2-but-3-ynoxyoxane

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

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

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

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

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

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

Procedure: The title compound was prepared from 2-but-3-ynyloxy-tetrahydro-pyran and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (2.5 M) (0.624 mL, 1.559 mmol) was added to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (0.244 mL, 1.559 mmol) in THF (10 mL) at −78° C. The solution was stirred 1 h at this temperature before warming to 0° C. for 30 min at which time it was slowly added by syringe to a solution of 2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinoline-3-carbaldehyde (0.324 g, 0.780 mmol) in THF (10 mL) cooled to −78° C. The resulting dark solution was stirred 10 min at this temperature before warming to 0° C. for 20 min. The reaction mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give (2-(2-(tert-butylamino)-3-(1-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-ynyl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as an orange oil. cooled to −78° C The resulting dark solution was stirred 10 min at this temperature before warming to 0° C. for 20 min extracted with EtOAc The combined organic extracts were washed with water, saturated sodium chloride dried over sodium sulfate The solution was filtered concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (2.5 M) (0.624 mL, 1.559 mmol) was added to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (0.244 mL, 1.559 mmol) in THF (10 mL) at −78° C. The solution was stirred 1 h at this temperature before warming to 0° C. for 30 min at which time it was slowly added by syringe to a solution of 2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinoline-3-carbaldehyde (0.324 g, 0.780 mmol) in THF (10 mL) cooled to −78° C. The resulting dark solution was stirred 10 min at this temperature before warming to 0° C. for 20 min. The reaction mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give (2-(2-(tert-butylamino)-3-(1-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-ynyl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as an orange oil. cooled to −78° C The resulting dark solution was stirred 10 min at this temperature before warming to 0° C. for 20 min extracted with EtOAc The combined organic extracts were washed with water, saturated sodium chloride dried over sodium sulfate The solution was filtered concentrated in vacuo

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

Procedure: Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(but-3-ynyloxy)tetrahydro-2H-pyran (3.05 g, 19.80 mmol) were dissolved in diethyl ether (20 ml). Triethylamine (0.668 g, 6.60 mmol) was diluted with diethyl ether (10 ml) and added dropwise into previous mixture. After addition the reaction mixture was extracted with water and the organic layer was dried with Na2SO4, filtered and evaporated. LC-MS: [M+1]=172.17. added dropwise into previous mixture After addition the reaction mixture was extracted with water the organic layer was dried with Na2SO4 filtered evaporated

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

Procedure: Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(but-3-ynyloxy)tetrahydro-2H-pyran (3.05 g, 19.80 mmol) were dissolved in diethyl ether (20 ml). Triethylamine (0.668 g, 6.60 mmol) was diluted with diethyl ether (10 ml) and added dropwise into previous mixture. After addition the reaction mixture was extracted with water and the organic layer was dried with Na2SO4, filtered and evaporated. LC-MS: [M+1]=172.17. added dropwise into previous mixture After addition the reaction mixture was extracted with water the organic layer was dried with Na2SO4 filtered evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add isopropylmagnesium chloride (368 mL, 736.00 mmol) drop-wise to a solution of 2-but-3-ynoxytetrahydropyran (113.50 g, 736.00 mmol) in tetrahydrofuran (1.4 L) at 15° C., maintaining the internal temperature less than 20° C. Remove the ice-water bath, allow the temperature to warm to 25° C., and hold at that temperature for 20 min to ensure gas evolution is complete. Heat the reaction mixture to 30-35° C., and add benzyl azide (70 g, 525.71 mmol) drop-wise to the mixture over 2 h while ensuring benzyl azide concentration in the reaction mixture does not rise to appreciable levels by a method such as LCMS. After a 4 h stir, cool the reaction mixture to 25° C., and quench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition. After a 16 h stir, dilute with methyltert-butyl ether (200 mL), separate the layers, and stir the organic layer with 3M hydrochloric acid (600 mL) for 4 h. When greater than 98% conversion is achieved by a method such as LCMS, raise the pH of the reaction mixture to pH>10 via dropwise addition of 6 M sodium hydroxide (ca. 350 mL). Extract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL). Concentrate the combined organic layers in vacuo, and purify the resulting crude product by silica gel column chromatography, eluting with ethyl acetate, to afford the title compound (53 g, 50%) as an off-white solid. MS (m/z): 204.1 (M+1). maintaining the internal temperature less than 20° C Remove the ice-water bath Heat the reaction mixture to 30-35° C. benzyl azide concentration in the reaction mixture cool the reaction mixture to 25° C. quench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition After a 16 h stir dilute with methyltert-butyl ether (200 mL) separate the layers stir the organic layer with 3M hydrochloric acid (600 mL) for 4 h raise the pH of the reaction mixture to pH>10 via dropwise addition of 6 M sodium hydroxide (ca. 350 mL) Extract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL) Concentrate the combined organic layers in vacuo purify the resulting crude product by silica gel column chromatography eluting with ethyl acetate

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add isopropylmagnesium chloride (368 mL, 736.00 mmol) drop-wise to a solution of 2-but-3-ynoxytetrahydropyran (113.50 g, 736.00 mmol) in tetrahydrofuran (1.4 L) at 15° C., maintaining the internal temperature less than 20° C. Remove the ice-water bath, allow the temperature to warm to 25° C., and hold at that temperature for 20 min to ensure gas evolution is complete. Heat the reaction mixture to 30-35° C., and add benzyl azide (70 g, 525.71 mmol) drop-wise to the mixture over 2 h while ensuring benzyl azide concentration in the reaction mixture does not rise to appreciable levels by a method such as LCMS. After a 4 h stir, cool the reaction mixture to 25° C., and quench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition. After a 16 h stir, dilute with methyltert-butyl ether (200 mL), separate the layers, and stir the organic layer with 3M hydrochloric acid (600 mL) for 4 h. When greater than 98% conversion is achieved by a method such as LCMS, raise the pH of the reaction mixture to pH>10 via dropwise addition of 6 M sodium hydroxide (ca. 350 mL). Extract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL). Concentrate the combined organic layers in vacuo, and purify the resulting crude product by silica gel column chromatography, eluting with ethyl acetate, to afford the title compound (53 g, 50%) as an off-white solid. MS (m/z): 204.1 (M+1). maintaining the internal temperature less than 20° C Remove the ice-water bath Heat the reaction mixture to 30-35° C. benzyl azide concentration in the reaction mixture cool the reaction mixture to 25° C. quench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition After a 16 h stir dilute with methyltert-butyl ether (200 mL) separate the layers stir the organic layer with 3M hydrochloric acid (600 mL) for 4 h raise the pH of the reaction mixture to pH>10 via dropwise addition of 6 M sodium hydroxide (ca. 350 mL) Extract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL) Concentrate the combined organic layers in vacuo purify the resulting crude product by silica gel column chromatography eluting with ethyl acetate