2-[di(propan-2-yloxy)phosphorylmethyl-propan-2-yloxyphosphoryl]oxypropane

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (700 mg, 0.29 mmol) was added in small portions under a stream of dry nitrogen to a vigorously stirred solution of tetraisopropyl methane-1,1-bisphosphonate (1) (5.0 gm, 14.5 mmol) in dry toluene (25 ml). After the effervescence had stopped, stirring was continued for 15 minutes. Ethylbromoacetate (3.2 gm, 19.2 mmol) was then added dropwise over a period (2 min) whereupon the flask became warm and a white precipitate began to form. Stirring was continued for a further 2 hours at room temperature. Water (20 ml) was added then carefully and the mixture vigorously stirred. The toluene layer was separated and extracted with water (20 ml). The aqueous extracts were combined, washed with ether (50 ml), acidified to pH 1 and re-extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and solvent evaporated under reduced pressure to leave the acid (3) as a pale yellow liquid (800 mg). The toluene layer was also dried (MgSO4), filtered, and solvent evaporated to leave an oil which was found to be the ethyl ester (2) and unreacted starting material. This oil was dissolved in a methanol:water mixture (20 ml, 3:1) containing lithium hydroxide (1 g, 24 mmol) and the solution stirred at room temperature for 16 h. The methanol was removed by evaporation and water (20 ml) was then added. This aqueous solution was washed with ether (2×20 ml), acidified to pH 1 with dilute HCl and then extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and volatile components removed under reduced pressure to leave the acid (3) (2.77 g) as a pale yellow liquid. The combined product (3) (3.57 g, 61%) was sufficiently pure to be used in subsequent reactions without further purification. became warm to form Stirring was continued for a further 2 hours at room temperature carefully and the mixture vigorously stirred The toluene layer was separated extracted with water (20 ml) washed with ether (50 ml) re-extracted with dichloromethane (2×25 ml) dried (MgSO4) filtered solvent evaporated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the procedure described in Example I, tetraisopropylmethanediphosphonate MDP was converted to the desired ester in 70% yield by reaction with dibromo-o-xylene at 80° C. for 3 h: mp 55°-57° C.; 1H NMR (CDCl3) 7.15 (s, 4H, aromatic), 5.00-4.55 (m, 4H, CH), 3.60 (t, 4H, J=17.6 Hz, CH2), 1.26 (t, 24H, J=6 Hz, CH3); 31P NMR (CDCl3) 24.7 ppm; Cl mass spectrum m/e 447 (MH+). Anal. calcd for C21H36O6P2 : C, 56.49; H, 8.13; P, 13.88. Found: C, 56.71; H, 8.24; P, 14.18.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the same procedure as in Example I, tetraisopropyl methane diphosphonic acid was converted to tetraisopropyl cycloheptane-1,1-diphosphonate by reaction with 1,6-dibromohexane at 80° C. for 18 h. 31P NMR (toluene) indicated that the reaction solution contained a mixture of the desired tetraisopropyl cycloheptane-1,1-diphosphonate (25.3 ppm) and octaisopropyl octane1,1,8,8-tetraphosphonate (22.1 ppm). The compounds were separated by chromatography (1:1 hexane:THF eluent) on silica gel, and the desired ester was hydrolyzed using 6N refluxing hydrochloric acid as in Example I. The compounds were separated by chromatography (1:1 hexane:THF eluent) on silica gel refluxing hydrochloric acid as in Example I

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the same procedure as in Example I, tetraisopropyl methane diphosphonic acid was converted to tetraisopropyl cycloheptane-1,1-diphosphonate by reaction with 1,6-dibromohexane at 80° C. for 18 h. 31P NMR (toluene) indicated that the reaction solution contained a mixture of the desired tetraisopropyl cycloheptane-1,1-diphosphonate (25.3 ppm) and octaisopropyl octane1,1,8,8-tetraphosphonate (22.1 ppm). The compounds were separated by chromatography (1:1 hexane:THF eluent) on silica gel, and the desired ester was hydrolyzed using 6N refluxing hydrochloric acid as in Example I. The compounds were separated by chromatography (1:1 hexane:THF eluent) on silica gel refluxing hydrochloric acid as in Example I