methyl (3S)-3-amino-3-phenylpropanoate

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

Procedure: A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25 M methanolic hydrogen chloride (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated aqueous sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g. under reflux for 2½ hours the phases separated The aqueous layer was extracted with dichloromethane (4×) The combined organic solutions were washed with brine dried (MgSO4) filtered evaporated under reduced pressure

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

Procedure: A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25 M methanolic hydrogen chloride (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated aqueous sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g. under reflux for 2½ hours the phases separated The aqueous layer was extracted with dichloromethane (4×) The combined organic solutions were washed with brine dried (MgSO4) filtered evaporated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ru(OAc)2((R)-dm-binap) (13.4 mg, 0.0140 mmol), methyl benzoylacetate (500 mg, 2.806 mmol), ammonium acetate (216 mg, 2.806 mmol) and methanol (2.5 mL) were placed in a 100 mL stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate/triethylamine=50/50/5-0/95/5) to give methyl (3S)-3-amino-3-phenylpropionate (201 mg) as a colorless oil in 40.0% yield. The enantiomeric excess of the product was determined to be 96.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.) after conversion into methyl (3S)-3-(4-nitrobenzoylamino)-3-phenylpropionate. The reaction mixture was cooled down to room temperature further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours After completion of the reaction the solvent was removed by evaporation the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate/triethylamine=50/50/5-0/95/5)

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

Procedure: Using a similar procedure to that described in Preparation 45, the title compound (19 mg) was prepared from methyl (3S)-3-amino-3-phenylpropanoate and 2,4-dinitrochlorobenzene, and liberated as the free acid using a procedure similar to that described in Preparation II. [LCMS (Method C, Mobile Phase I) RT=2.60 min, MH+ 312]. that described in Preparation 45

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

Procedure: To a solution of the amino ester from Example 6, Step A (4.2 mmol, 896 mg) and cyclobutanecarboxylic acid (5.0 mmol, 476 μL) in 10 mL of DCM containing N,N-diisopropylethylamine (12.5 mmol, 2.17 mL) was added 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (5.0 mmol, 958 mg). After 16 h the reaction mixture was washed with H2O (10 mL), 1 M citric acid (10 mL) and saturated NaHCO3 (10 mL). The organic phase was dried with MgSO4 and the solvent removed under reduced pressure to afford the product as a white solid. MS (ESI): m/z 485 (M+H). HPLC B: 1.58 min. After 16 h the reaction mixture was washed with H2O (10 mL), 1 M citric acid (10 mL) and saturated NaHCO3 (10 mL) The organic phase was dried with MgSO4 the solvent removed under reduced pressure

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

Procedure: 2.3 g (11.65 mmol) of (S)-3-amino-3-phenylpropionic acid are introduced in 100 ml of methanol and admixed with a catalytic amount of concentrated sulfuric acid (0.02 eq.). The reaction mixture is heated at reflux for 24 h and then concentrated. The crude product can be used without further purification in the next stage. The reaction mixture is heated at reflux for 24 h concentrated The crude product can be used without further purification in the next stage

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

Procedure: A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25M methanolic hydrogen chloride (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated aqueous sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g; under reflux for 2½ hours the phases separated The aqueous layer was extracted with dichloromethane (4×) The combined organic solutions were washed with brine dried (MgSO4) filtered evaporated under reduced pressure

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

Procedure: t-Butyl (3S)-3-amino-3-phenylpropanoate (1.0 g, 4.97 mmol) was dissolved in methanolic hydrochloric acid (2.25M, 25 ml). The reaction mixture was heated under reflux for 3 hours, after which time the solvent was evaporated under reduced pressure and the residue basified with aqueous saturated sodium carbonate solution. The product was then extracted using dichloromethane (x2), the combined organic layers were dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the title compound as a white solid, 778 mg. The reaction mixture was heated under reflux for 3 hours after which time the solvent was evaporated under reduced pressure The product was then extracted the combined organic layers were dried (MgSO4) filtered the solvent removed under reduced pressure

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

Procedure: A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25M methanolic hydrochloric acid (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×), the combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g. under reflux for 2½ hours the phases separated The aqueous layer was extracted with dichloromethane (4×) the combined organic solutions were washed with brine dried (MgSO4) filtered evaporated under reduced pressure

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

Procedure: A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25M methanolic hydrochloric acid (100 ml) was heated under reflux for 2 hours. The mixture was cooled to room temperature, basified with saturated sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×), the combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound 3.97 g. under reflux for 2 hours the phases separated The aqueous layer was extracted with dichloromethane (4×) the combined organic solutions were washed with brine dried (MgSO4) filtered evaporated under reduced pressure

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

Procedure: A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25 M methanolic hydrogen chloride (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated aqueous sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g. under reflux for 2½ hours the phases separated The aqueous layer was extracted with dichloromethane (4×) The combined organic solutions were washed with brine dried (MgSO4) filtered evaporated under reduced pressure