Strategies for the Preparation of (1-Acetyloxyethylidene)-1,1-bisphosphonic Acid Derivatives

Abstract

The novel strategies for the synthesis of acetylated etidronic acid derivatives were investigated. (1-Acetyloxyethylidene)-1,1-bisphosphonic acid and its P,P¢-dimethyl, trimethyl and tetramethyl esters were prepared in high 81-100% yields.Chemically and enzymatically stable bisphosphonates (BPs), characterized by a P-C-P bridge, are analogs of naturally occurring pyrophosphate and used as drugs in treatment of various bone diseases, like osteoporosis ( Figure 1). 1 They are tetra acidic compounds, unfortunately very hydrophilic and their bioavailabilities are very poor. 2 It is of great interest to prepare more lipophilic biodegradable derivatives of BPs. A rather straightforward method to improve lipophilicity is to mask one or more acidic P(O)-OH groups with ester functionality by using the prodrug approach. 3 Most of the clinically used BPs are so called hydroxybisphosphonates where the bridging carbon contains the OH group, which can be also derivatized with, e.g., ester function to improve lipophilicity. (1-Hydroxyethylidene)-1,1-bisphosphonic acid (HEBPA) disodium salt (etidronate) is an example of this kind of compound ( Figure 1).Our group has designed, synthesized and studied in vitro several different etidronic acid ester and amide derivatives to act as biodegradable prodrugs of etidronate. 4 We have previously reported that simple HEBPA tetra-and partial methyl esters do not act as prodrugs of etidronate, but acetylated pivaloyloxymethyl derivatives of HEBPA released etidronate in vitro. 4b There are two main limitations in the synthesis of etidronate derivatives: rearrangement and poor solubility. The rearrangement of the P-C(OH)-P structure to a P-C-O-P structure occurs in the reaction mixture at temperatures over 60°C and in basic conditions, even in phosphate buffer at pH 7.4 (physiological pH) (Scheme 1). 4b,d Due to the high hydrophilicity of the BP tetraacids, their reactivity and solubility in organic solvents is very low.Here we report that acetylated compounds are solutions to both of these problems. These compounds are used as model molecules and starting materials for our ongoing study to prepare new bioreversible derivatives of BPs. Tri-and dimethyl esters of HEBPA were chosen because of easy remove of methyl groups after molecule modification using alkalimetal salts or silylation method. 4b,d Scheme 1 Rearrangement of HEBPA tetraesters to tetraalkyl phosphono phosphateThe preparation of 1-4 was straightforward and the products were easily separated and purified. Synthesis of compounds 1-4 with observed yields is presented in Scheme 2. We have previously reported the preparation of 1 from 6 by stirring in excess acetyl chloride at 55 °C, but only with 46% yield after isolation. 4b We examined milder reaction conditions to obtain better yields. The tetramethyl ester 6 does not react in excess Ac 2 O or Ac 2 O/ HOAc (1:1) at 60 °C. If one equivalent of sodium acetate or an even milder base such as trichloroacetic acid sodium salt (0.1 equivalents) was used as the catalyst in Ac 2 O, the...

Unexpected degradation of the bisphosphonate P-C-P bridge under mild conditions

“…In our ongoing study to prepare novel biodegradable BP derivatives, a new carbonate derivative of etidronate was synthesised. The synthesis was started from the known acetylated etidronic acid [ 21 ] ( 5 , see Scheme 1 ) by treating it with ethyl chloroformate and sodium carbonate. The NMR spectroscopy results were surprising since they pointed to the formation of a novel etidronate derivative 1a (see Scheme 1 ).…”

“…Tetramethyl ( 1c ) or P,P'-dimethyl ester were not degraded under the same conditions, only the formation of phosphonate-phosphate derivative 8 from 1c was observed as expected in the light of the earlier results concern the rearrangement process. [ 17 , 20 , 21 , 29 - 32 ] This rearrangement of 1c to 8 was observed to happen rapidly and almost completely (98% conversion) when 1 equiv of triethyl amine was present in water (see Scheme 2 ).…”

Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives

“…Since the amine group of alendronic acid is protected due to zwitterion, we attempted to acetylate the middle carbon OH-group directly by using alendronic acid and its monosodium salt under dry conditions, as we did for etidronic acid, [ 27 ] but unfortunately this did not prove feasible. However, acetylation was successful with this method when starting with the disodium salt of HABBPA.…”

“…for 2a from 18.98 ppm to 14.65 ppm ( 1a )] as expected from the earlier results of the OH-group acylation from etidronic acid derivatives. [ 18 , 20 , 27 ]…”

Synthesis of inhibitors targeting the downstream enzymes in the isoprenoid biosynthetic pathways

“…This phenomenon was reported first by Fitch and Moedritzer 63 in 1962 and studied and supported more recently by numerous groups. [64][65][66][67] The structure of compound 52 was further confirmed by 2D NMR which is shown in Figure 16. Therefore, based on what has been observed and what has been reported in the past, α-hydroxy bisphosphonate 48…”