174227-18-0

Basic information

• Product Name: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide
• Synonyms: 4-(1,1-Dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-(2,2'-bipyrimidin)-4-yl)benzenesulfornamide;Benzenesulfonamide, 4-(1,1-dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'-bipyrimidin)-4-yl)-;Tracleer;Unii-xul93R30K2
• CAS NO: 174227-18-0
• Molecular Formula: C27H29N5O6S
• Molecular Weight: 0
• Mol File: 174227-18-0.mol

Chemical Properties

• Appearance: /
• CAS DataBase Reference: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide(174227-18-0)
• EPA Substance Registry System: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide(174227-18-0)

Safety Data

• Hazardous Substances Data: 174227-18-0(Hazardous Substances Data)

Upstream product

• 107-21-1 ethylene glycol 
• 150728-13-5 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine 
• 1206769-86-9 4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-iodo-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulfonamide 
• 153435-63-3 2-(tributylstannyl)pyrimidine 
• 1206769-81-4 N-[2-bromo-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide 
• 1334686-05-3 trifluoromethanesulfonic acid 4-(2-tert-butoxyethoxy)-6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)pyrimidin-2-yl ester 
• 301646-60-6 N-[6-[2-(1,1-dimethylethoxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(1,1-dimethylethyl)benzenesulfonamide 
• 1334686-03-1 N-[6-(2-tert-Butoxyethoxy)-2-hydroxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide 
• 1334686-04-2 Trifluoromethanesulfonic acid 4-(2-tert-butoxyethoxy)-6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)-pyrimidin-2-yl ester 
• 1334686-06-4 4-tert-Butyl-N-[2-hydroxy-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide 
• 1334686-10-0 C₂₈H₃₇N₃O₈S₂ 
• 1334686-08-6 trifluoromethanesulfonic acid 2-[6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)-[2,2']bipyrimidinyl-4-yloxy]ethyl ester 
• 42839-08-7 pyrimidine-2-carboxylic acid ethyl ester 
• 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) 

Downstream Products

• 1431507-36-6 4-(1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2’-bipyrimidin]-4-yl]benzenesulfonamide citrate 
• 1450829-49-8 N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide gentisic acid cocrystal 

Relevant articles and documents

A preparation method of bosentan monohydrate, novel intermediate useful for the preparation of bosentan monohydrate, and the preparation method thereof

The present invention provides a method for preparing bosentan monohydrate, a novel intermediate used therefor, and a method for preparing same. The novel intermediate composition of the present invention is produced at a high yield and high purity, and by using said intermediate composition, high-purity bosentan monohydrate can be economically mass produced at a high yield.

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.

METHOD FOR PRODUCING BOSENTAN OR HYDRATE THEREOF

PROBLEM TO BE SOLVED: To produce: high purity bosentan by suppressing the formation of 4-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide which is a reaction by-product or a hydrate thereof. SOLUTION: There is produced high purity bosentan by suppressing the formation of a reaction by-product by carrying out a reaction between 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide and ethylene glycol by using alkali metal salt of disilazane as a base and a dehydrating agent or a hydrate thereof. SELECTED DRAWING: Figure 4 COPYRIGHT: (C)2016,JPOandINPIT

METHOD FOR PRODUCING BOSENTAN USING DEHYDRATING AGENT OR HYDRATE THEREOF

PROBLEM TO BE SOLVED: To produce high purity bosentan by suppressing the formation of 4-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide which is a reaction by-product or a hydrate thereof. SOLUTION: There are produced: high purity bosentan by suppressing the formation of a reaction by-product by carrying out a reaction between 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide and ethylene glycol by adding sodium hydroxide as a base and further a dehydrating agent; and a hydrate thereof. SELECTED DRAWING: Figure 4 COPYRIGHT: (C)2016,JPOandINPIT

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.

Succinct synthesis of bosentan utilizing glycol Mono-THP ether

GRAPHICAL ABSTRACT A concise synthetic method for bosentan, a nonpeptide orally active dual endothelin (ET-1A/B) receptor antagonist used for the treatment of pulmonary artery hypertension (PAH), was developed. We developed a new succinct synthetic route for bosentan by employing an acid-labile tetrahydropyran (THP)-protected glycol. THP group is advantageous over the previously known protection groups used in bosentan synthesis in that it provides a clean and quantitative deprotection. Bosentan was constructed via two parallel reaction pathways, yet the better product yield was obtained from a pathway via 6. Deprotection of THP ether was achieved under a mild acidic condition to afford bosentan.

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.

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.

PROCESS FOR THE PREPARATION OF BOSENTAN MONOHYDRATE

The invention relates to improved processes for the preparation of bosentan monohydrate which provide higher yield and purity.

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%.