Interaction of acylating agents and phosphorus(III) sources. I. Intermediacy of condensed species in the formation of (1-hydrocyethylidene) diphosphonic acid

Prentice, J. B.; Quimby, Oscar T.; Grabenstetter, Robert J.; Nicholson, D. Allan

doi:10.1021/ja00772a032

Cited by 25 publications

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“…A route for the preparation of new triester compound 2 was also examined. There was no selectivity in the preparation of 2 from 1 as there was for the synthesis of 7 from 6, which we have reported previously, indicating that a free hydroxyl group is needed for the selective mono- Acetylated etidronic acid 4 has been reported to be one of the products described by Prentice et al 5 in their experiments, but its synthesis and separation required several steps and two recrystallizations for purification. Our strategy to obtain 4 was more straightforward.…”

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confidence: 60%

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

Turhanen¹,

Vepsäläinen²

2004

Synthesis

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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...

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confidence: 60%

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

Turhanen¹,

Vepsäläinen²

2004

Synthesis

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“…The major contribution was a paper of J. B. Prentice and collaborators [26], which reported the isolation of about five intermediates when acetic anhydride reacts with phosphorous acid to form condensed species. The overall hypothetical reaction is as follows (Scheme 3).…”

Section: Methodsmentioning

confidence: 99%

Synthesis of 1-hydroxy-1,1-bisphosphonates

Lecouvey

Leroux

2000

Heteroatom Chem.

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“…Scheme 4 shows a possible mechanism for the formation of dronic acids in the reaction of a heteroarylacetic acid 53 with phosphorus trichloride. In a related study, Nicholson et al prepared "condensates" that were claimed to be possible intermediates during the formation of ethane-1-hydroxy-1,1-diphosphonic acid in the reaction of acetylating agents and P(III) sources, such as H 3 PO 3 and PCl 3 [71]. In reaction with a second molecule of phosphorus trichloride, the acyl chloride is converted to an acyl phosphonium salt (55) whose carbonyl group may be attacked by a third molecule of phosphorus trichloride.…”

Section: Synthesis Of N-heterocyclic Dronic Acids; Mechanistic Aspectsmentioning

confidence: 99%

N-Heterocyclic Dronic Acids: Applications and Synthesis

Hudson

Wardle

Bligh

et al. 2012

MRMC

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Substituted hydroxymethylenebisphosphonic acid derivatives--either as dronic acids or their dronate sodium salts, are important pharmaceuticals in the treatment of diseases arising from excessive bone-resorption. Potential has also been identified in areas ranging from parasite-growth inhibition to immunological and cancer therapeutics. Representative clinically relevant N-heterocyclic derivatives include zoledronic and risedronic acids. The biochemical background and mechanism of action of these drugs are discussed, along with trends in structural development and future prospects. Synthetic routes to dronates are then summarized. The most popular route to valuable dronic acids involves the 3- component condensation of a substituted acetic acid, phosphorous acid, and phosphorus trichloride. However, the protocols recorded in the literature are very diverse. This review gives a critical account of reported methods, explores the contradictions and suggests a practical synthetic procedure after clarifying the inconsistencies described. Possible mechanisms of the reaction are also discussed.

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Interaction of acylating agents and phosphorus(III) sources. I. Intermediacy of condensed species in the formation of (1-hydrocyethylidene) diphosphonic acid

Cited by 25 publications

References 0 publications

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

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

Synthesis of 1-hydroxy-1,1-bisphosphonates

N-Heterocyclic Dronic Acids: Applications and Synthesis

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