methyl (2R)-2-(3-chlorophenyl)-2-hydroxyacetate

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

Procedure: Pyridium chlorochromate (32.4 g, 150.00 mmol, 2.01 equiv.) was added to a solution of (R)-Methyl 2-(3-chlorophenyl)-2-hydroxyacetate (15 g, 74.77 mmol, 1.00 equiv) in dichloromethane (500 mL). The resulting solution was stirred at about 30° C. for about 2 hours, and then fresh pyridinium chlorochromate (16.4 g, 75.93 mmol, 1.02 equiv.) was added. The resulting solution was stirred at about 30° C. for about 16 hours, and then fresh pyridinium chlorochromate (16.4 g, 75.93 mmol, 1.02 equiv) was added. The resulting solution was stirred at about 30° C. for about 16 hours, and then concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:20)) to give the title product as a yellow solid (13.8 g; yield=91%). 1H NMR (300 MHz, DMSO-d6) δ: 8.02 (t, J=1.8 Hz, 1H), 7.98 (m, 1H) 7.95 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 3.94 (s, 3H). The resulting solution was stirred at about 30° C. for about 16 hours The resulting solution was stirred at about 30° C. for about 16 hours concentrated in vacuo The resulting crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:20))

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

Procedure: At 0-5° C., sodium borohydride (2.3 g, 60.80 mmol, 2.50 equiv) was added in several batches to a solution of (R)-Methyl 2-(3-chlorophenyl)-2-hydroxyacetate (5 g, 24.92 mmol, 1.00 equiv.) in methanol (50 mL). The resulting solution was stirred at ambient temperature for about 2 hours, and then 10% ammonium chloride (20 mL) was added. The mixture was concentrated in vacuo, and extracted with ethyl acetate (3×50 mL). The organic layers were combined and concentrated in vacuo to give the title product as a colorless oil (4 g; yield=93%). 1H NMR (300 MHz, DMSO-d6) δ: 7.26-7.39 (m, 4H), 5.40 (d, J=1.5 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 4.54 (q, J=5.7 Hz, 1H), 3.48 (m, 2H). The mixture was concentrated in vacuo extracted with ethyl acetate (3×50 mL) concentrated in vacuo

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

Procedure: A solution of (R)-2-(3-chlorophenyl)-2-hydroxyacetic acid (25 g, 133.69 mmol, 1.00 equiv.) in methanol (300 mL) and sulfuric acid (3 mL) was heated at reflux for about 16 hours, and then concentrated in vacuo. After the solution was poured into a water/ice mixture (200 mL), the pH value of the solution was adjusted to 9 with sodium carbonate. Standard extractive workup with ethyl acetate (2×100 mL), gave the title product as an off-white solid (24.8 g; yield=93%). 1H NMR (300 MHz, CDCl3) δ: 7.45 (s, 1H), 7.32 (m, 3H), 5.17 (d, J=4.5 Hz, 1H), 3.80 (s, 3H). at reflux for about 16 hours concentrated in vacuo After the solution was poured into a water/ice mixture (200 mL)

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

Procedure: A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (21.0 g), imidazole (14.25 g), and tert-butyidimethylsilyl chloride (25.0 g) in N,N-dimethylformamide (250 ml) was stirred at room temperature for 18 h. The mixture was poured into water (2.5 l) and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried, and concentrated. The residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless oil (32.63 g). extracted with ethyl acetate The combined extracts were washed with water and saturated brine dried concentrated The residue was purified by flash chromatography eluting with cyclohexane:ethyl acetate (9:1)

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

Procedure: A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (21.0 g), imidazole (14.25 g), and tert-butyidimethylsilyl chloride (25.0 g) in N,N-dimethylformamide (250 ml) was stirred at room temperature for 18 h. The mixture was poured into water (2.5 l) and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried, and concentrated. The residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless oil (32.63 g). extracted with ethyl acetate The combined extracts were washed with water and saturated brine dried concentrated The residue was purified by flash chromatography eluting with cyclohexane:ethyl acetate (9:1)

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

Procedure: A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid (19.98 g) in methanol (250 ml) containing concentrated sulphuric acid (1 ml) was heated under reflux for 6.5 h. The solution was cooled, neutralised with aqueous sodium bicarbonate solution, and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried, and evaporated to give the title compound (21.13 g) as a pale-yellow oil. was heated under reflux for 6.5 h The solution was cooled concentrated The residue was dissolved in ethyl acetate washed with aqueous sodium bicarbonate solution dried evaporated

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

Procedure: Degassed toluene (0.17 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 46.5 mg, 0.0766 mmol), palladium (II) acetate (2.8 mg, 0.013 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (10.5 mg, 0.0256 mmol) and potassium phosphate (39.8 mg, 0.187 mmol), and the mixture was stirred in a nitrogen atmosphere for three minutes. Then, a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid methyl ester (Example 156-(1); 18.8 mg, 0.0937 mmol) in toluene (0.17 mL) and water (0.033 mL) were added, and the mixture was heated while stirring at an external temperature of 95 to 105° C. for one hour. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=8/1) to give the title compound (35 mg, 71%). Degassed toluene (0.17 mL) the mixture was heated while stirring at an external temperature of 95 to 105° C. for one hour filtered through cotton plug the filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=8/1)

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

Procedure: Degassed tetrahydrofuran (0.14 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 14.4 mg, 0.0237 mmol), palladium (II) acetate (1.2 mg, 0.0053 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4.5 mg, 0.011 mmol) and potassium phosphate (13.0 mg, 0.0612 mmol). The mixture was stirred in a nitrogen atmosphere for three minutes, followed by addition of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (Example 156-(1); 0.006 mL, 6.5 mg, 0.032 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 60 to 70° C. for four hours. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (3.6 mg, 24%). Degassed tetrahydrofuran (0.14 mL) After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 60 to 70° C. for four hours filtered through cotton plug the filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1)

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

Procedure: Degassed tetrahydrofuran (0.14 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 14.4 mg, 0.0237 mmol), palladium (II) acetate (1.2 mg, 0.0053 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4.5 mg, 0.011 mmol) and potassium phosphate (13.0 mg, 0.0612 mmol). The mixture was stirred in a nitrogen atmosphere for three minutes, followed by addition of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (Example 156-(1); 0.006 mL, 6.5 mg, 0.032 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 60 to 70° C. for four hours. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (3.6 mg, 24%). Degassed tetrahydrofuran (0.14 mL) After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 60 to 70° C. for four hours filtered through cotton plug the filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1)

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

Procedure: A solution of trimethylsilyldiazomethane in hexane (2 M, 1.5 mL, 3.0 mmol) was added to a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid (497 mg, 2.66 mmol) in benzene (2.6 mL)-methanol (1.3 mL) under cooling with ice. Then, the ice bath was removed and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (533 mg, 100%). under cooling with ice Then, the ice bath was removed The reaction mixture was concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1)

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

Procedure: Into methanol (20 ml) were added (R)-3-chloromandelic acid (5.0 g) and p-toluenesulfonic acid (0.1 g), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled, then neutralized and concentrated. Ethyl acetate and water were added to the resulting residue and the organic layer was collected by layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (5.27 g, 98.3%). the resulting mixture was heated under reflux for 2 hours The reaction mixture was cooled concentrated Ethyl acetate and water were added to the resulting residue the organic layer was collected by layer separation The organic layer was washed with a saturated aqueous sodium chloride solution dried with anhydrous magnesium sulfate The desiccant was filtered off the solvent was distilled off to obtain a colorless oily compound

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

Procedure: 18.3 g of a 10% w/v solution of trimethylsilyldiazomethane in hexane were added dropwise to a solution of 28 g of (R)-3-chloromandelic acid (prepared as described in Preparation 46) in a mixture of 300 ml of methanol and 700 ml of benzene, and the resulting mixture was stirred for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, to give the title compound having [α]D23 -119.3° (c=1.00, chloroform) and an Rf=0.36 (thin layer chromatography over silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane) as a crude product. At the end of this time, the solvent was removed by distillation under reduced pressure