Bosentan

Base Information

• Chemical Name: Bosentan
• CAS No.: 147536-97-8
• Deprecated CAS: 174227-18-0
• Molecular Formula: C27H29N5O6S
• Molecular Weight: 551.623
• Hs Code.: 29350090
• European Community (EC) Number: 643-099-1
• UNII: XUL93R30K2
• DSSTox Substance ID: DTXSID7046627
• Nikkaji Number: J594.472D
• Wikipedia: Bosentan
• Wikidata: Q419769
• NCI Thesaurus Code: C81107
• RXCUI: 1468845
• Pharos Ligand ID: 1YVKQVNNVWAJ
• Metabolomics Workbench ID: 42895
• ChEMBL ID: CHEMBL957
• Mol file: 147536-97-8.mol

Synonyms:4-t-butyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide;bosentan;bosentan anhydrous;bosentan monohydrate;Ro 47 0203;Ro 47-0203;Ro 470203;Ro-47-0203;Tracleer

Chemical Property of Bosentan

Chemical Property:

• Appearance/Colour: pale yellow to off-white solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 171-175°C(lit.)
• Refractive Index: 1.607
• Boiling Point: 742.3 ºC at 760 mmHg
• PKA: 4.01±0.10(Predicted)
• Flash Point: 402.8 ºC
• PSA: 154.03000
• Density: 1.326 g/cm³
• LogP: 5.35770
• Storage Temp.: -20°C Freezer
• Solubility.: DMSO (Slightly), Methanol (Slightly)
• XLogP3: 3.8
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 11
• Rotatable Bond Count: 11
• Exact Mass: 551.18385484
• Heavy Atom Count: 39
• Complexity: 839

Purity/Quality:

99% ^*data from raw suppliers

Bosentan ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xi
• Hazard Codes: Xi

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Pulmonary Arterial Hypertension Agents
• Canonical SMILES: CC(C)(C)C1=CC=C(C=C1)S(=O)(=O)NC2=C(C(=NC(=N2)C3=NC=CC=N3)OCCO)OC4=CC=CC=C4OC
• Recent ClinicalTrials: A Study in Healthy Men to Test Whether Bosentan Influences the Amount of BI 425809 in the Blood
• Recent EU Clinical Trials: Does cerebral hypoperfusion play a role in reduced axonal metabolism and clinical disability in patients with multiple sclerosis ?
• Recent NIPH Clinical Trials: Bosentan extension study for PAH pediatric patients
• Description: Bosentan was introduced in the US as a twice-daily oral treatment for pulmonary arterial hypertension. It can be synthesized in five steps via condensation of diethyl (2- methoxyphenoxy)malonate with pyrimidine-2-carboxamidine to give the precursor of the symmetrical central dichloropyrimidine ring which is then successively treated with the potassium salt of 4-tert-butylbenzenesulfonamide and the sodium salt of ethylene gycol. Bosentan is the first endothelin (ET) receptor antagonist to be launched. ET-1, the most potent endogenous vasoconstrictor known, has been demonstrated to play a major role in the functional and structural changes observed in pulmonary hypertension. Bosentan is a mixed ETA and ETB receptor antagonist that inhibits the pulmonary arterial vasoconstricting effect of ET-1 predominantly mediated via ETA receptors on smooth muscle cells. In a hypoxia-induced model of pulmonary hypertension in rat, it reduced the development of pulmonary hypertension as well as right ventricular hypertrophy and prevented pulmonary arterial remodeling. In clinical trials, patients treated with bosentan showed a 20% increase in exercise capacity compared to placebo as measured by the six minute walk test. Bosentan not only improved the distance walked by patients but also significantly decreased mean pulmonary artery pressure, mean pulmonary vascular resistance, mean capillary wedge pressure and mean right atrial pressure. It demonstrated a beneficial selectivity for the pulmonary vasculature since it had no significant effect on mean aortic blood pressure and systolic vascular resistance. The compound is hepatically metabolized into three major metabolites by CYP3A4 and 2C9 and almost exclusively eliminated in the bile. Although large interspecies differences in systemic plasma clearance was observed (1.5 mL/min/kg in dogs to 72 mL/min/kg in rabbits), a satisfactory systemic clearance (2 mL/min/kg) was measured in human. The most frequent adverse effect was reversible elevation of liver transaminases. This adverse reaction appears to be due to intracellular accumulation of cytotoxic bile salts resulting from inhibition of the hepatocanalicular bile salt export pump by bosentan.
• Uses: A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive. Bosentan is a mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.
• Therapeutic Function: Endothelin receptor antagonist
• Clinical Use: Bosentan is an orally administered, nonselective ET-1 receptor antagonist blocking ETA and ETB receptors and is approved for the treatment of patients with PAH. Following oral administration, bosentan attains peak plasma concentrations in approximately 3 hours, with an absolute bioavailability of approximately 50%. Food has no clinically relevant effect on its absorption recommended doses. Bosentan is approximately 98% bound to albumin, with a volume of distribution of 30 L. Its terminal half-life after oral administration is 5.4 hours and is unchanged at steady state.
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin - avoid. Antidiabetics: increased risk of hepatoxicity with glibenclamide - avoid. Antifungals: fluconazole, ketoconazole and itraconazole cause large increases in concentration of bosentan - avoid. Antivirals: concentration of bosentan increased by lopinavir and ritonavir - consider reducing bosentan dose; telaprevir concentration reduced and bosentan concentration possibly increased; avoid with tipranavir. Ciclosporin: When ciclosporin and bosentan are co-administered, initial trough concentrations of bosentan are 30 times higher than normal. At steady state, trough levels are 3-4 times higher than normal. Blood concentrations of ciclosporin decreased by 50% - avoid. Cytotoxics: concentration of bosutinib possibly reduced - avoid. Guanfacine: concentration of guanfacine possibly reduced - increase guanfacine dose. Lipid lowering agents: concentration of simvastatin reduced by 45% - monitor cholesterol levels and adjust dose of statin. Oestrogens, progestogens and ulipristal: may be failure of contraception - use alternative method.

Technology Process of Bosentan

There total 58 articles about Bosentan 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: 95.7%

ethylene glycol (107-21-1) + 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide (150727-06-3) → bosentan (147536-97-8,174227-18-0)

Guidance literature:

ethylene glycol; 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide; With sodium hydroxide; In tetrahydrofuran; at 60 - 65 ℃; for 12h;

With tartaric acid; In tetrahydrofuran; water; at 5 - 10 ℃; for 1h;

Reference yield: 95.0%

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butylbenzenesulphonamide sodium salt → bosentan (147536-97-8,174227-18-0)

Guidance literature:

With hydrogenchloride; In ethanol; water; at 20 - 30 ℃; for 3h;

Reference yield: 93.0%

4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide → bosentan (147536-97-8,174227-18-0)

Guidance literature:

4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide; With water; sodium hydroxide; In ethanol; at 25 - 30 ℃; for 1h;

With hydrogenchloride; In ethanol; water; for 1h; pH=5.5;

upstream raw materials:

ethylene glycol

4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine

5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidine-4,6(1H, 5H)-dione

sodium ethane-1,2-diolate

Downstream raw materials:

bosentan hydrochloride

bosentan hydrogensulphate

p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide

2,2-dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidinyl-4-yloxy]-ethyl ester

Refernces

• 1、 Lee, Chung Ryul,Lee, Sang Yeul,Nam, Tae-Gyu. "Succinct synthesis of bosentan utilizing glycol Mono-THP ether". . p. 2488 - 2493. Retrieved 2014.
• 2、 -. "A method for the treatment of pulmonary arterial hypertension drug preparation method". Paragraph 0118; 0129; 0138; 0139. . Retrieved 2017/10/07.
• 3、 -. "METHOD FOR PRODUCING BOSENTAN USING DEHYDRATING AGENT OR HYDRATE THEREOF". Paragraph 0039-0040. . Retrieved 2017/01/12.