heptan-3-one

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

Procedure: N-(1-ethylpentyl)aniline was prepared from aniline and heptan-3-one using the same method as in Example 2i).

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

Procedure: Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and 1-diethylamino-6-)m-methoxypheyl)heptan-3-one (10 g, obtained by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (7g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes or ether and benzene (50 cc). Wash the solution with 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g); infrared absorption peak at 5.80 μ. Reflux

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

Procedure: Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and 1-diethylamino-6-)m-methoxypheyl)heptan-3-one (10 g, obtained by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (7g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes or ether and benzene (50 cc). Wash the solution with 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g); infrared absorption peak at 5.80 μ. Reflux

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

Procedure: A mixture of (R)-1-azabicyclo 2.2.1!heptan-3-one (U.S. Pat. No. 5,306,718) (2.22 g, 20 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) in MeOH (75 mL) is stirred at 25° C. for 18 hours. The solvent is removed under reduced pressure, the residual solid dissolves in saturated Na2CO3, and is extracted with CHCl3. The organic extracts are dried (Na2CO3), and concentrated to give the oxime. The aqueous layer is concentrated, and re-extracted with CHCl3 to yield additional product. A mixture of (R)-1-azabicyclo 2.2.1 The solvent is removed under reduced pressure the residual solid dissolves in saturated Na2CO3 is extracted with CHCl3 The organic extracts are dried (Na2CO3) concentrated

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

Procedure: A mixture of 1-azabicyclo 2.2.1!heptan-3-one (8.83 g, 79 mmol) and hydroxylamine hydrochloride (5.52 g, 79 mmol) in MeOH (200 mL) was stirred at 25° C. for 18 hours. The solvent was removed under reduced pressure and the tan solid was partitioned between saturated Na2CO3 and CHCl3. The organic extracts were dried (Na2CO3), and concentrated to give the oxime, 5.48 g, 54.7%. The aqueous layer was concentrated, and re-extracted with CHCl3 to yield another 3.17 g product. Total yield, 8.65 g, 86%. The ratio is from 95% to 98% Z to E. A mixture of 1-azabicyclo 2.2.1 The solvent was removed under reduced pressure the tan solid was partitioned between saturated Na2CO3 and CHCl3 The organic extracts were dried (Na2CO3) concentrated

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

Procedure: A mixture of 1-azabicyclo 2.2.1!heptan-3-one (8.83 g, 79 mmol) and hydroxylamine hydrochloride (5.52 g, 79 mmol) in MeOH (200 mL) was stirred at 25° C. for 18 hours. The solvent was removed under reduced pressure and the tan solid was partitioned between saturated Na2CO3 and CHCl3. The organic extracts were dried (Na2CO3), and concentrated to give the oxime, 5.48 g, 54.7%. The aqueous layer was concentrated, and re-extracted with CHCl3 to yield another 3.17 g product. Total yield, 8.65 g, 86%. The ratio is from 95% to 98% Z to E. A mixture of 1-azabicyclo 2.2.1 The solvent was removed under reduced pressure the tan solid was partitioned between saturated Na2CO3 and CHCl3 The organic extracts were dried (Na2CO3) concentrated

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

Procedure: N-(1-ethylpentyl)aniline was prepared from aniline and heptan-3-one using the same method as in Example 2i).

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

Procedure: N-(1-ethylpentyl)aniline was prepared from aniline and heptan-3-one using the same method as in Example 2i).

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(S)-amino-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (100 mg, 0.265 mmol) and 3-heptanone (0.1 mL), acetic acid (0.2 mL), sodium sulfate and sodium cyanoborohydride (100 mg) in dichloroethane (2 mL) and methanol (1 mL) was stirred at 40° C. overnight. The mixture was quenched with water, basified by dilute sodium hydroxide, and extracted with methylene chloride. The organic layer was concentrated to dryness. The residue was purified by Biotage silica gel column chromatography to isolate 2-(S)-(1-propyl-butylamino)-pentanoic acid [5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide as a colorless oil, LC-MS, RT=2.2 min, M+1=426.5. The mixture was quenched with water extracted with methylene chloride The organic layer was concentrated to dryness The residue was purified by Biotage silica gel column chromatography

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(S)-amino-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (100 mg, 0.265 mmol) and 3-heptanone (0.1 mL), acetic acid (0.2 mL), sodium sulfate and sodium cyanoborohydride (100 mg) in dichloroethane (2 mL) and methanol (1 mL) was stirred at 40° C. overnight. The mixture was quenched with water, basified by dilute sodium hydroxide, and extracted with methylene chloride. The organic layer was concentrated to dryness. The residue was purified by Biotage silica gel column chromatography to isolate 2-(S)-(1-propyl-butylamino)-pentanoic acid [5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide as a colorless oil, LC-MS, RT=2.2 min, M+1=426.5. The mixture was quenched with water extracted with methylene chloride The organic layer was concentrated to dryness The residue was purified by Biotage silica gel column chromatography

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

Procedure: N-(1-ethylpentyl)aniline was prepared from aniline and heptan-3-one using the same method as in Example 2i).

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

Procedure: To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (3.00 g) synthesized in Example 69 (4) in tetrahydrofuran (50 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (13.7 mL) at −45° C. After stirring under an argon atmosphere for 1 hr, 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (13.7 mL) was added dropwise, and the mixture was stirred for 1 hr. 3-Heptanone (6.04 mL) was added dropwise, and the mixture was stirred at −45° C. for 1 hr, and at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title compound (3.06 g, quantitative) as a colorless oil. the mixture was stirred for 1 hr the mixture was stirred at −45° C. for 1 hr at room temperature for 1 hr to quench the reaction the mixture was extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio)