ethyl 3-amino-2-methylpropanoate;hydrochloride

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorobenzaldehyde (0.622 mL, 5.80 mmol), sodium acetate (0.951 g, 11.6 mmol), powdered/activated 4 Å molecular sieves (2.0 g) and sodium cyanoborohydride (0.729 g, 11.6 mmol) were added sequentially to a solution of racemic 3-amino-2-methyl-propionic acid ethyl ester hydrochloride (0.972 g, 5.80 mmol) in methanol (30 mL) at 25° C. The mixture was stirred at 25° C. for 20 h, and then was filtered through Celite. The Celite was washed with methanol (2×30 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.821 g, 3.43 mmol, 59%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, d, J=7.2 Hz), 1.26 (3H, t, J=6.9 Hz), 2.63-2.72 (2H, m), 2.84-2.91 (1H, m), 3.75 (1H, d, J=13.3 Hz), 3.79 (1H, d, J=13.4 Hz), 4.14 (2H, q, J=6.9 Hz), 6.97-7.01 (2H, m), 7.25-7.29 (2H, m). was filtered through Celite The Celite was washed with methanol (2×30 mL) the combined filtrate and washings were concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorobenzaldehyde (0.622 mL, 5.80 mmol), sodium acetate (0.951 g, 11.6 mmol), powdered/activated 4 Å molecular sieves (2.0 g) and sodium cyanoborohydride (0.729 g, 11.6 mmol) were added sequentially to a solution of racemic 3-amino-2-methyl-propionic acid ethyl ester hydrochloride (0.972 g, 5.80 mmol) in methanol (30 mL) at 25° C. The mixture was stirred at 25° C. for 20 h, and then was filtered through Celite. The Celite was washed with methanol (2×30 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.821 g, 3.43 mmol, 59%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, d, J=7.2 Hz), 1.26 (3H, t, J=6.9 Hz), 2.63-2.72 (2H, m), 2.84-2.91 (1H, m), 3.75 (1H, d, J=13.3 Hz), 3.79 (1H, d, J=13.4 Hz), 4.14 (2H, q, J=6.9 Hz), 6.97-7.01 (2H, m), 7.25-7.29 (2H, m). was filtered through Celite The Celite was washed with methanol (2×30 mL) the combined filtrate and washings were concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes)

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

Procedure: 3-{[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methyl-propionic acid ethyl ester was prepared in the same manner as 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1-hydroxymethyl-cyclopentylmethyl)amide from 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (300 mg, 83.3 mmol) and 3-aminoisobutyric acid ethyl ester, hydrochloride (168 mg, 0.10 mmol) giving 3-{[5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methylpropionic acid ethyl ester (204 mg, 51%).

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

Procedure: 3-Aminoisobutyric acid (1.00 g, 9.7 mmol) was stirred in DCM under nitrogen and thionyl chloride (1.4 ml, 19.4 mmol) was added at room temperature. The reaction was heated to 50° C. for 2 h. The solvent and any excess thionyl chloride were removed under reduced pressure and the oil obtained was dissolved in ethanol (20 ml) stirring at room temperature for 18 h. The solvent was removed under reduced pressure to give 3-aminoisobutyric acid ethyl ester hydrochloride as a viscous, cloudy oil (1.47 g, 90%). The solvent and any excess thionyl chloride were removed under reduced pressure the oil obtained The solvent was removed under reduced pressure

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

Procedure: 3-Aminoisobutyric acid (1.00 g, 9.7 mmol) was stirred in DCM under nitrogen and thionyl chloride (1.4 ml, 19.4 mmol) was added at room temperature. The reaction was heated to 50° C. for 2 h. The solvent and any excess thionyl chloride were removed under reduced pressure and the oil obtained was dissolved in ethanol (20 ml) stirring at room temperature for 18 h. The solvent was removed under reduced pressure to give 3-aminoisobutyric acid ethyl ester hydrochloride as a viscous, cloudy oil (1.47 g, 90%). The solvent and any excess thionyl chloride were removed under reduced pressure the oil obtained The solvent was removed under reduced pressure

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

Procedure: To a mixture of (rac)-3-amino-2-methylpropanoic acid ethyl ester hydrochloride (prepared from 3.09 g, 0.030 mole of (rac)-3-amino-2-methylpropanoic acid, thionyl chloride and ethanol) and 2.8 mL (0.0315 mole) of cyclopentanone and 100 mL of dichloromethane was added 5.4 g (0.066 mole) of sodium acetate and 9.54 g (0.045 mole) of sodium triacetoxyborohydride. The mixture was stirred at ambient temperature for 3 hrs and then quenched by the addition of 50 mL of 10% sodium bicarbonate solution. The aqueous layer was extracted with twice with 100 mL of dichloromethane, and the combined dichloromethane layers dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5 gradient) to give 2.86 g of (rac)-3-cyclopentylamino-2-methyl-propanoic acid ethyl ester. quenched by the addition of 50 mL of 10% sodium bicarbonate solution The aqueous layer was extracted with twice with 100 mL of dichloromethane the combined dichloromethane layers dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-95:5 gradient)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorobenzaldehyde (0.622 mL, 5.80 mmol), sodium acetate (0.951 g, 11.6 mmol), powdered/activated 4 Å molecular sieves (2.0 g) and sodium cyanoborohydride (0.729 g, 11.6 mmol) were added sequentially to a solution of racemic 3-amino-2-methyl-propionic acid ethyl ester hydrochloride (0.972 g, 5.80 mmol) in methanol (30 mL) at 25° C. The mixture was stirred at 25° C. for 20 h, and then was filtered through Celite. The Celite was washed with methanol (2×30 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.821 g, 3.43 mmol, 59%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, d, J=7.2 Hz), 1.26 (3H, t, J=6.9 Hz), 2.63-2.72 (2H, m), 2.84-2.91 (1H, m), 3.75 (1H, d, J=13.3 Hz), 3.79 (1H, d, J=13.4 Hz), 4.14 (2H, q, J=6.9 Hz), 6.97-7.01 (2H, m), 7.25-7.29 (2H, m). was filtered through Celite The Celite was washed with methanol (2×30 mL) the combined filtrate and washings were concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorobenzaldehyde (0.622 mL, 5.80 mmol), sodium acetate (0.951 g, 11.6 mmol), powdered/activated 4 Å molecular sieves (2.0 g) and sodium cyanoborohydride (0.729 g, 11.6 mmol) were added sequentially to a solution of racemic 3-amino-2-methyl-propionic acid ethyl ester hydrochloride (0.972 g, 5.80 mmol) in methanol (30 mL) at 25° C. The mixture was stirred at 25° C. for 20 h, and then was filtered through Celite. The Celite was washed with methanol (2×30 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.821 g, 3.43 mmol, 59%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, d, J=7.2 Hz), 1.26 (3H, t, J=6.9 Hz), 2.63-2.72 (2H, m), 2.84-2.91 (1H, m), 3.75 (1H, d, J=13.3 Hz), 3.79 (1H, d, J=13.4 Hz), 4.14 (2H, q, J=6.9 Hz), 6.97-7.01 (2H, m), 7.25-7.29 (2H, m). was filtered through Celite The Celite was washed with methanol (2×30 mL) the combined filtrate and washings were concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes)