(1R,2S)-反-2-苯基-1-环己醇

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The reaction and aftertreatment were conducted in the same manner as in Example 1a by using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 126 mg, 0.283 mmol), (1R,2S)-2-phenylcyclohexanol (50.0 mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0 mL), to yield the title compound (53.6 mg, 31%) as a colorless oil. The reaction and aftertreatment

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 790 g (4.48 mole) of pure (-)-(1R,2S)-2-phenylcyclohexanol, 1.5 L of methylene chloride, 450 mL (5.625 mole) of chloroacetyl chloride, and 2.2 g (0.96 mole) of 4-dimethylaminopyridine was heated at reflux for 8 hours. On cooling, the reaction mixture was stirred with 2 ×1.5 L=3.0 L of saturated NaHCO3 for 30 minutes. The organic layer was dried (Na2SO4) and evaporated to dryness, finally at 0.5 mm for 4 hours to afford 1.136 kg of the title compound (100%) as an oil. was heated at reflux for 8 hours On cooling The organic layer was dried (Na2SO4) evaporated to dryness, finally at 0.5 mm for 4 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 790 g (4.48 mole) of pure (-)-(1R,2S)-2-phenylcyclohexanol, 1.5 L of methylene chloride, 450 mL (5.625 mole) of chloroacetyl chloride, and 2.2 g (0.96 mole) of 4-dimethylaminopyridine was heated at reflux for 8 hours. On cooling, the reaction mixture was stirred with 2 ×1.5 L=3.0 L of saturated NaHCO3 for 30 minutes. The organic layer was dried (Na2SO4) and evaporated to dryness, finally at 0.5 mm for 4 hours to afford 1.136 kg of the title compound (100%) as an oil. was heated at reflux for 8 hours On cooling The organic layer was dried (Na2SO4) evaporated to dryness, finally at 0.5 mm for 4 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2.17 k9 (12.3 mole) of (±)-trans-2-phenylcyclohexanol, 1475 mL (18.43 mole) of chloroacetyl chloride, 6 g (0.049 mole) of 4-dimethylaminopyridine, and 5.5 L of methylene chloride was heated at reflux. After 8 hours, thin layer chromatography analysis (4:1 hexane-ethyl acetate: Spray 5% NH4MoO4 in 10% aqueous H2SO4) indicated complete reaction. The reaction mixture was allowed to cool to room temperature and was stirred with 2×4 L=8 L of saturated NaHC03. The organic layer was dried (Na2SO4) evaporated in vacuo on a rotary evaporator, and finally at 0.5 mmHg to afford 3.21 kg of crude (±)-trans-2-phenylcyclohexyl chloroacetate. Distillation of the tan liquid afforded 2.76 kg (88%) of the desired product as a colorless liquid, (b.p. 125-133°/0.3-0.5 mmHg). The chloroacetylation of other lots of (±)-trans-2-phenylcyclohexanol was accomplished in ← 95%. The particular lot of (±) alcohol used in this example was only about 91% pure. was heated at reflux reaction The organic layer was dried (Na2SO4) evaporated in vacuo on a rotary evaporator

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 50-L reactor equipped with a stirrer, a gas bubbler, and an addition funnel was placed under argon, charged with 27.36 L (27.63 mole) of phenylmagnesium bromide (1.0 M), which is known, in tetrahydrofuran and cooled to 15° C. whereupon 235 g (2.37 mole) of CuC1 was added. The resulting mixture was further cooled to -25° C. To this well-stirred mixture was added dropwise over 1.0 hour 1.82 L (18.0 mole, 1766g) of cyclohexene oxide, which is known. After the addition was completed, the mixture was stirred between -10° C. and 0° C. for 4 hours. The reaction mixture was subsequently quenched with 6 L of saturated NH4SO4 solution followed by 4L of water. The organic layer was separated and the aqueous layer was then extracted with 3×6L=18 L of ethyl acetate. The combined organic layers were evaporated in vacuo. When the residue was dissolved into 8 L of methylene chloride, a small aqueous layer separated and was discarded. The organic layer was dried (Na2SO4) and evaporated in vacuo, finally at 0.5 mmHg. The residue on crYstallization from hexane, afforded in 3 crops, 2.96 kg (93%) of (±)-trans-2-phenylcyclohexanol as colorless needles, m.p. 55-57° C. A 50-L reactor equipped with a stirrer was added The resulting mixture was further cooled to -25° C After the addition The reaction mixture was subsequently quenched with 6 L of saturated NH4SO4 solution The organic layer was separated the aqueous layer was then extracted with 3×6L=18 L of ethyl acetate The combined organic layers were evaporated in vacuo When the residue was dissolved into 8 L of methylene chloride a small aqueous layer separated The organic layer was dried (Na2SO4) evaporated in vacuo, finally at 0.5 mmHg The residue on crYstallization from hexane

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 50-L reactor equipped with a stirrer, a gas bubbler, and an addition funnel was placed under argon, charged with 27.36 L (27.63 mole) of phenylmagnesium bromide (1.0 M), which is known, in tetrahydrofuran and cooled to 15° C. whereupon 235 g (2.37 mole) of CuC1 was added. The resulting mixture was further cooled to -25° C. To this well-stirred mixture was added dropwise over 1.0 hour 1.82 L (18.0 mole, 1766g) of cyclohexene oxide, which is known. After the addition was completed, the mixture was stirred between -10° C. and 0° C. for 4 hours. The reaction mixture was subsequently quenched with 6 L of saturated NH4SO4 solution followed by 4L of water. The organic layer was separated and the aqueous layer was then extracted with 3×6L=18 L of ethyl acetate. The combined organic layers were evaporated in vacuo. When the residue was dissolved into 8 L of methylene chloride, a small aqueous layer separated and was discarded. The organic layer was dried (Na2SO4) and evaporated in vacuo, finally at 0.5 mmHg. The residue on crYstallization from hexane, afforded in 3 crops, 2.96 kg (93%) of (±)-trans-2-phenylcyclohexanol as colorless needles, m.p. 55-57° C. A 50-L reactor equipped with a stirrer was added The resulting mixture was further cooled to -25° C After the addition The reaction mixture was subsequently quenched with 6 L of saturated NH4SO4 solution The organic layer was separated the aqueous layer was then extracted with 3×6L=18 L of ethyl acetate The combined organic layers were evaporated in vacuo When the residue was dissolved into 8 L of methylene chloride a small aqueous layer separated The organic layer was dried (Na2SO4) evaporated in vacuo, finally at 0.5 mmHg The residue on crYstallization from hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In the next step, (±)-trans-2-phenylcyclohexanol is reacted with chloroacetyl chloride at reflux in a basic solvent such as a mixture of methylene chloride and pyridine or, more preferably, 4-dimethylaminopyridine and methylene chloride. The resulting (±)-trans-2-phenylcyclohexyl chloroacetate of the formula ##STR29## can be isolated by conventional means such as extraction followed by distillation of the organic layer.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Magnesium turnings (706 mg; 29 mmol; 1.45 equiv.) were combined with THF (3.5 mL). Bromobenzene (3.1 mL; 29.4 mmol; 1.47 equiv.) in 5 mL of THF was added slowly dropwise. After approximately 1 mL of the bromobenzene solution had been added 1 drop of 1,2-dibromoethane was added to initiate the reaction. Once all the bromobenzene was added and the magnesium consumed the reaction mixture was diluted with THF (20 mL) and cooled to -30° Copper(I) chloride (130 mg; 1.32 mmol; 0.066 equiv.) was added and the reaction mixture was stirred for 10 min. A solution of cyclohexene oxide (2.1 mL; 20 mmol) in THF (2 mL) was added slowly dropwise. After the addition was complete the reaction mixture was warmed to 0° and stirred for 2 h. The reaction mixture was then treated with saturated aqueous ammonium sulfate (10 mL) and the layers were separated. The organic layer was washed with 5 mL portions of saturated ammonium sulfate until the washes were colorless. The combined aqueous washes were extracted with ether (3×10 mL), and the combined organic solution was dried (MgSO4) and concentrated. The crude product was recrystallized from pentane to afford 850 mg (24%) of 1m as white crystals. 1H nmr (300 MHz, CDCl3): 7.369-7.221 (5H, m); 3.640 (1H, m); 2.438 (1H, dt, J=10.43 Hz, 3.34 Hz); 2.146-2.114 (1H, m); 1.892-1.847 (2H, m); 1.788-1.753 (1H, m); 1.639 (1H, s); 1.530-1.254 (4H, m). IR (KBr, cm-1): 3500 (s); 2900 (s); 1600 (m). FDMS (m/e): 176 (M+). was added the reaction the magnesium consumed the reaction mixture was diluted with THF (20 mL) was added After the addition was warmed to 0° stirred for 2 h the layers were separated The organic layer was washed with 5 mL portions of saturated ammonium sulfate until the washes The combined aqueous washes were extracted with ether (3×10 mL) the combined organic solution was dried (MgSO4) concentrated The crude product was recrystallized from pentane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Magnesium turnings (706 mg; 29 mmol; 1.45 equiv.) were combined with THF (3.5 mL). Bromobenzene (3.1 mL; 29.4 mmol; 1.47 equiv.) in 5 mL of THF was added slowly dropwise. After approximately 1 mL of the bromobenzene solution had been added 1 drop of 1,2-dibromoethane was added to initiate the reaction. Once all the bromobenzene was added and the magnesium consumed the reaction mixture was diluted with THF (20 mL) and cooled to -30° Copper(I) chloride (130 mg; 1.32 mmol; 0.066 equiv.) was added and the reaction mixture was stirred for 10 min. A solution of cyclohexene oxide (2.1 mL; 20 mmol) in THF (2 mL) was added slowly dropwise. After the addition was complete the reaction mixture was warmed to 0° and stirred for 2 h. The reaction mixture was then treated with saturated aqueous ammonium sulfate (10 mL) and the layers were separated. The organic layer was washed with 5 mL portions of saturated ammonium sulfate until the washes were colorless. The combined aqueous washes were extracted with ether (3×10 mL), and the combined organic solution was dried (MgSO4) and concentrated. The crude product was recrystallized from pentane to afford 850 mg (24%) of 1m as white crystals. 1H nmr (300 MHz, CDCl3): 7.369-7.221 (5H, m); 3.640 (1H, m); 2.438 (1H, dt, J=10.43 Hz, 3.34 Hz); 2.146-2.114 (1H, m); 1.892-1.847 (2H, m); 1.788-1.753 (1H, m); 1.639 (1H, s); 1.530-1.254 (4H, m). IR (KBr, cm-1): 3500 (s); 2900 (s); 1600 (m). FDMS (m/e): 176 (M+). was added the reaction the magnesium consumed the reaction mixture was diluted with THF (20 mL) was added After the addition was warmed to 0° stirred for 2 h the layers were separated The organic layer was washed with 5 mL portions of saturated ammonium sulfate until the washes The combined aqueous washes were extracted with ether (3×10 mL) the combined organic solution was dried (MgSO4) concentrated The crude product was recrystallized from pentane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (−)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg, 3.63 mmol) was prepared through esterification of benzyloxyacetyl chloride with (−)-(1R,2S)-2-phenyl-1-cyclohexanol followed by hydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) and imidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) was added and stirred at room temperature for 12-20 hours. The mixture was poured into pentane (25 mL), and washed with water and brine. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was subjected to a purification on a short silica gel column using hexane/chloroform (3/1) as the eluant to give pure (−)-(1R,2S)-2-phenyl-1-cyclohexyl triisopropylsilyloxyacetate (1.35 g, 95% yield) as a colorless oil: [α]D20 −17.1°© 3.15, CHCl3); IR (neat) 1759, 1730 (nCO) cm−1; 1H NMR (CDCl3) δ0.93-0.99 (m, 21H), 1.30-1.62 (m, 4H), 1.72-2.0 (m, 3H), 2.10-2.19 (m, 1H), 2.66 (dt, J=11.5, 4.0 Hz, 1H), 3.90 (d, J=16.6 Hz, 1H), 4.07 (d, J=16.6 Hz, 1H), 5.07 (dt, J=10.6, 4.0 Hz, 1H), 7.16-7.30 (m, 5H). Anal. Calcd for C23H38O3Si: C, 70.72; H, 9.81. Found: C, 70.79; H, 9.85. washed with water and brine The combined organic layers were dried over anhydrous MgSO4 concentrated in vacuo The crude product was subjected to a purification on a short silica gel column

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of trans-racemic-2-phenylcyclohexanol (4.63 g, 26.3 mmol) and tin(II)trifluoromethanesulfonate (219 mg, 0.525 mmol) under nitrogen in anhydrous DCM (100 ml) at room temperature was added acetic anhydride (3.72 ml, 4.02 g, 39.4 mmol) in one portion. The mixture was stirred for 18 hours at room temperature. The mixture was poured into saturated aqueous sodium bicarbonate (200 ml). The mixture was extracted with DCM (2×200 ml). The combined organic layers were washed with brine (70 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide the desired product as a light yellow oil. LC-MS: calculated for C14H18O2 218.29 observed m/e: 219.33 (M+H)+ (Rt 0.93/2 min) The mixture was extracted with DCM (2×200 ml) The combined organic layers were washed with brine (70 ml) dried over sodium sulfate concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (-)-(1R, 2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg, 3.63 mmol) was prepared through esterification of benzyloxyacetyl chloride with (-)-(1R,2S)-2-phenyl-1-cyclohexanol followed by hydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) and imidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) were stirred at room temperature for 12-20 hours. The mixture was poured into pentane (25 mL), and washed with water and brine. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was subjected to a purification on a short silica gel column using hexane/chloroform (3/1) as the eluant to give pure (-)-(1R, 2S)-2-phenyl-1-cyclohexyl triisopropylsilyloxyacetate (1.35 g, 95% yield) as a colorless oil. washed with water and brine The combined organic layers were dried over anhydrous MgSO4 concentrated in vacuo The crude product was subjected to a purification on a short silica gel column