Ambrisentan
From The Cure For The Needy
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Ambrisentan (Letairis, Volibris)
Effective Against
Ambrisentan functions as an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA).
Cost
"The wholesale acquisition cost for Letairis has been set at $3,940 per pack, a one-month supply."
From https://www.caremark.com/portal/asset/TrendsRxSpecialtyAlert_Letairis.pdf
Reported Routes of Synthesis
The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III), which by treatment with BF3/Et2O and methanol, followed by optical resolution, yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture (1,2).
Riechers, H.; Albrecht, H.-P.; Amberg, W.; et al. Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 1996, 39(11): 2123
Sorbera, L.A.; Castaner, J. Ambrisentan. Drugs Fut 2005, 30(8): 765
New carboxylic acid derivatives, their preparation and their use. Abbott GmbH & Co. KG. EP 1110952, US 2006160808, EP 0785926, WO 1996011914, US 2006276474, US 2006276645, US 2007203338, JP 1998507190, US 7109205, US 5932730, US 5969134, US 6197958, US 2002052495, US 6600043, JP 2007126488, US 7119097
Cost of Starting Material and Selected Reagents:
Starting Material Benzophenone from Sigma-Aldrich: 20.4 USD (1 g)
Methyl chloroacetate from Sigma-Aldrich: 35.4 USD (1 g)
Sodium methoxide from Sigma-Aldrich: 20.1 USD (25g)
Boron trifluoride from Sigma-Aldrich: 578 USD (20 g)
Methanol from Sigma-Aldrich: 42.3 USD (1 L)
Diethyl ether from Sigma-Aldrich: 32.9 USD (100 mL)
Potassium carbonate from Sigma-Aldrich: 35.6 USD (100 g)
Potassium hydroxide from Sigma-Aldrich: 27.3 USD (250 g)
4,6-dimethyl-2-methylsulfonyl-pyrimidine pricing not available from Sigma-Aldrich