methyl (2S)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoate

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

Procedure: A suspension of Cs2CO3 (0.65 g, 2.0 mmol), N-Cbz-L-tyrosine (1.3 g, 4.0 mmol; Bachem) and DMF (40 mL) at ambient temperature was treated with methyl iodide (0.5 mL, 4.0 mmol). After 2.0 h the reaction mixture was diluted with EtOAc and then washed with H2O and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 6-4 as a white solid. Rf 0.53 (silica, 50% EtOAc/hexanes). washed with H2O and brine dried (MgSO4) concentrated

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, dispersed between ethyl acetate and water, and the organic phase is mixed with hexane after drying (Na2SO4). The title compound crystallizes out. The solution is concentrated by evaporation dispersed between ethyl acetate and water the organic phase is mixed with hexane after drying (Na2SO4) The title compound crystallizes out

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, dispersed between ethyl acetate and water, and the organic phase is mixed with hexane after drying (Na2SO4). The title compound crystallizes out. The solution is concentrated by evaporation dispersed between ethyl acetate and water the organic phase is mixed with hexane after drying (Na2SO4) The title compound crystallizes out

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water, and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out. The solution is concentrated by evaporation after drying (Na2SO4) the organic phase is mixed with hexane The title compound crystallizes out

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water, and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out. The solution is concentrated by evaporation after drying (Na2SO4) the organic phase is mixed with hexane The title compound crystallizes out

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water, and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out. The solution is concentrated by evaporation after drying (Na2SO4) the organic phase is mixed with hexane The title compound crystallizes out

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyltyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 8.96 ml (110 mmol) of iodoethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out. The solution is concentrated by evaporation after drying (Na2SO4) the organic phase is mixed with hexane The title compound crystallizes out

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyltyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 8.96 ml (110 mmol) of iodoethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out. The solution is concentrated by evaporation after drying (Na2SO4) the organic phase is mixed with hexane The title compound crystallizes out

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

Procedure: H-D-Tyr-O-me hydrochloride 2.1 (25 g, 107.7 mmol) is dissolved in methylene chloride (150 mL) and aqueous sodium bicarbonate (22 g in 150 mL water), and then cooled to 0° C. To this resulting solution benzyl chloroformate (20 g, 118 mmol) is slowly added. After complete addition, the resulting solution is warmed to room temperature, and is then stirred for 2 h. The organic phase is separated, dried over Na2SO4, and concentrated under reduced pressure, to give the crude carbamate 2.2 (35 g). The crude CBZ-Tyr-OMe product is dissolved in methylene chloride (300 mL) containing concentrated H2SO4. Isobutene is bubbled though the solution for 6 h. The reaction is then cooled to 0° C., and neutralized with saturated NaHCO3 aqueous solution. The organic phase is separated, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to afford the tert-butyl ether 2.3 (25.7 g, 62%). Isobutene is bubbled though the solution for 6 h The organic phase is separated dried concentrated under reduced pressure purified by silica gel column chromatography

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

Procedure: In a similar manner to that described in Reference example 25, a reaction was carried out using N-benzyloxycarbonyl-L-tyrosine methyl ester (4.94 g), t-butyl 2-methanesulfonyloxyethylcarbamate (8.97 g) and potassium carbonate (10.4 g) and the reaction mixture was treated to afford the title compound (3.32 g) as colorless crystals. the reaction mixture was treated

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

Procedure: To a solution of 100 mg (0.30 mmol) of methyl (2S)-3-(4-hydroxyphenyl)-2-[(phenylmethoxy)carbonylamino]propanoate, as prepared in the preceding step, 67 mg (0.30 mmol) of 2-(3-hydroxypropoxy)isoindoline-1,3-dione, as prepared in step 2, and 88 mg (0.34 mmol) of triphenylphosphine in 10 mL THF at water/ice mixture temperature was added 66 mL (0.34 mmol) of DIAD dropwise. The solution was stirred at the same temperature for additional 20 min. Then the solution was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure. The mixture was chromatographed on a silica gel column using EtOAc/hexanes (3:7 to 2:3 v/v) as eluent to yield 89 mg (55%) of viscous liquid as product: 1H NMR (300 MH, CDCl3) δ7.85-7.80 (m, 2H), 7.77-7.71 (m, 2H), 7.38-7.27 (m, 5H), 6.98 (d, J=8.65 Hz, 2H), 6.82 (d, J=8.65 Hz, 2H), 5.19 (d, J=8.16 Hz, 1H), 5.09 (s, 2H), 4.61 (m, 1H), 4.40 (t,J=6.22, 2H), 4.19 (t, J=6.11 Hz, 2H), 3.71 (s, 3H), 3.08-2.96 (m, 2H), 2.23 (quintet, J=6.15 Hz, 2H). stirred overnight The solvent was removed under reduced pressure The mixture was chromatographed on a silica gel column

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

Procedure: 32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, dispersed between ethyl acetate and water, and the organic phase is mixed with hexane after drying (Na2SO4). The title compound crystallizes out. The solution is concentrated by evaporation dispersed between ethyl acetate and water the organic phase is mixed with hexane after drying (Na2SO4) The title compound crystallizes out