methyl (2R)-2-amino-3-phenylmethoxypropanoate

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

Procedure: To a solution of O-benzyl-D-serine methyl ester (3,13 g, 14.96 mmol) in MeOH, was added 2-fluoronitrobenzene (1.6 mL, 15.08 mmol) and NaHCO3 (1.3 g, 15.48 mmol), and the resulting solution was brought to a reflux for approximately one day. The reaction mixture was then cooled, filtered, concentrated and chased with benzene (4×50 ml). The residue was re-dissolved in EtOAc, cooled to 0° C. and HCl gas was bubbled into the resulting solution until it reached a pH of ˜4. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. Upon completion, the reaction mixture was washed with saturated NaHCO3 (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography eluting with 8%-30% EtOAc in Hexanes to give 1.09 g (3.30 mmol) of N-(2-nitrophenyl)-O-benzyl-D-serine methyl ester. a reflux for approximately one day The reaction mixture was then cooled filtered concentrated The residue was re-dissolved in EtOAc HCl gas was bubbled into the resulting solution until it to warm to room temperature Upon completion, the reaction mixture was washed with saturated NaHCO3 (3×50 mL) dried over sodium sulfate filtered concentrated under reduced pressure eluting with 8%-30% EtOAc in Hexanes

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

Procedure: To a solution of BOC-O-benzyl-D-serine (5.05 g, 17.12 mmol) in MeOH (100 mL) at −78° C., was added SOCl2 dropwise. The reaction mixture was warmed to 0° C. and stirred for ˜4 hours and then concentrated. The residue was taken up in EtOAc and washed with 10% Na2CO3 (3×80 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. To the crude material in EtOAc (100 mL) at 0° C. was bubbled HCl gas for approximately 10 minutes, and the reaction was capped and the mixture stirred at 0° C. for 30 minutes before it was concentrated in vacuo. The crude material was diluted with 50 mL of a 1:1 solution of saturated NaHCO3/10% Na2CO3 and extracted with EtOAc (4×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give O-benzyl-D-serine methyl ester (3.13 g, 14.96 mmol) which was used without further purification. LCMS (ES) m/z 210.1 (M+H)+. concentrated washed with 10% Na2CO3 (3×80 mL) The organic layer was dried over sodium sulfate filtered concentrated To the crude material in EtOAc (100 mL) at 0° C. was bubbled HCl gas for approximately 10 minutes the reaction was capped the mixture stirred at 0° C. for 30 minutes before it was concentrated in vacuo The crude material was diluted with 50 mL of a 1:1 solution of saturated NaHCO3/10% Na2CO3 extracted with EtOAc (4×50 mL) The combined organics were dried over sodium sulfate filtered concentrated

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

Procedure: To a solution of tert-butyloxycarbonyl-O-benzyl-D-serine methyl ester (BF8-EZ0-275) (5.0 g, 16 mmol) stirring in dichloromethane (40 mL) and anisole (1 mL) at 0° C. was added trifluoroacetic acid (10 mL). After 4 h at room temperature, a saturated aqueous solution of sodium bicarbonate was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sufate, and concentrated. The crude product was used in the next step without further purification. the resulting mixture extracted with ethyl acetate The combined organic extracts were washed with brine dried over sodium sufate concentrated The crude product was used in the next step without further purification

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

Procedure: A solution of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester (19 g, 78 mmol) in methanol (350 mL) under N2 was cooled to 0° C. and acetic acid (2 g, pH 2) was added, followed by the addition of 4-fluorobenzaldehyde, a compound of formula (N) (12.5 mL, 117 mmol) and sodium cyanoborohydride (7.3 g, 117 mmol) and 3 Å molecular sieves (15 g). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through Celite (MeOH). The filtrate was concentrated in vacuo to afford a clear liquid. This was taken up in ethyl acetate and washed sequentially with 10% aqueous Na2CO3 solution, water, then brine. The organic phase was then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 14.7 g (60% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)amino)propanoic acid methyl ester, a compound of formula (O), as a clear, colorless oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 4.5 (d, 2), 3.9-3.5 (m, 8) ppm, MS (LSIMS) 317. filtered through Celite (MeOH) The filtrate was concentrated in vacuo to afford a clear liquid washed sequentially with 10% aqueous Na2CO3 solution, water The organic phase was then dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel

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

Procedure: A solution of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester (19 g, 78 mmol) in methanol (350 mL) under N2 was cooled to 0° C. and acetic acid (2 g, pH 2) was added, followed by the addition of 4-fluorobenzaldehyde, a compound of formula (N) (12.5 mL, 117 mmol) and sodium cyanoborohydride (7.3 g, 117 mmol) and 3 Å molecular sieves (15 g). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through Celite (MeOH). The filtrate was concentrated in vacuo to afford a clear liquid. This was taken up in ethyl acetate and washed sequentially with 10% aqueous Na2CO3 solution, water, then brine. The organic phase was then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 14.7 g (60% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)amino)propanoic acid methyl ester, a compound of formula (O), as a clear, colorless oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 4.5 (d, 2), 3.9-3.5 (m, 8) ppm, MS (LSIMS) 317. filtered through Celite (MeOH) The filtrate was concentrated in vacuo to afford a clear liquid washed sequentially with 10% aqueous Na2CO3 solution, water The organic phase was then dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel

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

Procedure: A solution of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester (19 g, 78 mmol) in methanol (350 mL) under N2 was cooled to 0° C. and acetic acid (2 g, pH 2) was added, followed by the addition of 4-fluorobenzaldehyde, a compound of formula (N) (12.5 mL, 117 mmol) and sodium cyanoborohydride (7.3 g, 117 mmol) and 3 Å molecular sieves (15 g). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through Celite (MeOH). The filtrate was concentrated in vacuo to afford a clear liquid. This was taken up in ethyl acetate and washed sequentially with 10% aqueous Na2CO3 solution, water, then brine. The organic phase was then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 14.7 g (60% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)amino)propanoic acid methyl ester, a compound of formula (O), as a clear, colorless oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 4.5 (d, 2), 3.9-3.5 (m, 8) ppm, MS (LSIMS) 317. filtered through Celite (MeOH) The filtrate was concentrated in vacuo to afford a clear liquid washed sequentially with 10% aqueous Na2CO3 solution, water The organic phase was then dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel

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

Procedure: A solution of (2R)-3-benzyloxy-2-(N-(t-butoxycarbonyl)amino)propanoic acid (23 g, 78 mmol, [α]D−4.4° (c=2, H2O)) in methanol (250 mL) was cooled to 0° C. and HCl (g) bubbled into the solution until saturated. The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo to afford 17 g (100% yield) of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester, a compound of formula (M), as a white solid; NMR (DMSO-d6) 8.7 (br s, 3), 7.4-7.3 (m, 5), 4.5 (q, 2), 4.4 (br s, 1), 3.8 (s, 2), 3.7 (s, 3) ppm. HCl (g) bubbled into the solution until saturated concentrated in vacuo

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

Procedure: A solution of (2R)-3-benzyloxy-2-(N-(t-butoxycarbonyl)amino)propanoic acid (23 g, 78 mmol, [α]D−4.4° (c=2, H2O)) in methanol (250 mL) was cooled to 0° C. and HCl (g) bubbled into the solution until saturated. The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo to afford 17 g (100% yield) of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester, a compound of formula (M), as a white solid; NMR (DMSO-d6) 8.7 (br s, 3), 7.4-7.3 (m, 5), 4.5 (q, 2), 4.4 (br s, 1), 3.8 (s, 2), 3.7 (s, 3) ppm. HCl (g) bubbled into the solution until saturated concentrated in vacuo

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

Procedure: A solution of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester (19 g, 78 mmol) in methanol (350 mL) under N2 was cooled to 0° C. and acetic acid (2 g, pH 2) was added, followed by the addition of 4-fluorobenzaldehyde, a compound of formula (N) (12.5 mL, 117 mmol) and sodium cyanoborohydride (7.3 g, 117 mmol) and 3 A molecular sieves (15 g). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through Celite (MeOH). The filtrate was concentrated in vacuo to afford a clear liquid. This was taken up in ethyl acetate and washed sequentially with 10% aqueous Na2CO3 solution, water, then brine. The organic phase was then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 14.7 g (60% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)amino)propanoic acid methyl ester, a compound of formula (O), as a clear, colorless oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 4.5 (d, 2), 3.9-3.5 (m, 8) ppm, MS (LSIMS) 317. filtered through Celite (MeOH) The filtrate was concentrated in vacuo to afford a clear liquid washed sequentially with 10% aqueous Na2CO3 solution, water The organic phase was then dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel

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

Procedure: A solution of (2R)-3-benzyloxy-2-(N-(t-butoxycarbonyl)amino)propanoic acid (23 g, 78 mmol, [α]D −4.4° (c=2, H2O )) in methanol (250 mL) was cooled to 0° C. and HCl (g) bubbled into the solution until saturated. The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo to afford 17 g (100% yield) of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester, a compound of formula (M), as a white solid; NMR (DMSO-d6) 8.7 (br s, 3), 7.4-7.3 (m, 5), 4.5 (q, 2), 4.4 (br s, 1), 3.8 (s, 2), 3.7 (s, 3) ppm. HCl (g) bubbled into the solution until saturated concentrated in vacuo

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

Procedure: A solution of sodium ethoxide was generated by the addition of sodium metal (52.89 grams, 2.3007 mol) over 3 hours to ethanol (1500 mL). To the sodium ethoxide solution at ambient temperature was added a solution of diethylacetamidomalonate (499.75 grams, 2.3007 mol) dissolved in ethanol (225 mL). The reaction mixture was stirred for 1.5 hours at ambient temperature. 1-bromo-3-phenylpropane (458.07 grams, 2.3007 mol) was added over 15 minutes and the reaction mixture was refluxed until complete as determined by hplc (16 hours). The reaction mixture was concentrated to dryness and the residue partitioned between ethyl acetate (1×1500 mL and 2×500 mL) and water (1500 mL). The ethyl acetate layers were combined, washed with saturated sodium chloride solution (4×500 mL), dried using sodium sulfate, and concentrated to give 752.1 grams (98%) of the desired compound as a light yellow solid. A 1.0 gram sample was recrystallized from hexane:ethyl acetate (19:1, v:v) to give a mp 84-86° C. 1H nmr (CDCl3): δ1.18-1.23 (t, 6H), 1.37-1.50 (m, 2H), 2.02 (s, 3H), 2.34-2.41 (m, 2H), 2.58-2.62 (t, 2H), 4.16-4.24 (q, 4H), 6.76 (s, broad, 1H), 7.11-7.28 (m, 5H). 13C nmr (CDCl3): δ13.95, 23.03, 25.67, 31.85, 35.45, 62.46, 66.49, 125.40, 125.90, 128.27, 128.35, 141.77, 168.11, 168.94. MS (FIA) m/z 336.3 ([M+H]+). IR (KBr, cm−1) 1645.98 (amide), 1744.76 (C=O). Anal. Calcd. for C18H25NO5: C, 64.46; H, 7.51; N, 4.17. Found: C, 64.60; H, 7.37; N, 4.39. the reaction mixture was refluxed until complete as determined by hplc (16 hours) The reaction mixture was concentrated to dryness the residue partitioned between ethyl acetate (1×1500 mL and 2×500 mL) and water (1500 mL) washed with saturated sodium chloride solution (4×500 mL) dried concentrated

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

Procedure: A solution of sodium ethoxide was generated by the addition of sodium metal (52.89 grams, 2.3007 mol) over 3 hours to ethanol (1500 mL). To the sodium ethoxide solution at ambient temperature was added a solution of diethylacetamidomalonate (499.75 grams, 2.3007 mol) dissolved in ethanol (225 mL). The reaction mixture was stirred for 1.5 hours at ambient temperature. 1-bromo-3-phenylpropane (458.07 grams, 2.3007 mol) was added over 15 minutes and the reaction mixture was refluxed until complete as determined by hplc (16 hours). The reaction mixture was concentrated to dryness and the residue partitioned between ethyl acetate (1×1500 mL and 2×500 mL) and water (1500 mL). The ethyl acetate layers were combined, washed with saturated sodium chloride solution (4×500 mL), dried using sodium sulfate, and concentrated to give 752.1 grams (98%) of the desired compound as a light yellow solid. A 1.0 gram sample was recrystallized from hexane:ethyl acetate (19:1, v:v) to give a mp 84-86° C. 1H nmr (CDCl3): δ1.18-1.23 (t, 6H), 1.37-1.50 (m, 2H), 2.02 (s, 3H), 2.34-2.41 (m, 2H), 2.58-2.62 (t, 2H), 4.16-4.24 (q, 4H), 6.76 (s, broad, 1H), 7.11-7.28 (m, 5H). 13C nmr (CDCl3): δ13.95, 23.03, 25.67, 31.85, 35.45, 62.46, 66.49, 125.40, 125.90, 128.27, 128.35, 141.77, 168.11, 168.94. MS (FIA) m/z 336.3 ([M+H]+). IR (KBr, cm−1) 1645.98 (amide), 1744.76 (C=O). Anal. Calcd. for C18H25NO5: C, 64.46; H, 7.51; N, 4.17. Found: C, 64.60; H, 7.37; N, 4.39. the reaction mixture was refluxed until complete as determined by hplc (16 hours) The reaction mixture was concentrated to dryness the residue partitioned between ethyl acetate (1×1500 mL and 2×500 mL) and water (1500 mL) washed with saturated sodium chloride solution (4×500 mL) dried concentrated