1-prop-2-ynylpyrrolidin-2-one

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

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

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

Procedure: A mixture of 365 mg of (racemic)-3-methoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 180 mg of paraformaldehyde, 0.6 ml of acetic acid, 20 ml of dioxane and 10 mg of cuprous chloride was stirred at reflux under argon for 1 hour. The reaction was cooled and treated with a mixture of 3 ml of 5N sodium hydroxide and 2 ml of water. The mixture was extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. The oil was purified by chromatography (alumina), giving 520 mg of the desired product as a yellow oil. at reflux under argon for 1 hour The reaction was cooled The mixture was extracted twice with dichloromethane dried filtered concentrated in vacuo to an oil The oil was purified by chromatography (alumina)

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

Procedure: A mixture of 500 mg of (S)-3-acetoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 150 mg of paraformaldehyde and 50 mg of cupric chloride in 10 ml of dioxane was stirred at reflux under argon for 4 hours. The dioxane was evaporated, the residue was treated with 5 ml of 1N hydrochloric acid and extracted twice with ether. The aqueous acid was basified with 1 g of sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. This oil was purified by chromatography (alumina), giving 490 mg of the desired product as a yellow oil, [α]D26 =-3° (c, 1.02, methanol). at reflux under argon for 4 hours The dioxane was evaporated the residue was treated with 5 ml of 1N hydrochloric acid extracted twice with ether extracted twice with dichloromethane dried filtered concentrated in vacuo to an oil This oil was purified by chromatography (alumina)

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 1.0 g (2 equivalents) of 1-propargyl pyrrolidin-2-one prepared in Example 7, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) to obtain 352.2 mg (35.4% yield) of 1-(3-pyridin-3-yl-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 520 mg (2 equivalents) of 1-propargyl pyrrolidin-2-one prepared in Example 7, and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 10:1) as eluent to obtain 278.1 mg (50% yield) of 1-[3-(1-methyl-piperidin-3-yl)-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: As in Example 6, 15 g (0.18 mol) of 2-pyrrolidinone and 18.65 mL (1 equivalent) of propargyl bromide were reacted, then distilled in vacuo (66˜71° C./0.1 mmHg) to obtain 11.94 g (58% yield) of 1-propargyl pyrrolidin-2-one. distilled in vacuo (66˜71° C./0.1 mmHg)

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

Procedure: N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (250 mg, 0.42 mmol) and 1-prop-2-yn-1-ylpyrrolidin-2-one (103 mg, 0.84 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (30 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (84 mg, 0.84 mmol). The reaction was allowed to warm to room temperature and stirred 46 hr. then filtered through Celite and evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution, the organic layer separated, dried over magnesium sulphate and evaporated then purified by chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (98 mg, 40%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.12 (m, 4H), 2.44 (t, 2H), 2.49 (m, 4H), 2.57 (t, 2H), 3.55 (t, 2H), 3.72 (m, 4H), 4.00 (s,3H), 4.25 (t,2H), 4.35 (s,2H), 6.08 (s,2H), 7.03 (s,1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.30 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 594/596. then filtered through Celite evaporated The residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution the organic layer separated dried over magnesium sulphate evaporated then purified by chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent

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

Procedure: A mixture of 365 mg of (racemic)-3-methoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 180 mg of paraformaldehyde, 0.6 ml of acetic acid, 20 ml of dioxane and 10 mg of cuprous chloride was stirred at reflux under argon for 1 hour. The reaction was cooled and treated with a mixture of 3 ml of 5N sodium hydroxide and 2 ml of water. The mixture was extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. The oil was purified by chromatography (alumina), giving 520 mg of the desired product as a yellow oil. at reflux under argon for 1 hour The reaction was cooled The mixture was extracted twice with dichloromethane dried filtered concentrated in vacuo to an oil The oil was purified by chromatography (alumina)

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

Procedure: A mixture of 500 mg of (S)-3-acetoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 150 mg of paraformaldehyde and 50 mg of cupric chloride in 10 ml of dioxane was stirred at reflux under argon for 4 hours. The dioxane was evaporated, the residue was treated with 5 ml of 1N hydrochloric acid and extracted twice with ether. The aqueous acid was basified with 1 g of sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. This oil was purified by chromatography (alumina), giving 490 mg of the desired product as a yellow oil, [α]D26 =-3° (c, 1.02, methanol). at reflux under argon for 4 hours The dioxane was evaporated the residue was treated with 5 ml of 1N hydrochloric acid extracted twice with ether extracted twice with dichloromethane dried filtered concentrated in vacuo to an oil This oil was purified by chromatography (alumina)

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

Procedure: A mixture of 365 mg of (racemic)-3-methoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 180 mg of paraformaldehyde, 0.6 ml of acetic acid, 20 ml of dioxane and 10 mg of cuprous chloride was stirred at reflux under argon for 1 hour. The reaction was cooled and treated with a mixture of 3 ml of 5N sodium hydroxide and 2 ml of water. The mixture was extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. The oil was purified by chromatography (alumina), giving 520 mg of the desired product as a yellow oil. at reflux under argon for 1 hour The reaction was cooled The mixture was extracted twice with dichloromethane dried filtered concentrated in vacuo to an oil The oil was purified by chromatography (alumina)

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

Procedure: A mixture of 500 mg of (S)-3-acetoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 150 mg of paraformaldehyde and 50 mg of cupric chloride in 10 ml of dioxane was stirred at reflux under argon for 4 hours. The dioxane was evaporated, the residue was treated with 5 ml of 1N hydrochloric acid and extracted twice with ether. The aqueous acid was basified with 1 g of sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. This oil was purified by chromatography (alumina), giving 490 mg of the desired product as a yellow oil, [α]D26 =-3° (c, 1.02, methanol). at reflux under argon for 4 hours The dioxane was evaporated the residue was treated with 5 ml of 1N hydrochloric acid extracted twice with ether extracted twice with dichloromethane dried filtered concentrated in vacuo to an oil This oil was purified by chromatography (alumina)