3-cyclobutyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid

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

Procedure: (Trimethylsilyl)diazomethane (3.65 mL of a 1.0 M solution in diethyl ether, 7.3 mmol) was added over 2 min to a solution of racemic 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.89 g, 3.66 mmol) in a 1:1 mixture of methanol/benzene (50 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 40 min, then was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. and a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added. After stirring at 25° C. for 3.5 h, the reaction mixture was concentrated in vacuo to afford a sticky oil. This material was dissolved in toluene (80 mL) and the solution was concentrated in vacuo (the process was then repeated). The resulting residue was dissolved in methanol (25 mL) at 25° C. and 4-fluorobenzaldehyde (0.393 mL, 3.66 mmol), sodium acetate (0.600 g, 7.31 mmol), powdered/activated 4 Å molecular sieves (0.85 g) and sodium cyanoborohydride (0.46 g, 7.32 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were 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-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.424 g, 1.60 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.68-1.80 (2H, m), 1.82-1.89 (1H, m), 1.92-1.99 (1H, m), 2.04-2.11 (1H, m), 2.32-2.45 (2H, m), 2.94-2.99 (1H, m), 3.67 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.96-7.01 (2H, m), 7.25-7.30 (2H, m). was concentrated in vacuo The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added After stirring at 25° C. for 3.5 h the reaction mixture was concentrated in vacuo to afford a sticky oil the solution was concentrated in vacuo (the process The resulting residue was dissolved in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 16 h was filtered through Celite The Celite was washed with ethyl acetate (2×30 mL) the combined filtrate and washings were 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: To a solution of 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.300 g, 1.23 mmol) in THF (12 mL) was added BH3—SMe2 (1.70 mL, 3.33 mmol; 2.0 M solution in THF) at 0° C. After stirring at rt for 10 h, the reaction mixture was quenched with satd. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford (1-cyclobutyl-3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.100 g); LC-MS [M+H]+ 230.0. The product is sufficiently pure for the next step and used for the next step without further purification. the reaction mixture was quenched with satd NaHCO3, extracted with EtOAc washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: To a solution of 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.300 g, 1.23 mmol) in THF (12 mL) was added BH3—SMe2 (1.70 mL, 3.33 mmol; 2.0 M solution in THF) at 0° C. After stirring at rt for 10 h, the reaction mixture was quenched with satd. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford (1-cyclobutyl-3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.100 g); LC-MS [M+H]+ 230.0. The product is sufficiently pure for the next step and used for the next step without further purification. the reaction mixture was quenched with satd NaHCO3, extracted with EtOAc washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: (Trimethylsilyl)diazomethane (3.65 mL of a 1.0 M solution in diethyl ether, 7.3 mmol) was added over 2 min to a solution of racemic 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.89 g, 3.66 mmol) in a 1:1 mixture of methanol/benzene (50 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 40 min, then was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. and a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added. After stirring at 25° C. for 3.5 h, the reaction mixture was concentrated in vacuo to afford a sticky oil. This material was dissolved in toluene (80 mL) and the solution was concentrated in vacuo (the process was then repeated). The resulting residue was dissolved in methanol (25 mL) at 25° C. and 4-fluorobenzaldehyde (0.393 mL, 3.66 mmol), sodium acetate (0.600 g, 7.31 mmol), powdered/activated 4 Å molecular sieves (0.85 g) and sodium cyanoborohydride (0.46 g, 7.32 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were 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-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.424 g, 1.60 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.68-1.80 (2H, m), 1.82-1.89 (1H, m), 1.92-1.99 (1H, m), 2.04-2.11 (1H, m), 2.32-2.45 (2H, m), 2.94-2.99 (1H, m), 3.67 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.96-7.01 (2H, m), 7.25-7.30 (2H, m). was concentrated in vacuo The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added After stirring at 25° C. for 3.5 h the reaction mixture was concentrated in vacuo to afford a sticky oil the solution was concentrated in vacuo (the process The resulting residue was dissolved in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 16 h was filtered through Celite The Celite was washed with ethyl acetate (2×30 mL) the combined filtrate and washings were 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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Trimethylsilyl)diazomethane (3.65 mL of a 1.0 M solution in diethyl ether, 7.3 mmol) was added over 2 min to a solution of racemic 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.89 g, 3.66 mmol) in a 1:1 mixture of methanol/benzene (50 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 40 min, then was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. and a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added. After stirring at 25° C. for 3.5 h, the reaction mixture was concentrated in vacuo to afford a sticky oil. This material was dissolved in toluene (80 mL) and the solution was concentrated in vacuo (the process was then repeated). The resulting residue was dissolved in methanol (25 mL) at 25° C. and 4-fluorobenzaldehyde (0.393 mL, 3.66 mmol), sodium acetate (0.600 g, 7.31 mmol), powdered/activated 4 Å molecular sieves (0.85 g) and sodium cyanoborohydride (0.46 g, 7.32 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were 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-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.424 g, 1.60 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.68-1.80 (2H, m), 1.82-1.89 (1H, m), 1.92-1.99 (1H, m), 2.04-2.11 (1H, m), 2.32-2.45 (2H, m), 2.94-2.99 (1H, m), 3.67 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.96-7.01 (2H, m), 7.25-7.30 (2H, m). was concentrated in vacuo The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added After stirring at 25° C. for 3.5 h the reaction mixture was concentrated in vacuo to afford a sticky oil the solution was concentrated in vacuo (the process The resulting residue was dissolved in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 16 h was filtered through Celite The Celite was washed with ethyl acetate (2×30 mL) the combined filtrate and washings were 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: To a solution of 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.300 g, 1.23 mmol) in THF (12 mL) was added BH3—SMe2 (1.70 mL, 3.33 mmol; 2.0 M solution in THF) at 0° C. After stirring at rt for 10 h, the reaction mixture was quenched with satd. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford (1-cyclobutyl-3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.100 g); LC-MS [M+H]+ 230.0. The product is sufficiently pure for the next step and used for the next step without further purification. the reaction mixture was quenched with satd NaHCO3, extracted with EtOAc washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: (Trimethylsilyl)diazomethane (3.65 mL of a 1.0 M solution in diethyl ether, 7.3 mmol) was added over 2 min to a solution of racemic 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.89 g, 3.66 mmol) in a 1:1 mixture of methanol/benzene (50 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 40 min, then was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. and a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added. After stirring at 25° C. for 3.5 h, the reaction mixture was concentrated in vacuo to afford a sticky oil. This material was dissolved in toluene (80 mL) and the solution was concentrated in vacuo (the process was then repeated). The resulting residue was dissolved in methanol (25 mL) at 25° C. and 4-fluorobenzaldehyde (0.393 mL, 3.66 mmol), sodium acetate (0.600 g, 7.31 mmol), powdered/activated 4 Å molecular sieves (0.85 g) and sodium cyanoborohydride (0.46 g, 7.32 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were 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-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.424 g, 1.60 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.68-1.80 (2H, m), 1.82-1.89 (1H, m), 1.92-1.99 (1H, m), 2.04-2.11 (1H, m), 2.32-2.45 (2H, m), 2.94-2.99 (1H, m), 3.67 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.96-7.01 (2H, m), 7.25-7.30 (2H, m). was concentrated in vacuo The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added After stirring at 25° C. for 3.5 h the reaction mixture was concentrated in vacuo to afford a sticky oil the solution was concentrated in vacuo (the process The resulting residue was dissolved in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 16 h was filtered through Celite The Celite was washed with ethyl acetate (2×30 mL) the combined filtrate and washings were 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: To a solution of 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.300 g, 1.23 mmol) in THF (12 mL) was added BH3—SMe2 (1.70 mL, 3.33 mmol; 2.0 M solution in THF) at 0° C. After stirring at rt for 10 h, the reaction mixture was quenched with satd. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford (1-cyclobutyl-3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.100 g); LC-MS [M+H]+ 230.0. The product is sufficiently pure for the next step and used for the next step without further purification. the reaction mixture was quenched with satd NaHCO3, extracted with EtOAc washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: (Trimethylsilyl)diazomethane (3.65 mL of a 1.0 M solution in diethyl ether, 7.3 mmol) was added over 2 min to a solution of racemic 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.89 g, 3.66 mmol) in a 1:1 mixture of methanol/benzene (50 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 40 min, then was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. and a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added. After stirring at 25° C. for 3.5 h, the reaction mixture was concentrated in vacuo to afford a sticky oil. This material was dissolved in toluene (80 mL) and the solution was concentrated in vacuo (the process was then repeated). The resulting residue was dissolved in methanol (25 mL) at 25° C. and 4-fluorobenzaldehyde (0.393 mL, 3.66 mmol), sodium acetate (0.600 g, 7.31 mmol), powdered/activated 4 Å molecular sieves (0.85 g) and sodium cyanoborohydride (0.46 g, 7.32 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were 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-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.424 g, 1.60 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.68-1.80 (2H, m), 1.82-1.89 (1H, m), 1.92-1.99 (1H, m), 2.04-2.11 (1H, m), 2.32-2.45 (2H, m), 2.94-2.99 (1H, m), 3.67 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.96-7.01 (2H, m), 7.25-7.30 (2H, m). was concentrated in vacuo The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added After stirring at 25° C. for 3.5 h the reaction mixture was concentrated in vacuo to afford a sticky oil the solution was concentrated in vacuo (the process The resulting residue was dissolved in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 16 h was filtered through Celite The Celite was washed with ethyl acetate (2×30 mL) the combined filtrate and washings were 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)