2-bromoethyl 2,2-dimethylpropanoate

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (5)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.23 g, 98%). 1H NMR (CDCl3, 300 MHz): 5.08 (1H, bs), 4.27-4.07 (2H, m), 3.73 (1H, bs), 2.65-2.50 (3H, m), 2.48 (1H, bs), 2.30-2.24 (1H, m), 1.74-1.61 (1H, m), 1.58-1.47 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (5)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.23 g, 98%). 1H NMR (CDCl3, 300 MHz): 5.08 (1H, bs), 4.27-4.07 (2H, m), 3.73 (1H, bs), 2.65-2.50 (3H, m), 2.48 (1H, bs), 2.30-2.24 (1H, m), 1.74-1.61 (1H, m), 1.58-1.47 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (R)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 2 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (2.884 g, 88%). 1H NMR (CDCl3, 300 MHz): 5.09 (1H, bs), 4.25-4.07 (2H, m), 3.73 (1H, bs), 2.63-2.52 (3H, m), 2.49 (1H, bs), 2.31-2.24 (1H, m), 1.74-1.61 (1H, m), 1.59-1.49 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (R)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 2 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (2.884 g, 88%). 1H NMR (CDCl3, 300 MHz): 5.09 (1H, bs), 4.25-4.07 (2H, m), 3.73 (1H, bs), 2.63-2.52 (3H, m), 2.49 (1H, bs), 2.31-2.24 (1H, m), 1.74-1.61 (1H, m), 1.59-1.49 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: 2,2-Dimethylpropionyl chloride (10 mL, 81.2 mmol) was added over 10 min to an ice-cooled solution of 2-bromoethanol (5.48 mL, 77.4 mmol) and DIPEA (20.8 mL, 121.8 mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15 min, then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water. The organic fraction was dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (10.58 g, 65%). 1H NMR (CDCl3, 300 MHz): 4.37 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=6.0 Hz), 1.23 (9H, s). The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water The organic fraction was dried (Na2SO4) then concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane)

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

Procedure: 2,2-Dimethylpropionyl chloride (10 mL, 81.2 mmol) was added over 10 min to an ice-cooled solution of 2-bromoethanol (5.48 mL, 77.4 mmol) and DIPEA (20.8 mL, 121.8 mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15 min, then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water. The organic fraction was dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (10.58 g, 65%). 1H NMR (CDCl3, 300 MHz): 4.37 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=6.0 Hz), 1.23 (9H, s). The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water The organic fraction was dried (Na2SO4) then concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane)

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

Procedure: A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 31.4 g (150 mmol) of 2,2-dimethyl-propionic acid-2-bromoethyl ester is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 0° C. 300 ml of benzene is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/100 ml of water. 100 ml of 50% aqueous potassium hydroxide solution is added, and it is refluxed for eight hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 400 ml of ethyl acetate, and the pH of the aqueous phase is set at 5 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol=20:8:2). The product-containing fractions are concentrated by evaporation. It is stirred for two hours at 0° C solid is filtered out the filtrate is evaporated to the dry state in a vacuum 100 ml of 50% aqueous potassium hydroxide solution is added it is refluxed for eight hours It is cooled to 0° C. the solvent is distilled off (vacuum) while being stirred (10% aqueous hydrochloric acid) The organic phase is separated the aqueous phase is extracted once more with 200 ml of ethyl acetate The combined organic phases are dried on magnesium sulfate the solvent is distilled off in a vacuum the residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol=20:8:2) The product-containing fractions are concentrated by evaporation

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (5)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.23 g, 98%). 1H NMR (CDCl3, 300 MHz): 5.08 (1H, bs), 4.27-4.07 (2H, m), 3.73 (1H, bs), 2.65-2.50 (3H, m), 2.48 (1H, bs), 2.30-2.24 (1H, m), 1.74-1.61 (1H, m), 1.58-1.47 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (R)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 2 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (2.884 g, 88%). 1H NMR (CDCl3, 300 MHz): 5.09 (1H, bs), 4.25-4.07 (2H, m), 3.73 (1H, bs), 2.63-2.52 (3H, m), 2.49 (1H, bs), 2.31-2.24 (1H, m), 1.74-1.61 (1H, m), 1.59-1.49 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: 2,2-Dimethylpropionyl chloride (10 mL, 81.2 mmol) was added over 10 min to an ice-cooled solution of 2-bromoethanol (5.48 mL, 77.4 mmol) and DIPEA (20.8 mL, 121.8 mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15 min, then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water. The organic fraction was dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (10.58 g, 65%). 1H NMR (CDCl3, 300 MHz): 4.37 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=6.0 Hz), 1.23 (9H, s). The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water The organic fraction was dried (Na2SO4) then concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane)

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

Procedure: To a solution of 2-bromoethanol (0.36 mL) and pyridine (0.61 mL) in tetrahydrofuran (5 mL) was added pivaloyl chloride (0.62 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (2-bromoethyl) pivalate (1.04 g). A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.93 g), (2-bromoethyl)pivalate (0.82 g), cesium carbonate (1.27 g) and sodium iodide (0.2 g) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 6 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/1) to give the title compound (0.73 g). cooling the resulting mixture was extracted with diethyl ether The extract was washed with water a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate The solvent was removed under reduced pressure

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

Procedure: To a solution of 2-bromoethanol (0.36 mL) and pyridine (0.61 mL) in tetrahydrofuran (5 mL) was added pivaloyl chloride (0.62 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (2-bromoethyl) pivalate (1.04 g). A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.93 g), (2-bromoethyl)pivalate (0.82 g), cesium carbonate (1.27 g) and sodium iodide (0.2 g) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 6 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/1) to give the title compound (0.73 g). cooling the resulting mixture was extracted with diethyl ether The extract was washed with water a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate The solvent was removed under reduced pressure