5-chloropentanal

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

Procedure: Proceeding as in Example 4, Step (c), but replacing 1-4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-chloropentan-1-one and piperidine with azacycloheptane, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-(azacyclohept-1-yl)pentan-1-one, m.p. 137°-139° C.

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

Procedure: Proceeding as in Example 4, Step (c), but replacing 1-4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-chloropentan-1-one and piperidine with azacycloheptane, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-(azacyclohept-1-yl)pentan-1-one, m.p. 137°-139° C.

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

Procedure: The compound 5-chloropentan-1-ol (16.2 mL) was dissolved in cold 5 mM 2,2,6,6-tetramethylpiperidine-1-yloxy (tempo) in dichloromethane (240 mL) and cooled down to 0° C. with an ice bath. Potassium bromide (0.5 M in water, 24 mL) was added, and this was followed by the addition (in one portion at 5° C. under vigorous stirring) of a solution of sodium hydrogencarbonate (24 g) in aqueous sodium hypochlorite (0.3 M, 500 mL). The resulting mixture was stirred at 5° C. for 20 min, and the phases were separated. The water phase was extracted with dichloromethane (200 mL), and the combined organic phases were evaporated in vacuo giving 5-chloropentanal as a clear oil (16 g). Subsequently, 5-chloropentanal was suspended in water (100 mL) followed by addition of 4-fluorophenylhydrazine hydrochloride (19.5 g) and toluene (800 mL), and the mixture was stirred at room temperature for 15 min. Phosphoric acid (85%, 100 mL) was added and the mixture was boiled under reflux for 2 h. The mixture was cooled to room temperature and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogencarbonate, dried (MgSO4) and evaporated in vacuo to yield an orange oil. The crude product was purified by flash chromatography on silicagel (eluent:ethylacetate/heptane 1:4) to give the title compound as an orange oil (14 g). under reflux for 2 h The mixture was cooled to room temperature the phases were separated The organic phase was washed with saturated aqueous sodium hydrogencarbonate dried (MgSO4) evaporated in vacuo to yield an orange oil The crude product was purified by flash chromatography on silicagel (eluent:ethylacetate/heptane 1:4)

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

Procedure: 400 mg of 3-(3-thienyl)benzyl(triphenyl)phosphonium bromide was dissolved in 2 ml of dimethylformamide, and under ice cooling, 37 mg of 60% oily sodium hydride was added. The mixture was stirred for 15 minutes, and to this solution was added an ethyl ether solution (0.6 ml) of the foregoing aldehyde compound. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=19/1] to give 123 mg of the captioned compound (a mixture of E:Z=1:1) as a pale yellow oil. The mixture was stirred overnight at room temperature the solvent was evaporated purified by silica gel column chromatography [hexane/ethyl acetate=19/1]

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

Procedure: 5-Chloropentanal (ca. 70% pure, 8.0 g) was added to a suspension of 4-bromophenylhydrazine hydrochloride (13.4 g) in aqueous acetic acid (50%, 300 ml). The mixture was heated rapidly to boiling with vigorous stirring and maintained at reflux for 7 hours. The resulting dark brown solution was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with water (200 ml) and saturated aqueous sodium hydrogen carbonate (4×250 ml), dried (MgSO4), filtered and evaporated to a dark brown oil (14.7 g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate:light petroleum (b.p. 60°-80°) (1:2) followed by bulb to bulb distillation twice in vacuo to give the title compound as a yellow oil (4 g) b.p. 200° C., 0.5 mm, which rapidly darkened on storage. The mixture was heated rapidly maintained at reflux for 7 hours extracted with ethyl acetate (4×150 ml) The combined extracts were washed with water (200 ml) and saturated aqueous sodium hydrogen carbonate (4×250 ml) dried (MgSO4) filtered evaporated to a dark brown oil (14.7 g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate light petroleum (b.p. 60°-80°) (1:2) followed by bulb to bulb distillation twice in vacuo

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

Procedure: The compound 5-chloropentan-1-ol (16.2 mL) was dissolved in cold 5 mM 2,2,6,6-tetramethylpiperidine-1-yloxy (tempo) in dichloromethane (240 mL) and cooled down to 0° C. with an ice bath. Potassium bromide (0.5 M in water, 24 mL) was added, and this was followed by the addition (in one portion at 5° C. under vigorous stirring) of a solution of sodium hydrogencarbonate (24 g) in aqueous sodium hypochlorite (0.3 M, 500 mL). The resulting mixture was stirred at 5° C. for 20 min, and the phases were separated. The water phase was extracted with dichloromethane (200 mL), and the combined organic phases were evaporated in vacuo giving 5-chloropentanal as a clear oil (16 g). Subsequently, 5-chloropentanal was suspended in water (100 mL) followed by addition of 4-fluorophenylhydrazine hydrochloride (19.5 g) and toluene (800 mL), and the mixture was stirred at room temperature for 15 min. Phosphoric acid (85%, 100 mL) was added and the mixture was boiled under reflux for 2 h. The mixture was cooled to room temperature and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogencarbonate, dried (MgSO4) and evaporated in vacuo to yield an orange oil. The crude product was purified by flash chromatography on silicagel (eluent: ethylacetate/heptane 1:4) to give the title compound as an orange oil (14 g). under reflux for 2 h The mixture was cooled to room temperature the phases were separated The organic phase was washed with saturated aqueous sodium hydrogencarbonate dried (MgSO4) evaporated in vacuo to yield an orange oil The crude product was purified by flash chromatography on silicagel (eluent: ethylacetate/heptane 1:4)

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

Procedure: 435 parts of a 13.7% strength by weight solution of δ-chlorovaleraldehyde in xylene (prepared by catalytic hydrogenation of a solution of δ-chlorovaleryl chloride in xylene) were stirred with 96 parts of 3-(β-aminoethyl)-indole hydrochloride in 500 parts of isopropanol for 6 hours at 85° C., and the mixture was cooled and then filtered under suction to give 92 parts (62.8%) of 1-(δ-chlorobutyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride. After recrystallization, the substance had a melting point of 245°-247° C. the mixture was cooled filtered under suction

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

Procedure: A solution of 0.32 mL (2.2 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 0.92 mL (2.3 mmol) of 2.5 M n-butyllithium in sol'n in hexanes. The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 0.51 g (1.8 mmol) of (1-tert-butoxycarbonylpiperidin-4-yl)acetic acid, ethyl ester (from Piperidine 35, Step A) in 2 mL of THF was added. After stirring for 30 minutes, a solution of 0.26 g (2.1 mmol) 5-chloropentanal in 2 mL of THF was added (J. Org. Chem. 1981, 46, 2007). The reaction was stirred for 1.75 hours at −78° C. and 3.5 hours at 0° C. After quenching the reaction with saturated NH4Cl, volatiles were removed under reduced pressure. The residue was partitioned between 100 mL of Et2O and 100 mL of H2O. After separating phases, the organic layer was washed with 100 mL of 0.5 N HCl and 100 mL of 1 N NaHCO3, dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 3:1 v/v of hexanes/EtOAc as the eluant to afford impure title compound: RF: 0.27 (7:3 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.24–2.08 (m, 23H), 2.38 (t, J=6.2, 1H), 2.63–2.71 (m, 2H), 3.53–3.56 (m, 2H), 3.92 (m, 1H), 4.09–4.19 (m, 4H). cooled to −78° C After stirring for 30 minutes The reaction was stirred for 1.75 hours at −78° C. and 3.5 hours at 0° C After quenching the reaction with saturated NH4Cl, volatiles were removed under reduced pressure The residue was partitioned between 100 mL of Et2O and 100 mL of H2O After separating phases the organic layer was washed with 100 mL of 0.5 N HCl and 100 mL of 1 N NaHCO3 dried over MgSO4 concentrated The residue was purified with a 40M Biotage column

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

Procedure: Proceeding as in Example 4, Step (c), but replacing 1-4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-chloropentan-1-one and piperidine with azacycloheptane, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-(azacyclohept-1-yl)pentan-1-one, m.p. 137°-139° C.