methyl (2S)-2-hydroxypropanoate

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}-1-piperazinecarboxylate (657 mg) was dissolved in tetrahydrofuran (10 mL), oily sodium hydride (82.6 mg) was added thereto and stirred at 60° C. for 15 minutes, then methyl (S)-lactate (0.333 mL) was added thereto and heated under reflux for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 402 mg of the entitled compound as a colorless solid. heated under reflux for 1 hour extracted with ethyl acetate The organic layer was washed with saturated saline water dried with anhydrous sodium sulfate The solvent was evaporated away the resulting residue was isolated purified through silica gel column chromatography (hexane/ethyl acetate=1/1)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium tert-butoxide (0.87 ml, 1M in tetrahydrofuran) was added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (200 mg, 0.73 mmol), [prepared as described in Step 1 above], in tetrahydrofuran (10 ml) at -60° C. After 10 min., a solution of the triflate derivative of methyl (S)-lactate (604 mg, 2.56 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was allowed to warm to -30° C. over 30 min. The reaction mixture was quenched with saturated ammonium chloride and the product was extracted into ethyl acetate. The solvent was removed in vacuo and the residue was chromatographed (SiO2, 30% ethyl acetate/hexane) to give methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]-amino}propionate as a colorless oil (66%). The reaction mixture was quenched with saturated ammonium chloride the product was extracted into ethyl acetate The solvent was removed in vacuo the residue was chromatographed (SiO2, 30% ethyl acetate/hexane)

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

Procedure: To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (0.2 g, 1.5 mmol), methyl (S)-(−)-lactate (0.14 mL, 1.5 mmol) and triphenylphosphine (1.15 g, 4.4 mmol) at room temperature, diethyl azodicarboxylate (0.67 mL, 4.4 mmol) was added dropwise. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed successively with dilute aqueous sodium hydroxide, dilute aqueous hydrochloric acid, brine, and dried (Na2SO4). Solvents were stripped in vacuo. The resulting oil was washed with diethyl ether and the precipitate was filtered off. The mother liquor was adsorbed onto silica gel and the product purified by flash column chromatography (20% dichloromethane/hexane), affording 0.12 g of a pink oil (36% yield). washed successively with dilute aqueous sodium hydroxide, dilute aqueous hydrochloric acid, brine dried (Na2SO4) The resulting oil was washed with diethyl ether the precipitate was filtered off the product purified by flash column chromatography (20% dichloromethane/hexane)

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

Procedure: To a solution of 200g (1.92 mol) of methyl (2S)-lactate (5) and 295 g (2.11 mol) of triethylamine in toluene (1 L) at 0° C. was added 270 mL, 2.11 mol) of benzenesulfonyl chloride dropwise over a 2 hour period under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir there overnight. The reaction was worked-up by washing with water (3×1 L) and dried (MgSO4). Filtration, concentration and purification by vacuum distillation afforded 440 g (94%) of methyl (2S)-2-(phenylsulfonyl)oxypropanate (12) as a pale yellow liquid: bp 140°-142° C. (0.1 mm Hg); 1H NMR (CDCl3) δ1.51-1.56 (d, 3 H), 3.66 (s, 3 H), 4.95-5.01 (q, 1 H), 7.54-7.59 (m, 2 H), 7.65-7.70 (m, 1 H), 7.93-7.95 (d, 2 H); 13C NMR (CDCl3) δ169.3, 133.9, 129.1, 127.7, 112.3, 74.2, 52.5, 18.3; IR (neat) 2958 (w), 1762 (s), 1586 (m), 1451 (s), 1190 (vs), 1084 (s), 926 (m), 753 (m) cm-1. The cooling bath was removed by washing with water (3×1 L) dried (MgSO4) Filtration, concentration and purification by vacuum distillation

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

Procedure: To a solution of 200g (1.92 mol) of methyl (2S)-lactate (5) and 295 g (2.11 mol) of triethylamine in toluene (1 L) at 0° C. was added 270 mL, 2.11 mol) of benzenesulfonyl chloride dropwise over a 2 hour period under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir there overnight. The reaction was worked-up by washing with water (3×1 L) and dried (MgSO4). Filtration, concentration and purification by vacuum distillation afforded 440 g (94%) of methyl (2S)-2-(phenylsulfonyl)oxypropanate (12) as a pale yellow liquid: bp 140°-142° C. (0.1 mm Hg); 1H NMR (CDCl3) δ1.51-1.56 (d, 3 H), 3.66 (s, 3 H), 4.95-5.01 (q, 1 H), 7.54-7.59 (m, 2 H), 7.65-7.70 (m, 1 H), 7.93-7.95 (d, 2 H); 13C NMR (CDCl3) δ169.3, 133.9, 129.1, 127.7, 112.3, 74.2, 52.5, 18.3; IR (neat) 2958 (w), 1762 (s), 1586 (m), 1451 (s), 1190 (vs), 1084 (s), 926 (m), 753 (m) cm-1. The cooling bath was removed by washing with water (3×1 L) dried (MgSO4) Filtration, concentration and purification by vacuum distillation

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

Procedure: Prepared from 2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 13) and and commercially available methyl (S)-(−)-lactate according to the procedure of Example 30. White solid: mp 237-239° C.; [a]25/D=−1.99° (10.051 mg/mL, CHCl3); NMR (DMSO-d6); δ13.2 (broad s, 1H, COOH), 8.43 (d, J=8 Hz, 1H), 7.80 (s, 2H), 7.62-7.58 (m, 1H), 7.56-7.50 (m, 2H), 7.23-7.13 (m, 3H), 7.04-7.01 (m, 2H), 5.03 (quartet, J=7 Hz, 1H), 2.40 (s, 3H), 1.63 (s, 3H), 1.57 (d, J=8 Hz, 3H); MS (EI): [M+], 2 bromine isotope pattern, 640 (47%), 642 (100%), 644 (56%); Anal. calc. for C29H22Br2O3S2: C, 54.22; H, 3.45; N, 0.00. Found: C, 53.64; H, 3.33; N, 0.05.

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

Procedure: Prepared from 2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 13) and and commercially available methyl (S)-(−)-lactate according to the procedure of Example 30. White solid: mp 237-239° C.; [a]25/D=−1.99° (10.051 mg/mL, CHCl3); NMR (DMSO-d6); δ13.2 (broad s, 1H, COOH), 8.43 (d, J=8 Hz, 1H), 7.80 (s, 2H), 7.62-7.58 (m, 1H), 7.56-7.50 (m, 2H), 7.23-7.13 (m, 3H), 7.04-7.01 (m, 2H), 5.03 (quartet, J=7 Hz, 1H), 2.40 (s, 3H), 1.63 (s, 3H), 1.57 (d, J=8 Hz, 3H); MS (EI): [M+], 2 bromine isotope pattern, 640 (47%), 642 (100%), 644 (56%); Anal. calc. for C29H22Br2O3S2: C, 54.22; H, 3.45; N, 0.00. Found: C, 53.64; H, 3.33; N, 0.05.

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

Procedure: 2.50 g of 3-hydroxybenzaldehyde, 2.77 g of methyl L-(−)-lactate, and 6.44 g of triphenylphosphine were dissolved in 25.0 mL of THF, and 22.2 mL of a 2.2 M diethyl azodicarboxylate/toluene solution was added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1) to obtain 1.67 g of methyl (2R)-2-(3-formylphenoxy)propionate. The obtained methyl (2R)-2-(3-formylphenoxy)propionate was dissolved in 33.3 mL of methanol, and 394 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 30 minutes. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1.68 g of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate. under ice-cooling To the reaction liquid followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1)

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

Procedure: 2.50 g of 3-hydroxybenzaldehyde, 2.77 g of methyl L-(−)-lactate, and 6.44 g of triphenylphosphine were dissolved in 25.0 mL of THF, and 22.2 mL of a 2.2 M diethyl azodicarboxylate/toluene solution was added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1) to obtain 1.67 g of methyl (2R)-2-(3-formylphenoxy)propionate. The obtained methyl (2R)-2-(3-formylphenoxy)propionate was dissolved in 33.3 mL of methanol, and 394 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 30 minutes. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1.68 g of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate. under ice-cooling To the reaction liquid followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-methyl 2-hydroxypropanoate (1.5 g, 14.41 mmol), 1-(chloromethyl)-4-methoxybenzene (3.38 g, 21.61 mmol), DIPEA (4.03 ml, 23.05 mmol) and sodium iodide (0.150 g, 1.001 mmol) was heated to 150° C. for 2 h. Reaction mixture then was cooled to room temperature diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (2×50 mL) and brine. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The crude mixture was purified by flash chromatography on silica gel using an ISCO system (eluted with 9:1 Hexanes and EtOAc) to give (S)-methyl 2-((4-methoxybenzyl)oxy)propanoate (2 g) as a gummy liquid. Reaction mixture then was cooled to room temperature washed with saturated NaHCO3 solution (2×50 mL) and brine Combined organic extracts were dried over anhydrous Na2SO4 concentrated The crude mixture was purified by flash chromatography on silica gel using an ISCO system (eluted with 9:1 Hexanes and EtOAc)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium tert-butoxide (0.87 ml, 1M in tetrahydrofuran) was added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (200 mg, 0.73 mmol), [prepared as described in Step 1 above], in tetrahydrofuran (10 ml) at −60° C. After 10 min., a solution of the triflate derivative of methyl (S)-lactate (604 mg, 2.56 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was allowed to warm to −30° C. over 30 min. The reaction mixture was quenched with saturated ammonium chloride and the product was extracted into ethyl acetate. The solvent was removed in vacuo and the residue was chromatographed (SiO2, 30% ethyl acetate/hexane) to give methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]-amino}propionate as a colorless oil (66%). The reaction mixture was quenched with saturated ammonium chloride the product was extracted into ethyl acetate The solvent was removed in vacuo the residue was chromatographed (SiO2, 30% ethyl acetate/hexane)

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

Procedure: The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (S)-(+)- lactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 112-114° C.; MS m/e 448 (M+); was obtained as a white solid, mp 112-114° C.