1-prop-2-enylpyrrolidin-2-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A thick walled glass tube, equipped with stir bar, was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (15 mL), N-allyl-2-pyrrolidone (650 mg, 5.17 mmol), triethylamine (2.1 ml, 15.65 mmol), tri-o-tolylphosphine (275 mg, 0.9 mmol) and 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 11, 1.5 g, 4.7 mmol). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. for 24 hours. The reaction mixture was concentrated to dryness. The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL). The layers were separated. The aqueous layer was extracted with chloroform (2×25 mL). The combined organic fractions were concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane) to provide 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one. A thick walled glass tube, equipped The reaction mixture was purged with nitrogen sealed The reaction mixture was concentrated to dryness The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL) The layers were separated The aqueous layer was extracted with chloroform (2×25 mL) The combined organic fractions were concentrated to dryness purified by chromatography a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A thick walled glass tube, equipped with stir bar, was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (15 mL), N-allyl-2-pyrrolidone (650 mg, 5.17 mmol), triethylamine (2.1 ml, 15.65 mmol), tri-o-tolylphosphine (275 mg, 0.9 mmol) and 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 11, 1.5 g, 4.7 mmol). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. for 24 hours. The reaction mixture was concentrated to dryness. The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL). The layers were separated. The aqueous layer was extracted with chloroform (2×25 mL). The combined organic fractions were concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane) to provide 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one. A thick walled glass tube, equipped The reaction mixture was purged with nitrogen sealed The reaction mixture was concentrated to dryness The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL) The layers were separated The aqueous layer was extracted with chloroform (2×25 mL) The combined organic fractions were concentrated to dryness purified by chromatography a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane)

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

Procedure: To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, there were added 125.2 g (1.0 mol) of 1-allyl-2-oxopyrrolidine and 0.5 g of 4% isopropyl alcohol solution of H2PtCl6. Trimethoxysilane (122.2 g; 1.0 mol) was dropwise added through the dropping funnel at a temperature ranging from 100° to 110° C. over 2 hours and the reaction mixture was allowed to stand at 100° C. for 30 minutes. The reaction solution was distilled to give 183.8 g of a compound having a boiling point of 123° to 125° C./2 mmHg in an yield of 74.3%. To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser to stand at 100° C. for 30 minutes The reaction solution was distilled

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

Procedure: To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, there were added 125.2 g (1.0 mol) of 1-allyl-2-oxopyrrolidine and 0.5 g of 4% isopropyl alcohol solution of H2PtCl6. Trimethoxysilane (122.2 g; 1.0 mol) was dropwise added through the dropping funnel at a temperature ranging from 100° to 110° C. over 2 hours and the reaction mixture was allowed to stand at 100° C. for 30 minutes. The reaction solution was distilled to give 183.8 g of a compound having a boiling point of 123° to 125° C./2 mmHg in an yield of 74.3%. To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser to stand at 100° C. for 30 minutes The reaction solution was distilled

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

Procedure: To a 5 liter volume flask of glass equipped with a stirrer, a fractional distillation column, a thermometer and a dropping funnel, there were added 270.1 g (5.0 mol) of sodium methoxide and 2 liters of toluene. After 425.6 g (5.0 mol) of 2-pyrrolidone was dropwise added to the flask through the dropping funnel at room temperature, the resulting methanol was completely removed by the fractional distillation column. 6.9 g (25 mmol) of (Butyl-)4NCl was added as a phase transfer catalyst and 382.7 g (5.0 mol) of allyl chloride was dropwise added to the reaction mixture at a temperature ranging from 60° to 70° C. through the dropping funnel to react them. After the completion of the reaction, water was added to dissolve salts formed during the reaction and then the organic phase was removed. Then the organic phase was distilled to separate the fractions having a boiling point ranging from 75° to 76° C./4 mmHg. Thus, 562.5 g of 1-allyl-2-oxopyrrolidine was obtained in a yield of 89.9%. To a 5 liter volume flask of glass equipped with a stirrer a fractional distillation column the resulting methanol was completely removed by the fractional distillation column was dropwise added to the reaction mixture at a temperature ranging from 60° to 70° C. through the dropping funnel to react them was added to dissolve salts formed during the reaction the organic phase was removed Then the organic phase was distilled to separate the fractions ranging from 75° to 76° C.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A thick walled glass tube, equipped with stir bar, was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (15 mL), N-allyl-2-pyrrolidone (650 mg, 5.17 mmol), triethylamine (2.1 ml, 15.65 mmol), tri-o-tolylphosphine (275 mg, 0.9 mmol) and 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 11, 1.5 g, 4.7 mmol). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. for 24 hours. The reaction mixture was concentrated to dryness. The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL). The layers were separated. The aqueous layer was extracted with chloroform (2×25 mL). The combined organic fractions were concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane) to provide 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one. A thick walled glass tube, equipped The reaction mixture was purged with nitrogen sealed The reaction mixture was concentrated to dryness The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL) The layers were separated The aqueous layer was extracted with chloroform (2×25 mL) The combined organic fractions were concentrated to dryness purified by chromatography a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The desired compound was prepared by the method of Example 8 from 400 mg (2.813 mmol) of 3-pyrrolidin-1-yl-propionaldehyde oxime prepared in Example 1 and 704 mg (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6, and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 7:1) as eluent to obtain 148 mg (20% yield) of 1-[3-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution. purified by separation with silica gel column chromatography

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

Procedure: The desired compound was prepared by the method of Example 8 from 500 mg (4.09 mmol) of 3-pyridine aldoxime and 1.02 g (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) as eluent to obtain 578.4 mg (58% yield) of 1-(3-pyridin-3-yl-4,5-dihydro-isoxazol-5-yl-methyl)-pyrrolidin-2-one. purified by separation with silica gel column chromatography

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

Procedure: The desired compound was prepared by the method of Example 8 from 300 mg (2.11 mmol) of 1-methyl-piperidin-3-carbaldehyde oxime prepared in Example 5 and 528 mg (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6 and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 10:1) as eluent to obtain 230.1 mg (41% yield) of 1-[3-(1-methyl-piperidin-3-yl)-4,5-dihydro-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution. purified by separation with silica gel column chromatography

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

Procedure: To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, there were added 125.2 g (1.0 mol) of 1-allyl-2-oxopyrrolidine and 0.5 g of 4% isopropyl alcohol solution of H2PtCl6. Trimethoxysilane (122.2 g; 1.0 mol) was dropwise added through the dropping funnel at a temperature ranging from 100° to 110° C. over 2 hours and the reaction mixture was allowed to stand at 100° C. for 30 minutes. The reaction solution was distilled to give 183.8 g of a compound having a boiling point of 123° to 125° C./2 mmHg in an yield of 74.3%. To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser to stand at 100° C. for 30 minutes The reaction solution was distilled