ethyl 2-(butylamino)acetate

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: A mixture of 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) (0.30 g, 1.37 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.53, 2.74 mmol) and N-butylglycine ethyl ester (0.44 g, 2.7 mmol) was stirred in methylene chloride (70 mL). N-methylmorpholine (0.28 g, 2.74 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated to give a gum. The gum was dissolved in dimethylformamide (15 mL) and then treated with N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (0.25 g, 1 mmol) (which was obtained in Example 10), sodium triacetoxyborohydride (0.85 g, 4 mmol) and acetic acid (0.3 mL). After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture was poured into a saturated aqueous sodium bicarbonate. The aqueous layer was extracted with n-butanol and the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride) to give the title compound as a white solid; mp >60° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.70-1.60 (m, 12H), 1.75-1.95 (m, 2H), 2.50-3.50 (m, 7H), 2.91 (s, 3H), 3.60-3.75 (m, 2H), 4.00-4.15 (m, 4H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.90-7.00 (m, 3H), 7.05-7.25 (m, 3H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S(MH+): 591.2847. Found: 591.2840. The mixture was then washed with 0.05 N hydrochloric acid and water The resulting solution was dried with magnesium sulfate concentrated to give a gum After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture The aqueous layer was extracted with n-butanol the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride)

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

Procedure: A mixture of 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) (0.30 g, 1.37 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.53, 2.74 mmol) and N-butylglycine ethyl ester (0.44 g, 2.7 mmol) was stirred in methylene chloride (70 mL). N-methylmorpholine (0.28 g, 2.74 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated to give a gum. The gum was dissolved in dimethylformamide (15 mL) and then treated with N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (0.25 g, 1 mmol) (which was obtained in Example 10), sodium triacetoxyborohydride (0.85 g, 4 mmol) and acetic acid (0.3 mL). After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture was poured into a saturated aqueous sodium bicarbonate. The aqueous layer was extracted with n-butanol and the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride) to give the title compound as a white solid; mp >60° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.70-1.60 (m, 12H), 1.75-1.95 (m, 2H), 2.50-3.50 (m, 7H), 2.91 (s, 3H), 3.60-3.75 (m, 2H), 4.00-4.15 (m, 4H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.90-7.00 (m, 3H), 7.05-7.25 (m, 3H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S(MH+): 591.2847. Found: 591.2840. The mixture was then washed with 0.05 N hydrochloric acid and water The resulting solution was dried with magnesium sulfate concentrated to give a gum After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture The aqueous layer was extracted with n-butanol the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A quantity of 24.4 g (0.30 mole) of potassium cyanate is added portionwise, at room temperature, to a stirred solution of 31.80 g (0.20 mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1N hydrochloric acid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oil separates). After 10 minutes at 90° C., concentrated hydrochloric acid (250 mL) is cautiously added over 2 minutes and the resulting solution is heated at 90°-100° C. for 1/2 hour. The solution is concentrated at reduced pressure to dryness. The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol. The residue is extracted with 400 mL 50% ethanolmethylene chloride. The inorganics are filtered and the filtrate is concentrated to dryness. Trituration of the residue with 100 mL of water and filtration gives pure 1-butylhydantoin in 68% yield; mp 90°-92° C.; MS (EI) 156.1 (M+). the resulting solution is heated at 90°-100° C. for 1/2 hour The solution is concentrated at reduced pressure to dryness The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol The residue is extracted with 400 mL 50% ethanolmethylene chloride The inorganics are filtered the filtrate is concentrated to dryness Trituration of the residue with 100 mL of water and filtration

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A quantity of 24.4 g (0.30 mole) of potassium cyanate is added portionwise, at room temperature, to a stirred solution of 31.80 g (0.20 mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1N hydrochloric acid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oil separates). After 10 minutes at 90° C., concentrated hydrochloric acid (250 mL) is cautiously added over 2 minutes and the resulting solution is heated at 90°-100° C. for 1/2 hour. The solution is concentrated at reduced pressure to dryness. The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol. The residue is extracted with 400 mL 50% ethanolmethylene chloride. The inorganics are filtered and the filtrate is concentrated to dryness. Trituration of the residue with 100 mL of water and filtration gives pure 1-butylhydantoin in 68% yield; mp 90°-92° C.; MS (EI) 156.1 (M+). the resulting solution is heated at 90°-100° C. for 1/2 hour The solution is concentrated at reduced pressure to dryness The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol The residue is extracted with 400 mL 50% ethanolmethylene chloride The inorganics are filtered the filtrate is concentrated to dryness Trituration of the residue with 100 mL of water and filtration

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

Procedure: A mixture of 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) (0.30 g, 1.37 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.53, 2.74 mmol) and N-butylglycine ethyl ester (0.44 g, 2.7 mmol) was stirred in methylene chloride (70 mL). N-methylmorpholine (0.28 g, 2.74 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated to give a gum. The gum was dissolved in dimethylformamide (15 mL) and then treated with N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (0.25 g, 1 mmol) (which was obtained in Example 10), sodium triacetoxyborohydride (0.85 g, 4 mmol) and acetic acid (0.3 mL). After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture was poured into a saturated aqueous sodium bicarbonate. The aqueous layer was extracted with n-butanol and the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride) to give the title compound as a white solid; mp>60° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.70–1.60 (m, 12 H), 1.75–1.95 (m, 2 H), 2.50–3.50 (m, 7 H), 2.91 (s, 3 H), 3.60–3.75 (m, 2 H), 4.00–4.15 (m, 4 H), 4.47 (dd, J=8.0, 4.3 Hz, 1 H), 6.81 (d, J=8.5 Hz, 1 H), 6.90–7.00 (m, 3 H), 7.05–7.25 (m, 3 H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S (MH+): 591.2847. Found: 591.2840. The mixture was then washed with 0.05 N hydrochloric acid and water The resulting solution was dried with magnesium sulfate concentrated to give a gum After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture The aqueous layer was extracted with n-butanol the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride)

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

Procedure: A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 70 ml of methylene chloride, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at -10° to -5° C. The mixture was stirred at 0° C. for one hour and further at room temperature for 2 hours. After cooling to -10° to -5° C., 8.0 g (0.05 mole) of N-butylglycine ethyl ester was added dropwise to the mixture, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 2 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of methylene chloride, the reaction mixture was washed with 100 ml of water three times. The methylene chloride layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of impurities. Yield: 15.7 g (76.6%). with cooling After cooling to -10° to -5° C. was further added dropwise to the mixture The resulting mixture was stirred at 0° C. for 2 hours to stand overnight at room temperature the reaction mixture was washed with 100 ml of water three times The methylene chloride layer was dried concentrated in a vacuum to give an oily product, which

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A quantity of 24.4 g (0.30 mole) of potassium cyanate is added portionwise, at room temperature, to a stirred solution of 31.80 g (0.20 mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1 N hydrochloric acid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oil separates). After 10 minutes at 90° C., concentrated hydrochloric acid (250 mL) is cautiously added over 2 minutes and the resulting solution is heated at 90°100° C. for 1/2 hour. The solution is concentrated at reduced pressure to dryness. The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol. The residue is extracted with 400 mL 50% ethanol-methylene chloride. The inorganics are filtered and the filtrate is concentrated to dryness. Trituration of the residue with 100 mL of water and filtration gives pure 1-butylhydantoin in 68% yield; mp 90°92° C.; MS (EI) 156.1 (M+). the resulting solution is heated at 90°100° C. for 1/2 hour The solution is concentrated at reduced pressure to dryness The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol The residue is extracted with 400 mL 50% ethanol-methylene chloride The inorganics are filtered the filtrate is concentrated to dryness Trituration of the residue with 100 mL of water and filtration

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

Procedure: A mixture of 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) (0.30 g, 1.37 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.53, 2.74 mmol) and N-butylglycine ethyl ester (0.44 g, 2.7 mmol) was stirred in methylene chloride (70 mL). N-methylmorpholine (0.28 g, 2.74 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated to give a gum. The gum was dissolved in dimethylformamide (15 mL) and then treated with N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (0.25 g, 1 mmol) (which was obtained in Example 10), sodium triacetoxyborohydride (0.85 g, 4 mmol) and acetic acid (0.3 mL). After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture was poured into a saturated aqueous sodium bicarbonate. The aqueous layer was extracted with n-butanol and the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride) to give the title compound as a white solid; mp >60° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.70-1.60 (m, 12H), 1.75-1.95 (m, 2H), 2.50-3.50 (m, 7H), 2.91 (s, 3H), 3.60-3.75 (m, 2H), 4.00-4.15 (m, 4H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.90-7.00 (m, 3H), 7.05-7.25 (m, 3H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S(MH+): 591.2847. Found: 591.2840. The mixture was then washed with 0.05 N hydrochloric acid and water The resulting solution was dried with magnesium sulfate concentrated to give a gum After stirring at room temperature under a nitrogen atmosphere for 2 hours the mixture The aqueous layer was extracted with n-butanol the concentrated gum was purified by silica gel chromatography (methanol/methylene chloride)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A quantity of 24.4 g (0.30 mole) of potassium cyanate is added portionwise, at room temperature, to a stirred solution of 31.80 g (0.20 mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1N hydrochloric acid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oil separates). After 10 minutes at 90° C., concentrated hydrochloric acid (250 mL) is cautiously added over 2 minutes and the resulting solution is heated at 90°-100° C. for 1/2 hour. The solution is concentrated at reduced pressure to dryness. The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol. The residue is extracted with 400 mL 50% ethanolmethylene chloride. The inorganics are filtered and the filtrate is concentrated to dryness. Trituration of the residue with 100 mL of water and filtration gives pure 1-butylhydantoin in 68% yield; mp 90°-92° C.; MS (EI) 156.1 (M+). the resulting solution is heated at 90°-100° C. for 1/2 hour The solution is concentrated at reduced pressure to dryness The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol The residue is extracted with 400 mL 50% ethanolmethylene chloride The inorganics are filtered the filtrate is concentrated to dryness Trituration of the residue with 100 mL of water and filtration