Tolvaptan

Base Information

• Chemical Name: Tolvaptan
• CAS No.: 150683-30-0
• Molecular Formula: C26H25ClN2O3
• Molecular Weight: 448.949
• European Community (EC) Number: 691-537-5
• UNII: 21G72T1950
• DSSTox Substance ID: DTXSID3048780
• Nikkaji Number: J1.047.795F
• Wikipedia: Tolvaptan
• Wikidata: Q426132
• NCI Thesaurus Code: C77082
• RXCUI: 358257
• Pharos Ligand ID: JCWBL5XZ9URG
• ChEMBL ID: CHEMBL344159
• Mol file: 150683-30-0.mol

Synonyms:7-chloro-5-hydroxy-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)2,3,4,5-tetrahydro-1H-1-benzazepine;OPC 41061;OPC-41061;OPC41061;Samsca;tolvaptan

Chemical Property of Tolvaptan

Chemical Property:

• Vapor Pressure: 5.64E-15mmHg at 25°C
• Melting Point: 219-222°C
• Refractive Index: 1.663
• Boiling Point: 594.4 °C at 760 mmHg
• PKA: 13.00±0.70(Predicted)
• Flash Point: 313.3 °C
• PSA: 69.64000
• Density: 1.311 g/cm³
• LogP: 5.82110
• Storage Temp.: Refrigerator
• Solubility.: DMSO: ≥15mg/mL
• XLogP3: 4.8
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 3
• Exact Mass: 448.1553704
• Heavy Atom Count: 32
• Complexity: 674

Purity/Quality:

99%min ^*data from raw suppliers

Tolvaptan ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Diuretics, Vasopressin Antagonists
• Canonical SMILES: CC1=CC=CC=C1C(=O)NC2=CC(=C(C=C2)C(=O)N3CCCC(C4=C3C=CC(=C4)Cl)O)C
• Recent ClinicalTrials: A Study to See if Tolvaptan Can Delay Dialysis in Infants and Children Who at Enrollment Are 28 Days to Less Than 12 Weeks Old With Autosomal Recessive Polycystic Kidney Disease (ARPKD)
• Recent EU Clinical Trials: Metformin versus Tolvaptan in adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD): a phase 3a, independent, multi-centre, 2 parallel arms randomized controlled trial
• Recent NIPH Clinical Trials: Efficacy and safety of tolvaptan for better management of patients undergoing liver resection, prospective study
• Description: Tolvaptan(trade names Samsca and Jinarc) is an oral selective vasopressin antagonist developed by Otsuka for the treatment of hyponatremia, and it is a non-peptide selective antidiuretic hormone receptor antagonist. The drug can increase the concentration of sodium ions in the plasma, and help the excess water discharge from the urine. The drug could enhance the ability of the kidney to deal with water, and significantly reduce the weight and edema of patients while not accompanied by increased electrolyte excretion, without destroying the blood electrolyte balance. The drug can be used to treat hyponatremia caused by congestive heart failure, various edematous diseases, cirrhosis and antidiuretic hormone deficiency syndrome. The study found that, when the plasma sodium concentration decreased, in order to maintain the balance of sodium concentration inside and outside the cell, extracellular fluid will enter the cell, so the cells will swell. When the brain cells swell, it will lead to a variety of hyponatremia symptoms, including dizziness, weakness, headache, nausea, confusion, consciousness and convulsions. Severe hyponatremia can lead to coma and death. There is no corresponding study of tolvaptan tablets in patients with severe hyponatremia. Tolvaptan is a nonpeptide vasopressin V2 receptor antagonist (IC50 = 3 nM for rat receptor) and a diuretic agent. It is selective for V2 over V1 receptors (IC50 = 0.58 μM). Tolvaptan increases urine volume by 3-fold in rats when administered at a dose of 0.54 mg/kg. It also reduces left ventricular end-systolic volumes and improves left ventricular ejection fraction in a rat model of myocardial infarction. Formulations containing tolvaptan have been used to treat hyponatremia. The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-proteincoupled receptor subtypes:V1-vascular types a and b, V2-renal, and V3-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration <135 mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V2receptor promotes water excretion without perturbing electrolyte balance making it an appealing target for preventing disease progression. Following the introduction of the dual AVP V1a/V2 receptor antagonist conivaptan, tolvaptan has recently been launched as a nonpeptide, selective V2 receptor antagonist with potent aquaretic attributes for the treatment of hypervolemic and euvolemic hyponatremia (serum sodium concentration of <125 mmol/L or less distinct hyponatremia that is symptomatic and has resisted correction with fluid restriction). As a more potent and selective V2 receptor antagonist, tolvaptan is a follow-up to mozavaptan, which possesses weak V1 receptor antagonism and was approved for the treatment of SIADH in Japan. .
• Uses: Tolvaptan (OPC-41061) is a selective, competitive arginine vasopressin receptor 2 antagonist with an IC50 of 1.28μM for the inhibition of AVP-induced platelet aggregation. Tolvaptan (OPC-41061) is used to treat hyponatremia (low blood sodium levels) assoc Labelled Tolvaptan s, and the syndrome of inappropriate antidiuretic hormone (SIADH). It is a selective, competitive arginine vasopressin V2 receptor antagonist f inappropriate antidiuretic hormone (SIADH).
• Clinical Use: Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Otsuka Pharmaceutical licensed tolvaptan under the trade name Samsca after the FDA approved the drug in May 2009. Tolvaptan has also shown efficacy against polycystic kidney disease. In a 2004 trial, tolvaptan administered with traditional diuretics was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia (decreased blood levels of potassium). The drug also exhibited no adverse effect on kidney function.

Technology Process of Tolvaptan

There total 38 articles about Tolvaptan which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 90.0%

MOP-21826 (137973-76-3) → C34H32ClN3O4 + C42H36ClN3O5 + C42H38ClN3O5 + C42H38ClN3O5 + tolvaptan (150683-30-0)

Guidance literature:

MOP-21826; With sodium tetrahydroborate; In methanol; for 1h;

With hydrogenchloride; In methanol; water; at 20 ℃;

Reference yield: 81.0%

4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methanone + o-Methylbenzamid (527-85-5) → tolvaptan (150683-30-0)

Guidance literature:

With potassium phosphate; In toluene; at 50 ℃; for 20h; Inert atmosphere;

Reference yield: 72.0%

(±)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol (1310357-40-4) + 2-methyl-4-(2-methylbenzoylamino)benzoic acid chloride (331947-69-4) → tolvaptan (150683-30-0)

Guidance literature:

With 2,6-dimethylpyridine; In N,N-dimethyl acetamide; water; at 0 ℃; for 2h; Reagent/catalyst;

upstream raw materials:

MOP-21826

(rac)-7-chloro-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate

2,2-dimethylpropionic acid 7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester

2,2-dimethylpropionic acid 4-[(E)-hydroxyimino]-7-chloro-1,2,3,4-tetrahydronaphthalen-1-yl ester

Downstream raw materials:

{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} succinate

{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamate

{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} hexadecanoate

chloromethyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} carbonate

Refernces

• 1、 -. "Preparation method of high-purity tolvaptan". Paragraph 0080-0082. . Retrieved 2021/06/23.
• 2、 -. "IMPROVED METHODS OF PRODUCING SYNTHETIC INTERMEDIATES OF TOLVAPTAN". . . Retrieved 2018/04/07.