methyl (2R)-3-(2-bromophenyl)-2-(methoxycarbonylamino)propanoate

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

Procedure: Stir a mixture of methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate (29.1 g, 92.10 mmol) and paraformaldehyde (9.13 g, 101.3 mmol) in glacial acetic acid (115 mL, 2.01 mol) and concentrated sulfuric acid (38.4 mL, 719.9 mmol) at room temperature for 7 hours. Partition between water and ethyl acetate. Separate the layers and extract the aqueous layer with ethyl acetate. Combine the ethyl acetate extracts and dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (27.6 g, 84.0 mmol). MS (m/z): 328 (M+1). Partition between water and ethyl acetate Separate the layers extract the aqueous layer with ethyl acetate dry over sodium sulfate filter concentrate under reduced pressure Purify the residue by silica gel chromatography eluting with ethyl acetate

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add water (2.94 L) and sodium hydrogen carbonate (648.25 g, 7.64 mol) to methyl 2-bromo-D-phenylalaninate hydrochloride (580 g, 1.91 mol) in dichloromethane (9.86 L) at 10° C. in an appropriate vessel. After 5 minutes add methyl chloroformate (198.53 g, 2.10 mol) and stir the mixture at 20° C. After 3 hours add water (2.5 L) and separate the layers. Extract the aqueous with dichloromethane, dry the combined organic extracts over sodium sulfate and concentrate under reduced pressure to give the title compound (556 g, 1.74 mol). MS (m/z): 315.8 (M+1 (79Br)), 317.8 (M+1 (81Br)). separate the layers Extract the aqueous with dichloromethane dry the combined organic extracts over sodium sulfate concentrate under reduced pressure

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

Procedure: Dissolve methyl 2-bromo-D-phenylalaninate hydrochloride (27.2 g, 92.3 mmol) in dichloromethane (923 mL) and water (185 mL). Add sodium bicarbonate (31.0 g, 369.4 mmol) and methyl chloroformate (7.86 mL, 101.6 mmol) at room temperature. Stir the mixture 2.5 hours. Dilute with water and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate:hexanes (10-75% gradient) to give the title compound (29.1 g, 92.1 mmol). MS (m/z): 316 (M+1). at room temperature extract with dichloromethane Dry the dichloromethane filter concentrate under reduced pressure Purify the residue by silica gel chromatography eluting with ethyl acetate