1-bromo-2-diethoxyphosphorylethane

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: Diethyl 2-bromoethylphosphonate (25 g) and 4,4' bipyridine (7.35 g) in 125 mLs of water are refluxed for three days. An equal volume of concentrated hydrochloric acid is added and reflux continued for several hours. The solution is concentrated to 120 mLs by atmospheric distillation and 550 mL of isopropanol are added dropwise with stirring while chilling the mixture in an ice bath. The solid which forms is collected by vacuum filtration and washed with cold isopropanol to yield 1,1'-bisphosphonoethyl-4,4'-bipyridinium dichloride. (1H NMR (D2O) 9.1(d), 8.5(d), 4.2(m), 2.0(m) ppm; 13C NMR(D2O) 151, 147, 128, 58, 30 ppm; 31P NMR(D2O) 17.8 (s) ppm; IR (KBr) 3112, 3014, 1640, 1555, 1506, 1443, 1358, 1281, 1175, 1112, 1020, 936, 816, 485 cm-1.) reflux continued for several hours The solution is concentrated to 120 mLs by atmospheric distillation and 550 mL of isopropanol are added dropwise while chilling the mixture in an ice bath The solid which forms is collected by vacuum filtration washed with cold isopropanol

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of 60% NaH in mineral oil (32 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of 1,2-HS(C6H4)SH (14 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (30 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from the ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford 6 in 94% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 6 as a viscous, yellow-green oil with an overall yield of 91%. High resolution FAB/MS Anal. Calcd. for C18H32O6P2S2 : 470.1115; Found: [M+H+ ], m/z=471.1119. 1H NMR (CDCl3): δ 1.27 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 2.02 (m, 4H, PCH2CH2), 3.06 (m, 4H, PCH2CH2), 4.05 (m, 8H, OCH2CH3), 7.2 (m, 4H, C6H4). 13C NMR (CDCl3): δ 16.3 (d, 3JPC =6.0 Hz, OCH2CH3), 25.8 (d, 1JPC =136 Hz, PCH2CH2), 26.2 (s, PCH2CH2), 61.7 (d, 2JPC =6.0 Hz, OCH2CH3). 31P NMR (CDCl3): δ29.4 (s). after which the hexane-mineral oil layer was completely removed The flask was then charged with dry tetrahydrofuran (100 mL) with constant stirring over a period of 30 minutes Excess NaH was quenched by addition of 50 mL of deionized water The solution was extracted from the ethyl acetate (3×50 mL) washed with a saturated sodium chloride solution The organic layer was dried over anhydrous sodium sulfate Upon filtering the solvent was removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of 60% NaH in mineral oil (95 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of HS(CH2)3SH (46 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (95 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford compound 5 in 90% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 5 as a viscous, yellow-green oil with an overall yield of 88%. High resolution FAB/MS Anal. Calcd. for C15H34O6P2S2 : 436.1272; Found: [M+H+ ], m/z=437.1350. 1H NMR (CDCl3): δ 1.34 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 1.87 (qn, 2H, CH2CH2CH2), 2.03 (m, 4H, PCH2CH2), 2.65 (t, 3JHH =9.0 Hz, 4H, CHCH2CH2), 2.74 (m, 4H, PCH2CH2), 4.11 (m, 8H, OCH2CH3). 13C NMR (CHCl3): δ 16.3 (d, 3JPC =4.5 Hz, OCH2CH3), 24.8 (d, 2JPC =3.0 Hz, PCH2CH2), 26.6 (d, 1JPC =136.6 Hz, PCH2CH2), 28.5 (s, CH2CH2CH2), 30.5 (s, CH2CH2CH2), 61.6 (d, 2JPC= 6.0 Hz OCH2CH3). 31P NMR (CDCl3): δ 29.1 (s). after which the hexane-mineral oil layer was completely removed The flask was then charged with dry tetrahydrofuran (100 mL) with constant stirring over a period of 30 minutes Excess NaH was quenched by addition of 50 mL of deionized water The solution was extracted from ethyl acetate (3×50 mL) washed with a saturated sodium chloride solution The organic layer was dried over anhydrous sodium sulfate Upon filtering the solvent was removed in vacuo

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (30 mg, 0.06 mmol, Zimmermann et al., Bioorg. Med. Chem. Lett. 1996, 6, 1221), diethyl 2-bromoethylphosphonate (30 μL, 0.12 mmol) and K2CO3 (20 mg, 0.16 mmol) in 2.5 mL of DMF was heated at 110° C. for 8 hours when most of the starting materials were consumed as judged by LCMS analysis. The solid material was filtered off. The filtrate was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica gel chromatography using 10% MeOH/CH2Cl2 to provide 28 mg (55%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.32 (t, 6H), 1.92-20.3 (m, 4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56 (s, 2H), 4.05-4.14 (m, 4H), 7.07(s, 1H), 7.18 (d, 2H, J=5 Hz), 7.30 (dd, 1H, J=6, 8 Hz), 7.33-7.45 (m, 3H), 7.84 (d, 2H, J=8 Hz), 8.01 (s, 1H), 8.51 (dd, 2H, J=4, 9 Hz), 8.58 (d, 1H, J=2 Hz), 8.70 (dd, 1H, J=2, 5 Hz), 9.25 (s, 1H); 31P (121.4 MHz, CDCl3) δ 30.5; MS (m/z) 644 [M+H]+. were consumed The solid material was filtered off The filtrate was diluted with water extracted with EtOAc The organic layer was dried over Na2SO4 concentrated to dryness The crude material was purified by silica gel chromatography

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (30 mg, 0.06 mmol, Zimmermann et al., Bioorg. Med. Chem. Lett. 1996, 6, 1221), diethyl 2-bromoethylphosphonate (30 μL, 0.12 mmol) and K2CO3 (20 mg, 0.16 mmol) in 2.5 mL of DMF was heated at 110° C. for 8 hours when most of the starting materials were consumed as judged by LCMS analysis. The solid material was filtered off. The filtrate was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica gel chromatography using 10% MeOH/CH2Cl2 to provide 28 mg (55%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.32 (t, 6H), 1.92-20.3 (m, 4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56 (s, 2H), 4.05-4.14 (m, 4H), 7.07(s, 1H), 7.18 (d, 2H, J=5 Hz), 7.30 (dd, 1H, J=6, 8 Hz), 7.33-7.45 (m, 3H), 7.84 (d, 2H, J=8 Hz), 8.01 (s, 1H), 8.51 (dd, 2H, J=4, 9 Hz), 8.58 (d, 1H, J=2 Hz), 8.70 (dd, 1H, J=2, 5 Hz), 9.25 (s, 1H); 31P (121.4 MHz, CDCl3) δ 30.5; MS (m/z) 644 [M+H]+. were consumed The solid material was filtered off The filtrate was diluted with water extracted with EtOAc The organic layer was dried over Na2SO4 concentrated to dryness The crude material was purified by silica gel chromatography

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

実験手順: A solution of about 50 g of diethyl-2-bromoethyl-phosphonate in about 255 ml of about 48% hydrobromic acid was kept at reflux (about 95°-100° C.) overnight. The solvent was removed under reduced pressure and the residue evaporated twice with toluene, giving a syrup. This syrup was dissolved in about 65 ml of about 99% ethanol, about 20 g of aniline was added dropwise and the solid was collected, washed with cold about 99% ethanol (at about 0° C.) and dried in vacuo, giving about 30.6 g of the desired reagent, mp 157°-158° C. at reflux (about 95°-100° C.) overnight The solvent was removed under reduced pressure the residue evaporated twice with toluene giving a syrup the solid was collected washed with cold about 99% ethanol (at about 0° C.) dried in vacuo

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

実験手順: Diethyl 2-bromoethylphosphonate (25 g) and 4,4' bipyridine (7.35 g) in 125 mls of water are refluxed for three days. An equal volume of concentrated hydrochloric acid is added and reflux continued for several hours. The solution is concentrated to 120 mls by atmospheric distillation and 550 mL of isopropanol are added dropwise with stirring while chilling the mixture in an ice bath. The solid which forms is collected by vacuum filtration and washed with cold isopropanol to yield 1,1'-bisphosphonoethyl-4,4'-bipyridinium dichloride. (1H NMR (D2) 9.1(d), 8.5(d), 4.2(m), 2.0(m) ppm; 13C NMR(D2O) 151, 147, 128, 58, 30 ppm; 31P NMR(D2O) 17.8 (s) ppm; IR (KBr) 3112, 3014, 1640, 1555, 1506, 1443, 1358, 1281, 1175, 1112, 1020, 936, 816, 485 cm-1) reflux continued for several hours The solution is concentrated to 120 mls by atmospheric distillation and 550 mL of isopropanol are added dropwise while chilling the mixture in an ice bath The solid which forms is collected by vacuum filtration washed with cold isopropanol

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of 60% NaH in mineral oil (188 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir ten minutes, after which the hexane-mineral oil layer was removed by syringe. The flask was charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of HS(CH2)4SH (82 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (164 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford compound 2 in 90% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 2 as a viscous, yellow-green oil with an overall yield of 92% (36 g). Low resolution FAB/MS Anal. Calcd. for C16H36O6P2S2 : 450.1428. Found: [M+H+ ], m/z=451.2. after which the hexane-mineral oil layer was removed by syringe The flask was charged with dry tetrahydrofuran (100 mL) with constant stirring over a period of 30 minutes Excess NaH was quenched by addition of 50 mL of deionized water The solution was extracted from ethyl acetate (3×50 mL) washed with a saturated sodium chloride solution The organic layer was dried over anhydrous sodium sulfate Upon filtering the solvent was removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of 60% NaH in mineral oil (32 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of 1,2-HS(C6H4)SH (14 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (30 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from the ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford 6 in 94% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 6 as a viscous, yellow-green oil with an overall yield of 91%. High resolution FAB/MS Anal. Calcd. for C18H32O6P2S2 : 470.1115; Found: [M+H+], m/z= 471.1119. 1H NMR (CDCl3): δ1.27 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 2.02 (m, 4H, PCH2CH2), 3.06 (m, 4H, PCH2CH2), 4.05 (m, 8H, OCH2CH3), 7.2 (m, 4H, C6H4). 13C NMR (CDCl3): δ16.3 (d, 3JPC =6.0 Hz, OCH2CH3), 25.8 (d, 1JPC =136 Hz, PCH2CH2), 26.2 (s, PCH2CH2),61.7 (d, 2JPC =6.0 Hz, OCH2CH3). 31P NMR (CDCl3): δ29.4 (s). after which the hexane-mineral oil layer was completely removed The flask was then charged with dry tetrahydrofuran (100 mL) with constant stirring over a period of 30 minutes Excess NaH was quenched by addition of 50 mL of deionized water The solution was extracted from the ethyl acetate (3×50 mL) washed with a saturated sodium chloride solution The organic layer was dried over anhydrous sodium sulfate Upon filtering the solvent was removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of 60% NaH in mineral oil (32 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of 1,2-HS(C6H4)SH (14 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (30 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from the ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford 6 in 94% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 6 as a viscous, yellow-green oil with an overall yield of 91%. High resolution FAB/MS Anal. Calcd. for C18H32O6P2S2 : 470.1115; Found: [M+H+], m/z= 471.1119. 1H NMR (CDCl3): δ1.27 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 2.02 (m, 4H, PCH2CH2), 3.06 (m, 4H, PCH2CH2), 4.05 (m, 8H, OCH2CH3), 7.2 (m, 4H, C6H4). 13C NMR (CDCl3): δ16.3 (d, 3JPC =6.0 Hz, OCH2CH3), 25.8 (d, 1JPC =136 Hz, PCH2CH2), 26.2 (s, PCH2CH2),61.7 (d, 2JPC =6.0 Hz, OCH2CH3). 31P NMR (CDCl3): δ29.4 (s). after which the hexane-mineral oil layer was completely removed The flask was then charged with dry tetrahydrofuran (100 mL) with constant stirring over a period of 30 minutes Excess NaH was quenched by addition of 50 mL of deionized water The solution was extracted from the ethyl acetate (3×50 mL) washed with a saturated sodium chloride solution The organic layer was dried over anhydrous sodium sulfate Upon filtering the solvent was removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of 60% NaH in mineral oil (95 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of HS(CH2)3SH (46 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (95 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford compound 5 in 90% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 5 as a viscous, yellow-green oil with an overall yield of 88%. High resolution FAB/MS Anal. Calcd. for C15H34O6P2S2 : 436.1272; Found: [M+H+ ], m/z=437.1350. 1H NMR (CDCl3): δ1.34 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 1.87 (qn, 2H, CH2CH2CH2), 2.03 (m, 4H, PCH2CH2), 2.65 (t, 3JHH =9.0 Hz, 4H, CH2CH2CH2), 2.74 (m, 4H, PCH2CH2), 4.11 (m, 8H, OCH2CH3). 13C NMR (CHCl3): δ16.3 (d, 3JPC =4.5 Hz, OCH2CH3), 24.8 (d, 2JPC =3.0 Hz, PCH2CH2), 26.6 (d, 1JPC =136.6 Hz, PCH2CH2), 28.5 (s, CH2CH2CH2), 30.5 (s, CH2CH2CH2), 61.6(d, 2JPC =6.0 Hz, OCH2CH3). 31P MNR (CDCl3): δ29.1 (s). after which the hexane-mineral oil layer was completely removed The flask was then charged with dry tetrahydrofuran (100 mL) with constant stirring over a period of 30 minutes Excess NaH was quenched by addition of 50 mL of deionized water The solution was extracted from ethyl acetate (3×50 mL) washed with a saturated sodium chloride solution The organic layer was dried over anhydrous sodium sulfate Upon filtering the solvent was removed in vacuo