tert-butyl (2S)-2-aminobutanoate

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(2-chloro-5-trifluoromethyl-benzoylamino)-butyric acid tert-butyl ester (prepared from 2-chloro5-trifluoromethylbenzoic acid and (S)-2-aminobutyric acid, tert butyl ester in a procedure similar to that described in method F) (3 g) and benzylamine (1.1 ml) in N-methylpyrrolidine (40 ml) was added potassium carbonate (1.6 g), copper (30 mg) and copper (I) bromide (15 mg). The mixture was heated at 160° C. for 3 hours then cooled to room temp. and diluted with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic solution dried (magnesium sulfate), filtered and concentrated. The residue was purified on silica gel, eluting with 15% ethyl acetate/hexane. The sub-titled product was obtained as a white solid (950 mg, 27%). 1H NMR (400 MHz, CDCl3) δ 1.04 (3H, t), 1.50 (9H, s), 2.86 (1H, m), 2.02 (1H, m), 4.50 (2H, d), 4.65 (1H, m), 6.69 (2H, m), 7.21-7.70 (7H, m), 8.42 (1H, m) ppm; MS ES (−) 435.32 (M−H). then cooled to room temp. The mixture was extracted with ethyl acetate the organic solution dried (magnesium sulfate) filtered concentrated The residue was purified on silica gel eluting with 15% ethyl acetate/hexane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert butyl ester (22 g) were heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%). 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m) ppm. The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert butyl ester (22 g) were heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%). 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m) ppm. The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

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

Procedure: A solution of (R)-N-benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine (Method 17; 2.00 g, 6.64 mmol), (2S)-2-amino butanoic acid t-butyl ester (1.30 g, 6.64 mmol) and N-methylmorpholine (2.0 g, 19.8 mmol) in DCM (30 ml) was stirred at RT for 5 min, after which TBTU (2.60 g, 8.10 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel DCM:Acetone—60:40). The product was crystallized from toluene (20 ml) giving 1.85 g of the desired product as a white solid. NMR (400 MHz): 0.80 (3H, t), 1.45 (9H, s), 1.50–1.80 (2H, m), 4.10–4.20 (1H, m), 5.05 (1H, d(AB)), 5.15 (1H, d(AB)), 6.75 (2H, d), 7.20–7.40 (7H, m). The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel DCM The product was crystallized from toluene (20 ml)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-Chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert-butyl ester (22 g) was heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m),7.35-7.52 (1H, m), 8.05 (1H, m). The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-Chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert-butyl ester (22 g) was heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m),7.35-7.52 (1H, m), 8.05 (1H, m). The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(2-chloro-5-trifluoromethyl-benzoylamino)-butyric acid tert-butyl ester (prepared from 2-chloro-5-trifluoromethylbenzoic acid and (S)-2-aminobutyric acid, tert butyl ester in a procedure similar to that described in method F) (3 g) and benzylamine (1.1 ml) in N-methylpyrolidine (40 ml) was added potassium carbonate (1.6 g), copper (30 mg) and copper (I) bromide (15 mg). The mixture was heated at 160° C. for 3 hours then cooled to room temp. and diluted with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic solution dried (magnesium sulfate), filtered and concentrated. The residue was purified on silica gel, eluting with 15% ethyl acetate/hexane. The sub-titled product was obtained as a white solid (950 mg, 27%). 1H NMR (400 MHz, CDCl3) δ 1.04 (3H, t), 1.50 (9H, s), 2.86 (1H, m), 2.02 (1H, m), 4.50 (2H, d), 4.65 (1H, m), 6.69 (2H, m), 7.21-7.70 (7H, m), 8.42 (1H, m) ppm; MS ES(−) 435.32 (M−H). then cooled to room temp. The mixture was extracted with ethyl acetate the organic solution dried (magnesium sulfate) filtered concentrated The residue was purified on silica gel eluting with 15% ethyl acetate/hexane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert butyl ester (22 g) were heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%). 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m) ppm. The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-Chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert-butyl ester (22 g) was heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m). The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(2-chloro-5-trifluoromethyl-benzoylamino)-butyric acid tert-butyl ester (prepared from 2-chloro5-trifluoromethylbenzoic acid and (S)-2-aminobutyric acid, tert butyl ester in a procedure similar to that described in method F) (3 g) and benzylamine (1.1 ml) in N-methylpyrrolidine (40 ml) was added potassium carbonate (1.6 g), copper (30 mg) and copper (I) bromide (15 mg). The mixture was heated at 160° C. for 3 hours then cooled to room temp. and diluted with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic solution dried (magnesium sulfate), filtered and concentrated. The residue was purified on silica gel, eluting with 15% ethyl acetate/hexane. The sub-titled product was obtained as a white solid (950 mg, 27%). 1H NMR (400 MHz, CDCl3) δ 1.04 (3H, t), 1.50 (9H, s), 2.86 (1H, m), 2.02 (1H, m), 4.50 (2H, d), 4.65 (1H, m), 6.69 (2H, m), 7.21-7.70 (7H, m), 8.42 (1H, m) ppm; MS ES (−) 435.32 (M−H). then cooled to room temp. The mixture was extracted with ethyl acetate the organic solution dried (magnesium sulfate) filtered concentrated The residue was purified on silica gel eluting with 15% ethyl acetate/hexane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert butyl ester (22 g) were heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%). 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m) ppm. The mixture was then cooled purified by flash chromatography (5-25% ethyl acetate/hexane)

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

Procedure: A solution of (R)-N-benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine (Method 17; 2.00 g, 6.64 mmol), (2S)-2-amino butanoic acid t-butyl ester (1.30 g, 6.64 mmol) and N-methylmorpholine (2.0 g, 19.8 mmol) in DCM (30 ml) was stirred at RT for 5 min, after which TBTU (2.60 g, 8.10 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel DCM:Acetone—60:40). The product was crystallized from toluene (20 ml) giving 1.85 g of the desired product as a white solid. NMR (400 MHz): 0.80 (3H, t), 1.45 (9H, s), 1.50–1.80 (2H, m), 4.10–4.20 (1H, m), 5.05 (1H, d(AB)), 5.15 (1H, d(AB)), 6.75 (2H, d), 7.20–7.40 (7H, m). The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel DCM The product was crystallized from toluene (20 ml)