1H-indole-3-carbonyl chloride

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

Procedure: 1H-indole-3-carboxylic acid (3.00 g, 18.6 mmol) was suspended in 1,2-dichloroethane (15 mL), and oxalyl chloride (2.42 mL, 25.38 mmol) was added dropwise. To this reaction liquor, a catalytic amount of DMF (one drop) was added, and the reaction liquor was stirred for one hour at room temperature. The solvent of the reaction mixture was distilled off under reduced pressure, to obtain 1H-indole-3-carboxylic acid chloride as a solid. The obtained acid chloride was suspended in 1,2-dichloroethane (20 mL), and (4-amino-2,5-dichlorophenyl)acetic acid ethyl ester hydrochloride (4.82 g, 16.92 mmol) was added thereto. The mixture was heated to ref lux for 18 hours with stirring. The reaction mixture was left to cool naturally to room temperature, and then the solvent was distilled off under reduced pressure. The obtained solids were dissolved in chloroform (100 mL), washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained solids were collected by filtration using hexane, to obtain [2,5-d]chloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid ethyl ester (5.95 g, 90%) as a solid. This compound was used in the subsequent reaction without performing further purification. The solvent of the reaction mixture was distilled off under reduced pressure

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

Procedure: Indole-3-carboxylic acid (51 mg, 0.316 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and indole-3-carboxylic acid chloride mentioned above, the title compound (40 mg, yield 55%) was obtained in the same manner as that of Example 1, (4).

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

Procedure: To an ice-cooled solution of (1-methyl-2-piperidyl)-1-ethanol (19.4 g, 140 mmol), obtained according to the procedures in Reference Example 4 starting with pyridine-1-ethanol, and 1,3-dimethyl-2-imidazolidinone (30 ml, 270 mmol) in THF (300 ml) was dropwise added 1.6M hexane solution of n-butyllithium (85 ml, 140 mmol) over a period of 25 min. After stirring for 30 min., a THF (100 ml) solution of indole-3-carboxylic acid chloride (17.0 g, 95 mmol) and 1,3-dimethyl-2-imidazolidinone (10 ml, 90 mmol) was added at a temperature of -5° C. or below over a period of 50 min. The mixture was stirred under cooling for 30 min. followed by removal of the ice bath and stirring for additional one hour. A reaction mixture was poured onto water (500 ml) followed by extraction with ethyl acetate (500 ml). The organic layer was washed with water and then transferred to diluted hydrochloric acid (500 ml). The acid layer was washed with ethyl acetate, adjusted with sodium carbonate to a pH >10 and extracted with ethyl acetate (3×200 ml). The organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give a crude product (9.5 g) as a yellow oil, which was found by NMR to be an approximately 5:1 diastereomeric mixture. Thus, the oil was crystallized from a chloroform-isopropyl ether to afford a less polar major product as colorless crystals, which were a single diastereoisomer of the title compound (6.10 g). m.p. (HCl salt): 185° C. obtained of 25 min The mixture was stirred under cooling for 30 min. followed by removal of the ice bath stirring for additional one hour A reaction mixture was poured onto water (500 ml) followed by extraction with ethyl acetate (500 ml) The organic layer was washed with water The acid layer was washed with ethyl acetate extracted with ethyl acetate (3×200 ml) The organic layer was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to give a crude product (9.5 g) as a yellow oil, which Thus, the oil was crystallized from a chloroform-isopropyl ether to afford a less polar major product as colorless crystals, which

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

Procedure: To an ice-cooled solution of (1-methyl-2-piperidyl)-1-ethanol (19.4 g, 140 mmol), obtained according to the procedures in Reference Example 4 starting with pyridine-1-ethanol, and 1,3-dimethyl-2-imidazolidinone (30 ml, 270 mmol) in THF (300 ml) was dropwise added 1.6M hexane solution of n-butyllithium (85 ml, 140 mmol) over a period of 25 min. After stirring for 30 min., a THF (100 ml) solution of indole-3-carboxylic acid chloride (17.0 g, 95 mmol) and 1,3-dimethyl-2-imidazolidinone (10 ml, 90 mmol) was added at a temperature of -5° C. or below over a period of 50 min. The mixture was stirred under cooling for 30 min. followed by removal of the ice bath and stirring for additional one hour. A reaction mixture was poured onto water (500 ml) followed by extraction with ethyl acetate (500 ml). The organic layer was washed with water and then transferred to diluted hydrochloric acid (500 ml). The acid layer was washed with ethyl acetate, adjusted with sodium carbonate to a pH >10 and extracted with ethyl acetate (3×200 ml). The organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give a crude product (9.5 g) as a yellow oil, which was found by NMR to be an approximately 5:1 diastereomeric mixture. Thus, the oil was crystallized from a chloroform-isopropyl ether to afford a less polar major product as colorless crystals, which were a single diastereoisomer of the title compound (6.10 g). m.p. (HCl salt): 185° C. obtained of 25 min The mixture was stirred under cooling for 30 min. followed by removal of the ice bath stirring for additional one hour A reaction mixture was poured onto water (500 ml) followed by extraction with ethyl acetate (500 ml) The organic layer was washed with water The acid layer was washed with ethyl acetate extracted with ethyl acetate (3×200 ml) The organic layer was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure to give a crude product (9.5 g) as a yellow oil, which Thus, the oil was crystallized from a chloroform-isopropyl ether to afford a less polar major product as colorless crystals, which

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

Procedure: To a dry THF solution (30 ml) of 2-(1-methyl-2-pyrrolidine)ethanol at -10° to 5° C. was dropwise added a 1.5M hexane solution of n-BuLi (16.0 ml, 24.0 mmol) over a period of 10 min. Stirring was continued for 30 min. To a mixture was then dropwise added at -5° to 5° C. a dry THF solution (20 ml) of indole-3-carboxylic acid chloride (4.20 g, 24.0 mmol) over a period of 45 min. The cooling bath was removed. After stirring overnight at room temperature, a reaction solution was poured onto a cold diluted hydrochloric acid, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of the title compound as a yellow viscous material. A foamy solid; The cooling bath was removed After stirring overnight at room temperature a reaction solution was poured onto a cold diluted hydrochloric acid the aqueous layer was washed with ethyl acetate extracted with ethyl acetate The organic layer was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

Procedure: To a dry THF solution (30 ml) of 2-(1-methyl-2-pyrrolidine)ethanol at -10° to 5° C. was dropwise added a 1.5M hexane solution of n-BuLi (16.0 ml, 24.0 mmol) over a period of 10 min. Stirring was continued for 30 min. To a mixture was then dropwise added at -5° to 5° C. a dry THF solution (20 ml) of indole-3-carboxylic acid chloride (4.20 g, 24.0 mmol) over a period of 45 min. The cooling bath was removed. After stirring overnight at room temperature, a reaction solution was poured onto a cold diluted hydrochloric acid, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of the title compound as a yellow viscous material. A foamy solid; The cooling bath was removed After stirring overnight at room temperature a reaction solution was poured onto a cold diluted hydrochloric acid the aqueous layer was washed with ethyl acetate extracted with ethyl acetate The organic layer was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

Procedure: To a dry THF solution of 2-(1-pyrrolidinyl)ethanol (1.10 g, 9.6 mmol) was dropwise added under ice-cooling a 1.5M hexane solution of n-BuLi (6.4 ml, 9.6 mmol) over a period of 10 min. followed by stirring for 30 min. The solvent was removed under reduced pressure. To the residue was added dry THF (20 ml). To the resulting pale yellow suspension was added a dry THF solution (5 ml) of indole-3-carboxylic acid chloride (1.00 g, 5.6 mmol) with stirring at room temperature over a period of 10 min. After stirring overnight, a reaction solution was then concentrated under reduced pressure. The residue was extracted with diluted hydrochloric acid followed by washing with ether. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and again extracted with ether. The organic layer was washed successively with water and saturated aqueous sodium chloride, then dried (MgSO4) and concentrated under reduced pressure to give 1.10 g of the title compound as colorless plates. m.p. 145°-146° C.; The solvent was removed under reduced pressure To the residue was added dry THF (20 ml) with stirring at room temperature over a period of 10 min After stirring overnight a reaction solution was then concentrated under reduced pressure The residue was extracted with diluted hydrochloric acid by washing with ether again extracted with ether The organic layer was washed successively with water and saturated aqueous sodium chloride dried (MgSO4) concentrated under reduced pressure

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

Procedure: eq-1-Hydroxyquinolizidine (H. S. Aaron et al, J. Org. Chem. 1964, 29, 2248) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether to afford the title compound (E11a) as a white solid, mp 230°-232° C. The product was chromatographed on silica gel eluting with ether

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

Procedure: eq-1-Hydroxyquinolizidine (H. S. Aaron et al, J. Org. Chem. 1964, 29, 2248) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether to afford the title compound (E11a) as a white solid, mp 230°-232° C. The product was chromatographed on silica gel eluting with ether

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

Procedure: eq-2-(2-Hydroxyethyl)quinolizidine (D5) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The resulting beige solid was recrystallised from ethyl acetate/petrol (60-80) to afford the title compound (E10) as a white solid mp 170°-172° C. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (95:5) The resulting beige solid was recrystallised from ethyl acetate/petrol (60-80)

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

Procedure: The title compound was prepared from eq-2-hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem., 1957, 22, 1445) and indole-3-carboxylic acid chloride using the method of Example 1. The yellow oil obtained was crystallised from ether to afford the title compound (E9b) as a beige solid mp 154°-157° C. The yellow oil obtained was crystallised from ether

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

Procedure: The title compound was prepared from ax-2-hydroxymethylquinolizidine (D4) and indole-3-carboxylic acid chloride using the method of Example 1. The product was purified by chromatography on neutral alumina eluting with ethyl acetate, followed by crystallisation from ether/pentane, to give the title compound (E9a) as a white solid mp 156°-157° C. The product was purified by chromatography on neutral alumina eluting with ethyl acetate followed by crystallisation from ether/pentane