(S)-叔丁氧羰基-3-氨基-2-吡咯烷酮

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (0.096 g, 2.4 mmol, 60% by weight) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.4 g, 2 mmol) in 15 mL, of THF at 0° C. The mixture is stirred for 30 minutes then a solution of 6-bromomethyl-4-chloroquinoline (0.513 g, 2 mmol) in 15 mL THF is added slowly. The resulting solution is warmed to room temperature over 4 hours. The reaction mixture is quenched with saturated ammonium chloride solution then diluted with EtOAc. The organic layer is separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue is dissolved in ethyl acetate (50 mL), and saturated with HCl gas at 0° C. The solution is stirred at 0° C. for 15 minutes, then the solution is warmed to room temperature. After four hours at room temperature, the solid that precipitates is collected, and washed with ether to give the title compound (0.445 g, 1.43 mmol) as a pale yellow solid. The reaction mixture is quenched with saturated ammonium chloride solution then diluted with EtOAc The organic layer is separated washed with brine dried over Na2SO4 filtered concentrated The residue is dissolved in ethyl acetate (50 mL) at 0° C The solution is stirred at 0° C. for 15 minutes the solution is warmed to room temperature After four hours at room temperature the solid that precipitates is collected washed with ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidin-3-ylcarbamate was prepared from compound (s)-tert-butyl 2-oxopyrrolidin-3-ylcarbamate (Example 6) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 80% ethyl acetate/hexanes, to provide compound (2b) in 37% yield. The crude product was purified by column chromatography eluting with 80% ethyl acetate/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-tert-butyl 1-methyl-2-oxopyrrolidin-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxopyrrolidin-3-ylcarbamate (Example 6) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% acetone/hexanes to provide compound (2a) in 45% yield. The crude product was purified by column chromatography eluting with 25% acetone/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-tert-butyl 1-methyl-2-oxopyrrolidin-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxopyrrolidin-3-ylcarbamate (Example 6) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% acetone/hexanes to provide compound (2a) in 45% yield. The crude product was purified by column chromatography eluting with 25% acetone/hexanes

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (R)-6-bromo-4-((1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.039 mmol), (S)-tert-butyl (2-oxopyrrolidin-3-yl)carbamate (21.6 mg, 0.108 mmol), copper(I) iodide (1.5 mg, 7.70 mmol), potassium carbonate (16.0 mg, 0.116 mmol) in dioxane (0.5 mL) was pumped under vacuum and backfilled with nitrogen twice. N1,N2-dimethylethane-1,2-diamine (8.3 μl, 0.077 mmol) was added. The reaction tube was sealed and heated at 100° C. for 17 h. The mixture was diluted with a 1:1 mixture of methanol-dichloromethane (2 mL) and filtered. The filtrate was concentrated to give crude product (48.3 mg) as brown solid. Part of the material (15.6 mg) was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water; Mobile Phase B: acetonitrile; Buffer: 20-mM ammonium acetate; Gradient: 15-100% B over 10.9 minutes, then a 4.0 minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give tert-butyl ((S)-1-(3-carbamoyl-4-(((R)-1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-2-oxopyrrolidin-3-yl)carbamate (4.4 mg, 20% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J=8.9 Hz, 2H), 4.41 (t, J=9.4 Hz, 1H), 4.09 (dd, J=10.2, 3.7 Hz, 1H), 3.91-3.72 (m, 3H), 3.57 (d, J=12.9 Hz, 1H), 3.25-3.16 (m, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.66-2.57 (m, 1H), 2.25-2.07 (m, 2H), 1.96-1.84 (m, 1H), 1.44 (s, 9H), 1.16 (s, 3H), 1.08 (s, 3H); MS (ES+) m/z: 587.1 (M+H); LC retention time: 1.78 min (analytical LCMS Method I). The reaction tube was sealed filtered The filtrate was concentrated to give crude product (48.3 mg) as brown solid Part of the material (15.6 mg) was purified via preparative LC/MS with the following conditions a 4.0 minute hold Fractions containing the desired product dried via centrifugal evaporation

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester (1 g, 5 mmol) is dissolved in THF (100 mL) under nitrogen, and cooled to 0° C. Potassium-tert-butoxide (0.62 g, 5.5 mmol) is added in one portion to the vigorously stirring solution, followed by 18-crown-6 (10 mg, 0.038 mmol), and the reaction mixture allowed to warm to room temperature and stirred for 1 hour. The solution is cooled to 0° C. and 2-amino-4-(bromomethyl)benzonitrile (1.16 g, 5.5 mmol) added dropwise as a solution in THF (10 mL), before leaving the reaction mixture to warm to room temperature and stir overnight. The reaction is quenched with 0.25M HCl (20 mL), then neutralized with saturated aqueous NaHCO3, and brine added. The solution is extracted with ethyl acetate, and the organic phase dried over MgSO4, concentrated, and purified by column chromatograph on silica with 0.5-5% methanol/dichloromethane. The product fractions are combined, concentrated, and the semi-solid oily residue triturated with hexanes/dichloromethane=100/1 (25 mL). The product is isolated as a pale yellow powder (1.24 g, 3.75 mmol). to warm to room temperature The solution is cooled to 0° C. before leaving the reaction mixture to warm to room temperature stir overnight The reaction is quenched with 0.25M HCl (20 mL) added The solution is extracted with ethyl acetate the organic phase dried over MgSO4 concentrated purified by column chromatograph on silica with 0.5-5% methanol/dichloromethane concentrated the semi-solid oily residue triturated with hexanes/dichloromethane=100/1 (25 mL)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester (1 g, 5 mmol) is dissolved in THF (100 mL) under nitrogen, and cooled to 0° C. Potassium-tert-butoxide (0.62 g, 5.5 mmol) is added in one portion to the vigorously stirring solution, followed by 18-crown-6 (10 mg, 0.038 mmol), and the reaction mixture allowed to warm to room temperature and stirred for 1 hour. The solution is cooled to 0° C. and 2-amino-4-(bromomethyl)benzonitrile (1.16 g, 5.5 mmol) added dropwise as a solution in THF (10 mL), before leaving the reaction mixture to warm to room temperature and stir overnight. The reaction is quenched with 0.25M HCl (20 mL), then neutralized with saturated aqueous NaHCO3, and brine added. The solution is extracted with ethyl acetate, and the organic phase dried over MgSO4, concentrated, and purified by column chromatograph on silica with 0.5-5% methanol/dichloromethane. The product fractions are combined, concentrated, and the semi-solid oily residue triturated with hexanes/dichloromethane=100/1 (25 mL). The product is isolated as a pale yellow powder (1.24 g, 3.75 mmol). to warm to room temperature The solution is cooled to 0° C. before leaving the reaction mixture to warm to room temperature stir overnight The reaction is quenched with 0.25M HCl (20 mL) added The solution is extracted with ethyl acetate the organic phase dried over MgSO4 concentrated purified by column chromatograph on silica with 0.5-5% methanol/dichloromethane concentrated the semi-solid oily residue triturated with hexanes/dichloromethane=100/1 (25 mL)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: [2-Oxo-pyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (4.0 g, 20 mmol) is dissolved in THF (150 mL), cooled in an ice bath and treated with 60% sodium hydride (0.95 g, 24 mmol). The reaction mixture is stirred for 30 min., then treated with tetra-butylammonium iodide (0.16 g, 0.44 mmol) and bromoacetonitrile (1.7 mL, 24 mmol). After 3 h the reaction is quenched with water, concentrated to a small volume and extracted with methylene chloride (4×). The combined organic extracts are concentrated and the residue is chromatographed (2% MeOH/CH2Cl2) to give [1-cyanomethyl-2-oxo-pyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (3.4 g 14 mmol). ). EI MS m/z: 240, [M+1]+; 1H NMR (CDCl3, 300 MHz) δ5.08 (br, 1H), 4.27 (m, 2H), 4.15 (m, 1H), 3.47 (m, 2H), 2.68 (m, 1H), 2.00 (m, 1H), 1.45 (s, 9H). This material (3.0 g, 12.6 mmol) is dissolved in ethanol (80 mL) and treated with platinum oxide (0.8 g) at 50 PSI of hydrogen gas for 24 h. The catalyst is removed by filtration and the solution is concentrated to yield the title compound (2.9 g, 12 mmol). EI MS m/z: 244, [M+1]+; 1H NMR (CDCl3, 300 MHz) δ5.13 (br, 1H), 4.13 (m, 1H), 3.34 (m, 5H), 2.85 (t, 1H), 2.60 (m, 1H), 1.90 (m, 1H), 1.40 (s, 9H). cooled in an ice bath After 3 h the reaction is quenched with water concentrated to a small volume extracted with methylene chloride (4×) The combined organic extracts are concentrated the residue is chromatographed (2% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using propargyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated from Et2O/hexanes to give the title compound as a white solid. The crude product is triturated from Et2O/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using propargyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated from Et2O/hexanes to give the title compound as a white solid. The crude product is triturated from Et2O/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 1-benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridine in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 15% EtOAc/hexanes to 50% EtOAc/hexanes to give the title compound as a beige solid. The crude product is purified by column chromatography eluting with a gradient of 15% EtOAc/hexanes to 50% EtOAc/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (0.081 g, 2.02 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.404 g, 2.02 mmol) in DMF (5 mL) at 0° C. The mixture is stirred for 10 minutes, then cannulated dropwise to a solution of 1-benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridine (0.74 g, 1.92 mmol) in DMF (10 mL) at 0° C. The resulting yellow solution is stirred for 1 hour at 0° C. then quenched with saturated ammonium chloride solution and diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The solid product (0.94 g, 1.86 mmol) is used in the subsequent step without further purification. The resulting yellow solution is stirred for 1 hour at 0° C. then quenched with saturated ammonium chloride solution diluted with EtOAc The organic layer is washed with water and brine dried over MgSO4 filtered concentrated