 receptors in the renal collecting duct, thereby reducing water reabsorption and promoting aquaresis . Tolvaptan is available under the brand names Samsca® for hyponatremia and Jinarc® for ADPKD . Tolvaptan has been extensively studied for its role in modulating antidiuretic hormone receptor function and its effects on aquaporin channel activity and osmotic regulation . The compound is a racemic mixture (1:1 mixture of R and S enantiomers) with a molecular weight of 448.94 g/mol and a melting point of 219–222 °C .

Product Parameters

Pharmacological A ction

Vasopressin is the most important hormone for regulating water balance in the human body, and its secretion is regulated by osmoreceptors and baroreceptors. Tolvaptan, a benzazepine derivative, has an affinity for V2 receptors more than 29 times that for V1a receptors, and 1.8 times that of natural arginine vasopressin. Tolvaptan binds to V2 receptors on the collecting duct and blocks their activity, causing AQP2 to detach from the inner membrane and reducing its expression, thus inhibiting V2 receptor-mediated renal water reabsorption; it increases the excretion of free water in urine, reduces water retention, lowers volume load, does not affect electrolytes, and restores sodium ion levels; it inhibits the production and accumulation of cAMP, increases the concentration of sodium ions in plasma, and helps excess water be excreted from urine; the therapeutic mechanism of tolvaptan for polycystic kidney disease: it inhibits the accumulation of cAMP in polycystic kidney cells, and suppresses cyst growth by reducing cyst fluid secretion and thus the proliferation of lining cells.

Synthetic Route

Using the compound methyl 2-amino-5-chlorobenzoate as the raw material, methyl 2-amino-5-chlorobenzoate undergoes an amino group protection reaction with p-toluenesulfonic acid, and then reacts with ethyl bromobutyrate to form compound 2. Compound 2 undergoes Dieckmann condensation and cyclization to form the parent ring 3 of benzazepine. Compound 3 removes the ethyl carboxylate group under acidic conditions to obtain compound 4, and compound 4 removes the p-toluenesulfonyl protecting group in a polyphosphoric acid solution to form compound 5. Compound 5 is a key intermediate of tolvaptan. Place compound 5 and triethylamine in dichloromethane, slowly add 2-methyl-4-nitrobenzoyl chloride dropwise, and separate through a silica gel chromatography column to obtain intermediate 6. Compound 6 undergoes a hydrogenation reduction reaction with platinum dioxide at room temperature, followed by post-treatment and concentration. The residue is separated through a silica gel chromatography column to obtain intermediate 7. Repeat the operation of the fifth step to obtain compound 8. Add intermediate 8 to methanol, add sodium borohydride in batches at room temperature for the reduction reaction, extract with chloroform and concentrate, then recrystallize with anhydrous methanol-anhydrous ether to obtain the product tolvaptan.

Bioactivity

Tolvaptan (OPC-41061) is a selective, competitive arginine vasopressin receptor 2 antagonist that inhibits AVP-induced platelet aggregation, with an IC50 of 1.28µM.

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