2,8-dimethylnonan-5-one

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

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

Procedure: A solution of 5.63 g (33 mmol) of 2,8-dimethylnonan-5-one in 150 ml of methanol was cooled to 0° C. and treated with 0.8 g (21 mmol) of sodium borohydride. After 1 h, the solution was quenched with 1N HCl; diluted with 1:1 hexane/ether; washed sequentially with 1N NaOH, water, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 2.30 g (40%) of the desired compound (Rf 0.36, 20% ethyl acetate in hexane) as a colorless oil. 1H NMR (CDCl3) δ0.88 (d, J=7 Hz, 6H), 0.89 (d, J=7 Hz, 6H), 1.1-1.6 (m, 10H), 3.56 (m, 1H). the solution was quenched with 1N HCl diluted with 1:1 hexane/ether washed sequentially with 1N NaOH, water, and saturated brine dried over MgSO4 and concentrated in vacuo

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

Procedure: To a solution of 1.70 g of 2,8-dimethylnonan-5-one and 1.98 g of 1-(7-aminoheptyl)piperidine in 50 ml of methanol was added 6 N hydrochloric acid-ethanol to have a pH value of approx. 7 (pH test paper). To the resulting solution was added under cooling 1.26 g of sodium borohydride all at once. The resulting mixture was stirred under chilling with ice for one hour, and then stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was extracted with chloroform after addition of water and an aqueous sodium hydroxide solution. The chloroform portion was dried and evaporated under reduced pressure to remove the solvent, yielding an oily product. The oily product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1) to give the desired compound as a colorless oil. To the resulting solution was added under chilling with ice for one hour stirred overnight at room temperature The reaction mixture was concentrated the residue was extracted with chloroform after addition of water The chloroform portion was dried evaporated under reduced pressure to remove the solvent yielding an oily product The oily product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1)

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

Procedure: To a solution of 5.11 g of 2,8-dimethylnonan-5-one (b.p.: 103°-105° C./19 mmHg, prepared by oxidizing 2,8-dimethylnonan-5-ol with a bleaching powder; 2,8-dimethylnonan-5-ol was prepared by reaction of ethyl formate and isoamylmagnesium bromide) in 20 ml of ethanol were successively added an aqueous solution of 3.47 of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The mixture was heated under reflux. The reaction mixture was then poured into 150 ml of ice-containing water. The aqueous mixture was made acidic by addition of 2N hydrochloric acid and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. There was obtained 5.21 g of 2,8-dimethylnonan-5-one oxime as a pale brown oil, yield: 93.7%. The mixture was heated under reflux extracted with benzene The organic layer was washed with saturated aqueous sodium chloride dried over anhydrous sodium sulfate evaporated under reduced pressure to remove the solvent

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

Procedure: To a solution of 5.11 g of 2,8-dimethylnonan-5-one (b.p.: 103°-105° C./19 mmHg, prepared by oxidizing 2,8-dimethylnonan-5-ol with a bleaching powder; 2,8-dimethylnonan-5-ol was prepared by reaction of ethyl formate and isoamylmagnesium bromide) in 20 ml of ethanol were successively added an aqueous solution of 3.47 of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The mixture was heated under reflux. The reaction mixture was then poured into 150 ml of ice-containing water. The aqueous mixture was made acidic by addition of 2N hydrochloric acid and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. There was obtained 5.21 g of 2,8-dimethylnonan-5-one oxime as a pale brown oil, yield: 93.7%. The mixture was heated under reflux extracted with benzene The organic layer was washed with saturated aqueous sodium chloride dried over anhydrous sodium sulfate evaporated under reduced pressure to remove the solvent

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

Procedure: A solution of 5.63 g (33 mmol) of 2,8-dimethylnonan-5-one in 150 ml of methanol was cooled to 0° C. and treated with 0.8 g (21 mmol) of sodium borohydride. After 1 h, the solution was quenched with 1N HCl; diluted with 1:1 hexane/ether; washed sequentially with 1N NaOH, water, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 2.30 g (40%) of the desired compound (Rf 0.36, 20% ethyl acetate in hexane) as a colorless oil. 1H NMR (CDCl3) 0.88 (d, J=7 Hz, 6H), 0.89 (d, J=7 Hz, 6H), 1.1-1.6 (m, 10H), 3.56 (m, 1H). the solution was quenched with 1N HCl diluted with 1:1 hexane/ether washed sequentially with 1N NaOH, water, and saturated brine dried over MgSO4 and concentrated in vacuo

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

Procedure: A solution of 5.63 g (33 mmol) of 2,8-dimethylnonan-5-one in 150 ml of methanol was cooled to 0° C. and treated with 0.8 g (21 mmol) of sodium borohydride. After 1 h, the solution was quenched with 1N HCl; diluted with 1:1 hexane/ether; washed sequentially with 1N NaOH, water, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 2.30 g (40%) of the desired compound (Rf 0.36, 20% ethyl acetate in hexane) as a colorless oil. 1H NMR (CDCl3) 0.88 (d, J=7 Hz, 6H), 0.89 (d, J=7 Hz, 6H), 1.1-1.6 (m, 10H), 3.56 (m, 1H). the solution was quenched with 1N HCl diluted with 1:1 hexane/ether washed sequentially with 1N NaOH, water, and saturated brine dried over MgSO4 and concentrated in vacuo

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

Procedure: (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.04 g. 2.87 mmol, Example 2, Step A) and diisoamyl ketone (0.490 g, 2.87 mmol Aldrich, Milwaukee. Wis.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.910 g, 4.30 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (25 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (25% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.45 g (30%) of the pure titled compound as a white solid; mp 114-115° C. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for 30 minutes at 0° C. followed by an additional 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The two layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The crude product was further purified by flash chromatography (25% EtOAc in hexanes) The free amine was dissolved in 10 mL of ethyl ether treated with ethereal HCl

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

Procedure: (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.04 g, 2.87 mmol, Example 2, Step A) and diisoamyl ketone (0.490 g, 2.87 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.910 g, 4.30 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (25 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (25% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.45 g (30%) of the pure titled compound as a white solid; mp 114-115° C. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for 30 minutes at 0° C. followed by an additional 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The two layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The crude product was further purified by flash chromatography (25% EtOAc in hexanes) The free amine was dissolved in 10 mL of ethyl ether treated with ethereal HCl

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

Procedure: (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.04 g, 2.87 mmol, Example 2, Step A) and diisoamyl ketone (0.490 g, 2.87 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.910 g, 4.30 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (25 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (25% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.45 g (30%) of the pure titled compound as a white solid; mp 114-115° C. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for 30 minutes at 0° C. followed by an additional 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The two layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The crude product was further purified by flash chromatography (25% EtOAc in hexanes) The free amine was dissolved in 10 mL of ethyl ether treated with ethereal HCl

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

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

Procedure: To a solution of 1.70 g of 2,8-dimethylnonan-5-one and 1.98 g of 1-(7-aminoheptyl)piperidine in 50 ml of methanol was added 6 N hydrochloric acid-ethanol to have a pH value of approx. 7 (pH test paper). To the resulting solution was added under cooling 1.26 g of sodium borohydride all at once. The resulting mixture was stirred under chilling with ice for one hour, and then stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was extracted with chloroform after addition of water and an aqueous sodium hydroxide solution. The chloroform portion was dried and evaporated under reduced pressure to remove the solvent, yielding an oily product. The oil product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1) to give the desired compound as a colorless oil. To the resulting solution was added under chilling with ice for one hour stirred overnight at room temperature The reaction mixture was concentrated the residue was extracted with chloroform after addition of water The chloroform portion was dried evaporated under reduced pressure to remove the solvent yielding an oily product The oil product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1)