2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethyl methanesulfonate

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: (3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D) (30 mg, 78.7 mmol), 2-(2-(tert-butoxycarbonylamino)ethoxy)ethyl methanesulfonate (26.8 mg, 94.5 mmol) and Cs2CO3 (30.8 mg, 94.5 mmol) were dissolved in DMF (3 ml) at room temperature and stirred overnight. The mixture was then extracted with EtOAc, washed with NH4Cl and NaCl, dried over Na2SO4, and evaporated to get the crude product, tert-butyl 2-(2-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethoxy)ethylcarbamate (intermediate U) (40 mg), which was used for the next step without further purification. The crude intermediate U was dissolved in MeOH (0.5 mL), MeSO3H (6 μL) was added, and the mixture was stirred overnight at room temperature. Then the reaction was quenched with NaHCO3, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, concentrated, and separated by preparative HPLC to obtain compound V (11.6 mg). 1H NMR (CD3OD): δ 7.40˜7.27 (m, 3H), 7.14˜7.10 (m, 2 H), 6.87˜6.85 (m, 2 H), 4.54 (d, J=16, 1H), 4.19˜4.18 (m, 1H), 4.16˜4.14 (m, 2H), 4.05˜4.01 (m, 4 H), 3.94˜3.93 (m, 1H), 3.88˜3.86 (m, 2H), 3.83˜3.76 (m, 3H), 3.67˜3.57 (m, 1H), 3.16˜3.13 (m, 2 H); MS ESI (m/z): 468 (M+H)+, calc. 467. The mixture was then extracted with EtOAc washed with NH4Cl and NaCl dried over Na2SO4 evaporated

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, sodium azide (29.8 g, 458 mmol) was added to a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (118 g, 416 mmol) in DMF, and the reaction was heated at 90° C. for six hours. The reaction was allowed to cool to room temperature overnight, and then the solvent was removed under reduced pressure. Water (1 L) was added, and the resulting solution was extracted with diethyl ether (4×500 mL). The combined extracts were washed with water (1×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 93.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a colorless oil. to cool to room temperature overnight the solvent was removed under reduced pressure Water (1 L) was added the resulting solution was extracted with diethyl ether (4×500 mL) The combined extracts were washed with water (1×250 mL) dried over magnesium sulfate filtered concentrated under reduced pressure

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

Procedure: Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (89.0 g, 434 mmol) in dichloromethane (1.5 L) was cooled to 0° C.; triethylamine (90.7 mL, 650 mmol) was added dropwise. Methanesulfonyl chloride (36.9 mL, 477 mmol) was then added over a period of 45 minutes. A precipitate formed, and the reaction became yellow. The reaction was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (750 mL) was added. The organic layer was then sequentially washed with water (3×500 mL) and brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 119.2 g of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a light orange oil. A precipitate formed The organic layer was then sequentially washed with water (3×500 mL) and brine (250 mL) dried over magnesium sulfate filtered concentrated under reduced pressure

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

Procedure: Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (48.53 g, 236 mmol) in anhydrous dichloromethane (1 L) was cooled to 0° C. Triethylamine (49.4 mL, 354 mmol)) was added. Methanesulfonyl chloride (20.10 mL, 260 mmol) was added dropwise over a period of 10 minutes. The reaction was allowed to warm to ambient temperature and stir overnight. The reaction was quenched with saturated sodium bicarbonate solution (500 mL). The organic layer was washed with water (3×500 mL) and brine (1×500 mL), dried over sodium sulfate and then concentrated under reduced pressure to provide 66.9 g of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil. The reaction was quenched with saturated sodium bicarbonate solution (500 mL) The organic layer was washed with water (3×500 mL) and brine (1×500 mL) dried over sodium sulfate concentrated under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90° C. under N2. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold H2O. The reaction mixture was then extracted with Et2O (3×300 mL). The combined organic extracts were washed with H2O (4×100 mL) and brine (2×100 mL). The organic portion was dried over MgSO4 and concentrated to give 52.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil. the solution was cooled to room temperature The reaction mixture was then extracted with Et2O (3×300 mL) The combined organic extracts were washed with H2O (4×100 mL) and brine (2×100 mL) The organic portion was dried over MgSO4 concentrated

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

Procedure: A rapidly stirred solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CH2Cl2 was cooled to 0° C. under N2 and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 mL saturated NaHCO3 solution and the organic layer was separated. The organic phase was then washed with H2O (3×500 mL) and brine. The organic portion was dried over Na2SO4 and concentrated to give 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g). The reaction was quenched by addition of 500 mL saturated NaHCO3 solution the organic layer was separated The organic phase was then washed with H2O (3×500 mL) and brine The organic portion was dried over Na2SO4 concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (28 g, 99 mmol) and sodium thiomethoxide (8.3 g, 119 mmol) in N,N-dimethylformamide (DMF, 200 mL) was heated to 80° C. and maintained at that temperature until analysis by thin layer chromatography (TLC) indicated that the starting material had been consumed. The reaction mixture was allowed to cool to ambient temperature and was then quenched with water (200 mL). The reaction mixture was extracted with diethyl ether (2×200 mL). The combined extracts were washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to provide 22.5 g of tert-butyl 2-[2-(methylthio)ethoxy]ethylcarbamate as a light yellow oil. maintained at that temperature until analysis by thin layer chromatography (TLC) had been consumed to cool to ambient temperature was then quenched with water (200 mL) The reaction mixture was extracted with diethyl ether (2×200 mL) The combined extracts were washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure