Sorafenib
From The Cure For The Needy
Contents |
Sorafenib (Nexavar)
Effective Against
Primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).
The tosylate salt of sorafenib, a synthetic compound targeting growth signaling and angiogenesis. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.
Cost
From LC Laboratories: 49 USD (100 mg)
Reported Routes of Synthesis
"Sorafenib tosylate is synthesised in six steps. The manufacture involves the synthesis of a key isolated intermediate, which is synthesized via three reaction steps, from the starting material. The next two steps involve the formation of sorafenib followed by the salt formation and crystallisation, resulting in sorafenib tosylate. The final step involves micronization in an air-jet mill."
European Public Assessment Report on Nexavar, Scientific Discussion, accessed 6/30/2009
If the above PDF doesn't work, try http://www.emea.europa.eu/humandocs/Humans/EPAR/nexavar/nexavar.htm
Reaction of picolinic acid (I) with hot thionyl chloride in DMF gives 4-chloropyridine-2-carbonyl chloride (II), which is treated with methanol to give ester (III). Subsequent displacement of the methyl ester function with methylamine provides amide ( IV). Alternatively, acid chloride (II) is directly converted into amide (IV) by reaction with a cold solution of methylamine. In a different synthetic procedure, amide (IV) can be obtained from 4-chloropyridine (V) via the Menisci reaction using N-methylformamide and hydrogen peroxide in the presence of FeSO4 and H2SO4. Coupling of the amide (IV) with potassium 4-aminophenolate (VI)-obtained by treatment of 4-aminophenol (VII) with potassium tert-butoxide-in hot DMF yields the pyridyloxyaniline (VIII). Aniline (VIII) is finally condensed with either 4-chloro-3-(trifluoromethyl) phenyl isocyanate (IX) in CH2Cl2 or 4-chloro-3-(trifluoromethyl) aniline (X) by means of CDI in CH2Cl2.
Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan, M.-K.; Sibley, R. A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer. Org Process Res Dev 2002, 6(6) 777
Sorbera, L.A.; Castaner, J.; Bozzo, J.; Leeson, P.A. Bay-43-9006. Drugs Fut 2002, 27(12): 1141
Bayer Healthcare LLC. omega-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors. EP 1140840, JP 2003526613, EP 1690853, JP 2006328075, CA 2359510, CA 2549558, WO 2000042012
Bayer Healthcare LLC. omega-Carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors. JP 2002534468, WO 2000041698
Cost of Starting Materials and Selected Reagents:
Picolinic Acid from Sigma-Aldrich:' 20.7 USD (5g)
Methylamine solution (2.0 M in methanol) from Sigma-Aldrich: 96.6 USD (100mL)
4-Chloropyridine hydrochloride from Sigma-Aldrich: 70.80 USD (25g)
N-Methylformamide from Sigma-Aldrich: 34.60 USD (250mL, 1.011g/mL)
4-Chloro-3-(trifluoromethyl)phenyl isocyanate from Sigma-Aldrich: 61.6 USD (5g)
4-Chloro-3-(trifluoromethyl)aniline from Sigma-Aldrich: 58.2 USD (25g)