Synthesis of [(thiazol-2-ylamino)-methylene]bisphosphonic acids

Abstract

Among bisphosphonate derivatives containing heterocycles biologically active compounds are found [1][2][3]. We have synthesized a series of 3-substituted (thiazol-2-ylaminomethylene)bisphosphonates [4,5] with phytotoxic activity by the condensation of (thioureidomethylene)bisphosphonic acids with halo ketones. Biological activity has also been found for tetraesters of [(thiazol-2-yl)aminomethylene]bisphosphonic acids unsubstituted at the position N-3 synthesized by the condensation of aminothiazoles with triethyl orthoformate [7].In the present work, we attempted to extend our method for the Hantzsch condensation to the synthesis of [(thiazolylamino)methylene]bisphosphonic acids unsubstituted at position N-3. (Thioureidomethylene)bisphosphonic acid 1 required for this reaction was synthesized by the acid-catalyzed decomposition of [(tertbutylthioureido)methylene]bisphosphonic acid 2, which we obtained previously as the disodium salt from (aminomethylene)bisphosphonic acid 3 [8]. Since acid 2 is unstable in the free state, it was used in situ without separation from the reaction mixture. Acid 2 decomposes in hydrochloric acid with loss of the tert-butyl residue to give (thioureidomethylene)bisphosphonic acid 1. This reaction proceeds under milder conditions than the decomposition described for tert-butylthiourea [9], which was carried out by heating in concentrated hydrochloric acid at reflux. However, the decomposition of acid 2 proceeds with formation of (aminomethylene)bisphosphonic acid 3 as a side product. The optimal conditions for the formation of desired acid 1 according to the 31 P NMR spectrum of the reaction mixture are obtained using 10% hydrochloric acid at 90°C. Under these conditions, the decomposition of acid 2 requires 10 min and leads to a mixture consisting of 83% of the desired acid 1 and 17% of the by-product acid 3. An attempt to use concentrated hydrochloric acid led to a mixture of not readily identifiable side products. Acid 1 precipitated from the mixture as fine-crystalline mono-(triethylammonium) salt 4, which is stable and can be stored under ordinary conditions without decomposition.

Synthetic Procedures Leading towards Aminobisphosphonates

“…Classical ones include the formation of Schiff bases, which are then alkylated [150] or reduced [126], and synthesis of thioureido derivatives as intermediates in the preparation of heterocyclic compounds [151][152][153].…”