Bosentan
From The Cure For The Needy
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Bosentan (Tracleer)
Effective Against
Bosentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes pulmonary vasoconstriction. By blocking this interaction, bosentan decreases pulmonary vascular resistance. Bosentan has a slightly higher affinity for ET-A than ET-B.
Cost
"The cost of bosentan is about $50,000 per year. " "Bosentan is a pill that is taken orally twice a day. The initial dose for most patients is 62.5 mg twice a day. If there are no problems or side effects after one month, the dose is increased to 125 mg twice a day, which is the FDA approved dose. "
Obtained from http://www.phassociation.org/learn/treatment/bosentan.asp
Reported Route of Synthesis
The condensation of diethyl (2-methoxyphenoxy)malonate (I) with pyrimidine-2-carboxamidine (II) by means of NaOMe (Na in MeOH), followed by treatment with NaOH, provides the dihydroxy pyrimidine derivative (III), which is converted into the dichloro derivative (IV) by treatment with refluxing PCl5 and DIEA (1). Compound (IV) can also be obtained from the pyrimidinedione (V) by reaction with phosphorus oxychloride at 90 C (2,3). Reaction of compound (IV) with 4-tert-butylbenzenesulfonamide (VI), performed either directly in DMSO (1) or by means of benzyltriethylammonium chloride (BTEAC) or tetrabutylammonium bromide (TBAB) and K2CO3 in refluxing toluene (2,3), gives compound (VII). Finally, this compound is converted into bosentan by reaction with sodium and ethylene glycol (VIII) (1-3). Alternatively, the conversion of compound (VII) into bosentan can also be performed by reaction of compound (VII) with ethylene glycol mono tert-butyl ether (IX) by means of NaOH in toluene, yielding the tert-butyl ether derivative (X), which is then treated with formic acid at 85-90 C in toluene to give the 2-(formyloxy)ethoxy derivative (XI). Finally, the formyl group is removed by treatment of (XI) with NaOH in H2O (1-3).
Mealy, N.E., Bayes, M., Del Fresno, M. Bosentan. Drugs of the Future 2001, 26(12) 1149
Sulfonamide, preparation and use thereof as medicine and intermediate. F. Hoffmann-La Roche AG. EP 0526708, JP 1993222003, US 4292740
Preparation of sulfonamides. Roche Colorado Corp. US 6136971
Preparation of sulfonamides. F. Hoffmann-La Roche AG. JP 2003520857, WO 2001055120
Cost of Starting Materials and Selected Reagents:
Starting Material Diethyl 2-(2-methoxyphenoxy)propanedioatepricing not available from Sigma-Aldrich
Starting Material Pyrimidine-2-carboximidamide pricing not available from Sigma-Aldrich
Starting Material 5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-1H-pyrimidine-4,6-dione pricing not available from Sigma-Aldrich
Sodium Hydroxide (10M in H2O) from Sigma-Aldrich: 61.6 USD (100 mL)
N,N-Diisopropylethylamine DIEA from Sigma-Aldrich: 65.7 USD (100 mL)
Ethylene Glycol from Sigma-Aldrich: 30.6 USD (100 mL)
Sodium Methoxide from Sigma-Aldrich: 20.1 USD (25g)
Phosphorus(V) oxychloride from Sigma-Aldrich: 87.9 USD (10g)
Potassium carbonate from Sigma-Aldrich: 35.6 USD (100g)
Benzyl Triethyl Ammonium Bromide (BTEAC) pricing not available from Sigma-Aldrich
Tetrabutylammonium bromide (TBAB) from Sigma-Aldrich: 27.8 USD (25g)
Formic acid (1 M in H2O) from Sigma-Aldrich: 124 USD (100 mL)
4-tert-butylbenzenesulfonamide pricing not available from Sigma-Aldrich
2-tert-Butoxyethanol pricing not available from Sigma-Aldrich
Sodium from Sigma-Aldrich: 74.3 USD (100 g)
The conversion of 2-chloropyrimidine (I) to pyrimidine-2-carboxamidine (III) is performed by known methods through the intermediate pyrimidine-2-carbonitrile (II). The cyclization of (III) with 2-(2-methoxyphenoxy)malonic acid diethyl ester (IV) -prepared by condensation of 2-chloromalonic acid diethyl ester (V) with guaiacol (VI)- yields the bipyrimidinedione (VII). This compound is treated with refluxing POCl3 to afford the dichlorobipyrimidine (VIII). The chlorine monosubstitution in (VIII) with 4-tert-butylphenylsulfonamide (IX), K2CO3 and tetrabutylammonium bromide (TBAB) in toluene provides the substituted sulfonamide (X), which is submitted to a second chlorine substitution with ethyleneglycol mono-tert-butyl ether (XI) by means of NaOH in hot toluene to give the tert-butyl-intermediate (XII). Finally, this compound is deprotected by reaction with formic acid yielding the formate ester (XIII), which is hydrolyzed with NaOH in ethanol/water, and submitted to crystallization in refluxing ethanol/water to afford the target bosentan.
Harrington, P.J.; et al. Research and development of a second-generation process for bosentan, and endothelin receptor antagonist. Org Process Res Dev 2002, 6(2): 120
Cost of Starting Materials and Selected Reagents:
Starting Material pricing not available from Sigma-Aldrich
Phosphorus oxychloride from Sigma-Aldrich: 34.6 USD (25 mL)
Toluene from Sigma-Aldrich: 25 USD (100 mL)
Benzenesulfonamide from Sigma-Aldrich: 17.3 USD (5g)
Potassium Carbonate from Sigma-Aldrich: 35.6 USD (100g)
Tetrabutylammonium bromide (TBAB) from Sigma-Aldrich: 27.8 USD (25g)
Sodium Hydroxide (10M in H2O) from Sigma-Aldrich: 61.6 USD (100 mL)
Formic acid (1 M in H2O) from Sigma-Aldrich: 124 USD (100 mL)