(2S)-2-phenylmethoxypropanal

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6° C. and then an ethereal solution of 2-(1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8° C. The mixture was stirred at 4° C. for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate =9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil. was added below 8° C After cooling the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered The filtrate was extracted with ethyl acetate the extract was washed with brine dried concentrated in vacuo

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6° C. and then an ethereal solution of 2-(1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8° C. The mixture was stirred at 4° C. for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate =9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil. was added below 8° C After cooling the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered The filtrate was extracted with ethyl acetate the extract was washed with brine dried concentrated in vacuo

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

Procedure: Trimethylsulfoxonium iodide (1.22 g) was added to a stirred suspension of sodium hydride (60% in mineral oil, 234 mg) in dimethylsulfoxide (12 ml) and dimethoxyethane (10 ml) at −3° C. to −4° C. under nitrogen atmosphere. After 10 minutes, a solution of (S)-2-(benzyloxy)propionaldehyde (obtained in Preparation 8) (800 mg) in dimethoxyethane (2 ml) was added dropwise to the mixture for a period of 5 minutes at the same temperature, and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was poured into a cold saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (3S)-3-benzyloxy-1,2-epoxybutane (507 mg). extracted with ethyl acetate (100 ml) The organic layer was washed with brine (50 ml) dried over magnesium sulfate concentrated in vacuo The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1)

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

Procedure: Trimethylsulfoxonium iodide (1.22 g) was added to a stirred suspension of sodium hydride (60% in mineral oil, 234 mg) in dimethylsulfoxide (12 ml) and dimethoxyethane (10 ml) at −3° C. to −4° C. under nitrogen atmosphere. After 10 minutes, a solution of (S)-2-(benzyloxy)propionaldehyde (obtained in Preparation 8) (800 mg) in dimethoxyethane (2 ml) was added dropwise to the mixture for a period of 5 minutes at the same temperature, and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was poured into a cold saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (3S)-3-benzyloxy-1,2-epoxybutane (507 mg). extracted with ethyl acetate (100 ml) The organic layer was washed with brine (50 ml) dried over magnesium sulfate concentrated in vacuo The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1)

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

Procedure: A solution of 1.0M DIBAL (diisobutylaluminum hydride) in hexane (10 ml) was added dropwise to a stirred solution of ethyl (S)-2-(benzyloxy)propionate (obtained in Preparation 7) (2.08 g) in methylene chloride (20 ml) at −78° C. (dry-ice/acetone) for 5 minutes under nitrogen atmosphere. After 20 minutes, methanol (1.6 ml) was added dropwise to the mixture at −78° C., and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of Celite, and the solid on the filter was washed with methylene chloride. The combined filtrates were concentrated in vacuo. The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (S)-2-(benzyloxy)propionaldehyde (810 mg). The mixture was filtered through a pad of Celite the solid on the filter was washed with methylene chloride The combined filtrates were concentrated in vacuo The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1)

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

Procedure: A solution of 1.0M DIBAL (diisobutylaluminum hydride) in hexane (10 ml) was added dropwise to a stirred solution of ethyl (S)-2-(benzyloxy)propionate (obtained in Preparation 7) (2.08 g) in methylene chloride (20 ml) at −78° C. (dry-ice/acetone) for 5 minutes under nitrogen atmosphere. After 20 minutes, methanol (1.6 ml) was added dropwise to the mixture at −78° C., and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of Celite, and the solid on the filter was washed with methylene chloride. The combined filtrates were concentrated in vacuo. The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (S)-2-(benzyloxy)propionaldehyde (810 mg). The mixture was filtered through a pad of Celite the solid on the filter was washed with methylene chloride The combined filtrates were concentrated in vacuo The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1)

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a pre-cooled solution of formyl hydrazine (40.3 g) in methanol (290 ml) at 0-5° C., toluene layer containing (S)-2-(benzyloxy)propanal compound of formula-15 obtained in step-b) was added. Slowly raised the temperature of reaction mixture to 25-30° C. and stirred for 4 hours at 25-30° C. After completion of the reaction, distilled off the solvent under reduced pressure to get title compound. Ethyl acetate (210 ml) was added to the obtained compound and stirred for 1 hour at 25-30° C. Filtered the reaction mixture to remove the unwanted solid and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure to get semi-solid. Petroleum ether (210 ml) was added to the obtained semi-solid and stirred for 2 hours at 25-30° C. Filtered the precipitated solid, washed with petroleum ether and then dried to get title compound. obtained in step-b) was added Slowly raised the temperature of reaction mixture to 25-30° C. After completion of the reaction distilled off the solvent under reduced pressure

Conditions: temp:-2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-methyl 2-(benzyloxy)propanoate compound of formula-14 obtained in example-11 (100 g) and toluene (200 ml) was cooled to −75 to 70° C. under nitrogen atmosphere. DIBAL (500 ml) was added to the reaction mixture and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with methanol and 30% hydrochloric acid was added to it at −75 to −70° C. Temperature of reaction mixture was raised to 25-30° C. Both organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both organic layers were combined, washed with 5% sodium bicarbonate and 10% sodium chloride solution. The organic layer containing title compound is carried for the next step without distillation. After completion of the reaction the reaction mixture was quenched with methanol and 30% hydrochloric acid was added to it at −75 to −70° C Temperature of reaction mixture was raised to 25-30° C Both organic and aqueous layers were separated the aqueous layer was extracted with toluene washed with 5% sodium bicarbonate and 10% sodium chloride solution The organic layer containing title compound is carried for the next step without distillation

Conditions: temp:-2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-methyl 2-(benzyloxy)propanoate compound of formula-14 obtained in example-11 (100 g) and toluene (200 ml) was cooled to −75 to 70° C. under nitrogen atmosphere. DIBAL (500 ml) was added to the reaction mixture and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with methanol and 30% hydrochloric acid was added to it at −75 to −70° C. Temperature of reaction mixture was raised to 25-30° C. Both organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both organic layers were combined, washed with 5% sodium bicarbonate and 10% sodium chloride solution. The organic layer containing title compound is carried for the next step without distillation. After completion of the reaction the reaction mixture was quenched with methanol and 30% hydrochloric acid was added to it at −75 to −70° C Temperature of reaction mixture was raised to 25-30° C Both organic and aqueous layers were separated the aqueous layer was extracted with toluene washed with 5% sodium bicarbonate and 10% sodium chloride solution The organic layer containing title compound is carried for the next step without distillation

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6° C. and then an ethereal solution of 2-(1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8° C. The mixture was stirred at 4° C. for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate =9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil. was added below 8° C After cooling the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered The filtrate was extracted with ethyl acetate the extract was washed with brine dried concentrated in vacuo

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

Procedure: Trimethylsulfoxonium iodide (1.22 g) was added to a stirred suspension of sodium hydride (60% in mineral oil, 234 mg) in dimethylsulfoxide (12 ml) and dimethoxyethane (10 ml) at −3° C. to −4° C. under nitrogen atmosphere. After 10 minutes, a solution of (S)-2-(benzyloxy)propionaldehyde (obtained in Preparation 8) (800 mg) in dimethoxyethane (2 ml) was added dropwise to the mixture for a period of 5 minutes at the same temperature, and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was poured into a cold saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (3S)-3-benzyloxy-1,2-epoxybutane (507 mg). extracted with ethyl acetate (100 ml) The organic layer was washed with brine (50 ml) dried over magnesium sulfate concentrated in vacuo The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1)

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

Procedure: A solution of 1.0M DIBAL (diisobutylaluminum hydride) in hexane (10 ml) was added dropwise to a stirred solution of ethyl (S)-2-(benzyloxy)propionate (obtained in Preparation 7) (2.08 g) in methylene chloride (20 ml) at −78° C. (dry-ice/acetone) for 5 minutes under nitrogen atmosphere. After 20 minutes, methanol (1.6 ml) was added dropwise to the mixture at −78° C., and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of Celite, and the solid on the filter was washed with methylene chloride. The combined filtrates were concentrated in vacuo. The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (S)-2-(benzyloxy)propionaldehyde (810 mg). The mixture was filtered through a pad of Celite the solid on the filter was washed with methylene chloride The combined filtrates were concentrated in vacuo The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1)