(S)-3-氨基吡咯烷-2-酮

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

实验步骤: To a stirred solution of 5-(2,4-Difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (16.3 g, 44.7 mmol) in a mixture of DCM (180 mL) and DMF (60 mL) at ambient temperature was added HOBt hydrate (6.85 g, 44.7 mmol). Once all of the HOBt had dissolved, (S)-3-aminopyrrolidin-2-one 4.84 g, 48.3 mmol) was added. To the resulting stirred solution at ambient temperature was added EDC (9.43 g, 49.2 mmol), and the resulting cloudy mixture was stirred at ambient temperature. After stirring for a total of 24 hr the DCM was evaporated under reduced pressure. The residual DMF solution was stirred and diluted with water (300 mL), and the resulting mixture was stirred at ambient temperature. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the crude product (20.7 g, 104%). This material was combined with a second batch (37.8 g) and recrystallized as follows: The two batches were combined in a 1000 mL Erlenmeyer flask. Acetone (250 mL) was added, and the mixture stirred with gentle heating on a hot plate. All solid dissolved as the solution boiled (52° C.). While the solution was boiling and stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel. Shortly after completion of addition, the product began to crystallize. A second portion of hexanes (250 mL) was added slowly as crystallization continued. The resulting mixture was stored at 2° C. for 14 hr. The crystals that formed were collected by filtration, washed with cold 2:1 hexane:acetone, and dried under vacuum to afford the title compound as an off-white powder (48.2 g, 83% recovery). 1H NMR (CDCl3). δ 1.37 (d, J=2.8 Hz, 3H); 1.42 (d, J=3.2 Hz, 3H); 2.02-2.17 (m, 1H); 2.85-2.91 (m, 1H); 3.42-3.46 (m, 2H); 4.53-4.60 (m, 3H); 5.97 (broad s, 1H); 6.88-6.93 (m, 1H); 6.98-7.03 (m, 2H); 7.12-7.18 (m, 1H); 7.90 (s, 1H); 8.20 (d, J=5.2 Hz, 1H); 8.42 (s, 1H). MS (LC/MS/pos): 469.1 (M+Na)+. Chiral purity is >99% ee (done by chiral HPLC). the resulting cloudy mixture was stirred at ambient temperature was evaporated under reduced pressure The residual DMF solution was stirred diluted with water (300 mL) the resulting mixture was stirred at ambient temperature The precipitate that formed was collected by filtration washed with water dried under vacuum to afford the crude product (20.7 g, 104%) recrystallized Acetone (250 mL) was added the mixture stirred with gentle heating on a hot plate All solid dissolved as the solution (52° C.) stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel Shortly after completion of addition to crystallize A second portion of hexanes (250 mL) was added slowly as crystallization The crystals that formed were collected by filtration washed with cold 2:1 hexane acetone, and dried under vacuum

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

实验步骤: To a stirred solution of 5-(2,4-Difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (16.3 g, 44.7 mmol) in a mixture of DCM (180 mL) and DMF (60 mL) at ambient temperature was added HOBt hydrate (6.85 g, 44.7 mmol). Once all of the HOBt had dissolved, (S)-3-aminopyrrolidin-2-one 4.84 g, 48.3 mmol) was added. To the resulting stirred solution at ambient temperature was added EDC (9.43 g, 49.2 mmol), and the resulting cloudy mixture was stirred at ambient temperature. After stirring for a total of 24 hr the DCM was evaporated under reduced pressure. The residual DMF solution was stirred and diluted with water (300 mL), and the resulting mixture was stirred at ambient temperature. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the crude product (20.7 g, 104%). This material was combined with a second batch (37.8 g) and recrystallized as follows: The two batches were combined in a 1000 mL Erlenmeyer flask. Acetone (250 mL) was added, and the mixture stirred with gentle heating on a hot plate. All solid dissolved as the solution boiled (52° C.). While the solution was boiling and stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel. Shortly after completion of addition, the product began to crystallize. A second portion of hexanes (250 mL) was added slowly as crystallization continued. The resulting mixture was stored at 2° C. for 14 hr. The crystals that formed were collected by filtration, washed with cold 2:1 hexane:acetone, and dried under vacuum to afford the title compound as an off-white powder (48.2 g, 83% recovery). 1H NMR (CDCl3). δ 1.37 (d, J=2.8 Hz, 3H); 1.42 (d, J=3.2 Hz, 3H); 2.02-2.17 (m, 1H); 2.85-2.91 (m, 1H); 3.42-3.46 (m, 2H); 4.53-4.60 (m, 3H); 5.97 (broad s, 1H); 6.88-6.93 (m, 1H); 6.98-7.03 (m, 2H); 7.12-7.18 (m, 1H); 7.90 (s, 1H); 8.20 (d, J=5.2 Hz, 1H); 8.42 (s, 1H). MS (LC/MS/pos): 469.1 (M+Na)+. Chiral purity is >99% ee (done by chiral HPLC). the resulting cloudy mixture was stirred at ambient temperature was evaporated under reduced pressure The residual DMF solution was stirred diluted with water (300 mL) the resulting mixture was stirred at ambient temperature The precipitate that formed was collected by filtration washed with water dried under vacuum to afford the crude product (20.7 g, 104%) recrystallized Acetone (250 mL) was added the mixture stirred with gentle heating on a hot plate All solid dissolved as the solution (52° C.) stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel Shortly after completion of addition to crystallize A second portion of hexanes (250 mL) was added slowly as crystallization The crystals that formed were collected by filtration washed with cold 2:1 hexane acetone, and dried under vacuum

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

实验步骤: To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (prepared according to Example 26; 100 mg, 0.217 mmol) in dichloromethane (1 mL) was added (S)-3-aminopyrrolidin-2-one (4a) 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 447 (M+1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 8.21 (br, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 6.59 (br, 1H), 4.58 (m, 1H), 4.55 (d, 2H), 3.43 (m, 2H), 2.84 (m, 1H), 2.06 (m, 1H), 1.40 (d, 3H), 1.39 (d, 3H). washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride The organic layer was dried over anhydrous sodium sulfate filtered concentrated The residue was purified by column chromatography on a silica gel column eluting with 50% acetone/hexanes

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

实验步骤: 5-(2,4-Difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylic acid (200 mg, 0.552 mmol) was dissolved in N,N-dimethylformamide (2 mL). To his was added (S)-3-aminopyrrolidin-2-one (4a) (111 mg, 1.10 mmol), 4-(dimethylamino)pyridine (6.7 mg, 0.055 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.607 mmol) successively, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ij) (83 mg, 34%). Mass spec: 445 (M+1). 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.26 (brd, 1H), 7.93 (s, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 6.04 (br, 1H), 4.59 (ddd, 1H), 4.37 (s, 2H), 3.64 (brs, 1H), 3.45 (m, 2H), 2.87 (m, 1H), 2.09 (m, 1H), 1.21 (s, 3H), 1.12 (s, 3H). The reaction mixture was partitioned between water and ethyl acetate the aqueous layer was extracted twice with ethyl acetate The combined organic layers were dried over anhydrous sodium sulfate filtered concentrated The crude product was purified by flash chromatography on a silica gel column eluting with 100% acetone

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

实验步骤: To a solution of 2,5-dioxopyrrolidin-1-yl 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (700 mg, 1.58 mmol) in dichloromethane (5 mL) was added (S)-3-aminopyrrolidin-2-one (prepared according to Example 2, 205 mg, 2.05 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 25-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ia) (520 mg, 77%). Mass spec: 429 (M+1). 1H NMR (CDCl3) δ 8.37 (s, 1H), 8.26 (d, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.03 (br, 1H), 4.59 (ddd, 1H), 4.22 (d, 2H), 3.46 (m, 2H), 2.87 (m, 1H), 2.36 (m, 1H), 2.10 (m, 1H), 0.92 (d, 6H). washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride The organic layer was dried over anhydrous sodium sulfate filtered concentrated The residue was purified by column chromatography on a silica gel column eluting with a gradient of 25-100% acetone/hexanes

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

实验步骤: To a solution of 2,5-dioxopyrrolidin-1-yl 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (700 mg, 1.58 mmol) in dichloromethane (5 mL) was added (S)-3-aminopyrrolidin-2-one (prepared according to Example 2, 205 mg, 2.05 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 25-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ia) (520 mg, 77%). Mass spec: 429 (M+1). 1H NMR (CDCl3) δ 8.37 (s, 1H), 8.26 (d, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.03 (br, 1H), 4.59 (ddd, 1H), 4.22 (d, 2H), 3.46 (m, 2H), 2.87 (m, 1H), 2.36 (m, 1H), 2.10 (m, 1H), 0.92 (d, 6H). washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride The organic layer was dried over anhydrous sodium sulfate filtered concentrated The residue was purified by column chromatography on a silica gel column eluting with a gradient of 25-100% acetone/hexanes

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

实验步骤: To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol), prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Å molecular sieves and 0.77 g NaBH3CN (12 mmol) were added; after 10 minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldehyde in 40 ml of anhydrous methanol were added. The reaction was carried out for 3 hours, then the mixture filtered, the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to give the title compound m.p. 140.5-143.5° C. were added The reaction was carried out for 3 hours the mixture filtered the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%) The free base thus obtained

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

实验步骤: To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol), prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Å molecular sieves and 0.77 g NaBH3CN (12 mmol) were added; after 10 minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldeyde in 40 ml of anhydrous methanol were added. The reaction was carried out for 3 hours, then the mixture filtered, the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to give the title compound m.p. 140.5-143.5° C. were added The reaction was carried out for 3 hours the mixture filtered the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%) The free base thus obtained

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

实验步骤: To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol), prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Å molecular sieves and 0.77 g NaBH3CN (12 mmol) were added; after 10 minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldeyde in 40 ml of anhydrous methanol were added. The reaction was carried out for 3 hours, then the mixture filtered, the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to give the title compound m.p. 140.5-143.5° C. were added The reaction was carried out for 3 hours the mixture filtered the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%) The free base thus obtained

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

实验步骤: 6-(1-Chloroethyl)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine hydrochloride (Described in Example 91) was coupled with (3S)-3-aminopyrrolidin-2-one (prepared from (2S)-2,4-diaminobutanoic acid according to the method in Synthesis 1978, 614) using an analogous method to that described for the equivalent step in Example 62 to give (3S)-3-[(1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)amino]pyrrolidin-2-one as a 1:1 mixture of diastereoisomers; 1H NMR Spectrum: (DMSO d6) 1.42 and 1.46 (both d, 1.5H); 1.71 and 1.81 (both m, 0.5H); 2.09 and 2.31 (both m, 0.5H); 3.00 (t, 0.5H); 3.11 (m, 1.5H); 3.23 (t, 1H); 4.03 (s, 3H); 4.27 and 4.52 (both m, 0.5H); 7.25 and 7.27 (both s, 0.5H); 7.34 (m, 1H); 7.53 (m, 1H); 7.61 (m, 1H); 7.74 and 7.77 (both s, 0.5H); 8.49 (m, 2H); 9.79 and 9.88 (both s, 0.5H); Mass Spectrum: (M+H)+ 430.

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

实验步骤: To a stirred solution of 5-(2,4-Difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (16.3 g, 44.7 mmol) in a mixture of DCM (180 mL) and DMF (60 mL) at ambient temperature was added HOBt hydrate (6.85 g, 44.7 mmol). Once all of the HOBt had dissolved, (S)-3-aminopyrrolidin-2-one 4.84 g, 48.3 mmol) was added. To the resulting stirred solution at ambient temperature was added EDC (9.43 g, 49.2 mmol), and the resulting cloudy mixture was stirred at ambient temperature. After stirring for a total of 24 hr the DCM was evaporated under reduced pressure. The residual DMF solution was stirred and diluted with water (300 mL), and the resulting mixture was stirred at ambient temperature. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the crude product (20.7 g, 104%). This material was combined with a second batch (37.8 g) and recrystallized as follows: The two batches were combined in a 1000 mL Erlenmeyer flask. Acetone (250 mL) was added, and the mixture stirred with gentle heating on a hot plate. All solid dissolved as the solution boiled (52° C.). While the solution was boiling and stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel. Shortly after completion of addition, the product began to crystallize. A second portion of hexanes (250 mL) was added slowly as crystallization continued. The resulting mixture was stored at 2° C. for 14 hr. The crystals that formed were collected by filtration, washed with cold 2:1 hexane:acetone, and dried under vacuum to afford the title compound as an off-white powder (48.2 g, 83% recovery). 1H NMR (CDCl3). δ 1.37 (d, J=2.8 Hz, 3H); 1.42 (d, J=3.2 Hz, 3H); 2.02-2.17 (m, 1H); 2.85-2.91 (m, 1H); 3.42-3.46 (m, 2H); 4.53-4.60 (m, 3H); 5.97 (broad s, 1H); 6.88-6.93 (m, 1H); 6.98-7.03 (m, 2H); 7.12-7.18 (m, 1H); 7.90 (s, 1H); 8.20 (d, J=5.2 Hz, 1H); 8.42 (s, 1H). MS (LC/MS/pos): 469.1 (M+Na)+. Chiral purity is >99% ee (done by chiral HPLC). the resulting cloudy mixture was stirred at ambient temperature was evaporated under reduced pressure The residual DMF solution was stirred diluted with water (300 mL) the resulting mixture was stirred at ambient temperature The precipitate that formed was collected by filtration washed with water dried under vacuum to afford the crude product (20.7 g, 104%) recrystallized Acetone (250 mL) was added the mixture stirred with gentle heating on a hot plate All solid dissolved as the solution (52° C.) stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel Shortly after completion of addition to crystallize A second portion of hexanes (250 mL) was added slowly as crystallization The crystals that formed were collected by filtration washed with cold 2:1 hexane acetone, and dried under vacuum

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

实验步骤: To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (prepared according to Example 26; 100 mg, 0.217 mmol) in dichloromethane (1 mL) was added (S)-3-aminopyrrolidin-2-one (4a) 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 447 (M+1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 8.21 (br, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 6.59 (br, 1H), 4.58 (m, 1H), 4.55 (d, 2H), 3.43 (m, 2H), 2.84 (m, 1H), 2.06 (m, 1H), 1.40 (d, 3H), 1.39 (d, 3H). washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride The organic layer was dried over anhydrous sodium sulfate filtered concentrated The residue was purified by column chromatography on a silica gel column eluting with 50% acetone/hexanes