Eltrombopag
From The Cure For The Needy
Contents |
Eltrombopag (Promacta, Revolade)
Effective Against
Conditions that lead to Thrombocytopenia (abnormally low platelet counts)
Eltrombopag is in a class of medications called thrombopoietin receptor agonists. It works by causing the cells in the bone marrow to produce more platelets.
Cost
"Eltrombopag carries a wholesale acquisition price (WAC) of $1,650 for a 30-day supply of 25 mg tablets and $3,300 for the 50 mg dose. To obtain the 75 mg dosage, multiple tablets must be administered each day. At a maximum dose of 75 mg, eltrombopag would cost just shy of $5,000 per month."
Reported Routes of Synthesis
The nitration of 2-bromophenol (I) with NaNO3 and H2SO4 in water gives 2-bromo-6-nitrophenol (II), which is methylated by means of CH3-I and K2CO3 in refluxing acetone to yield 2-bromo-6-nitroanisole (III). The condensation of (III) with 3-carboxyphenyl boronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing dioxane affords 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid (V), which is demethylated by means of aq. 48% HBr in refluxing acetic acid to provide 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (VI). The reduction of the nitro group of (VI) by means of H2 over Pd/C in ethanol/aq. NaOH gives the 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (VII), which is treated with NaNO2 and HCl in water, and condensed with 1-(3,4-dimethylphenyl)-3-methyl-2,5-dihydro-1H-pyrazol-5-one (VIII) to provide the target pyrazolone derivative. The intermediate 1-(3,4-dimethylphenyl)-3-methyl-2,5-dihydro-1H-pyrazol-5-one (VIII) has been obtained by cyclization of 3,4-dimethylphenyl-hydrazine (IX) with ethyl acetoacetate (X) by means of NaOAc in refluxing acetic acid (1,2).
Revill, P., Serradell, N., Bolos, J. Eltrombopag. Drugs of the Future 2006, 31(9) 767
GlaxoSmithKline Inc., Ligand Pharmaceuticals, Inc. Regulated activation of cell-membrane receptors by metal-chelating agonists. WO 2002057300, CA 2432800, EP 1351979, JP 2004532614
Cost of Starting Materials and Selected Reagents:
Starting Material 2-bromophenol from Sigma-Aldrich: 46.4 USD (10g)
Sodium Nitrate from Sigma-Aldrich: 26.9 USD (250g)
Sulfuric Acid from Sigma-Aldrich: 67.2 USD (100 mL)
Iodomethane from Sigma-Aldrich: 67.2 USD (100g)
Potassium Carbonate from Sigma-Aldrich: 35.6 USD (100g)
Triphenyl phospine from Sigma-Aldrich: 19 USD (25 g)
Sodium Carbonate from Sigma-Aldrich: 52.1 USD (500g)
Hydrobromic Acid from Sigma-Aldrich: 154.5 USD (1 L)
Hydrochloric Acid from Sigma-Aldrich: 46.5 USD (100 mL)
Ethanol from Sigma-Aldrich: 37.6 USD (100 mL)
Sodium Acetate from Sigma-Aldrich: 24.1 USD (250g)
Starting Material 3,4-Dimethylphenylhydrazine hydrochloride from Sigma-Aldrich: 250.5 USD (25g)
Ethyl acetoacetate from Sigma-Aldrich: 30.3 USD (100 mL)