chloro-[chloro-di(propan-2-yl)silyl]oxy-di(propan-2-yl)silane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′,3′,4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′, 3′, 4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′, 3′, 4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′,3′,4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1R,2S,3R,5R)-3-(6-chloro-purin-9-yl)-5-hydroxymethylcyclopentane-1,2-diol (Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-308) (0.44 g, 1.55 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.461 mL, 3.1 mmol) in AcCN (15 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.581 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 14 h then concentrated. The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.545 g, 67%) then concentrated The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1R,2S,3R,5R)-3-(6-chloro-purin-9-yl)-5-hydroxymethylcyclopentane-1,2-diol (Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-308) (0.44 g, 1.55 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.461 mL, 3.1 mmol) in AcCN (15 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.581 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 14 h then concentrated. The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.545 g, 67%) then concentrated The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of triol 10 (5.8 g, 44.6 mmol) and imidazole (21.2 g, 312.3 mmol) in DMF (300 mL), 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (14.7 mL, 46.8 mmol) was added drop wise at 0° C. under nitrogen. The mixture was stirred at room temperature for 2.5 h, quenched with water (200 mL) and extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (2×100 ml), followed by with water and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc: Hexane 1:30 to 1:5) to give 11 (13.7 g, 82%) as an oil. [α]24D +45.87° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.93-1.04 (m, 28H), 2.90 (m, 1H), 3.16 (d, J=2.0 Hz, 1H), 3.51 (m, 1H), 4.01 (dd, J=3.0, 11.0 Hz, 1H), 4.21 (t, 5.6 Hz, 1H), 4.47-4.45 (m, 1H), 5.60 (dd, J=1.5, 6.0 Hz, 1H), 5.86 (dd, J=3.0, 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6, 12.7, 12.9, 13.2, 13.3, 13.4, 17.0, 17.1, 17.2, 17.3, 17.4, 17.6, 54.6, 66.7, 74.7, 76.3, 132.5, 134.4; HR-MS Calcd. For (C18H36O4Si2+Na)+ 395.2152. found 395.2052. was added drop wise at 0° C. under nitrogen quenched with water (200 mL) extracted with ethyl acetate (3×200 ml) The combined organic layer was washed with brine (2×100 ml) dried over Na2SO4 The solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (EtOAc: Hexane 1:30 to 1:5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, l′-H and H-5), 4.14-4.18 (m, 3H, 2′, 3′, 4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, l′-H and H-5), 4.14-4.18 (m, 3H, 2′, 3′, 4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′,3′,4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2). the reaction was quenched by adding methanol (20 mL) concentrated under reduced pressure The residue was partitioned between ethyl acetate (1.5 L) and water (2 L) The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL) dried over solid sodium sulfate (50 g) filtered concentrated under reduced pressure to the crude product, ca 250 g The residue was subjected to a filtration column concentrated under reduced pressure dried (40° C., 0.2 mm Hg, 24 h)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As shown above, Gemcitabine (4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one) can be treated with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSiCl2) in dry pyridine to provide 4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one. It is contemplated that other 1,3-dihalo-1,1,3,3-tetraalkyldisiloxanes can be used in place of TIPDSiCl2. It is also contemplated that two monofunctional halosiloxane protecting groups can be used in place of the difunctional TIPDSiCl2. Further, it is also contemplated that other hydroxyl protecting groups (e.g., tetrahydropyranyl (THP) or acetyl (Ac)) can be used in place of TIPDSiCl2.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As shown above, Gemcitabine (4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one) can be treated with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSiCl2) in dry pyridine to provide 4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one. It is contemplated that other 1,3-dihalo-1,1,3,3-tetraalkyldisiloxanes can be used in place of TIPDSiCl2. It is also contemplated that two monofunctional halosiloxane protecting groups can be used in place of the difunctional TIPDSiCl2. Further, it is also contemplated that other hydroxyl protecting groups (e.g., tetrahydropyranyl (THP) or acetyl (Ac)) can be used in place of TIPDSiCl2.