2-phenylacetamide

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: (±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-phenyl-pyrrolidine-2,5-dione was prepared according to the Example 40 replacing 2-chloro-4-fluorophenylacetamide with phenylacetamide. 1H NMR (DMSO-d6) 400 MHz δ: 11.511 (s, 1H), 7.24-7.36 (m, 6H), 7.13 (d, 1H, J=7.2), 6.8-6.88 (m, 2H), 4.49 (d, 1H, J=8.0 Hz), 4.3 (d, 1H, J=7.6 Hz), 4.08 (m, 2H), 2.88 (m, 2H), 2.088 (m, 2H).

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

Procedure: (±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-phenyl-pyrrolidine-2,5-dione was prepared according to the Example 40 replacing 2-chloro-4-fluorophenylacetamide with phenylacetamide. 1H NMR (DMSO-d6) 400 MHz δ: 11.511 (s, 1H), 7.24-7.36 (m, 6H), 7.13 (d, 1H, J=7.2), 6.8-6.88 (m, 2H), 4.49 (d, 1H, J=8.0 Hz), 4.3 (d, 1H, J=7.6 Hz), 4.08 (m, 2H), 2.88 (m, 2H), 2.088 (m, 2H).

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

Procedure: To a suspension of 2-phenylacetamide (68 mg, 0.5 mmol) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.0 mmol). The suspension dissolved quickly and a new suspension formed. LC/MS analysis of the reaction mixture after 5 min indicated none of the desired product had formed. The mixture was warmed to 80° C., LC/MS after 30 min indicated a small amount of product. The reaction was heated at 70° C. for 2 days and became mostly clear. LC/MS analysis indicated mostly product. The mixture was shaken and heated at 80° C. for another 4 h. Almost all of the yellow solid on the walls of the reaction vessel had dissolved. The mixture was concentrated in vacuo. The residue dissolved in dichloroethane (1.5 mL), concentrated, and redissolved in dichloroethane (2 mL). The resulting 0.25 M solution was used without further purification. The suspension dissolved quickly a new suspension formed

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

Procedure: In substantially the same manner as in Reference Example 31, phenylacetamide was allowed to react with 1,3-dichloroacetone to give 2-benzyl-4-chloromethyl oxazole. The yield was 33%. Recrystallization from hexane gave colorless prisms, mp 31-32° C.

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

Procedure: 2-(Hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (0.46 g, 2.07 mmol) was dissolved with stirring in anhydrous dimethyl sulphoxide (20 mL) and 60% sodium hydride (0.10 g, 2.5 mmol) added. The reaction mixture was stirred at room temperature for 20 minutes and a solution of 2-(2,2-dimethylethyl)-2-(5-methyl-6-methylsulphonyl-3-pyridinyl)-1,3-dioxolane (0.62 g, 2.07 mmol) in anhydrous dimethyl sulphoxide (5 mL) added. The reaction mixture was heated to 45° C. and stirred overnight. It was then cooled to room temperature and poured into water. This was extracted with ethyl acetate (2×40 mL), the organic extracts combined and washed with water and brine, and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (10-50% ethyl acetate:pentane) gave the desired product (0.37 g, 40%) as a clear gum. The reaction mixture was heated to 45° C. stirred overnight It was then cooled to room temperature This was extracted with ethyl acetate (2×40 mL) washed with water and brine dried (Na2SO4) Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (10-50% ethyl acetate:pentane)

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

Procedure: Phenylacetamide intermediate AG3 was prepared using standard methods as shown in Scheme AG (E. Profft, J. Prakt. Chem. 1965, 30, 18). A mixture of AG1 (0.47 mol), EtOH (100 mL), NH4OAc (0.47 mol), and malonic acid (0.70 mol) was heated at reflux for 6 h, cooled, and filtered. The white solid was washed with EtOH and MeOH and dried. This solid was dissolved in 2:1 acetone/water (360 mL), treated with triethylamine (0.72 mol) and phenylacetyl chloride (0.36 mol), and stirred for 22 h. The mixture was evaporated and the residue dissolved in water (500 mL) and adjusted to pH 12 (1 N NaOH). The aqueous layer was adjusted to pH 2 (conc. HCl), extracted with Et2O, and evaporated to a white foam. The foam was purified by silica gel chromatography (10% MeOH/DCM) to give AG3. A solution of compound AG3 (0.22 mol) in water (600 mL) at RT was adjusted to pH 7.5 using KOH (3.0 N) and treated with penicillin amidase (91520 units, Sigma). This mixture was stirred for 47 h, acidified to pH 1 with HCl (conc), and the resultant ppt filtered through Celite. The filtrate was extracted with Et2O (3×300 mL), concentrated in vacuo, and treated with MeOH/conc. NH4OH (9:1). This product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:18:4) to give (S)-3-phenylacetamido-3-(3-pyridyl)propionic acid ammonium salt (19.5 g, 58%). This product was treated with HCl (6.0 N, 292 mL), heated at reflux for 5 h, cooled to RT, and extracted with Et2O (3×200 mL). The aqueous layer was adjusted to pH 12, concentrated in vacuo, and the resultant solid triturated with MeOH (2×300 mL). This solution was evaporated to give ca. 14 g sodium salt. This material was treated with MeOH (500 mL), 2,2-dimethoxypropane (44 mL), and HCl (4 N in dioxane, 84 mL), and stirred for 90 h at RT. This mixture was filtered and the filtrate concentrated in vacuo. The resultant off-white solid was triturated with Et2O (2×150 mL) and dried to give compound AG5 (16.7 g, 96% ee) as a white, amorphous solid. was heated at reflux for 6 h cooled filtered The white solid was washed with EtOH and MeOH dried This solid was dissolved in 2:1 acetone/water (360 mL) The mixture was evaporated the residue dissolved in water (500 mL) extracted with Et2O evaporated to a white foam The foam was purified by silica gel chromatography (10% MeOH/DCM) to give AG3 at RT This mixture was stirred for 47 h the resultant ppt filtered through Celite The filtrate was extracted with Et2O (3×300 mL) concentrated in vacuo treated with MeOH/conc This product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:18:4)

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

Procedure: Phenylacetamide intermediate AG3 was prepared using standard methods as shown in Scheme AG (E. Profft, J. Prakt. Chem. 1965, 30, 18). A mixture of AG1 (0.47 mol), EtOH (100 mL), NH4OAc (0.47 mol), and malonic acid (0.70 mol) was heated at reflux for 6 h, cooled, and filtered. The white solid was washed with EtOH and MeOH and dried. This solid was dissolved in 2:1 acetone/water (360 mL), treated with triethylamine (0.72 mol) and phenylacetyl chloride (0.36 mol), and stirred for 22 h. The mixture was evaporated and the residue dissolved in water (500 mL) and adjusted to pH 12 (1 N NaOH). The aqueous layer was adjusted to pH 2 (conc. HCl), extracted with Et2O, and evaporated to a white foam. The foam was purified by silica gel chromatography (10% MeOH/DCM) to give AG3. A solution of compound AG3 (0.22 mol) in water (600 mL) at RT was adjusted to pH 7.5 using KOH (3.0 N) and treated with penicillin amidase (91520 units, Sigma). This mixture was stirred for 47 h, acidified to pH 1 with HCl (conc), and the resultant ppt filtered through Celite. The filtrate was extracted with Et2O (3×300 mL), concentrated in vacuo, and treated with MeOH/conc. NH4OH (9:1). This product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:18:4) to give (S)-3-phenylacetamido-3-(3-pyridyl)propionic acid ammonium salt (19.5 g, 58%). This product was treated with HCl (6.0 N, 292 mL), heated at reflux for 5 h, cooled to RT, and extracted with Et2O (3×200 mL). The aqueous layer was adjusted to pH 12, concentrated in vacuo, and the resultant solid triturated with MeOH (2×300 mL). This solution was evaporated to give ca. 14 g sodium salt. This material was treated with MeOH (500 mL), 2,2-dimethoxypropane (44 mL), and HCl (4 N in dioxane, 84 mL), and stirred for 90 h at RT. This mixture was filtered and the filtrate concentrated in vacuo. The resultant off-white solid was triturated with Et2O (2×150 mL) and dried to give compound AG5 (16.7 g, 96% ee) as a white, amorphous solid. was heated at reflux for 6 h cooled filtered The white solid was washed with EtOH and MeOH dried This solid was dissolved in 2:1 acetone/water (360 mL) The mixture was evaporated the residue dissolved in water (500 mL) extracted with Et2O evaporated to a white foam The foam was purified by silica gel chromatography (10% MeOH/DCM) to give AG3 at RT This mixture was stirred for 47 h the resultant ppt filtered through Celite The filtrate was extracted with Et2O (3×300 mL) concentrated in vacuo treated with MeOH/conc This product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:18:4)

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

Procedure: Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-phenylacetamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.47 min, m/z 388 [M+H]+; 1H NMR (CDCl3): δ 4.22 (s, 2H), 4.84 (s, 2H), 7.04 (d, 1H), 7.25 (m, 5H), 7.43 (d, 1H), 8.06 (s, 1H), 8.69 (s, 1H), 13 (br s, 1H).