ethyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: L-Tyrosine ethyl ester (0.28 g, 1.35 mmol) was dissolved in DMF (9 mL). Benzoic acid (1 eq, 1.35 mmol, 0.17 g) was added, followed by N-methylmorpholine (3 eq, 4.06 mmol, 0.45 mL), 1-hydroxybenzotriazole hydrate (1.2 eq, 1.62 mmol, 0.22 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.2 eq, 1.62 mmol, 0.31 g). The yellow solution was allowed to stir at room temperature under nitrogen for three days. The DMF was then removed by rotary evaporation and the resulting residue partitioned between ethyl acetate and water. The organic portion was separated and washed 3×H2O and 1×aq. saturated NaHCO3. It was dried over MgSO4, filtered, and concentrated to an oil. Trituration with diethyl ether induced formation of a white powder (0.32 g, 76%). MS (ES+) m/e 314 [M+H]+, 627. The DMF was then removed by rotary evaporation the resulting residue partitioned between ethyl acetate and water The organic portion was separated washed 3×H2O and 1×aq It was dried over MgSO4 filtered concentrated to an oil

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

Procedure: L-Tyrosine ethyl ester (0.28 g, 1.35 mmol) was dissolved in DMF (9 mL). Benzoic acid (1 eq, 1.35 mmol, 0.17 g) was added, followed by N-methylmorpholine (3 eq, 4.06 mmol, 0.45 mL), 1-hydroxybenzotriazole hydrate (1.2 eq, 1.62 mmol, 0.22 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.2 eq, 1.62 mmol, 0.31 g). The yellow solution was allowed to stir at room temperature under nitrogen for three days. The DMF was then removed by rotary evaporation and the resulting residue partitioned between ethyl acetate and water. The organic portion was separated and washed 3×H2O and 1×aq. saturated NaHCO3. It was dried over MgSO4, filtered, and concentrated to an oil. Trituration with diethyl ether induced formation of a white powder (0.32 g, 76%). MS (ES+) m/e 314 [M+H]+, 627. The DMF was then removed by rotary evaporation the resulting residue partitioned between ethyl acetate and water The organic portion was separated washed 3×H2O and 1×aq It was dried over MgSO4 filtered concentrated to an oil

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

Procedure: Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. the product was purified by silica gel chromatography

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

Procedure: The free base was obtained by neutralizing commercially available material with sodium bicarbonate and extracting with ethyl acetate (250 mL EtOAc per 1 g amino ester). (R,S)-2-Amino-3-(3-hydroxy-phenyl)-propionic acid methyl ester: The methyl ester was prepared from commercially available D,L-meta-tyrosine (10 g, 55 mmole) with thionyl chloride (8 mL, 110 mmole) in 276 mL MeOH (100%). The free base was obtained by neutralizing with sodium bicarbonate and extracting with ethyl acetate (250 mL EtOAc per 1 g amino ester (100% recovery). LC-MS: Rt=0.94 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer), MH+=196. Procedure for N-alkylation of Tyrosine (S,S)-2-[1-Ethoxycarbonyl-2-(4-hydroxy-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester (55-1A). D-Benzyl protected leucic acid triflate (55-0) (23.3 mmole) was added to a cooled solution (−78° C.) of L-tyrosine methyl ester (3.2 g, 15.5 mmole), 2,6 lutidine (2.0 mL, 17.1 mmole) and acetonitrile (155 mL). The solution was stirred overnight and slowly warmed to room temperature. Water was added and the product was extracted with ethyl acetate, washed with brine and dried over NaSO4. The product was purified by silica gel flash chromatography (ISCO-combiflash system; gradient—0–50% ethyl acetate in hexanes). A yellow oil was isolated (4.54 g, 70%). LC-MS Rt=2.82 min: (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer) MH+=414. 55-1B: (S,S)-2-[1-Methoxycarbonyl-2-(3-hydroxy-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. 55-1B diastereomer: (S,R)-2-[1-Methoxycarbonyl-2-(3-hydroxy-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. Racemic meta-tyrosine was used for the alkylation. The resulting diastereomeric mixture was separated via reverse phase gravity chromatography (C18, 30/70 MeOH/H2O). The early fractions yielded the (S,S) diastereomer 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 7.14 (t, 1H, J=7.7 Hz, 6.9 (m, 3H,), 5.09 (dd, 2H, J=12.2, 17.8 Hz), 3.64 (s, 3H), 3.54 (t, 1H, J=7.1 Hz), 3.35 (t, 1H, J=7.1 Hz), 2.89 (ddd, 2H, J=6.5, 13.8, 38.6 Hz), 1.67 (m, 1H), 1.42 (t, 2H, J=7.1 Hz), 0.86 (t, 6H, J=6.9 Hz). LC-MS Rt=2.62, 2.76 min (gradient: 5–100% CH3CN in 0.1% Formic Acid Aqueous Solution), Molecular ion ES+=401. The later fractions yielded the (R,S) diastereomer. 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 7.12 (t, 1H, J=7.5 Hz), 6.74 (d, 1H, J=7.3 Hz), 6.68 (m, 2H), 5.09 (s, 2H), 3.59 (s, 3H), 3.44 (t, 1H, J=7.1 Hz), 3.20 (t, 1H, J=6.71 Hz), 2.89 (ddd, 2H, J=6.1, 13.4, 33.6 Hz), 1.63 (1H, m), 1.42 (2H, J=7.1 Hz), 0.79 (dd, 6H, J=6.5, 22.0 Hz); LC-MS Rt=2.71 min (gradient 5–100% CH3CN in 1.0% formic acid buffer); MH+=401. Procedure for Tyrosine Phenyl Triflate 55-2A: (S,S) 2-[1-Ethoxycarbonyl-2-(4-trifluoromethanesulfonyloxy-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. A solution of phenol (6.1 g, 14.6 mmole), dichloromethane (146 mL) and pyridine (8.24 mL, 102.5 mmole) was cooled to 0° C. Triflic anhydride (3.0 mL, 17.6 mmole) was added dropwise to the stirring solution. After 3 hours, the reaction mixture was treated with 1N HCl, extracted with dichloromethane, washed with brine, dried over MgSO4, filtered and concentrated. A yellow oil was obtained and used without further purification (8.0 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 7.23 (m, 2H), 7.15 (m, 2H), 5.12 (2H, m), 4.06 (2H, t, 7.53 Hz), 3.52 (1H, t, J=7.1 Hz), 3.37 (1H, t, J=7.1 Hz), 2.94 (2H, q, 5.6 Hz), 1.8 (1H, br s), 1.66 (1H, m), 1.46 (m, 2H), 1.14 (3H, t, J=7.1 Hz), 0.88 (6H, t, J=6.5 Hz). LC-MS Rt=3.64 min (gradient 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=546. 55-2B: (S,S)-2-[1-Methoxycarbonyl-2-(3-trifluoromethanesulfonyloxy-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. TLC (1/1 hexane/ethyl acetate Rf=0.4); LC-MS: Rt=3.51 min (gradient: 5–100% CH3CN in 1.0% formic acid buffer); MH+=532. Procedure for Palladium Catalyzed 3- and 4-Substituted Biphenyl Couplings 55-3A-a: (S,S)-2-[1-Ethoxycarbonyl-2-(4-thiophen-3-yl-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. Triflate 55-2, (249 mg, 0.47 mmole), potassium phosphate tribasic (193 mg, 0.91 mmole), thiophen-3-yl boronic acid (116 mg, 0.91 mmole), and dioxane (2.4 mL) were added to screw cap vial. N2(g) was bubbled through the solution for 60 sec. Pd(dppf)Cl2 (10 mg, 0.01 mmole) was added and the solution was again flushed with N2(g). The vial was capped and the solution was heated to 90° C. for 18 h. The reaction mixture was cooled to room temperature, filtered through celite, and purified by silica gel flash chromatography (isco combi-flash system; gradient—10–30% ethyl acetate in hexanes). A pale yellow oil was isolated (167 mg, 73%). LC-MS: Rt=3.60 min (gradient: 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+ 480. 55-3B-b: (S,S)-2-[2-(3′,5′-Dichloro-biphenyl-4-yl)-1-ethoxycarbonyl-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=4.02 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+ 452. 55-3A-c: (S,S)-2-[1-Ethoxycarbonyl-2-(4′-methyl-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.79 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=488. 55-3A-d: (S,S)-2-[1-Ethoxycarbonyl-2-(4′-fluoro-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.60 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=492. 55-3A-e: (S,S)-2-[1-Ethoxycarbonyl-2-(4-trifluoromethyl-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid ester benzyl. LC-MS Rt=3.73 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer r); MH+=542. 55-3A-f: (S,S)-2-[2-(4-Benzo[1,3]dioxol-2-yl-phenyl)-1-ethoxycarbonyl-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.49 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=518. 55-3A-g: (S,S)-2-[2-(4-Benzo[b]thiophen-3-yl-phenyl)-1-ethoxycarbonyl-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.77 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=530. 55-3B-a: (S,S)-2-[1-Methoxycarbonyl-2-(3-thiophen-3-yl-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.52 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=466. 55-3B-b: (S,S)-2-[2-(3′,5′-Dichloro-biphenyl-3-yl)-1-methoxycarbonyl-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.89 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=528. 55-3B-c: (S,S)-2-[1-Methoxycarbonyl-2-(4′-methyl-biphenyl-3-yl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.67 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH=474. 55-3B-h: (S,S)-2-[2-(3′5′-Dimethoxy-biphenyl-3-yl)-1-methoxycarbonyl-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.38 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=520. 55-3B-i: (S,S)-2-[1-Methoxycarbonyl-2-(3-naphthalen-1-yl-phenyl)-ethylamino]-4-methyl-pentanoic acid benzyl ester. LC-MS Rt=3.81 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=510. Procedure for Ester Hydrolysis 55-4A-a: (S,S)-2-[1-Carboxy-2-(4-thiophen-3-yl-phenyl)-ethylamino]-4-methyl-pentanoic acid (Compound NF). Ethanol (3.4 mL) and a solution of 1N NaOH (3.4 mL) was added to the diester, 55-3A-a, (167 mg, 0.34 mmole). The solution stirred overnight at room temperature. The solution was concentrated then desalted using a HP20 column (0 to 100% MeOH/H2O) to yield 97.5 mg of a white solid (79%). LC-MS Rt=1.35 min (gradient: 5–100% CH3CN in 10 mM NH4OAc Buffer); MH+=362. Anal Cald for C19H22NO4Na1.5S×H2O: C, 55.26; H, 5.86; N, 3.39. Found: C, 55.66; H, 5.93, N, 3.42. 55-4A-b: (S,S)-2-[1-Carboxy-2-(3′,5′-dichloro-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid (Compound NG). LC-MS Rt=1.75 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=424. Anal Cald for C21H22NO4Cl2Na1.5×1.3H2O: C, 52.41; H, 5.15; N, 2.91. Found: C, 52.58; H, 5.16; N, 2.99. 55-4A-c: (S,S)-2-[1-Carboxy-2-(4′-methyl-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid (Compound NH). LC-MS Rt=1.54 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=370. Anal Calcd for C22H26NO4Cl2Na2: C, 61.1; H, 6.53; N, 3.24. Found: C, 61.34; H, 6.45; N, 3.40. 55-4A-d: (S,S)-[1-Carboxy-2-(4′-fluoro-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid (Compound OY). LC-MS Rt=1.39 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=374 Anal. Calcd. for C21H24NO4FNa2×0.7H2O: C, 58.88; H, 5.93; N, 3.24. Found: C, 58.56; H, 5.85; N, 3.34. 55-4A-e: (S,S)-2-[1-Carboxy-2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylamino]-4-methyl-pentanoic acid (Compound PC). LC-MS Rt=1.72 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=424. Anal. Calcd. for C22H22NO4FNa1.5×H2O C, 55.76; H, 5.10; N, 2.6. Found: C, 57.66; H, 5.39; N, 2.97. 55-4A-f: (S,S)-2-[2-(4-Benzo[1,3]dioxol-2-yl-phenyl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid. LC-MS Rt=1.36 min (gradient 5–100% CH3CN/H2O with 10 mM NH4Ac Buffer); MH+=400. Anal. Calcd. for C21H24NO4FNa2: C, 54.52; H, 6.27; N, 3.03. Found: C, 54.45; H, 5.29; N, 2.88. 55-4A-g: 2-[2-(4-Benzo[b]thiophen-3-yl-phenyl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid (Compound PA). LC-MS Rt=1.60 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=412. Anal. Calcd. for C23H25NO4FSNa2: C, 60.38; H, 5.51; N, 3.06. Found: C, 60.00; H, 5.46, N, 2.87. 55-4B-a: (S,S)-2-[1-Carboxy-2-(3-thiophen-3-yl-phenyl)-ethylamino]-4-methyl-pentanoic acid (Compound MJ). LC-MS Rt=1.36 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=360. Anal. Calcd. for C19H23NO4FS.0.25H2O: C, 62.36; H, 6.47; N, 3.83. Found: C, 62.54; H, 6.31, N, 3.80. 55-4B-b: (S,S)-2-[1-Carboxy-2-(3,′5′-dichloro-biphenyl-3-yl)-ethylamino]-4-methyl-pentanoic acid (Compound MI). 1HNMR (300 MHz, DMSO) δ 7.71 (m, 2H), 7.63 (br s, 1H), 7.56 (m, 2H) 7.31 (m, 2H) 3.43 (t, 1H, J=6.3 Hz), 3.39 (br s, 1H), 3.08 (t, 1H, J=6.3 Hz), 3.0 (ddd, 2H, J=7.3, 20.7, 33.9 Hz), 1.71 (m, 1H), 1.37 (t, 2H, J=6.7 Hz), 0.79 (d, 6H, J=6.5 Hz), LC-MS Rt=2.22 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=424. 55-4B-c: (S,S)-2-[1-Carboxy-2-(4′-methyl-biphenyl-3-yl)-ethylamino]-4-methyl-pentanoic acid (Compound LY). LC-MS Rt=1.33 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=416. 55-4B-h: (S,S)-2-[1-Carboxy-2-(3-naphthalen-1-yl-phenyl)-ethylamino]-4-methyl-pentanoic acid (Compound MX). LC-MS Rt=1.59 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+=406. Anal. Calcd. for C25H27NO4Na.0.80H2O: C, 67.80; H, 6.51; N, 3.16. Found: C, 67.97; H, 6.39; N, 3.19. 55-4B-i: (S,S)-2-[1-Carboxy-2-(3′,5′-dimethoxy-biphenyl-3-yl)-ethylamino]-4-methyl-pentanoic acid (Compound MK). LC-MS Rt=1.86 min (gradient 5–100% CH3CN in 10 mM NH4Ac Buffer); MH+370. Anal. Calcd. for C22H27NO4Cl: C, 65.26; H, 6.72; N, 3.46. Found: C, 64.98; H, 7.04; N, 3.44.

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

Procedure: Into a 2L round bottom flask was added 21 g (100 mmol) of (L)-tyrosine ethyl ester (1) (Bachem) and 500 mL of tetrahydrofuran (THF). The mixture was magnetically stirred at room temperature until dissolved, and 500 mL of aqueous NaHCO3 (0.5 M) was added. The mixture was cooled in an ice bath and 19.3 g (110 mmol) of 2-chlorobenzoyl chloride (Aldrich) was added slowly via a glass syringe. The ice bath was removed and the reaction was allowed to warm to room temperature with stirring. After 30 min., the reaction mixture was rotory evaporated under reduced pressure to remove the THF and the remaining aqueous bicarbonate solution was extracted twice with 400 mL ethyl acetate. The combined extracts were washed with 400 mL of satd. aqueous NaHCO3, 400 mL of 0.1 N HCl, 400 mL of water, and 400 mL of satd. aqueous NaCl. The remaining organic layer was dried over Na2SO4 and evaporated to dryness to afford ˜40 g of crude (2) as a pale yellow oil. The crude product (2) was recrystallized from ˜800 mL of boiling ethyl acetate/hexane (˜1:3) and cooled to 4° C. overnight. The resulting crystalline product was filtered and dried under a stream of nitrogen to afford 32 g (92% isolated yield) of purified (2). The N-(2-chlorobenzoyl)-(L)-tyrosine ethyl ester product (2) was confirmed by NMR and electrospray mass spectrometry (see attached) and judged >95% pure by HPLC and TLC (Rf=0.6, 1:1 ethyl acetate/hexane). The remaining 5% impurity (Rf=0.7) was identified as 2-chlorobenzoic acid by HPLC and TLC versus authentic material. Synthesis of Thiochloroformate Intermediate (3) until dissolved The mixture was cooled in an ice bath The ice bath was removed to warm to room temperature with stirring the reaction mixture was rotory evaporated under reduced pressure to remove the THF the remaining aqueous bicarbonate solution was extracted twice with 400 mL ethyl acetate The combined extracts were washed with 400 mL of satd The remaining organic layer was dried over Na2SO4 evaporated to dryness