(1S)-1-(2-bromophenyl)ethanol

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

Procedure: A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (340 mg, 1.1 mmol), (1S)-1-(2-bromophenyl)ethanol (205 mg, 1.0 mmol) and copper(I) iodide (0.95 g, 4.99 mmol) in dimethyl sulfoxide (10 mL) was degassed and the flask placed in an oil bath at 110° C. The reaction mixture was stirred at this temperature for 2 hours. The cooled reaction mixture was poured into concentrated ammonia/water (1:1; 100 mL) and extracted with diethyl ether (4×50 mL). The extracts were washed with water then brine, combined, dried (MgSO4) and evaporated. The residue was purified by two flash columns, the first eluting with 5-10% diethyl ether/dichloromethane and the second eluting with 40-60% diethyl ether/isohexane, to give the title compound (120 mg, 29%). 1H NMR (500 MHz, CDCl3) δ 8.55 (1H, s), 8.17 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.6 Hz), 8.02 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.5, 8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.69-7.63 (3H, m), 7.49 (1H, t, J=7.2 Hz), 7.19 (2H, t, 8.6 Hz), 5.68-5.62 (1H, m), 2.49 (1H, d, J=3.1 Hz), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 389 [(M-OH)+]. was degassed the flask placed in an oil bath at 110° C The cooled reaction mixture extracted with diethyl ether (4×50 mL) The extracts were washed with water dried (MgSO4) evaporated The residue was purified by two flash columns the first eluting with 5-10% diethyl ether/dichloromethane the second eluting with 40-60% diethyl ether/isohexane

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium 6-(2,4-difluorophenyl)naphthalene-2-sulfinate (Step 3, 486 mg, 1.49 mmol), (1S)-1-(2-bromophenyl)ethanol (260 mg, 1.29 mmol) and copper(I) iodide (1.23 g, 6.46 mmol) were combined in dimethylsulfoxide (10 mL) and degassed. The reaction was heated to 110° C. for 2 hours. The cooled reaction mixture was poured into conc. ammonia solution and extracted with diethyl ether (x4). The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% then 10% diethyl ether/dichloromethane, followed by trituration with isohexane. A second column, eluting with 60% diethyl ether/isohexane, followed by trituration with isohexane, gave the title compound (145 mg). 1H NMR (500 MHz, CDCl3) δ 8.56 (1H, s), 8.17 (1H, d, J=7.9 Hz), 8.06-7.98 (3H, m), 7.79-7.76 (3H, m), 7.66 (1H, t, J=7.5 Hz), 7.54-7.48 (2H, m), 7.03-6.95 (2H, m), 5.65 (1H, q, J=6.2 Hz), 2.51 (1H, s), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 407 [(M-OH)+]. degassed The cooled reaction mixture extracted with diethyl ether (x4) The combined organic layers were washed with brine dried over MgSO4 evaporated in vacuo The residue was purified by flash column chromatography on silica eluting with 5% A second column, eluting with 60% diethyl ether/isohexane

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

Procedure: In a similar manner as described for example B31, 1.68 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 960 mg of (1S)-1-(2-bromophenyl)ethanol, 2.67 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.842 g of di-tert-butyl azodicarboxylate in 50 ml anhydrous dichloromethane yield the title compound.

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

Procedure: To each of three identical Emrys microwave reaction vessels was added (S)-1-(2-bromophenyl)ethanol (1.67 g, 8.3 mmol), CuI (189 mg, 1.0 mmol), 1,4-dioxane (12.4 ml), N,N′-dimethylethylenediamine (0.18 ml, 1.7 mmol) and sodium iodide dihydrate (3.1 g, 16.6 mmol). Each vessel was sealed and heated in an Emrys microwave reactor to 150° C. for 2 h. On cooling, the mixtures were combined and partitioned between water (20 ml) and EtOAc (20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was taken up in isohexane (50 ml) and the solution held at −15° C. for 16 h to afford (S)-1-(2-iodophenyl)ethanol as a white crystalline solid (4.95 g). To each of three identical Emrys microwave reaction vessels Each vessel was sealed On cooling partitioned between water (20 ml) and EtOAc (20 ml) The organic phase was washed with brine (20 ml) dried (MgSO4) filtered concentrated in vacuo

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

Procedure: Interesterification was carried out by using 3 g of Lipase QL, 50 g of (R,S)-1-(2-bromophenyl)ethanol, and 150 g of tribehen at 120° C. for 20 hours in the same manner as in Example 12. The water content of the reaction system was 0.01% by weight, and 90% of the lipase particles had a particle size of 30 to 50 μm. Gas chromatography of the reaction mixture revealed that 44 mol % of (R,S)-1-(2-bromophenyl)ethanol had been converted to 1-(2-bromophenyl)ethyl behenate. The reaction mixture was treated in the same manner as in Example 12, and the filtrate was subjected to simple distillation at 110° C. and 5 mmHg to recover unreacted (S)-(-)-1-(2-bromophenyl)ethanol (yield: 88%; chemical purity: 99.9%; optical purity: 99% ee or higher). at 120° C. for 20 hours The reaction mixture was treated in the same manner as in Example 12 the filtrate was subjected to simple distillation at 110° C.

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

Procedure: Interesterification was carried out by using 5 g of Lipase P of Pseudomonas fluorescens origin (a product of Amano Pharmaceutical Co., Ltd.), 10 g of (R,S)-1-2-(bromophenyl)ethanol, 30 g of tribehen and 450 ml of cyclohexane at 50° C. for 72 hours in the same manner as in Example 8. The water content of the reaction system was 0.01% by weight, and 90% of the lipase particles had a particle size of 30 to 50 μm. Gas chromatography of the reaction mixture revealed that 48 mol % of (R,S)-1-(2-bromophenyl)ethanol had been converted to 1-(2-bromophenyl)ethyl behenate. The reaction mixture was treated in the same manner as in Example 8, and the residue was subjected to simple distillation at 110° C. and 5 mmHg to recover unreacted (S)-(-)-1-(2-bromophenyl)ethanol (yield: 82%; chemical purity: 99.9%; optical purity: 98% ee). The reaction mixture was treated in the same manner as in Example 8 the residue was subjected to simple distillation at 110° C.

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

Procedure: Interesterification was carried out by using 3 g of Lipase QL, 50 g of (R,S)-1-(2-bromophenyl)ethanol, and 150 g of tribehen under the same conditions as in Example 3 at 105° C. for a period of 20 hours. The water content of the reaction system was 0.01% by weight, and 90% of the lipase particles had a particle size of 30 to 50 μm. Gas chromatography of the reaction mixture revealed that 45 mol % of (R,S)-1-(2-bromophenyl)ethanol had been converted to 1-(2-bromophenyl)ethyl behenate. The reaction mixture was treated in the same manner as in Example 3 and subjected to simple distillation at 110° C. and 5 mmHg to give (S)-(-)-1-(2-bromophenyl)ethanol (yield: 82%; chemical purity: 99.9%; optical purity: 81.5% ee). On the other hand, the residue, i.e., (R)-(+)-1-(2-bromophenyl)ethanol behenic acid ester was acid-hydrolyzed in the same manner as in Example 2 to obtain (R)-(+)-1-(2-bromophenyl)ethanol (yield: 75.6%; chemical purity: 99.8%; optical purity: 99.0% ee). at 105° C. of 20 hours The reaction mixture was treated in the same manner as in Example 3 subjected to simple distillation at 110° C.

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

Procedure: To a 25 mL flask containing (S)-(−)-2-bromo-alpha-methylbenzyl alcohol (200 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (165 mg, 1.1 mmol), and imidazole (203 mg, 3.0 mmol) flushed with nitrogen was added 5 mL of dimethylformamide. After stirring overnight, the mixture was quenched with saturated sodium bicarbonate, diluted with ethyl acetate, washed with NaH2PO4, saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) gave about 260 mg (0.82 mmol, 82%) of (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane as a colorless oil. GC/MS (EI): 315 (M). The (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 321.5 (M+1) flushed with nitrogen was added 5 mL of dimethylformamide the mixture was quenched with saturated sodium bicarbonate diluted with ethyl acetate washed with NaH2PO4, saturated aqueous sodium bicarbonate, water, brine dried (Na2SO4) filtered concentrated Purification by flash chromatography (10 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes)

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

Procedure: To each of three identical Emrys microwave reaction vessels was added (S)-1-(2-bromophenyl)ethanol (1.67 g, 8.3 mmol), CuI (189 mg, 1.0 mmol), 1,4-dioxane (12.4 ml), N,N′-dimethylethylenediamine (0.18 ml, 1.7 mmol) and sodium iodide dihydrate (3.1 g, 16.6 mmol). Each vessel was sealed and heated in an Emrys microwave reactor to 150° C. for 2 h. On cooling, the mixtures were combined and partitioned between water (20 ml) and EtOAc (20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was taken up in isohexane (50 ml) and the solution held at −15° C. for 16 h to afford (S)-1-(2-iodophenyl)ethanol as a white crystalline solid (4.95 g). To each of three identical Emrys microwave reaction vessels Each vessel was sealed On cooling partitioned between water (20 ml) and EtOAc (20 ml) The organic phase was washed with brine (20 ml) dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An enzyme (Amano CES, tradename of a lipase made by Amano Seiyaku Company) (10 g), ±-1-(2-bromophenyl)ethanol (7.0 g, 35 mmol) and tributyrin (15.9 g, 52.5 mmol) were placed in a three-necked flask, followed by agitating these materials at 35° C. for 15 days, stopping the reaction, thereafter filtering off the enzyme, concentrating the filtrate and subjecting the concentrate to silica gel chromatography to isolate the respective objective products. As a result, (S)-1-(2-bromophenyl)ethanol ([α]D23.5° C. : -26.3° (C 3.72, CHCl3)) (2.6g) and R-1-(2-bromophenyl)-1'-butanoyloxyethane (25 g) were obtained, followed by hydrolyzing the latter compound to obtain R-1-(2-bromophenyl)ethanol ([α]D23.5° : 30 33.5° (C 3.52, CHCl3)) (1.7 g). were placed in a three-necked flask the reaction filtering off the enzyme concentrating the filtrate concentrate to silica gel chromatography to isolate the respective objective products

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

Procedure: A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (340 mg, 1.1 mmol), (1S)-1-(2-bromophenyl)ethanol (205 mg, 1.0 mmol) and copper(I) iodide (0.95 g, 4.99 mmol) in dimethyl sulfoxide (10 mL) was degassed and the flask placed in an oil bath at 110° C. The reaction mixture was stirred at this temperature for 2 hours. The cooled reaction mixture was poured into concentrated ammonia/water (1:1; 100 mL) and extracted with diethyl ether (4×50 mL). The extracts were washed with water then brine, combined, dried (MgSO4) and evaporated. The residue was purified by two flash columns, the first eluting with 5-10% diethyl ether/dichloromethane and the second eluting with 40-60% diethyl ether/isohexane, to give the title compound (120 mg, 29%). 1H NMR (500 MHz, CDCl3) δ 8.55 (1H, s), 8.17 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.6 Hz), 8.02 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.5, 8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.69-7.63 (3H, m), 7.49 (1H, t, J=7.2 Hz), 7.19 (2H, t, 8.6 Hz), 5.68-5.62 (1H, m), 2.49 (1H, d, J=3.1 Hz), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 389 [(M-OH)+]. was degassed the flask placed in an oil bath at 110° C The cooled reaction mixture extracted with diethyl ether (4×50 mL) The extracts were washed with water dried (MgSO4) evaporated The residue was purified by two flash columns the first eluting with 5-10% diethyl ether/dichloromethane the second eluting with 40-60% diethyl ether/isohexane

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium 6-(2,4-difluorophenyl)naphthalene-2-sulfinate (Step 3, 486 mg, 1.49 mmol), (1S)-1-(2-bromophenyl)ethanol (260 mg, 1.29 mmol) and copper(I) iodide (1.23 g, 6.46 mmol) were combined in dimethylsulfoxide (10 mL) and degassed. The reaction was heated to 110° C. for 2 hours. The cooled reaction mixture was poured into conc. ammonia solution and extracted with diethyl ether (x4). The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% then 10% diethyl ether/dichloromethane, followed by trituration with isohexane. A second column, eluting with 60% diethyl ether/isohexane, followed by trituration with isohexane, gave the title compound (145 mg). 1H NMR (500 MHz, CDCl3) δ 8.56 (1H, s), 8.17 (1H, d, J=7.9 Hz), 8.06-7.98 (3H, m), 7.79-7.76 (3H, m), 7.66 (1H, t, J=7.5 Hz), 7.54-7.48 (2H, m), 7.03-6.95 (2H, m), 5.65 (1H, q, J=6.2 Hz), 2.51 (1H, s), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 407 [(M-OH)+]. degassed The cooled reaction mixture extracted with diethyl ether (x4) The combined organic layers were washed with brine dried over MgSO4 evaporated in vacuo The residue was purified by flash column chromatography on silica eluting with 5% A second column, eluting with 60% diethyl ether/isohexane