ethyl (2S)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

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

Procedure: A mixture of N-(BOC)-(S)-tyrosine ethyl ester (1.79 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 12 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40° for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colourless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.81 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colourless oil (0.87 g, 62%) δH (CDCl3) 9.77 (1H, s), 8.75 (1H, d, J. 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1 H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 4.22 (2H, q, J 7/1 Hz), 3.80-3.70 (1H, obscured m), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) 1.30 (3H, t, J 7.1 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+). at 40° for 18 h The DMF was removed in vacuo the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml) The phases were separated the aqueous layer re-extracted with EtOAc (2×20 ml) The combined organic extracts were washed with brine (10 ml) dried (Na2SO4) evaporated in vacuo to afford a new colourless oil

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS(APCI) m/z 327(M+NH4), 310(M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS(APCI) m/z 327(M+NH4), 310(M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: A mixture of N-(BOC)-(S)-tyrosine ethyl ester (1.79 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 12 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40° for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colourless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.81 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colourless oil (0.87 g, 62%) δH (CDCl3) 9.77 (1H, s), 8.75 (1H, d, J. 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1 H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 4.22 (2H, q, J 7/1 Hz), 3.80-3.70 (1H, obscured m), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) 1.30 (3H, t, J 7.1 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+). at 40° for 18 h The DMF was removed in vacuo the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml) The phases were separated the aqueous layer re-extracted with EtOAc (2×20 ml) The combined organic extracts were washed with brine (10 ml) dried (Na2SO4) evaporated in vacuo to afford a new colourless oil

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

Procedure: A mixture of N-(BOC)-(S)-tyrosine ethyl ester (1.79 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 12 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40° for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colourless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.81 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colourless oil (0.87 g, 62%) δH (CDCl3) 9.77 (1H, s), 8.75 (1H, d, J. 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1 H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 4.22 (2H, q, J 7/1 Hz), 3.80-3.70 (1H, obscured m), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) 1.30 (3H, t, J 7.1 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+). at 40° for 18 h The DMF was removed in vacuo the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml) The phases were separated the aqueous layer re-extracted with EtOAc (2×20 ml) The combined organic extracts were washed with brine (10 ml) dried (Na2SO4) evaporated in vacuo to afford a new colourless oil

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS(APCI) m/z 327(M+NH4), 310(M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane

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

Procedure: To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H). The organic layer was washed with H2O dried (Na2SO4) evaporated The residue was recrystallized from a mixture of diethyl ether and hexane