Issue 18, 2003

First synthesis of etidronate partial amides starting from PCl3

Abstract

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.

Graphical abstract: First synthesis of etidronate partial amides starting from PCl3

Article information

Article type
Paper
Submitted
28 May 2003
Accepted
05 Aug 2003
First published
15 Aug 2003

Org. Biomol. Chem., 2003,1, 3223-3226

First synthesis of etidronate partial amides starting from PCl3

P. A. Turhanen, R. Niemi, M. Peräkylä, T. Järvinen and J. J. Vepsäläinen, Org. Biomol. Chem., 2003, 1, 3223 DOI: 10.1039/B305979K

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