8-iodo-1,4-dioxaspiro[4.5]decane

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight. the internal temperature below 65° C The resulting mixture was stirred for 1 hour a degassed to rinse the remaining zinc dust the solution was added to the above mixture The resulting mixture was heated to 80° C. under nitrogen stirred overnight

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

Procedure: A mixture of imidazole (111 g, 1.63 mol, 1.2 eq.), PPh3 (428 g, 1.63 mol, 1.2 eq.) and 1,4-dioxaspiro[4.5]decan-8-ol (215 g, 1.36 mol, 1.0 eq.) in THF (1.5 L) was cooled using an ice bath under N2. To this reaction mixture was added slowly a solution of I2 (414 g, 1.63 mol, 1.2 eq.) in THF (1 L) keeping the internal temperature <12° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L). The aqueous layer was extracted with EtOAc (1 L×2). The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L), dried over Na2SO4, filtered, and evaporated. The crude product was dissolved in diethyl ether (6 L), filtered, and the solid was washed with diethyl ether (300 mL×3). The filtrate was concentrated and purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes) to give 340 g (93.4% yield) of 8-iodo-1,4-dioxaspiro[4.5]decane. GC-MS: 269 (M+1). was cooled the internal temperature <12° C After the addition The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L) The aqueous layer was extracted with EtOAc (1 L×2) The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L) dried over Na2SO4 filtered evaporated The crude product was dissolved in diethyl ether (6 L) filtered the solid was washed with diethyl ether (300 mL×3) The filtrate was concentrated purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes)

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

Procedure: A mixture of imidazole (111 g, 1.63 mol, 1.2 eq.), PPh3 (428 g, 1.63 mol, 1.2 eq.) and 1,4-dioxaspiro[4.5]decan-8-ol (215 g, 1.36 mol, 1.0 eq.) in THF (1.5 L) was cooled using an ice bath under N2. To this reaction mixture was added slowly a solution of I2 (414 g, 1.63 mol, 1.2 eq.) in THF (1 L) keeping the internal temperature <12° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L). The aqueous layer was extracted with EtOAc (1 L×2). The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L), dried over Na2SO4, filtered, and evaporated. The crude product was dissolved in diethyl ether (6 L), filtered, and the solid was washed with diethyl ether (300 mL×3). The filtrate was concentrated and purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes) to give 340 g (93.4% yield) of 8-iodo-1,4-dioxaspiro[4.5]decane. GC-MS: 269 (M+1). was cooled the internal temperature <12° C After the addition The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L) The aqueous layer was extracted with EtOAc (1 L×2) The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L) dried over Na2SO4 filtered evaporated The crude product was dissolved in diethyl ether (6 L) filtered the solid was washed with diethyl ether (300 mL×3) The filtrate was concentrated purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight. the internal temperature below 65° C The resulting mixture was stirred for 1 hour a degassed to rinse the remaining zinc dust the solution was added to the above mixture The resulting mixture was heated to 80° C. under nitrogen stirred overnight

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

Procedure: To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight. the internal temperature below 65° C The resulting mixture was stirred for 1 hour a degassed to rinse the remaining zinc dust the solution was added to the above mixture The resulting mixture was heated to 80° C. under nitrogen stirred overnight

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

Procedure: A mixture of imidazole (111 g, 1.63 mol, 1.2 eq.), PPh3 (428 g, 1.63 mol, 1.2 eq.) and 1,4-dioxaspiro[4.5]decan-8-ol (215 g, 1.36 mol, 1.0 eq.) in THF (1.5 L) was cooled using an ice bath under N2. To this reaction mixture was added slowly a solution of I2 (414 g, 1.63 mol, 1.2 eq.) in THF (1 L) keeping the internal temperature <12° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L). The aqueous layer was extracted with EtOAc (1 L×2). The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L), dried over Na2SO4, filtered, and evaporated. The crude product was dissolved in diethyl ether (6 L), filtered, and the solid was washed with diethyl ether (300 mL×3). The filtrate was concentrated and purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes) to give 340 g (93.4% yield) of 8-iodo-1,4-dioxaspiro[4.5]decane. GC-MS: 269 (M+1). was cooled the internal temperature <12° C After the addition The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L) The aqueous layer was extracted with EtOAc (1 L×2) The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L) dried over Na2SO4 filtered evaporated The crude product was dissolved in diethyl ether (6 L) filtered the solid was washed with diethyl ether (300 mL×3) The filtrate was concentrated purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes)

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

Procedure: To a mixture of zinc powder (5.52 g, 84.5 mmol) and Celite (1.1 g) in N,N-dimethylacetamide (14 ml) was added dropwise chlorotrimethylsilane (0.930 ml, 7.33 mmol) in 1,2-dibromoethane (0.665 ml, 7.54 mmol) at 0° C. under nitrogen atmosphere. The mixture was warmed to room temperature, and stirred for 20 minutes. 8-Iodo-1,4-dioxa-spiro[4.5]decane (18.1 g, 67.6 mmol) in N,N-dimethylacetamide (34 ml) was then added dropwise at 0° C. The mixture was stirred for 30 minutes at room temperature, and the supernatant solution was added dropwise to the mixture of (4-bromobenzyloxy) (tert-butyl)dimethylsilane (15.7 g, 52.0 mmol), copper iodide(I) (792 mg, 4.16 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II)dichloromethane complex (1.70 g, 2.08 mmol) in N,N-dimethylacetamide (74 ml) at room temperature under nitrogen atmosphere. The mixture was stirred at 80° C. for 5 hours. The mixture was poured into the cold water, and extracted with ethyl acetate. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=92/8) to afford tert-butyl-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)benzyloxy]dimethylsilane as a pale yellow oil (14.0 g, 38.6 mmol, 74%). The mixture was stirred for 30 minutes at room temperature The mixture was stirred at 80° C. for 5 hours extracted with ethyl acetate The organic layer was washed with water (three times) dried over sodium sulfate concentrated in vacuo The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=92/8)

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

Procedure: To a mixture of 1,4-dioxa-spiro[4.5]decan-8-ol (18.0 g, 114 mmol), imidazole (10.1 g, 148 mmol) and triphenylphosphine (34.3 g, 131 mmol) in tetrahydrofuran (57 ml) was added iodine (33.2 g, 131 mmol) in tetrahydrofuran (57 ml) at 0° C. The mixture was warmed to room temperature, and stirred for 6 hours. The mixture was poured into 10 wt % aqueous sodium hydrogen sulfite, and the organic compound was extracted with hexane (three times). The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved into hexane again, and filtrated to remove triphenylphosphine oxide. The filtrate was concentrated in vacuo to afford 8-iodo-1,4-dioxa-spiro[4.5]decane as a colorless oil (18.1 g, 67.6 mmol, 59%). the organic compound was extracted with hexane (three times) The organic layer was washed with water dried over sodium sulfate concentrated in vacuo The residue was dissolved into hexane again filtrated to remove triphenylphosphine oxide The filtrate was concentrated in vacuo

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

Procedure: To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight. the internal temperature below 65° C The resulting mixture was stirred for 1 hour a degassed to rinse the remaining zinc dust the solution was added to the above mixture The resulting mixture was heated to 80° C. under nitrogen stirred overnight

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

Procedure: A mixture of imidazole (111 g, 1.63 mol, 1.2 eq.), PPh3 (428 g, 1.63 mol, 1.2 eq.) and 1,4-dioxaspiro[4.5]decan-8-ol (215 g, 1.36 mol, 1.0 eq.) in THF (1.5 L) was cooled using an ice bath under N2. To this reaction mixture was added slowly a solution of I2 (414 g, 1.63 mol, 1.2 eq.) in THF (1 L) keeping the internal temperature <12° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L). The aqueous layer was extracted with EtOAc (1 L×2). The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L), dried over Na2SO4, filtered, and evaporated. The crude product was dissolved in diethyl ether (6 L), filtered, and the solid was washed with diethyl ether (300 mL×3). The filtrate was concentrated and purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes) to give 340 g (93.4% yield) of 8-iodo-1,4-dioxaspiro[4.5]decane. GC-MS: 269 (M+1). was cooled the internal temperature <12° C After the addition The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L) The aqueous layer was extracted with EtOAc (1 L×2) The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L) dried over Na2SO4 filtered evaporated The crude product was dissolved in diethyl ether (6 L) filtered the solid was washed with diethyl ether (300 mL×3) The filtrate was concentrated purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes)