phenyl 2-bromoacetate

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

Procedure: To a solution of 5-nitro-1H-pyrrolo[2,3-b]pyridine (0.200 g, 1.226 mmol) and anhydrous potassium carbonate (254.2 mg, 1.839 mmol) in anhydrous DMF (6.0 mL) at room temperature was added phenyl 2-bromoacetate (0.755 mg, 3.678 mmol). After 20 h stirring at room temperature, additional phenyl 2-bromoacetate (1.256 g, 6.13 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with methylene chloride (70 mL), quenched with an aqueous pH 7 phosphate buffer solution (30 mL). The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) to give phenyl 2-(5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (C-7) as a beige solid (50.0 mg, 13% yield). MS (M+1): m/e 298. the mixture was stirred at room temperature for 24 h quenched with an aqueous pH 7 phosphate buffer solution (30 mL) The aqueous layer was extracted with methylene chloride (3×50 mL) The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (50 mL) and brine (50 mL) dried over MgSO4 filtered concentrated The crude residue was purified by C18 reverse phase chromatography (H2O:CH3CN eluant gradient)

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

Procedure: Compound 48 was prepared by the general procedure for compound 45, by using compound 44 and phenyl 2-bromoacetate as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.22 (br s, 1H), 8.29 (m, 1H), 8.08 (m, 1H), 7.96 (dd, 1H, J=3.5, 13.3 Hz), 7.58 (m, 1H), 7.45 (m, 1H), 7.34 (m, 2H), 7.07 (d, 1H, J=8.5 Hz), 6.99 (t, 1H, J=7.4 Hz), 6.85 (m, 1H), 4.84 (s, 2H), 4.15 (d, 1H, J=13.2 Hz), 4.10 (d, 1H, J=13.6 Hz), 3.06 (t, 1H, J=12.0 Hz), 2.76 (dd, 1H, J=11.0, 12.3 Hz), 1.71 (m, 3H), 1.54 (m, 1H), 1.15 (m, 1H); 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 527.

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

Procedure: These compounds, namely (R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octane bromide and (R)-1-(2-Acetoxy-ethyl)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide are prepared by an analogous method to (R)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]octane bromide (Example 109) by replacing bromo-acetic acid phenyl ester with the appropriate alkyl halide.

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

Procedure: To a solution of fluoro-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester [Example 109(i)] (0.034 g, 0.1 mmol) in DMSO (0.25 ml) is added bromo-acetic acid phenyl ester (0.071 ml, 0.5 mmol). The reaction mixture is left standing at room temperature overnight. Purification is carried out by chromatography on C18 silica, eluting with water:acetonitrile to yield the titled compound as a colourless oil. The reaction mixture is left Purification eluting with water

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

Procedure: Phenyl bromoacetate (45.0 g, 0.209 mol) was added to a stirring solution of tetramethylammonium lactate (40.7 g of an 88% aq soln, 1.05 eq) in 50 mL of dimethylformamide at room temperature. The resulting tetramethylammonium bromide which separated from the reaction mixture as a solid was removed by filtration and washed with ethyl acetate. The dimethylformamide and ethyl acetate solutions were combined and washed with a NaHCO3 /brine solution, the separated aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was chromatographed on silica gel (ethyl acetate/hexane) to give the title compound (14.7 g, 31%): 1H NMR δ 1.50 (d, 3H, J=7.0), δ 3.12 (d, 1H, J=5.3), δ 4.40-4.49 (m, 1H), δ 4.87 (d, 1H, J=16.1), δ 4.99 (d, 1H, J=16.2), d 7.09-7.40 (5H, phenyl); HRMS calcd for C10H8O5TMS (M--CH3) 281.0845, obsd 281.0856. The resulting tetramethylammonium bromide which separated from the reaction mixture as a solid was removed by filtration washed with ethyl acetate washed with a NaHCO3 /brine solution the separated aqueous phase was extracted with CH2Cl2 dried with MgSO4 The solvent was removed the resulting residue was chromatographed on silica gel (ethyl acetate/hexane)

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

Procedure: A mixture of 55 g (0.26 mol) phenyl bromoacetate and 62 g (0.26 mol) of tetradecyldimethylamine was allowed to stand at room temperature for three days. The resultant crystalline mass was washed well with ether and dried to 114 g. Recrystallized from ethyl acetate and vacuum dried, the compound melted at 87°-91.5°. The resultant crystalline mass was washed well with ether dried to 114 g Recrystallized from ethyl acetate and vacuum dried

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

Procedure: Phenyl bromoacetate (45.0 g, 0.209 mol) was added to a stirring solution of tetramethylammonium lactate (40.7 g of an 88% aq soln, 1.05 eq) in 50 mL of dimethylformamide at room temperature. The resulting tetramethylammonium bromide which separated from the reaction mixture as a solid was removed by filtration and washed with ethyl acetate. The dimethylformamide and ethyl acetate solutions were combined and washed with a NaHCO3 /brine solution, the separated aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was chromatographed on silica gel (ethyl acetate/hexane) to give the title compound (14.7 g, 31%): 1H NMR δ1.50 (d, 3H, J=7.0), δ3.12 (d, 1H, J=5.3), δ4.40-4.49 (m, 1H), δ4.87 (d, 1H, J=16.1), δ4.99 (d, 1H, J=16.2), d 7.09-7.40 (5H, phenyl); HRMS calcd for C10H8O5TMS (M-CH3) 281.0845, obsd 281.0856. The resulting tetramethylammonium bromide which separated from the reaction mixture as a solid was removed by filtration washed with ethyl acetate washed with a NaHCO3 /brine solution the separated aqueous phase was extracted with CH2Cl2 dried with MgSO4 The solvent was removed the resulting residue was chromatographed on silica gel (ethyl acetate/hexane)

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

Procedure: To a solution of 5-nitro-1H-pyrrolo[2,3-b]pyridine (0.200 g, 1.226 mmol) and anhydrous potassium carbonate (254.2 mg, 1.839 mmol) in anhydrous DMF (6.0 mL) at room temperature was added phenyl 2-bromoacetate (0.755 mg, 3.678 mmol). After 20 h stirring at room temperature, additional phenyl 2-bromoacetate (1.256 g, 6.13 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with methylene chloride (70 mL), quenched with an aqueous pH 7 phosphate buffer solution (30 mL). The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) to give phenyl 2-(5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (C-7) as a beige solid (50.0 mg, 13% yield). MS (M+1): m/e 298. the mixture was stirred at room temperature for 24 h quenched with an aqueous pH 7 phosphate buffer solution (30 mL) The aqueous layer was extracted with methylene chloride (3×50 mL) The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (50 mL) and brine (50 mL) dried over MgSO4 filtered concentrated The crude residue was purified by C18 reverse phase chromatography (H2O:CH3CN eluant gradient)

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

Procedure: Compound 48 was prepared by the general procedure for compound 45, by using compound 44 and phenyl 2-bromoacetate as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.22 (br s, 1H), 8.29 (m, 1H), 8.08 (m, 1H), 7.96 (dd, 1H, J=3.5, 13.3 Hz), 7.58 (m, 1H), 7.45 (m, 1H), 7.34 (m, 2H), 7.07 (d, 1H, J=8.5 Hz), 6.99 (t, 1H, J=7.4 Hz), 6.85 (m, 1H), 4.84 (s, 2H), 4.15 (d, 1H, J=13.2 Hz), 4.10 (d, 1H, J=13.6 Hz), 3.06 (t, 1H, J=12.0 Hz), 2.76 (dd, 1H, J=11.0, 12.3 Hz), 1.71 (m, 3H), 1.54 (m, 1H), 1.15 (m, 1H); 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 527.