150727-06-3

Usage

Uses

1. Pharmaceutical Industry:
4-tert-Butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide is used as an intermediate in the synthesis of Bosentan for its role as a mixed endothelin receptor antagonist. Bosentan is prescribed for the treatment of pulmonary arterial hypertension and digital ulcers associated with systemic sclerosis. The compound's ability to block the action of endothelin, a potent vasoconstrictor, makes it a valuable asset in managing these conditions.
2. Quality Control and Regulatory Compliance:
4-tert-Butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide is also used as an intermediate for Bosentan USP Related Compound A. This application is essential for ensuring the quality, safety, and efficacy of Bosentan as a pharmaceutical product. By using 4-tert-Butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide as a reference, manufacturers can verify the identity, purity, and strength of Bosentan, adhering to the United States Pharmacopeia (USP) standards.

Upstream product

• 90-05-1 2-methoxy-phenol 
• 150726-89-9 (2-methoxyphenoxy)-malonic acid dimethyl ester 
• 14080-23-0 2-cyanopyrimidine 
• 329923-17-3 5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidine-4,6-dione 
• 6292-59-7 4-tert-butylbenzenesulphonamide 
• 1268612-27-6 C₁₅H₁₁ClN₄O₃ 
• 42839-08-7 pyrimidine-2-carboxylic acid ethyl ester 
• 150728-12-4 5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidine-4,6(1H, 5H)-dione 
• 57871-18-8 methyl ester of imino-pyrimidine acid 
• 20730-58-9 2-(2-Methoxyphenoxy)propanedioic acid diethyl ester 
• 329923-15-1 4,6-dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine 
• 150728-13-5 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine 

Downstream Products

• 147536-97-8 bosentan 
• 1065472-77-6 d4-4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yl]-benzenesulfonamide 
• 174227-14-6 p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide 
• 1174918-31-0 bosentan potassium 
• 1448588-52-0 N,N′-(6,6′-(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis-(methylene)bis(oxy)bis(5-(2-methoxy phenoxy)-2,2′-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) 
• 1448588-53-1 N,N′-(6,6′-(2,3-dihydroxybutane-1,4-diyl)bis(oxy)bis-(5-(2-methoxyphenoxy)-2,2′-bipyrimidine-6,4-diyl))bis-(4-tert-butylbenzenesulfonamide) 
• 1632289-55-4 4-tert-butyl-N-[6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzenesulfonamide 
• 1632289-54-3 4-tert-butyl-N-{6-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl}benzenesulfonamide 
• 157212-55-0 bosentan monohydrate 
• 1431507-36-6 4-(1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2’-bipyrimidin]-4-yl]benzenesulfonamide citrate 
• 1097263-60-9 N,N'-(6,6''-(ethane-1,2-diylbis(oxy))bis(5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-6,4-diyl))bis(4-(tert-butyl)benzenesulfonamide) 
• 180576-46-9 methyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetate 
• 1174918-30-9 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide 
• 1447959-38-7 4-tert-butyl-N-(6-(cyanomethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide 

Relevant academic research and scientific papers

A method for the treatment of pulmonary arterial hypertension drug preparation method

The invention provides a preparation method of a therapeutic medicine for treating pulmonary arterial hypertension and particularly provides a preparation method of a key intermediate compound as shown in a formula (IV). According to the method, the compound as shown in the formula (IV) is obtained by means of reaction of a compound as shown in a formula (II) and a compound as shown in a formula (III). The preparation method is easily available in raw materials, low in cost, mild in condition and suitable for industrialized production. The formulae (IV), (II) and (III) are as shown in the specification.

Metabolism study and biological evaluation of bosentan derivatives

Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogues are often designed to block the major sites of metabolism. In this paper bosentan analogues were synthesized, and their metabolism and biological activity were evaluated. All synthesized compounds showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.

PROCESS FOR PREPARATION OF BOSENTAN MONOHYDRATE OF PHARMACEUTICAL PURITY

A process for the preparation of bosentan monohydrate of pharmaceutical purity is characterized by that crude bosentan is suspended in methyl alcohol / dichloromethane mixture at a volume ratio from 8:1 to 1:2, the mixture is stirred at room temperature, crystalline bosentan monohydrate is isolated, dried to constant weight and optionally crystallized to obtain appropriate crystal shape.

ACID ADDITION SALTS OF BOSENTAN

The present invention relates to the stable acid addition salts of Bosentan that are useful for the purification of Bosentan base. In particular, the Bosentan acid addition salt is selected from Bosentan citrate and Bosentan tartrate.

An alternate synthesis of bosentan monohydrate, an endothelin receptor antagonist 1

An alternate synthesis of an endothelin receptor antagonist bosentan monohydrate is reported. This new synthetic route involves the coupling of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)(2,2′-bipyrimidin)-4-yl] benzene sulfonamide with commercially available raw material (2,2-dimethyl-1,3-dioxolan-4-yl)methanol as the key step. Attractive features of this approach are its versatileness, commercial availability of raw materials, usage of eco-friendly reagents, and it efficiently provides the desired bosentan monohydrate free from reported impurities such as dimer, N-alkylated, and pyrimidinone impurities. Georg Thieme Verlag Stuttgart, New York.

PROCESS FOR THE PREPARATION OF BOSENTAN

The present invention relates to a process for the preparation of Bosentan (Formula 1) or pharmaceutically acceptable salts or hydrates thereof which results the product substantially free of impurities like ethylene glycol bis-sulfonamide dimer and 6-hydroxy sulfonamide. The process according to present invention is also producing Bosentan sodium and Bosentan ammonium which gives Bosentan or pharmaceutically acceptable salts or hydrates thereof in improved yield and quality as compared to prior art processes.

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.

ACID ADDITION SALTS OF BOSENTAN

The present invention relates to the stable acid addition salts of Bosentan that are useful for the purification of Bosentan base. In particular, the Bosentan acid addition salt is selected from Bosentan citrate and Bosentan tartrate.