This study presents the selective chloromethylation of calix[4](aza)crown ethers 2a-c, using chloromethyl n-octyl ether and SnCl 4 in chloroform at room temperature in good yield for the first time. Chloromethylated products 2a-c are used as key intermediates to synthesize new water-soluble p-phosphonato calix[4](aza)crown ethers 5a-c. Liquid-liquid phase extraction and phase solubility studies with poor water soluble drug molecules such as nifedipine, niclosamide and furosemide are performed to evaluate their binding properties. Among the studied drugs, furosemide was the most effectively dissolved drug by p-phosphonato calix[4](aza)crown ethers 5a-c in water. © 2012 Springer Science+Business Media B.V.