Novel Procedure for the Synthesis of 1‐Hydroxy‐1,1‐bisphosphonic Acids using Phenols as Medium

A facile synthetic route for the synthesis of bisphosphonates in phenols is described. Preparations of some of bisphosphonates, which are presently in clinical use such as risedronic acid and alendronate sodium, are synthesized following this new, simple method. This procedure can be useful for the synthesis of this class of bone‐resorptive inhibitors in bulk quantities.     

Synthesis and structural characterization of geminal and non-geminal 1,1,3,3-tetramethylguanidine substituted derivatives of cyclotriphosphazene: Thermal and spectroscopic investigations of the products

Abstract

The reactions of hexachlorocyclotriphosphazene, N₃P₃Cl₆ (1) with 1,1,3,3-tetramethyl-guanidine (2) in (1:1:2, 1:2:4 and 1:3:6) stoichiometries in THF and dichloromethane solutions under reflux yield a total of 4 novel products: three non-geminal derivatives, N₃P₃Cl₄[NCN₂(CH₃)₄]₂ (3), N₃P₃Cl₃[NCN₂(CH₃)₄]₃ (4) and N₃P₃Cl₂[NCN₂(CH₃)₄]₄ (5); and one hexa-substituted product, N₃P₃[NCN₂(CH₃)₄]₆ (6). The structures of 3-6 have been determined mainly by elemental analysis, MS, ³¹P and ¹H NMR spectral data. Furthermore, thermal characteristics of the synthesized compounds 4 and 6 were evaluated using Differential Scanning Calorimetric (DSC) measurements. NMR spectroscopic data, product types and relative yields are compared with those of the previously investigated derivatives of N₃P₃Cl₆ (1) with mono and difunctional reagents.     

The reactions of non-gem-hexanedioxytetrachlorocyclotriphosphazene with 2-(2-hydroxyethyl)thiophene,benzyl alcohol and 1,1,3,3-tetramethylguanidine. Spectroscopic studies of the derived products

Abstract

Reactions of non-gem-hexanedioxytetrachlorocyclotriphosphazene (1) with monofunctional nucleophilic reagents, 2-(2-hydroxyethyl)thiophene (2), benzyl alcohol (3) and 1,1,3,3-tetramethylguanidine (4) were investigated. The reactions, using an excess of NaH, in THF solutions, under refluxing conditions and with 1:2?mole ratios allow the synthesis of the following novel cyclotriphosphazene derivatives: 2,4-dichloro-2,4-(hexane-1,6-dioxy)-6,6-[2-(2-ethoxy)hiophene]-cyclotriphosphazatriene, N₃P₃Cl₂[O(CH₂)₆O-(C₆H₈OS)₂] (5); 2,4-(hexane-1,6-dioxy)-2,4,6,6-[2-(2-ethoxy) thiophene]-cyclotriphosphazatriene, N₃P₃[O(CH₂)₆O-(C₆H₈OS)₄] (6); 2,4-dichloro-2,4-(hexane-1,6-dioxy)-6,6-(methoxybenzene)-cyclotriphosphazatriene, N₃P₃Cl₂[O(CH₂)₆O-(C₆H₅CH₂O)₂] (7); 2,4-(hexane-1,6-dioxy)-2,4,6,6-(methoxybenzene)-cyclotriphosphazatriene, N₃P₃[O(CH₂)₆O-(C₆H₅CH₂O)₄] (8); and 2,4-dichloro-2,4-(hexane-1,6-dioxy)-6,6-(1,1,3,3-tetramethyguanidine)-cyclotriphosphazatriene, N₃P₃Cl₂[O(CH₂)₆O-HN-CN₂(CH₃)₄] (9). The structures of the synthesized compounds (5–9) have been characterized by elemental analysis, TLC-MS, ¹H, ¹³C and ³¹P {+¹H} and {?¹H} NMR spectral data.     

One-pot two-step synthesis of fused thiazinofuranone linked geminal bis 1,2,3-triazole hybrids and their in vitro cytotoxic screening

In this study, a series of novel geminal bis 1,2,3-triazoles linked to 2H-furo[2,3-d][1,3]thiazine-2,4,5(1H,6H)-trione ( 3a-3m ) were prepared in one pot starting from 5-Acetyl-4-Hydroxy-1,3-thiazine-2,6-dione ( 1 ) to 6,6-diazido-2H-furo[2,3-d][1,3]thiazine-2,4,5(1H,6H)-trione ( 2 ) followed by Cu(I)-catalyzed azide-alkyne cycloaddition. The synthesized compounds were further explored for in vitro cytotoxic activity against PC3, A549, MCF-7, and HeLa cell lines and results revealed that the five compounds 3c , 3d , 3g , 3l , and 3m have displayed comparable in vitro cytotoxic activity with the standard drug Etoposide.     

Drug-Inclusive Inorganic–Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr²⁺ and Ba²⁺) in an effort to synthesize new materials. These metal–ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr²⁺ or Ba² and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs.     

Stereoselective synthesis of substituted trifluoromethylated ethenylphosphonates via sequential transformations of bisphosphonate

Substituted trifluoromethylated ethenylphosphonates have been synthesized via sequential transformations of bisphosphonates in 66-92% (three steps) yields with E-isomers exclusively or predominantly.     

Mono and Bisphosphonates from Perfluoro Olefins and Polyfunctional Fluoro Ketones. Syntheses,Molecular Structure and Derivatives

Perfluoroalkenyl phosphonates were formed along with Me₃SiF using CF₃CF=CF₂, CF₃CH=CF₂, F₅SCF=CF₂ or F₅SCH=CF₂ and silylated phosphites, (R¹O)₂POSiMe₃ (R¹=Et, SiMe₃). This straightforward method could be extended to perfluorobutadienes CF₂=C(R^F)C(R^F)=CF₂ (R^F F=F, CF₃). The formation of CF₃C(=O)P(=O)(OSiMe₃)₂ and further reactions to yield bisphosphonates will be described. Acetylphosphonates, R²C(=O)P(=O)(OSiMe₃)₂ (R²=CH₃, CF₃) reacted with the ketimine, CH₃C(=NiPr)Ph to give α-hydroxy-γ-imino phosphonates. Trifluoroacetylphenol and 2,6-bis(trifluoracetyl)-4-methyl-phenol have been proven to be versatile precursors for α-and γ-hydroxy phosphonates. Intermediates in these reactions were found to be cyclic λ⁵σ⁵P species.     

Selective C−C Coupling of Vinyl Epoxides with Diborylmethide Lithium Salts

Vinyl epoxides and styrene oxide can react with diborylmethide lithium salts through an exclusive S_N2 borylmethylation/ring opening in a regio- and diastereoselective way, depending on the nature of the substrate. The ring-opening protocol provides homoallylboronates that can be transformed into challenging diastereomeric bishomoallylic alicyclic 1,3-diols. Unprecedented 3-borylated 1,2-oxaborolan-2-ol products were prepared by borylmethylation/ring opening of 2-methyl-2-vinyloxirane followed by intramolecular cyclization.     

Reactions of α-elimination of silanones as a path for formation and destruction of siloxane structures

Based on modern stereoelectronic concepts, our results, and published data, we explained the paths of formation and destruction of linear and cyclic oligo- and polysiloxanesvia intramolecular geminal decomposition of Si(OR)X groups, which results in the intermediate formation of short-lived silanones R₂Si=0. The latter are subsequently oligomerized, polymerized, or inserted into the Si−X bonds (X=0, Cl,etc.) of the trapping agents. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 824–835, May, 1998.     

孪函数N电子基组的组态

分析了各类孪函数Ｎ电子基组态展开式的特点以及它们对体系相关能的贡献，提出了一种在享函数Ｎ电子基矢下进行多组态自洽场计算时的组态选取方法，并依此方法在ＳＴＯ－６－３１Ｇ基组下对ＬｉＨ分子的基态能量做了计算，结果表明，用该组态选取方法只需选取少量的组态波函数便可得到相当精确的计算结果。