3-chloro-N,N-diethylpropan-1-amine;hydrochloride

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 49 mg of the title compound. was then returned to room temperature liquid separation and extraction mixed solvent The organic layer was dried over sodium sulfate concentrated

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

Procedure: 12.9 g. of 2-methoxy-4'-hydroxy-α-ethyl-benzhydrol are dissolved in 100 ml. of methyl isobutyl ketone, 23 g. of anhydrous potassium carbonate 0.4 ml. of a 40% tetrabutyl ammoniumhydroxide solution and 10.3 g. of 3-diethylamino-propyl chloride hydrochloride are added, and the solution is heated up to the boiling point. The reaction mixture is boiled for 4 hours, and the solvent is distilled off under reduced pressure. To the residue water is added, and it is extracted with benzene. The benzene phase is washed with a 5% potassium hydroxide solution and subsequently with water. After drying over anhydrous potassium carbonate, benzene is distilled off under reduced pressure, and the residue is fractionated in vacuo to yield 13.2 g. of the title compound, boiling at 200° to 203° C./13.3 Pa. the solution is heated up to the boiling point the solvent is distilled off under reduced pressure To the residue water is added it is extracted with benzene The benzene phase is washed with a 5% potassium hydroxide solution and subsequently with water After drying over anhydrous potassium carbonate, benzene is distilled off under reduced pressure to yield 13.2 g

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

Procedure: To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 27.9 g (0.15 mole) of 3-diethylaminopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-diethylaminopropoxy)-fluoranthene which is converted to the dihydrochloride salt with ethereal HCl and recrystallized from methanolbutanone, M.P. 235°-236.5°C. at reflux for 24 hours After cooling the organic layer is washed with water dried over magnesium sulfate concentrated in vacuo The residue is crystallized from ether

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

Procedure: To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 27.9 g (0.15 mole) of 3-diethylaminopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-diethylaminopropoxy)-fluoranthene which is converted to the dihydrochloride salt with ethereal HCl and recrystallized from methanolbutanone, M.P. 235°-236.5°C. at reflux for 24 hours After cooling the organic layer is washed with water dried over magnesium sulfate concentrated in vacuo The residue is crystallized from ether

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 49 mg of the title compound. was then returned to room temperature liquid separation and extraction mixed solvent The organic layer was dried over sodium sulfate concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethylacetate) to obtain 49 mg of the title compound. was then returned to room temperature liquid separation and extraction mixed solvent The organic layer was dried over sodium sulfate concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.7g (2.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-methylmethanesulfonamide (Example 15b) was stirred at RT for 1 h with 1.6 g (5.2 mmol) of phosphazene base [tert-butylimino-tri(pyrrolidino)phosphorane] in 2.5 ml of DMF. 0.48 g (2.6 mmol) of diethylaminopropyl chloride hydrochloride was then added and the mixture was heated to 100° C. for 8 h. After stripping off the solvent in vacuo, the residue was taken up in EA and the mixture was washed with water. After drying over magnesium sulfate and chromatography through a short silica gel column, 0.48 g of N-[6-(3-diethylaminopropoxy)-2,2-dimethylchroman-4-yl]-N-methylmethanesulfonamide was obtained as a glassy solid. the mixture was washed with water After drying over magnesium sulfate and chromatography through a short silica gel column

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.7g (2.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-methylmethanesulfonamide (Example 15b) was stirred at RT for 1 h with 1.6 g (5.2 mmol) of phosphazene base [tert-butylimino-tri(pyrrolidino)phosphorane] in 2.5 ml of DMF. 0.48 g (2.6 mmol) of diethylaminopropyl chloride hydrochloride was then added and the mixture was heated to 100° C. for 8 h. After stripping off the solvent in vacuo, the residue was taken up in EA and the mixture was washed with water. After drying over magnesium sulfate and chromatography through a short silica gel column, 0.48 g of N-[6-(3-diethylaminopropoxy)-2,2-dimethylchroman-4-yl]-N-methylmethanesulfonamide was obtained as a glassy solid. the mixture was washed with water After drying over magnesium sulfate and chromatography through a short silica gel column

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

Procedure: By the procedure described for Compound I, 6-bromobenz[cd]indol-2(1H)-one and 3-diethylaminopropyl chloride hydrochloride yield 6-bromo-1-(3-diethylaminopropylbenz[cd]-indol-2 (1H)-one (Ie), HCl salt, mp. 183°-185° C., while 3-dimethylaminopropyl chloride hydrochloride yields 6bromo-1-(3-dimethylaminopropyl) benz[cd]-2(1H)-one (If), HCl salt, mp. 264°-267° C. Similarly, 6-chlorobenz[cd]indol-2(1H)-one and methyl iodide yield 6-chloro-1-methylbenz[cd]-2(1H)-one (Ig), while benz[cd]indol-2(1H)-one and 4-chlorobenzyl chloride yield 1-(4-chlorobenzyl)benz[cd]indol-2(1H)-one (Ih), mp. 128°-129.5° C.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 49 mg of the title compound. was then returned to room temperature liquid separation and extraction mixed solvent The organic layer was dried over sodium sulfate concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 49 mg of the title compound. was then returned to room temperature liquid separation and extraction mixed solvent The organic layer was dried over sodium sulfate concentrated

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

Procedure: 12.9 g. of 2-methoxy-4'-hydroxy-α-ethyl-benzhydrol are dissolved in 100 ml. of methyl isobutyl ketone, 23 g. of anhydrous potassium carbonate 0.4 ml. of a 40% tetrabutyl ammoniumhydroxide solution and 10.3 g. of 3-diethylamino-propyl chloride hydrochloride are added, and the solution is heated up to the boiling point. The reaction mixture is boiled for 4 hours, and the solvent is distilled off under reduced pressure. To the residue water is added, and it is extracted with benzene. The benzene phase is washed with a 5% potassium hydroxide solution and subsequently with water. After drying over anhydrous potassium carbonate, benzene is distilled off under reduced pressure, and the residue is fractionated in vacuo to yield 13.2 g. of the title compound, boiling at 200° to 203° C./13.3 Pa. the solution is heated up to the boiling point the solvent is distilled off under reduced pressure To the residue water is added it is extracted with benzene The benzene phase is washed with a 5% potassium hydroxide solution and subsequently with water After drying over anhydrous potassium carbonate, benzene is distilled off under reduced pressure to yield 13.2 g