3-(3-bromophenyl)propan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To suspension of LiAlH4 (0.5 g, 1.3 mmol) in diethyl ether (25 mL) was added 3-bromocinnamic acid (83, 1.0 g, 4 mmol), in portions, at RT. The resulting suspension was stirred for 3 hours. The reaction was quenched by the successive addition of 15% aq. NaOH solution (1 mL) and water. The resulting white suspension was filtered through a pad of Celite. The filter cake was washed with ether and then ethyl acetate. The filtrate was concentrated to afford crude 8 as yellow oil. Yield (0.7 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.10-7.35 (m, 4H), 3.65 (t, J=6.5 Hz, 2H), 2.68 (t, J=7.8 Hz, 2H), 1.82-1.91 (m, 2H). at RT The reaction was quenched by the successive addition of 15% aq. NaOH solution (1 mL) and water The resulting white suspension was filtered through a pad of Celite The filter cake was washed with ether The filtrate was concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 3-(3-bromophenyl)propan-1-ol (8) (0.95 g, 4.5 mmol) and 2-methyl-3-butyn-2-ol (9) (1.6 mL, 16 mmol) in triethylamine (25 mL) was added PdCl2(PPh3)3 (0.095 g, 0.14 mmol) and CuI (0.027 g, 0.14 mmol). The resulting mixture was degassed and stirred under argon at 70° C. for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL). The solution was filtered through filter paper, washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient) gave 4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (10) as a light brown oil: Yield (0.78 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.18 (m, 4H), 5.46 (s, 1H), 4.48 (t, J=5.2 Hz, 1H), 3.38 (q, J=6.0 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.66-1.73 (m, 2H), 1.46 (s, 6H). The resulting mixture was degassed The reaction mixture was concentrated under reduced pressure diluted with EtOAc (50 mL) The solution was filtered through filter paper washed with water (50 mL) and brine (50 mL) dried over Na2SO4 concentrated under reduced pressure Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient)

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

Procedure: Compound 40-2 (2.78 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.72 g) and N-bromosuccinimide (2.53 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.34 g) as a colorless oil. cooling cooling for 2 hr The reaction mixture was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure Diethyl ether (100 ml) was added the precipitated triphenylphosphine oxide was filtered off The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone)

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

Procedure: Compound 40-2 (2.78 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.72 g) and N-bromosuccinimide (2.53 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.34 g) as a colorless oil. cooling cooling for 2 hr The reaction mixture was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure Diethyl ether (100 ml) was added the precipitated triphenylphosphine oxide was filtered off The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 3-(3-bromophenyl)propan-1-ol (47) (0.95 g, 4.5 mmol) and 2-methyl-3-butyn-2-ol (48) (1.6 mL, 16 mmol) in triethylamine (25 mL) was added PdCl2(PPh3)3 (0.095 g, 0.14 mmol) and CuI (0.027 g, 0.14 mmol). The resulting mixture was degassed and stirred under argon at 70° C. for 15 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL). Trace solids were removed by filtration then the filtrate was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient) gave 4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (49) as a light brown oil: Yield (0.78 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 7.18-7.29 (m, 4H), 5.46 (s, 1H), 4.48 (t, J=4.0 Hz, 1H), 3.38 (q, J=4.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 2.46 (m, 2H), 1.46 (s, 6H). The resulting mixture was degassed After cooling to room temperature the reaction mixture was concentrated under reduced pressure diluted with EtOAc (50 mL) Trace solids were removed by filtration the filtrate was washed with water and brine dried over Na2SO4 concentrated under reduced pressure Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.57 g (6.7 mmol) of 3-(3-bromophenyl)propan-1-ol, prepared in step 7.1., and 1.73 ml (10.1 mmol) of diisopropylethylamine in 38 ml of dichloromethane, cooled to 0° C., is admixed with 0.63 ml (8.14 mmol) of methanesulphonyl chloride. Stirring is continued in the cold for 0.5 hour and then at ambient temperature for 2 hours. The mixture is concentrated under reduced pressure and then the residue is suspended in 35 ml of acetonitrile. 1.34 g (5.35 mmol) of 2-(methylamino)-2-oxoethyl piperazine-1-carboxylate hydrochloride, prepared in accordance with Example 3.3., and 2.2 g (16 mmol) of potassium carbonate are added. The mixture is heated at 75° C. for 16 hours. After cooling to ambient temperature it is concentrated under reduced pressure and then the residue is taken up in water. It is extracted with ethyl acetate and dried over sodium sulphate. Following filtration, the organic phase is concentrated under reduced pressure. It is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. Crystallization from diisopropyl ether gives 0.84 g (2.10 mmol) of white crystals. cold for 0.5 hour The mixture is concentrated under reduced pressure After cooling to ambient temperature it is concentrated under reduced pressure It is extracted with ethyl acetate dried over sodium sulphate filtration the organic phase is concentrated under reduced pressure It is purified by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol Crystallization from diisopropyl ether

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

Procedure: A suspension of 1.84 g (8 mmol) of 3-(3-bromophenyl)propionic acid and 0.91 g (24 mmol) of sodium borohydride in 20 ml of THF, cooled to 0° C., is admixed in small portions with 3.2 ml (25 mmol) of trifluoroborane-diethyl ether complex. Stirring is continued in the cold for 1 hour, and then at ambient temperature for 16 hours. The reaction mixture is cooled to 0° C. and neutralized to a pH of 7˜8 by adding a 1N solution of aqueous sodium hydroxide. It is concentrated under reduced pressure and then the residue is taken up in water. It is extracted with dichloromethane and dried over sodium sulphate. Following filtration, the organic phase is concentrated under reduced pressure. This gives 1.62 g (7.53 mmol) of product in the form of an oil, which is used as it is in the following step. cold for 1 hour The reaction mixture is cooled to 0° C. and neutralized to a pH of 7˜8 It is concentrated under reduced pressure It is extracted with dichloromethane dried over sodium sulphate filtration the organic phase is concentrated under reduced pressure

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

Procedure: A suspension of 1.84 g (8 mmol) of 3-(3-bromophenyl)propionic acid and 0.91 g (24 mmol) of sodium borohydride in 20 ml of THF, cooled to 0° C., is admixed in small portions with 3.2 ml (25 mmol) of trifluoroborane-diethyl ether complex. Stirring is continued in the cold for 1 hour, and then at ambient temperature for 16 hours. The reaction mixture is cooled to 0° C. and neutralized to a pH of 7˜8 by adding a 1N solution of aqueous sodium hydroxide. It is concentrated under reduced pressure and then the residue is taken up in water. It is extracted with dichloromethane and dried over sodium sulphate. Following filtration, the organic phase is concentrated under reduced pressure. This gives 1.62 g (7.53 mmol) of product in the form of an oil, which is used as it is in the following step. cold for 1 hour The reaction mixture is cooled to 0° C. and neutralized to a pH of 7˜8 It is concentrated under reduced pressure It is extracted with dichloromethane dried over sodium sulphate filtration the organic phase is concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 3-(3-bromophenyl)propan-1-ol (47) (0.95 g, 4.5 mmol) and 2-methyl-3-butyn-2-ol (48) (1.6 mL, 16 mmol) in triethylamine (25 mL) was added PdCl2(PPh3)3 (0.095 g, 0.14 mmol) and CuI (0.027 g, 0.14 mmol). The resulting mixture was degassed and stirred under argon at 70° C. for 15 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL). Trace solids were removed by filtration then the filtrate was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient) gave 4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (49) as a light brown oil: Yield (0.78 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 7.18-7.29 (m, 4H), 5.46 (s, 1H), 4.48 (t, J=4.0 Hz, 1H), 3.38 (q, J=4.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 2.46 (m, 2H), 1.46 (s, 6H). The resulting mixture was degassed After cooling to room temperature the reaction mixture was concentrated under reduced pressure diluted with EtOAc (50 mL) Trace solids were removed by filtration the filtrate was washed with water and brine dried over Na2SO4 concentrated under reduced pressure Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient)

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

Procedure: To suspension of LiAlH4 (0.5 g, 1.3 mmol) in diethyl ether (25 mL) was added 3-bromocinnamic acid (83, 1.0 g, 4 mmol), in portions, at RT. The resulting suspension was stirred for 3 hours. The reaction was quenched by the successive addition of 15% aq. NaOH solution (1 mL) and water. The resulting white suspension was filtered through a pad of Celite. The filter cake was washed with ether and then ethyl acetate. The filtrate was concentrated to afford crude 8 as yellow oil. Yield (0.7 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.10-7.35 (m, 4H), 3.65 (t, J=6.5 Hz, 2H), 2.68 (t, J=7.8 Hz, 2H), 1.82-1.91 (m, 2H). at RT The reaction was quenched by the successive addition of 15% aq. NaOH solution (1 mL) and water The resulting white suspension was filtered through a pad of Celite The filter cake was washed with ether The filtrate was concentrated