ethyl (2S)-2,3-dihydro-1H-indole-2-carboxylate

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (1.1 g, 4.18 mmol, Eq: 1.6) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (738 mg, 3.4 mmol, Eq: 1.3) and diisopropylethylamine (1.4 mL, 7.84 mmol, Eq: 3) in DCM (10 mL) and the resulting solution was stirred at rt for 1 h. (S)-Ethyl indoline-2-carboxylate (0.5 g, 2.61 mmol, Eq: 1.00) was added and the reaction mixture was stirred at rt over the weekend. The reaction mixture was diluted with EtOAc (50 mL) and washed with 0.1 M aqueous HCl (50 mL), 0.1 M aqueous NaOH (50 mL) and brine (25 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 20% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylate (0.58 g), m/z=391 (M+H). was added washed with 0.1 M aqueous HCl (50 mL), 0.1 M aqueous NaOH (50 mL) and brine (25 mL) The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 20% EtOAc in hexanes)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (5.26 g, 20.9 mmol, Eq: 2) and pyridine (2.8 mL, 34.5 mmol, Eq: 3.3) in DCM (60 mL), cyanuric fluoride (4.66 g, 2.99 mL, 34.5 mmol, Eq: 3.3) was added. The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was filtered off and the mother liquor was concentrated in vacuo. The residue was taken up in EtOAc, and washed with saturated aqueous NaHCO3, 0.5 M aqueous citric acid and brine, and concentrated in vacuo. The light brown oil was taken up in DCM (20 mL) and cooled in an ice bath. To this acid fluoride solution was added a solution of (S)-ethyl indoline-2-carboxylate (2 g, 10.5 mmol, Eq: 1) and 2,6-di-tert-butylpyridine (4.00 g, 4.62 mL, 20.9 mmol, Eq: 2) in DCM (20 mL). The resulting mixture was stirred at rt overnight. The reaction was concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 5% to 20% EtOAc in hexanes) to give (S)-1-((S)-2-tert-butoxycarbonylamino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.78 g) as a light yellow foam, m/z=425 (M+H). The resulting precipitate was filtered off the mother liquor was concentrated in vacuo washed with saturated aqueous NaHCO3, 0.5 M aqueous citric acid and brine concentrated in vacuo cooled in an ice bath The resulting mixture was stirred at rt overnight The reaction was concentrated in vacuo the crude material was purified by flash chromatography (silica gel, 5% to 20% EtOAc in hexanes)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyanuric fluoride (3.25 g, 2.08 mL, 24.1 mmol) was added to a solution of (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid (5.4 g, 17.9 mmol) and pyridine (1.95 mL, 24.1 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at 23° C. for 2.5 h. The resulting precipitate was filtered off and the mother liquor was concentrated. The residue was dissolved in EtOAc (250 mL), and the solution was washed with saturated NaHCO3, 0.5 M citric acid and brine. The organic layer was dried over Na2SO4, filtered, concentrated and dried under vacuum. The resulting yellow oil was taken up in CH2Cl2 (35 mL) and cooled in a dry ice-MeOH bath. To this solution was added a solution of (S)-ethyl indoline-2-carboxylate (2.3 g, 12.0 mmol) and 2,6-di-tert-butylpyridine (4.6 g, 5.31 mL, 24.1 mmol) in 25 mL of CH2Cl2. The resulting mixture was stirred at rt overnight. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.93 g), m/z=476 (M+H). The resulting precipitate was filtered off the mother liquor was concentrated The residue was dissolved in EtOAc (250 mL) the solution was washed with saturated NaHCO3, 0.5 M citric acid and brine The organic layer was dried over Na2SO4 filtered concentrated dried under vacuum cooled in a dry ice-MeOH bath The resulting mixture was stirred at rt overnight The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes)

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.

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

Procedure: HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%). When the acid was completely dissolved to reflux the solution was cooled the solvent removed in vacuo The residue was triturated with diethyl ether the resulting off-white solid was collected by filtration washed with hexanes dried overnight in a vacuum oven at 30° C.