4-chlorobutanal

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An amount of 100 mg (0.27 mmol) of 9-(2,4-dichloroanilino)-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinoline-8-carbonitrile, was stirred in N,N-dimethylformamide (2 mL), and to this was added a solution of 4-chloro-butyraldehyde (719 mg, 6.8 mmol) in tetrahydrofuran (2 mL) and trifluoroacetic acid (1.4 mL). The reaction mixture was stirred at room temperature, and to this was added sodium borohydride (128 mg, 3.4 mmol) portionwise, in 1.5 hours. The mixture was stirred for 16 hours, basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate and evaporated to an oil. Purification was done by flash chromatography (10% acetone in dichloromethane) to give a yellow solid (66 mg, 53% yield), m.p 56-57° C.; 1H NMR (DMSO-d6) δ 9.92 (bs, 1H), 8.59 (s, 1H), 7.81 (d, 2H), 7.51 (m, 2H), 6.98 (s, 1H), 4.30 (t, 2H), 3.70 (t, 2H), 3.57 (t, 2H), 3.51 (t, 2H), 1.80 (m, 4H); HRMS (EI) m/z 461.06917 (M+1). Analysis for C22H19Cl3N4O.0.7CH3CO2C2H5.3.9H2O Found: C, 49.81; H, 3.78; N, 9.65. Calcd: C, 50.12; H, 5.46; N, 9.43. The mixture was stirred for 16 hours extracted with ethyl acetate After separation of the layers the organic layer was washed with saturated brine solution dried over sodium sulfate evaporated to an oil Purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1.12 g of 4-chlorobutanal and 5.3 ml of 3M sulfuric acid in 11 ml of tetrahydrofuran, at 0° C., was added an solution of 2.0 g of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-3-quinolinecarbonitrile in 40 ml of dimethylforamide. To this was added portionwise 0.4 g of sodium borohydride. After 1 hr another 1.0 g of aldehyde, 10 ml of dimethylforamide, and 5 ml of 3M sulfuric acid was added followed by the portionwise addition of 0.8 g of sodium borohydride. After 2 hrs, the mixture was poured into water and the Ph was adjusted to 9. The mixture was extracted with ethyl acetate several times. The organic solution was dried over magnesium sulfate and the solvent was removed giving the title compound as an oil which was used without additional purification. The mixture was extracted with ethyl acetate several times The organic solution was dried over magnesium sulfate the solvent was removed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol) in THF (600 mL) was added 4-chlorobutanal prepared as described in Example 5 (9.0 g, 84 mmol) followed by dropwise addition of triethylamine (8.6 g, 85 mmol) in THF (20 mL). Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2 % NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. ##STR40## To a stirred, cooled prepared Upon complete addition the cooling bath was removed The reaction mixture was filtered the filter cake washed with THF (100 mL) The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) The solution was transferred to a sealable tube purged with nitrogen for 10 minutes The tube was sealed preheated to 95° C After heating for 14 hours concentrated under reduced pressure The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform The organic phase was dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel (15% methanol, 0.2 % NH4OH, in chloroform as eluent) The fractions containing product concentrated under reduced pressure The residue was dissolved in methanol treated with dry HCl concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added 4-chlorobutanal (9.0 g, 84 mmol.) followed by dropwise addition of triethylamine (8.6 g, 85 mmol.) in THF (20 mL). Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. ##STR30## To a stirred, cooled Upon complete addition the cooling bath was removed The reaction mixture was filtered the filter cake washed with THF (100 mL) The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) The solution was transferred to a sealable tube purged with nitrogen for 10 minutes The tube was sealed preheated to 95° C After heating for 14 hours concentrated under reduced pressure The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform The organic phase was dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent) The fractions containing product concentrated under reduced pressure The residue was dissolved in methanol treated with dry HCl concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added 4-chlorobutanal (9.0 g, 84 mmol.) followed by dropwise addition of triethylamine (8.6 g, 85 mmol.) in THF (20 mL). Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. ##STR30## To a stirred, cooled Upon complete addition the cooling bath was removed The reaction mixture was filtered the filter cake washed with THF (100 mL) The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) The solution was transferred to a sealable tube purged with nitrogen for 10 minutes The tube was sealed preheated to 95° C After heating for 14 hours concentrated under reduced pressure The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform The organic phase was dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent) The fractions containing product concentrated under reduced pressure The residue was dissolved in methanol treated with dry HCl concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added 4-chlorobutanal (9.0 g, 84 mmol.) followed by dropwise addition of triethylamine (8.6 g, 85 mmol.) in THF (20 mL). Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. ##STR30## To a stirred, cooled Upon complete addition the cooling bath was removed The reaction mixture was filtered the filter cake washed with THF (100 mL) The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) The solution was transferred to a sealable tube purged with nitrogen for 10 minutes The tube was sealed preheated to 95° C After heating for 14 hours concentrated under reduced pressure The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform The organic phase was dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent) The fractions containing product concentrated under reduced pressure The residue was dissolved in methanol treated with dry HCl concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added 4-chlorobutanal prepared as described in Example 5 (9.0 g, 84 mmol.) followed by dropwise addition of triethylamine (8.6 g, 85 mmol.) in THF (20 mL). Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform:2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. To a stirred, cooled prepared Upon complete addition the cooling bath was removed The reaction mixture was filtered the filter cake washed with THF (100 mL) The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) The solution was transferred to a sealable tube purged with nitrogen for 10 minutes The tube was sealed preheated to 95° C After heating for 14 hours concentrated under reduced pressure The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform The organic phase was dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent) The fractions containing product concentrated under reduced pressure The residue was dissolved in methanol treated with dry HCl concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added 4-chlorobutanal (9.0 g, 84 mmol.) followed by dropwise addition of triethylamine (8.6 g, 85 mmol.) in THF (20 mL) Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform:2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. To a stirred, cooled the cooling bath was removed The reaction mixture was filtered the filter cake washed with THF (100 mL) The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) The solution was transferred to a sealable tube purged with nitrogen for 10 minutes The tube was sealed preheated to 95° C After heating for 14 hours concentrated under reduced pressure The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform The organic phase was dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent) The fractions containing product concentrated under reduced pressure The residue was dissolved in methanol treated with dry HCl concentrated