First synthesis of etidronate partial amides starting from PCl3.
Methods for the preparation of mixed tetra-amide esters 1 and 2, the partial amide ester 3, and tri- and P,P-diamides 4 and 5 from monophosphorus spieces 12, 8 and 9, respectively, were developed. Compounds 8 and 9 were obtained from phosphorus trichloride via MeOPCl2, which was treated with 2 eq. and 4 eq. of piperidine, followed by water or acetyl chloride, respectively. Tetrasubstituted amide bisphosphonates 1 and 2 were selectively dealkylated with lithium or silyl halide to achieve target compounds 3-5. Piperidine was found to be a good desilylation reagent. Quantum mechanical calculations illustrate why derivative 2 was produced in low yield. The usefulness of compounds 1, 3 and 4 as prodrugs of etidronate was determined in aqueous buffer and human serum.
Turhanen
Petri A
PA
University of Kuopio, Department of Chemistry, Finland. Petri.Turhanen@uku.fi
Niemi
Riku
R
Peräkylä
Mikael
M
Järvinen
Tomi
T
Vepsäläinen
Jouko J
JJ
D000478:Alkylation; D000577:Amides / Q000737:chemistry; D002625:Chemistry, Organic / Q000379:methods*; D002712:Chlorides / Q000737:chemistry*; D012968:Etidronic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D017553:Phosphorus Compounds / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*
D000577:Amides; D002712:Chlorides; D017553:Phosphorus Compounds; D010880:Piperidines; C032727:piperidine; D012968:Etidronic Acid; C043693:phosphorus chloride