3-amino-1-methylpyrrolidin-2-one

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

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

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzophenone imine (200.04 g, 1103.8 mmol) was added dropwise over 20 minutes to a stirred solution of 3-amino-1-methylpyrrolidine-2-one (120 g, 1051.2 mmol) in DCE (1000 mL) at ambient temp under nitrogen in a 2 L flask fitted with a magnetic stirrer bar. The reagent was washed with further DCE (100 mL). The stirred solution was heated at reflux on a heat-on block at a block temp of 95° C. for 7 h, using a N2 bubbler with exhaled gas passing through a safety trap then into 2 L of water via an upturned funnel (for scrubbing NH3 gas, estimated to be approx 23 L). The reaction was left to stand at ambient temp overnight under N2. The mixture was evaporated to a thick, off-white oil. To this was added Et2O (700 ml) and to this stirred solution, as it began to crystallize, was added iso-hexane (700 ml) over 2 minutes. The mixture was stirred for 1 h then filtered under suction and washed with Et2O/iso-hexane (1:1) (500 ml). The white solid was dried at 35° C. under vacuum for 3 h to afford 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) (259.4 g, 88.6%). The NMR was consistent with pure material. fitted with a magnetic stirrer bar The reagent was washed with further DCE (100 mL) The stirred solution was heated The reaction was left The mixture was evaporated to a thick, off-white oil To this was added Et2O (700 ml) to crystallize was added iso-hexane (700 ml) over 2 minutes then filtered under suction washed with Et2O/iso-hexane (1:1) (500 ml) The white solid was dried at 35° C. under vacuum for 3 h

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzophenone imine (200.04 g, 1103.8 mmol) was added dropwise over 20 minutes to a stirred solution of 3-amino-1-methylpyrrolidine-2-one (120 g, 1051.2 mmol) in DCE (1000 mL) at ambient temp under nitrogen in a 2 L flask fitted with a magnetic stirrer bar. The reagent was washed with further DCE (100 mL). The stirred solution was heated at reflux on a heat-on block at a block temp of 95° C. for 7 h, using a N2 bubbler with exhaled gas passing through a safety trap then into 2 L of water via an upturned funnel (for scrubbing NH3 gas, estimated to be approx 23 L). The reaction was left to stand at ambient temp overnight under N2. The mixture was evaporated to a thick, off-white oil. To this was added Et2O (700 ml) and to this stirred solution, as it began to crystallize, was added iso-hexane (700 ml) over 2 minutes. The mixture was stirred for 1 h then filtered under suction and washed with Et2O/iso-hexane (1:1) (500 ml). The white solid was dried at 35° C. under vacuum for 3 h to afford 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) (259.4 g, 88.6%). The NMR was consistent with pure material. fitted with a magnetic stirrer bar The reagent was washed with further DCE (100 mL) The stirred solution was heated The reaction was left The mixture was evaporated to a thick, off-white oil To this was added Et2O (700 ml) to crystallize was added iso-hexane (700 ml) over 2 minutes then filtered under suction washed with Et2O/iso-hexane (1:1) (500 ml) The white solid was dried at 35° C. under vacuum for 3 h

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

Procedure: Benzophenone imine [CAS: 1013-88-3] (16.67 g, 91.98 mmol) was added dropwise to a solution of 3-amino-1-methylpyrrolidine-2-one [CAS 119329-48-5] (10 g, 87.60 mmol) in DCE (100 mL) under N2 and the reaction was heated at reflux for 18 hours. The solvent was evaporated to afford an amber oil. This was purified using flash silica in a large sinter funnel, eluting with 4:1 to 3:7 i-hexane:EtOAc. An incomplete separation was achieved. 3-(Benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) was isolated (25 g) with approximately 11% of an impurity present, but was used in the next step without further purification; the reaction was heated at reflux for 18 hours The solvent was evaporated to afford an amber oil This was purified eluting with 4:1 to 3:7 i-hexane An incomplete separation

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzophenone imine (200.04 g, 1103.8 mmol) was added dropwise over 20 minutes to a stirred solution of 3 amino-1-methylpyrrolid-2-one (120 g, 1051.2 mmol) in DCE (1000 mL) at ambient temp under nitrogen in a 2 L flask fitted with a magnetic stirrer bar. The reagent was washed with further DCE (100 mL). The stirred solution was heated at reflux on a heat-on block at a block temp of 95° C. for 7 h, using a N2 bubbler with exhaled gas passing through a safety trap then into 2 L of water via an upturned funnel (for scrubbing NH3 gas, estimated to be approx 23 L). The reaction was left to stand at ambient temp overnight under N2. The mixture was evaporated to a thick, off-white oil. To this was added Et2O (700 ml) and to this stirred solution, as it began to crystallize, was added iso-hexane (700 ml) over 2 minutes. The mixture was stirred for 1 h then filtered under suction and washed with Et2O/iso-hexane (1:1) (500 ml). The white solid was dried at 35° C. under vacuum for 3 h to afford 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D5) (259.4 g, 88.6%); fitted with a magnetic stirrer bar The reagent was washed with further DCE (100 mL) The stirred solution was heated The reaction was left The mixture was evaporated to a thick, off-white oil To this was added Et2O (700 ml) to crystallize was added iso-hexane (700 ml) over 2 minutes then filtered under suction washed with Et2O/iso-hexane (1:1) (500 ml) The white solid was dried at 35° C. under vacuum for 3 h

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

Procedure: To a stirred solution of 4-bromopyridine-2-carbaldehyde (2232.1 mg, 12 mmol) in anhydrous DCM (60 mL) under nitrogen at room temperature, was added racemic 3-amino-1-methyl-pyrrolidin-2-one (1506.8 mg, 13.2 mmol) [CAS: 2483-65-0] and magnesium sulfate (4500 mg, 37.4 mmol). The resulting mixture was left to stir at room temperature overnight. It was filtered and the filtrate washed with half saturated brine. The organic layer was dried (Na2SO4) and evaporated to give 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]-1-methyl-pyrrolidin-2-one (D1) (3.15 g, 11.2 mmol, 93% yield), as a cream solid; The resulting mixture was left It was filtered the filtrate washed with half saturated brine The organic layer was dried (Na2SO4) evaporated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with 3-amino-1-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reaction was heated at 140° C. for 20 minutes. The reaction mixture was cooled to room temperature and then treated with 0.5 mL of 25% NaOMe in MeOH and heated at 50° C. for 15 min. The mixture was then partitioned between aqueous saturated Na2CO3 solution and EtOAc. The aqueous layer was extracted with EtOAc twice more and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product. The reaction mixture was cooled to room temperature heated at 50° C. for 15 min The mixture was then partitioned between aqueous saturated Na2CO3 solution and EtOAc The aqueous layer was extracted with EtOAc twice more the combined organic phases were concentrated in vacuo The crude material was purified by preparative HPLC The isolated product was filtered through basic resin to remove residual TFA

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

Procedure: Benzophenone imine [CAS: 1013-88-3] (16.67 g, 91.98 mmol) was added dropwise to a solution of 3-amino-1-methylpyrrolidine-2-one [CAS 119329-48-5] (10 g, 87.60 mmol) in DCE (100 mL) under N2 and the reaction was heated at reflux for 18 hours. The solvent was evaporated to afford an amber oil. This was purified using flash silica in a large sinter funnel, eluting with 4:1 to 3:7 i-hexane:EtOAc. An incomplete separation was achieved. 3-(Benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) was isolated (25 g) with approximately 11% of an impurity present, but was used in the next step without further purification; the reaction was heated at reflux for 18 hours The solvent was evaporated to afford an amber oil This was purified eluting with 4:1 to 3:7 i-hexane An incomplete separation

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzophenone imine (200.04 g, 1103.8 mmol) was added dropwise over 20 minutes to a stirred solution of 3-amino-1-methylpyrrolidine-2-one (120 g, 1051.2 mmol) in DCE (1000 mL) at ambient temp under nitrogen in a 2 L flask fitted with a magnetic stirrer bar. The reagent was washed with further DCE (100 mL). The stirred solution was heated at reflux on a heat-on block at a block temp of 95° C. for 7 h, using a N2 bubbler with exhaled gas passing through a safety trap then into 2 L of water via an upturned funnel (for scrubbing NH3 gas, estimated to be approx 23 L). The reaction was left to stand at ambient temp overnight under N2. The mixture was evaporated to a thick, off-white oil. To this was added Et2O (700 ml) and to this stirred solution, as it began to crystallize, was added iso-hexane (700 ml) over 2 minutes. The mixture was stirred for 1 h then filtered under suction and washed with Et2O/iso-hexane (1:1) (500 ml). The white solid was dried at 35° C. under vacuum for 3 h to afford 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) (259.4 g, 88.6%). The NMR was consistent with pure material. fitted with a magnetic stirrer bar The reagent was washed with further DCE (100 mL) The stirred solution was heated The reaction was left The mixture was evaporated to a thick, off-white oil To this was added Et2O (700 ml) to crystallize was added iso-hexane (700 ml) over 2 minutes then filtered under suction washed with Et2O/iso-hexane (1:1) (500 ml) The white solid was dried at 35° C. under vacuum for 3 h

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

Procedure: To a stirred mixture of 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbaldehyde (which may be prepared as described in Description 141) (2980 mg, 10.904 mmol) and 3-amino-1-methyl-pyrrolidin-2-one (508.12 mg, 4.4514 mmol) in anhydrous DCM (10 mL) at room temperature, was added magnesium sulfate (3937.5 mg, 32.711 mmol). The resulting mixture was left to stir at room temperature for 3 h. The reaction mixture was filtered through a plug of cotton wool and the filtrate was washed with brine. The organic layer was collected by means of a PhaseSep cartridge. Evaporation of solvent under reduced pressure gave yellow oil, 3-[(E)-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]methyleneamino]-1-methyl-pyrrolidin-2-one (3.97 g, 10.746 mmol, 98.6% yield). To a portion of this material (3920 mg, 10.611 mmol) in anhydrous THF (35 mL) under nitrogen at room temperature, was added phenyl vinyl sulfone (2141.9 mg, 12.733 mmol) and silver acetate (1771.1 mg, 10.611 mmol). The resulting mixture was left to stir in the dark for 10 min. DBU (0.7932 mL, 5.3055 mmol) was added. The resulting mixture was left to stir in the dark for 2 h. The dark filtrate was evaporated and further dried under house vac. It was purified by silica gel chromatography (100 g SiO2) eluting with ethyl acetate in iso-hexane (30-100%) followed by methanol in ethyl acetate (0-15%). Evaporation of desired fractions gave 3-(benzenesulfonyl)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (3880 mg, 7.2166 mmol, 68.0% yield) as brown solid. To a stirred solution of this material in anhydrous THF (30 mL) under nitrogen at 0° C., was added potassium tert-butoxide (4048.9 mg, 36.083 mmol). The resulting mixture was left to stir for 2 h and acetic acid (2.07 mL, 36.08 mmol) was added. Stirring was continued for 15 min at room temperature. Evaporation of solvent under reduced pressure gave a dark oily residue. It was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (30-100%). Evaporation of desired fractions gave brown oil, 2-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D142) (543 mg, 1.373 mmol, 19.0% yield); The resulting mixture was left The reaction mixture was filtered through a plug of cotton wool the filtrate was washed with brine The organic layer was collected by means of a PhaseSep cartridge Evaporation of solvent under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of phenyl vinyl sulfone (7307.08 mg, 43.44 mmol) in methanol (80 mL) was added 3-amino-1-methyl-pyrrolidin-2-one (4958.41 mg, 43.44 mmol), 4-bromo-5-ethyl-pyridine-2-carbaldehyde (CAS: 1256833-98-3) (9300 mg, 43.44 mmol) and calcium triflate (734.57 mg, 2.17 mmol). The reaction was stirred for 10 minutes, and then the reaction was cooled to −10° C., and then triethylamine (6.04 mL, 43.44 mmol) was added dropwise. The reaction was then stirred at room temperature for 4 hours. The reaction was concentrated in vacuo, and redissolved in THF (150 mL). The reaction was cooled to 00° C., and to the reaction mixture was added potassium tert-butoxide (14622.41 mg, 130.31 mmol) portionwise. The reaction was then stirred for 2 hours while allowing to warm to room temperature. The reaction was then filtered through celite, and the celite was washed with DCM (150 mL). The filtrate was then concentrated in vacuo. The residue was purified by column chromatography over silica (340 g, Biotage SNAP cartridge), eluting with EtOAc:isohexane from 0% to 100%. Fractions containing the desired product were combined and concentrated in vacuo to give 2-(4-bromo-5-ethyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D121) (3091 mg, 9.1931 mmol, 21.2% yield) as a brown oil approximately 85% pure and used directly in the next step; The reaction was then stirred at room temperature for 4 hours The reaction was concentrated in vacuo redissolved in THF (150 mL) The reaction was cooled to 00° C The reaction was then stirred for 2 hours to warm to room temperature The reaction was then filtered through celite the celite was washed with DCM (150 mL) The filtrate was then concentrated in vacuo The residue was purified by column chromatography over silica (340 g, Biotage SNAP cartridge) eluting with EtOAc Fractions containing the desired product concentrated in vacuo