ethyl 2-(benzylamino)propanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-benzylamino-propionic acid ethyl ester (24.72 g, 1 eq.) in 114 mL of dry DCM under nitrogen was added MgSO4 (10.80 g, 0.75 eq.). The reaction was cooled to 0° C. then acetic acid (6.82 mL, 1 eq) and the above solution of chloroacetaldehyde in dry DCM (solution I) were added. Sodium triacetoxyborohydride (38 g, 1.5 eq.) was added portionwise. The reaction was stirred for 2 h at 0° C. The crude was carefully quenched with 160 mL of a saturated aqueous solution of NaHCO3. Then 75 mL of an aqueous solution of NaOH (2N) was added. The aqueous layer was extracted twice with 120 mL of DCM. The combined organic layers were washed twice with 120 mL of a saturated aqueous solution of NaHCO3, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 100/0 to 93/7) to afford 2-[benzyl-(2-chloro-ethyl)-amino]-propionic acid ethyl ester (27.40 g, yield=85%). The crude was carefully quenched with 160 mL of a saturated aqueous solution of NaHCO3 Then 75 mL of an aqueous solution of NaOH (2N) was added The aqueous layer was extracted twice with 120 mL of DCM The combined organic layers were washed twice with 120 mL of a saturated aqueous solution of NaHCO3 dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 100/0 to 93/7)

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromo-propionic acid ethyl ester (17.90 mL, 1 eq.) in 250 mL of MeCN were added benzylamine (13.45 mL, 0.9 eq.) and potassium carbonate (28.60 g, 1.5 eq.). The reaction was refluxed for 2 h then cooled to 20° C. The crude was filtered, washed with EtOAc. The filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1 to 7/3) to afford 2-benzylamino-propionic acid ethyl ester (24.74 g, yield=97%). The reaction was refluxed for 2 h The crude was filtered washed with EtOAc The filtrate was concentrated under reduced pressure purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1 to 7/3)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-benzylamino-propionic acid ethyl ester (1 eq.) in dry DCM was added MgSO4 (0.75 eq.). The reaction was cooled to 0° C. then the above solution of chloroacetaldehyde in dry DCM (solution I) and acetic acid (1 eq.) were added. Sodium triacetoxyborohydride (1.5 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C. The crude was carefully quenched with a saturated aqueous solution of NaHCO3. Then aqueous NaOH (2N) was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with an aqueous saturated solution of NaHCO3, then dried over MgSO4 and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc 98/2 to 95/5) to afford 2-[benzyl-(2-chloro-ethyl)-amino]-propionic acid ethyl ester. The crude was carefully quenched with a saturated aqueous solution of NaHCO3 Then aqueous NaOH (2N) was added The aqueous layer was extracted with DCM The combined organic layers were washed with an aqueous saturated solution of NaHCO3 dried over MgSO4 concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with heptane/EtOAc 98/2 to 95/5)

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromo-propionic acid ethyl ester (1 eq.) in MeCN was added benzylamine (0.9 eq.) and potassium carbonate (1.5 eq.). The reaction was refluxed for 4 h then cooled to 20° C. and diluted with EtOAc. The crude was filtered, the filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 7/3) to afford 2-benzylamino-propionic acid ethyl ester. The reaction was refluxed for 4 h The crude was filtered the filtrate was concentrated under reduced pressure purified by chromatography on silica gel (elution with heptane/EtOAc: 7/3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), TEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1). The reaction is partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl alanine hydrochloride (5.5 g, 36.8 mmol), benzaldehyde (7.9 mL, 77.8 mmol), TEA (10.8 mL, 77.8 mmol) and NaBH(Oac)3 (16.5 g, 77.8 mmol) are taken up in 1,2-DCE (200 mL) and stirred at rt for 4 h. The reaction is then partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 208.2 (M+1). The reaction is then partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H). quenched by the addition of saturated aqueous NaHCO3 solution The layers were separated the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Chromatography on SiO2 column eluting with EtOAc/Hex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H). quenched by the addition of saturated aqueous NaHCO3 solution The layers were separated the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Chromatography on SiO2 column eluting with EtOAc/Hex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of DL-alanine ethyl ester hydrochloride (913 mg, 5.9 mmol) in DCE (15 mL) was added TEA (1.2 mL, 8.8 mmol) followed by benzaldehyde (0.538 mL), 5.3 mmol) and Na(OAc)3BH (2.0 g, 9.4 mmol). The mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting EtOAc/Hex afforded the desired compound as a colorless liquid (798 mg, 73%). MS (ESI) mass calcd. C12H17NO2, 207.1. m/z found 208.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.39-7.23 (m, 5H), 4.23-4.16 (m, 2H), 3.83-3.65 (m, 2H), 3.37 (q, J=7.0 Hz, 1H), 1.34-1.27 (m, 6H). quenched with saturated aqueous NaHCO3 solution The layers were separated the aqueous layer extracted with DCM The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Chromatography on SiO2 eluting EtOAc/Hex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1). The reaction is partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl alanine hydrochloride (5.5 g, 36.8 mmol), benzaldehyde (7.9 mL, 77.8 mmol), TEA (10.8 mL, 77.8 mmol) and NaBH(Oac)3 (16.5 g, 77.8 mmol) are taken up in 1,2-DCE (200 mL) and stirred at rt for 4 h. The reaction is then partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 208.2 (M+1). The reaction is then partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification