benzyl (2S)-2-hydroxypropanoate

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

Procedure: A solution of triflic anhydride (10.86 g, 38.5 mmol) in dry CH2Cl2 (20 mL) was added dropwise to a solution of benzyl (S)-lactate (1a) (6.31 g, 35 mmol) in dry CH2Cl2 (100 mL) with cooling (−68˜−72° C.) and stirring. After 5˜7 min, a solution of 2,6-lutidine (4.31 g, 40.3 mmol) in dry CH2Cl2 (15 mL) was added dropwise at the same temperature and the reaction mixture was stirred for 30 min at −68˜−72° C. A solution of O-allylhydroxylamine (4.55 g, 77 mmol) in dry CH2Cl2 (15 mL) was added dropwise to the prepared solution of the alkylating reagent with cooling (−68˜−72° C.) and stirring. The reaction mixture was stirred for 15 min at ca. −72° C. and then was allowed to warm up to RT. After stirring for 15 h at RT, the reaction mixture was thoroughly shaken with sat. aqueous NaHCO3 (200 mL) and dried over MgSO4. After removal of the solvent, the residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 10% EtOAc-hexanes) to afford 8.20 g (99.6%) of the product 2a as a pale yellowish oil. 1H NMR (100 MHz) in CDCl3+1 drop of D2O (J, Hz): δ 1.28 (3H, d, 3J=7.1, MeCH), 3.82 (1H, q, 3J=7.1, MeCH), 4.22 (2H, dt, 3J=5.7, 4J=1.2, OCH2CH═CH2), 5.16-5.37 (2H, m, CH═CH2), 5.23 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=5.7, 3Jcis=9.9, 3Jtrans=17.1, CH═CH2), 7.38 (5H, Ph). 13C (100 MHz) in CDCl3: δ 14.81, 59.09, 66.63, 75.22, 117.53, 128.06, 128.24, 128.56, 134.37, 135.84, 174.01. IR (film), cm−1: 3264, 1740, 1456, 1208, 1170. Anal. Calcd for C13H17NO3: C, 66.4; H, 7.3; N, 5.95. Found: C, 66.3; H, 7.4; N, 6.15%. with cooling (−68˜−72° C.) After 5˜7 min the reaction mixture was stirred for 30 min at −68˜−72° C with cooling (−68˜−72° C.) stirring The reaction mixture was stirred for 15 min at ca. −72° C. After stirring for 15 h at RT dried over MgSO4 After removal of the solvent the residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 10% EtOAc-hexanes)

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

Procedure: To a mixture of benzyl (S)-lactate (30.6 g), pyridine (13.4 g) and diethyl ether (300 ml), a solution of chloromethyl chloroformate (21.9 g) in diethyl ether (100 ml) was added dropwise under ice cooling over the period of 30 minutes. After stirring at room temperature for 5 hours, the resulting solid was removed off by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (100 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [(1S)-1-(benzyloxycarbonyl)ethyl] chloromethyl carbonate (45.0 g) as a colorless liquid. the resulting solid was removed off by filtration The filtrate was concentrated under reduced pressure the residue was dissolved in ethyl acetate (200 ml) The solution was washed with water (100 ml×2) After drying over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure

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

Procedure: Commercially available L-lactide 1 (16 g, 0.14 mol) and p-toluenesulfonic acid monohydrate (catalytic amount) in benzyl alcohol (40 mL, 0.38 mol) was heated to 110° C. overnight. Excess benzyl alcohol was removed under vacuum to obtain a light yellow oil. The desired product was distilled under vacuum (0.9 mm Hg, 85-95° C.) to obtain 50.3 g of 2 as a clear oil. The distilled oil was used without further purification. Excess benzyl alcohol was removed under vacuum to obtain a light yellow oil The desired product was distilled under vacuum (0.9 mm Hg, 85-95° C.)

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

Procedure: To a solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol, 1 eq) and (S)-benzyl-2-hydroxypropanoate (21 μL, 0.125 mmol, 1.1 eq, Aldrich, Milwaukee, Wis., USA) in THF (2 mL) at 0° C. was added diethyl azodicarboxylate (20 μL, 0.125 mmol, 1.1 eq) and triphenylphosphine (33 mg, 0.125 mmol, 1.1 eq). After stirring at 0° C. for 4 h, the mixture was extracted between saturated sodium bicarbonate and EtOAc, dried (Na2SO4), concentrated in vacuo, and purified on via silica gel chromatography (linear gradient of 5-10% EtOAc/hexane). The isolated material was further purified via reversed phase semi-preparative HPLC to give 12 mg of benzyl-(R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate. This intermediate was stirred in the presence of 10 mg of 10% Pd/C under a hydrogen atmosphere in EtOH. (5 mL) at room temperature for 16 h. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated in vacuo. The crude residue was purified via reversed phase semi-preparative HPLC to give 7.8 mg of (R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanoic acid (Example 35). 1HNMR (CDCl3, 400 MHz): δ 7.78 (m, 3H), 7.64(d, 1H), 7.48 (m, 2H), 7.25 (m, 3H), 7.17 (d, 1H), 6.73 (d, 1H), 4.87 (m, 1H), 4.04 (s, 2H), 2.53 (s, 3H), 1.32 (d, 3H). MS (ESI): MH+=512.1. HPLC (Method B) tR=3.48 min. the mixture was extracted between saturated sodium bicarbonate and EtOAc dried (Na2SO4) concentrated in vacuo purified on via silica gel chromatography (linear gradient of 5-10% EtOAc/hexane) The isolated material was further purified via reversed phase semi-preparative HPLC

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

Procedure: To a solution of (10.0 g, 55.5 mmol) of 3-hydroxy-benzoic acid methyl ester in tetrahydrofuran (125 mL), cooled to 0° C., is added (8.44 g, 55.5 mmol) of (S)-2-hydroxy-propionic acid benzyl ester, and (14.5 g, 55.5 mmol) of triphenyl phosphine. To this mixture is added a solution of (11.3 mL, 72.2 mmol) of diethylazodicarboxylate in tetrahydrofuran (25 mL) via a syringe pump over a 1 hour period. The reaction mixture is warmed to room temperature and stirred for 18 h then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 13 g of 3-((R)-1-benzyloxycarbonyl-ethoxy)-benzoic acid methyl ester as an oil. then concentrated under reduced pressure The residue is purified by flash silica gel chromatography

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

Procedure: (S)-Lactic acid (60 g) and 75 g of benzyl bromide were dissolved in 500 ml of dimethylformamide, to which 72.5 g of potassium iodide and 150 g of potassium carbonate were added with ice cooling. After the mixture was stirred at room temperature for 6 hours, 500 ml of ethyl acetate and 500 ml of diisopropyl ether were added thereto. The supernatant layer was obtained by decantation and the precipitate was washed with 100 ml of diisopropyl ether. The organic solutions thus obtained were combined and poured into 200 ml of 5N-hydrochloric acid under ice-cooling. The separated organic layer was washed with 250 ml of 2N-hydrochloric acid, 100 ml of an aqueous solution of sodium thiosulfate and 100 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure to give 29.3 g of (S)-benzyl lactate (yield: 37%) as a colorless oil. were added with ice cooling The supernatant layer was obtained by decantation the precipitate was washed with 100 ml of diisopropyl ether The organic solutions thus obtained cooling The separated organic layer was washed with 250 ml of 2N-hydrochloric acid, 100 ml of an aqueous solution of sodium thiosulfate and 100 ml of an aqueous solution of sodium chloride successively dried over magnesium sulfate After the solvent was distilled off under reduced pressure the residue was distilled under reduced pressure

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

Procedure: The title compound was prepared from 242 mg (1.3 mmol) of (S)-lactic acid, benzyl ester (from EXAMPLE 7, Step A) and 310 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 301 mg (62%) of the title compound: RF: 0.47 (4:1 v/v hexanes/EtOAc). 1H NMR (300 MHz) δ 0.0 (s, 6H), 0.85 (s, 9H), 1.41 (d, J=6.0 Hz, 3H), 2.41-3.62 (m, 9H), 5.17 (s, 2H), 7.16-7.38 (m, 10H).

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

Procedure: To a solution of 6 g 4-{2-[(4-Hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester and 2.5 g benzyl-L-lactate in 97 ml THF were added 5.5 g triphenylphosphine and 3.6 g diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was then extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 5.5 g was added to the reaction mixture which was then extracted with ethyl acetate The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient

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

Procedure: To a solution of 2 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester and 647 mg benzyl-L-lactate in 25 ml THF were added 1.4 g triphenylphosphine and 938 mg diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.7 g. was added to the reaction mixture which was subsequently extracted with ethyl acetate The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient

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

Procedure: To a solution of 1.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester hydrochloride and 0.83 g benzyl-L-lactate in 30 ml THF were added 1.81 g triphenylphosphine and 1.20 g diethylazodicarboxylate. After 2 h LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.80 g. was subsequently extracted with ethyl acetate The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient

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

Procedure: To a solution of 1.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester hydrochloride and 0.83 g benzyl-L-lactate in 30 ml THF were added 1.81 g triphenylphosphine and 1.20 g diethylazodicarboxylate. After 2 h LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.80 g was subsequently extracted with ethyl acetate The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient

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

Procedure: To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 341 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 15 ml of THF, 744 mg of Triphenyl-phosphane and 494 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g. extracted with ethyl acetate The organic phase was dried over MgSO4 the solvents were removed under reduced pressure The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate The fractions containing the product the solvent evaporated under reduced pressure