Bosentan Monohydrate Research Articles

A New Efficient Synthetic Process for an Endothelin Receptor Antagonist, Bosentan Monohydrate

A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14) as a key step. This new process provides desired bosentan monohydrate (1) with better quality and yields. Our new methodology consists of technical innovations/improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13 in the final drug substance.

New Approaches to Endothelin Receptor Antagonist-Bosentan

An improved and efficient synthetic process developed for an endothelin receptor antagonist, bosentan monohydrate by condensing a key intermediate 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2’-bipyrimidine-4- yl)benezenesulfonamide 5 with commercially cheaper chloro acetonitrile and α-halo esters. This synthetic approach efficiently provides highly pure bosentan without formation of the major impurity 2 (dimer) and less than 0.15% of Nalkylated impurity 3 and pyrimidinone impurity 5 in the final product. In the present process upon purification of bosentan monohydrate gave overall yield of 62-65%.

Stability-Indicating Gradient RP-LC Method for the Determination of Process and Degradation Impurities in Bosentan Monohydrate: An Endothelin Receptor Antagonist

Described is a simple, rapid, selective, and stability-indicating RP-LC method for the determination of process and degradation-related impurities of bosentan monohydrate. Chromatographic separation was achieved on Zorbax SB-Phenyl column thermostated at 35°C under gradient elution by a binary mixture of solvent A (60% phosphate buffer, pH 2.5, and 40% methanol) and solvent B (acetonitrile) at a flow rate of 1.0 mL/min. Forced degradation was carried out under acidic, alkaline, oxidative, photolytic, and thermal conditions. Significant degradation is observed in acid and alkali stress conditions. Process- and degradation-related impurities were characterized by mass spectrometry, 1H NMR, and FT-IR spectral data. Validation of the developed method was carried out as per ICH requirements. Regression analysis shows an “r” value (correlation coefficient) of greater than 0.999 for bosentan and five potential impurities. This method was capable to detect the five impurities at 0.01% of the test concentration of 1.0 mg mL-1.

Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist

Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.

Arterial Ischaemic Stroke in Children with Heart Disease: Experience in a Single Centre Over 17 Years

therapies have not been trialled in children and there is little information about long-term survival in treated children. Methods: A multicentre, web-based Australian and New Zealand registry for children with PAH was established to better understand the profile of children with IPAH, aiming to describe demographics, presenting features, clinical course and outcomes of children aged three months to 18years at timeofPAHdiagnosis, from1/1/2002. A group of historic controlswith IPAHdiagnosed between 1970 and 1990 were used for comparison. Results:Of the 24 patients enrolled with IPAH, 54% are female and 75% Caucasian. The mean (SD) age at diagnosis was 9.3 (4.90) years and 50% were WHO functional class III at presentation. Baseline cardiac catheterisation data for both groups is shown. During follow-up, 20 (83%) subjects were treated with an endothelin receptor antagonist (exclusively Bosentan monohydrate), 17 (71%) with a phosphodiesterase 5 inhibitor (sildenafil) and 10 (42%) with either epoprostenol or iloprost; 19 (79%) are anticoagulated with warfarin. Themean duration of follow-up was 3.45 years, with an annualisedmortality of 6%. Study endpoints of death/transplant occurred in 6/24, compared to 10/12 controls (p= .001). Severity of PAH from cardiac catheterisationwas similar between patients and controls. Conclusions: Multiple medical therapies have resulted in improved survival for children with IPAH diagn c d r