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147536-97-8

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  • Pharmaceutical Intermediate Used to Whiten and Remove Spots Bosentan Endothelin Antagonists Pharmaceutical Raw Material Bosentan Treatment of Pulmonary Hypertension 100% Free Custom Clearance

    Cas No: 147536-97-8

  • USD $ 3.5-3.5 / Gram

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147536-97-8 Usage

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.

Chemical Properties

Pale Yellow to Off-White Solid

Originator

Roche (Switzerland)

Uses

Different sources of media describe the Uses of 147536-97-8 differently. You can refer to the following data:
1. A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.
2. Bosentan is a mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.

Manufacturing Process

4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4- yl]benzenesulphonamide were heated to 100°C, cooled for a further 4 hours, poured on to ice and adjusted to pH 3 with 1 M tartaric acid. The suspension obtained was extracted with ethyl acetate, the organic extracts were combined, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel with CH2Cl2-ethyl acetate 9:1 and yielded 4-t-butyl-N-[6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulphonamide as a solid. Sodium salt melted at 195°-198°C. The 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl)-pyrimidin- 4-yl]benzenesulfonamide was prepared starting from pyrimidine-2- carboxamidine hydrochloride via rac-5-(2-methoxyphenoxy)-2-(pyrimidin-2- yl)tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxyphenoxy)- 2,2'-bipyrimidine.

Brand name

Tracleer (Actelion).

Therapeutic Function

Endothelin receptor antagonist

General Description

Bosentan, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tertbutyl-benzenesulfonamide (Tracleer, Bozentan), was thefirst endothelin receptor antagonist marketed in the UnitedStates. Bosentan works by competitively blocking the endothelinreceptor subtypes ETA and ETB. In binding to thereceptors, it blocks the effects of endothelin, which includeconstriction of the vascular smooth muscle, which leads tonarrowing of the blood vessels and hypertension. Althoughit is not selective for the ETA receptors, it does have a higheraffinity for that subtype over ETB. However, the clinical significanceof selectivity over preferential receptor bindinghas not been demonstrated. Bosentan is an inducer ofCYP2C9 and CYP3A4, and patients using bosentan must bemonitored for liver toxicity.

Hazard

A reproductive hazard.

Pharmacokinetics

Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by CYP2C9 and CYP3A4. The pharmacokinetics of bosentan are dose-proportional up to 500 mg/day (multiple doses). The pharmacokinetics of bosentan in pediatric patients with PAH are comparable to those in healthy subjects, whereas adult patients with PAH show a twofold increase in clearance. Severe renal impairment and mild hepatic impairment do not have a clinically relevant influence on its pharmacokinetics. Bosentan generally should be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Inhibitors of CYP3A4 increase the plasma concentration of bosentan as well as cause an increase in the clearance of drugs metabolized by CYP3A4 and CYP2C9 because of induction of these metabolizing enzymes. The possibility of reduced efficacy of CYP2C9 and CYP3A4 substrates coadministered with bosentan is increased. No clinically relevant interaction was detected for P-glycoprotein. Bosentan can increase plasma levels of ET-1.

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.

Side effects

Adverse effects include hypotension, headache, flushing, increased liver aminotransferases, leg edema, and anemia. Bosentan may cause birth defects and, therefore, is contraindicated in pregnancy. It also can cause liver injury.

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.

Metabolism

Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50%-65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolising liver enzymes. Steadystate conditions are reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is greater than in healthy subjects. In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased.

Check Digit Verification of cas no

The CAS Registry Mumber 147536-97-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,7,5,3 and 6 respectively; the second part has 2 digits, 9 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 147536-97:
(8*1)+(7*4)+(6*7)+(5*5)+(4*3)+(3*6)+(2*9)+(1*7)=158
158 % 10 = 8
So 147536-97-8 is a valid CAS Registry Number.
InChI:InChI=1/C27H29N5O6S/c1-27(2,3)18-10-12-19(13-11-18)39(34,35)32-23-22(38-21-9-6-5-8-20(21)36-4)26(37-17-16-33)31-25(30-23)24-28-14-7-15-29-24/h5-15,33H,16-17H2,1-4H3,(H,30,31,32)

147536-97-8SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 19, 2017

Revision Date: Aug 19, 2017

1.Identification

1.1 GHS Product identifier

Product name bosentan

1.2 Other means of identification

Product number -
Other names Actelion

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:147536-97-8 SDS

147536-97-8Synthetic route

ethylene glycol
107-21-1

ethylene glycol

4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide
150727-06-3

4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: 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;
Stage #2: With tartaric acid In tetrahydrofuran; water at 5 - 10℃; for 1h;
95.7%
With sodium hydroxide In tetrahydrofuran at 50 - 65℃; for 7h; Time;92%
Stage #1: ethylene glycol; 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide With sodium hydroxide at 100℃; for 2h;
Stage #2: With DL-tartaric acid In tetrahydrofuran; water Reagent/catalyst; Cooling with ice;
88.3%
N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butylbenzenesulphonamide sodium salt

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butylbenzenesulphonamide sodium salt

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With hydrogenchloride In ethanol; water at 20 - 30℃; for 3h;95%
With hydrogenchloride In ethanol; water pH=3;116 g
4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide

4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: 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;
Stage #2: With hydrogenchloride In ethanol; water for 1h; pH=5.5;
93%
Stage #1: 4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide With sodium hydroxide In water at 25℃; for 1h;
Stage #2: In ethanol Reflux;
91.2%
bosentan p-toluenesulfonate

bosentan p-toluenesulfonate

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With sodium hydrogencarbonate In ethanol; water at 20 - 25℃; for 1h;93%
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide potassium salt

4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide potassium salt

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With hydrogenchloride In water; isopropyl alcohol at 20℃; for 3h;90%
With hydrogenchloride In water; 4-methyl-2-pentanone at 75℃; Inert atmosphere;
With hydrogenchloride In water; 4-methyl-2-pentanone at 75℃;
With hydrogenchloride In water32 g
trifluoromethanesulfonic acid 2-[6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)-[2,2']bipyrimidinyl-4-yloxy]ethyl ester
1334686-08-6

trifluoromethanesulfonic acid 2-[6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)-[2,2']bipyrimidinyl-4-yloxy]ethyl ester

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: trifluoromethanesulfonic acid 2-[6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)-[2,2']bipyrimidinyl-4-yloxy]ethyl ester With ethanol; sodium hydroxide at 20℃; for 1h;
Stage #2: With hydrogenchloride In dichloromethane; water at 0℃; pH=3 - 3.5;
90%
Stage #1: trifluoromethanesulfonic acid 2-[6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)-[2,2']bipyrimidinyl-4-yloxy]ethyl ester With sodium hydroxide In ethanol at 20℃; for 1h;
Stage #2: With hydrogenchloride In ethanol; dichloromethane; water pH=3 - 3.5;
90%
4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt

4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt

ethylene glycol
107-21-1

ethylene glycol

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: ethylene glycol With potassium carbonate In acetonitrile for 0.25h;
Stage #2: 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt In acetonitrile at 80 - 85℃; for 12h; Temperature; Time; Solvent;
89%
Stage #1: ethylene glycol With sodium hydroxide In acetonitrile at 75 - 80℃; for 8 - 12h;
Stage #2: 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt In acetonitrile for 12 - 14h;
Stage #3: With hydrogenchloride; water In acetonitrile at 25℃; for 2h; pH=2 - 3; Product distribution / selectivity;
Stage #1: 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt; ethylene glycol With barium(II) hydroxide In toluene at 110℃;
Stage #2: With hydrogenchloride In water pH=1 - 2; Product distribution / selectivity;
4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide

4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With pyridinium p-toluenesulfonate In methanol at 20℃; for 24h; Inert atmosphere;84%
bosentan potassium
1174918-31-0

bosentan potassium

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With hydrogenchloride In dichloromethane; water at 20 - 30℃; pH=0.5 - 1;80.8%
4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide
1174918-30-9

4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With sodium tetrahydroborate In methanol at 0 - 5℃; Solvent;80%
With sodium tetrahydroborate In methanol at 0 - 20℃;80%
With sodium tetrahydroborate In methanol at 0 - 5℃;75%
Stage #1: 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide With sodium tetrahydroborate In methanol at 0 - 5℃; for 2h;
Stage #2: With hydrogenchloride In methanol; water pH=2; Product distribution / selectivity;
With methanol; sodium tetrahydroborate for 4h;
2,2-dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidinyl-4-yloxy]-ethyl ester
1374293-39-6

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

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: 2,2-dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidinyl-4-yloxy]-ethyl ester With water; sodium hydroxide In ethanol at 10 - 25℃;
Stage #2: With hydrogenchloride In ethanol; water at 10 - 15℃; for 2h;
80%
ethyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetate

ethyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetate

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With sodium tetrahydroborate In methanol at 0 - 5℃;80%
4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-iodo-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulfonamide
1206769-86-9

4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-iodo-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulfonamide

2-(tributylstannyl)pyrimidine
153435-63-3

2-(tributylstannyl)pyrimidine

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With cesium fluoride; bis(tri-t-butylphosphine)palladium(0) In 1,4-dioxane at 100 - 110℃; for 16h; Inert atmosphere;70%
trifluoromethanesulfonic acid 4-(2-tert-butoxyethoxy)-6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)pyrimidin-2-yl ester
1334686-05-3

trifluoromethanesulfonic acid 4-(2-tert-butoxyethoxy)-6-(4-tert-butylbenzenesulfonylamino)-5-(2-methoxyphenoxy)pyrimidin-2-yl ester

2-(tributylstannyl)pyrimidine
153435-63-3

2-(tributylstannyl)pyrimidine

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl acetamide at 130℃; for 6h; Stille Coupling;70%
tetrakis(triphenylphosphine) palladium(0) In ISOPROPYLAMIDE at 130℃; for 6h;70%
N-[6-[2-(1,1-dimethylethoxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(1,1-dimethylethyl)benzenesulfonamide

N-[6-[2-(1,1-dimethylethoxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(1,1-dimethylethyl)benzenesulfonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: N-[6-[2-(1,1-dimethylethoxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(1,1-dimethylethyl)benzenesulfonamide With formic acid at 85℃; for 1.5h;
Stage #2: With potassium carbonate In methanol for 1h;
70%
Stage #1: N-[6-[2-(1,1-dimethylethoxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(1,1-dimethylethyl)benzenesulfonamide With formic acid at 85℃; for 1.5h;
Stage #2: With potassium carbonate In methanol for 1h;
Stage #3: With hydrogenchloride In methanol; water; ethyl acetate pH=3 - 3.5;
70%
With phosphoric acid In acetonitrile at 25℃; Product distribution / selectivity; Reflux;
Multi-step reaction with 2 steps
1.1: 4 h / 85 °C
2.1: sodium hydroxide / water / 1 h / 25 °C
2.2: Reflux
View Scheme
N-[2-bromo-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide
1206769-81-4

N-[2-bromo-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide

2-(tributylstannyl)pyrimidine
153435-63-3

2-(tributylstannyl)pyrimidine

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With cesium fluoride; bis(tri-t-butylphosphine)palladium(0) In N,N-dimethyl-formamide at 140 - 150℃; for 16h; Inert atmosphere;47%
2-(5-(2-methoxy-phenoxy)-6-chloro-2-(pyrimidin-2-yl)pyrimidin-4-yloxy) ethanol
184779-15-5

2-(5-(2-methoxy-phenoxy)-6-chloro-2-(pyrimidin-2-yl)pyrimidin-4-yloxy) ethanol

4-tert-butylbenzenesulphonamide
6292-59-7

4-tert-butylbenzenesulphonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With potassium phosphate; copper(l) iodide; glycine In 1,4-dioxane at 120℃; for 44h; Product distribution / selectivity;31%
With potassium phosphate; copper(l) iodide; glycine In 1,4-dioxane at 120℃; for 44h; Product distribution / selectivity;31%
With potassium phosphate In N,N-dimethyl acetamide at 20 - 100℃; for 18h; Product distribution / selectivity;
With potassium carbonate; tetrabutylammomium bromide In toluene at 100 - 110℃; for 15h;
ethylene glycol
107-21-1

ethylene glycol

4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine
150728-13-5

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

potassium 4-tert-butylbenzenesulfonate

potassium 4-tert-butylbenzenesulfonate

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With sodium 1.) DMSO, rt, 2.) 100 deg C; Multistep reaction;
5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidine-4,6(1H, 5H)-dione
150728-12-4

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

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: POCl3, PCl5 / Heating
2: 2.) Na / 1.) DMSO, rt, 2.) 100 deg C
View Scheme
Multi-step reaction with 5 steps
1.1: trichlorophosphate / 4 h / Reflux
2.1: potassium hydroxide / acetone / 0.08 h / 30 °C
2.2: 6.5 h / 30 °C / Reflux
3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 30 - 50 °C
3.2: 0.5 h / 30 °C
4.1: hydrogenchloride; water / 1 h
5.1: sodium tetrahydroborate; methanol / 4 h
View Scheme
Multi-step reaction with 5 steps
1.1: trichlorophosphate / 90 - 105 °C
2.1: potassium carbonate; tetrabutylammomium bromide / toluene / 50 °C / Reflux; Dean-Stark
3.1: sodium hydroxide / toluene / 55 °C
4.1: 4 h / 85 °C
5.1: sodium hydroxide / water / 1 h / 25 °C
5.2: Reflux
View Scheme
Multi-step reaction with 3 steps
1.1: phosphorus pentachloride / toluene / 2 h / Reflux
2.1: sodium hydroxide
2.2: 3 h / 90 °C
3.1: sodium hydroxide / tetrahydrofuran / 7 h / 50 - 65 °C
View Scheme
4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide
150727-06-3

4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
In ethylene glycol
ethylene glycol
107-21-1

ethylene glycol

4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide
150727-06-3

4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide

A

p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide
174227-14-6

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

B

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: ethylene glycol With sodium hydroxide In tetrahydrofuran at 50℃; for 0.5h;
Stage #2: 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide In tetrahydrofuran at 50 - 65℃; for 12h;
bosentan barium

bosentan barium

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With hydrogenchloride In dichloromethane; water pH=1 - 2; Product distribution / selectivity;
p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide
174227-14-6

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

2-chloro-ethanol
107-07-3

2-chloro-ethanol

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide With sodium carbonate In N,N-dimethyl-formamide at 110 - 115℃; for 4h;
Stage #2: 2-chloro-ethanol In N,N-dimethyl-formamide for 16h;
Stage #3: With hydrogenchloride; water In N,N-dimethyl-formamide pH=2; Product distribution / selectivity;
Stage #1: p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide; 2-chloro-ethanol With potassium tert-butylate In N,N-dimethyl-formamide at 120℃; for 15h;
Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 20 - 25℃; pH=2;
Stage #1: p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide With sodium carbonate In dimethyl sulfoxide; toluene at 105 - 110℃;
Stage #2: 2-chloro-ethanol In dimethyl sulfoxide; toluene at 105 - 110℃;
Stage #3: With hydrogenchloride In water; dimethyl sulfoxide; toluene at 20℃;
bosentan hydrochloride
1196074-08-4

bosentan hydrochloride

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
With sodium hydrogencarbonate In ethanol; water for 2h; pH=7;
ethylene sulfite
3741-38-6

ethylene sulfite

p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide
174227-14-6

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

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: ethylene sulfite; p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide With potassium carbonate; tetrabutylammomium bromide In butanone Reflux;
Stage #2: With water; sodium hydroxide In ethyl acetate
N-(6-chloro-5-(2-methoxyphenoxy))-[2,2'-bipyrimidinyl]-4-t-butyl benzenesulfonamide cesium salt

N-(6-chloro-5-(2-methoxyphenoxy))-[2,2'-bipyrimidinyl]-4-t-butyl benzenesulfonamide cesium salt

ethylene glycol
107-21-1

ethylene glycol

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Stage #1: ethylene glycol With sodium carbonate; dmap at 60 - 65℃; for 3h;
Stage #2: N-(6-chloro-5-(2-methoxyphenoxy))-[2,2'-bipyrimidinyl]-4-t-butyl benzenesulfonamide cesium salt In tetrahydrofuran for 135h; Product distribution / selectivity; Reflux;
4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide
150727-06-3

4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)2,2'-bipyrimidin-4-yl)benzene sulfonamide

A

p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide
174227-14-6

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

B

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
In water; isopropyl alcohol at 115℃; for 5h;A 5.88 %Chromat.
B n/a
2-methoxy-phenol
90-05-1

2-methoxy-phenol

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: sodium hydroxide / toluene / 20 °C / Reflux
1.2: 3.5 h / 60 °C / Reflux
2.1: sodium ethanolate / methanol / 6 h / 0 - 35 °C
3.1: trichlorophosphate / 4 h / 103 - 105 °C
3.2: 20 - 80 °C
4.1: potassium carbonate / tetrabutylammomium bromide / toluene / 2 h / Reflux
5.1: isopropyl alcohol; water / 5 h / 115 °C
View Scheme
Multi-step reaction with 6 steps
1.1: sodium hydroxide / toluene / 20 °C / Reflux
1.2: 3.5 h / 60 °C / Reflux
2.1: sodium ethanolate / methanol / 6 h / 0 - 35 °C
3.1: trichlorophosphate / 4 h / 103 - 105 °C
3.2: 20 - 80 °C
4.1: potassium carbonate / tetrabutylammomium bromide / toluene / 2 h / Reflux
5.1: water / 5 h / 115 °C
5.2: 1 h / 55 - 85 °C
6.1: hydrogenchloride / dichloromethane; water / 20 - 30 °C / pH 0.5 - 1
View Scheme
(2-methoxyphenoxy)-malonic acid dimethyl ester
150726-89-9

(2-methoxyphenoxy)-malonic acid dimethyl ester

bosentan
147536-97-8

bosentan

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: sodium ethanolate / methanol / 6 h / 0 - 35 °C
2.1: trichlorophosphate / 4 h / 103 - 105 °C
2.2: 20 - 80 °C
3.1: potassium carbonate / tetrabutylammomium bromide / toluene / 2 h / Reflux
4.1: isopropyl alcohol; water / 5 h / 115 °C
View Scheme
Multi-step reaction with 5 steps
1.1: sodium ethanolate / methanol / 6 h / 0 - 35 °C
2.1: trichlorophosphate / 4 h / 103 - 105 °C
2.2: 20 - 80 °C
3.1: potassium carbonate / tetrabutylammomium bromide / toluene / 2 h / Reflux
4.1: water / 5 h / 115 °C
4.2: 1 h / 55 - 85 °C
5.1: hydrogenchloride / dichloromethane; water / 20 - 30 °C / pH 0.5 - 1
View Scheme
Multi-step reaction with 6 steps
1.1: sodium methylate / methanol / 3 h / 25 - 30 °C
1.2: 3 h / 25 - 30 °C
2.1: trichlorophosphate / 4 h / Reflux
3.1: potassium hydroxide / acetone / 0.08 h / 30 °C
3.2: 6.5 h / 30 °C / Reflux
4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 30 - 50 °C
4.2: 0.5 h / 30 °C
5.1: hydrogenchloride; water / 1 h
6.1: sodium tetrahydroborate; methanol / 4 h
View Scheme
pivaloyl chloride
3282-30-2

pivaloyl chloride

bosentan
147536-97-8

bosentan

2,2-dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidinyl-4-yloxy]-ethyl ester
1374293-39-6

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

Conditions
ConditionsYield
Stage #1: bosentan In dichloromethane at 20 - 25℃; for 1h;
Stage #2: pivaloyl chloride In dichloromethane at 20 - 25℃; for 15h;
97.5%
2,5-dihydroxybenzoic acid.
490-79-9

2,5-dihydroxybenzoic acid.

bosentan
147536-97-8

bosentan

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide gentisic acid cocrystal
1450829-49-8

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide gentisic acid cocrystal

Conditions
ConditionsYield
In n-heptane; acetone at 55℃; for 2.33333h; Concentration; Solvent; Temperature; Time; Sonication;96%
di(succinimido) carbonate
74124-79-1

di(succinimido) carbonate

bosentan
147536-97-8

bosentan

C32H32N6O10S

C32H32N6O10S

Conditions
ConditionsYield
In acetonitrile at 65℃; for 32h; Temperature; Solvent;95.5%
zinc(II) nitrate hexahydrate

zinc(II) nitrate hexahydrate

ethanol
64-17-5

ethanol

bosentan
147536-97-8

bosentan

C54H56N10O12S2Zn*2.5C2H6O

C54H56N10O12S2Zn*2.5C2H6O

Conditions
ConditionsYield
With potassium hydroxide for 4h; Thermodynamic data; Reflux;74%
maleic acid
110-16-7

maleic acid

bosentan
147536-97-8

bosentan

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide maleic acid cocrystal

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide maleic acid cocrystal

Conditions
ConditionsYield
In ethyl acetate; acetone at 4 - 80℃; for 12h; Concentration; Time; Temperature; Solvent;63%
In acetonitrile at 4 - 20℃;
pentafluorophenol 4-nitroxybutyrate
838878-70-9

pentafluorophenol 4-nitroxybutyrate

bosentan
147536-97-8

bosentan

C31H34N6O10S

C31H34N6O10S

Conditions
ConditionsYield
With dmap; triethylamine In dichloromethane at 0℃;57%
chloromethyl (4-(nitrooxy)butyl) carbonate
959639-85-1

chloromethyl (4-(nitrooxy)butyl) carbonate

bosentan
147536-97-8

bosentan

C33H38N6O12S

C33H38N6O12S

Conditions
ConditionsYield
With caesium carbonate In N,N-dimethyl-formamide for 48h;38%
1-chloro-ethyl 4-nitooxy-butyl carbonate
959639-82-8

1-chloro-ethyl 4-nitooxy-butyl carbonate

bosentan
147536-97-8

bosentan

C34H40N6O12S

C34H40N6O12S

Conditions
ConditionsYield
With caesium carbonate In N,N-dimethyl-formamide for 60h;30%
[4-(nitrooxy)methyl]benzoic acid pentafluorophenyl ester
874446-96-5

[4-(nitrooxy)methyl]benzoic acid pentafluorophenyl ester

bosentan
147536-97-8

bosentan

C35H34N6O10S

C35H34N6O10S

Conditions
ConditionsYield
With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at 0℃;23%
4-(nitrooxy)butyl 4-nitrophenyl carbonate
935472-60-9

4-(nitrooxy)butyl 4-nitrophenyl carbonate

bosentan
147536-97-8

bosentan

C32H36N6O11S

C32H36N6O11S

Conditions
ConditionsYield
With dmap; scandium tris(trifluoromethanesulfonate) In dichloromethane at 0℃;15%
pyridine-2-carbonyl azide
4013-71-2

pyridine-2-carbonyl azide

bosentan
147536-97-8

bosentan

pyridin-2-ylcarbamic acid 2-[6-(4-tert-butyl-phenylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester

pyridin-2-ylcarbamic acid 2-[6-(4-tert-butyl-phenylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester

Conditions
ConditionsYield
With dmap In toluene at 100℃;

147536-97-8Relevant articles and documents

Research and development of a second-generation process for bosentan, an endothelin receptor antagonist

Harrington, Peter J.,Khatri, Hiralal N.,DeHoff, Brad S.,Guinn, Martin R.,Boehler, Mark A.,Glaser, Karl A.

, p. 120 - 124 (2002)

A second-generation manufacturing process from 5-(2-methoxyphenoxy)-[2,2′-bipyrimidine]-4,6-(1H,5H)-dione to bosentan is based on the synthesis and deprotection of the tert-butyl ether of bosentan using available and inexpensive ethylene glycol mono-tert-butyl ether. This new strategy triggered a cascade of process improvements. Isolations are reduced from six to three, and drying operations, from five to two. Process solvents are reduced from six to two. The isolations of two sensitizers are eliminated. Toluene is used in place of methylene chloride. Two aqueous waste streams are eliminated by replacing DMF and ethylene glycol by toluene. Two methanol - isopropyl acetate recrystallizations of bosentan are replaced by the decantation of a suspension of bosentan formate monoethanolate in ethanol - toluene. Finally, the overall yield is increased from 67 to 84% and the final product purity improved from 99.3 to 99.7%.

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

-

Paragraph 0130-0143, (2019/10/08)

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.

METHOD FOR PRODUCING BOSENTAN OR HYDRATE THEREOF

-

Paragraph 0042; 0043, (2017/01/09)

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

PROCESS FOR PREPARATION OF BOSENTAN MONOHYDRATE OF PHARMACEUTICAL PURITY

-

Page/Page column 14; 15, (2014/07/21)

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.

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