tert-butyl 2,4-dioxopiperidine-1-carboxylate

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (Ark Pharm, Inc., Libertyville, Ill.; 2.0 g, 9.389 mmol) in THF (1 L) at 20° C. was added LHMDS (1.0M in THF; 23.47 mL, 23.47 mmol) (dropwise), and the resulting mixture was stirred at 20° C. for 30 min. Isobutyl iodide (6.9 g, 37.55 mmol) was added, and the resulting mixture was stirred at 20° C. for 1 h. The mixture was neutralized with 10M aq. KHSO4 solution and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude rac-tert-butyl 5-isobutyl-2,4-dioxopiperidine-1-carboxylate (0.75 g) (used without further purification in subsequent transformations): m/z (ESI, +ve) 170.0 [(M+H)-100]+. the resulting mixture was stirred at 20° C. for 1 h extracted with EtOAc The organic extract was dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (Ark Pharm, Inc., Libertyville, Ill.; 2.0 g, 9.389 mmol) in THF (1 L) at 20° C. was added LHMDS (1.0M in THF; 23.47 mL, 23.47 mmol) (dropwise), and the resulting mixture was stirred at 20° C. for 30 min. Benzyl bromide (3.1 g, 18.77 mmol) was added, and the resulting mixture was stirred at 20° C. for 1 h. The mixture was neutralized with 10M aq. KHSO4 solution and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude rac-tert-butyl 5-benzyl-2,4-dioxopiperidine-1-carboxylate (1.0 g) (used without further purification in subsequent transformations): m/z (ESI, +ve) 204.0 [(M+H)-100]+. the resulting mixture was stirred at 20° C. for 1 h extracted with EtOAc The organic extract was dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (Ark Pharm, Inc., Libertyville, Ill.; 2.0 g, 9.389 mmol) in THF (1 L) at 20° C. was added LHMDS (1.0M in THF; 23.47 mL, 23.47 mmol) (dropwise), and the resulting mixture was stirred at 20° C. for 30 min. Benzyl bromide (3.1 g, 18.77 mmol) was added, and the resulting mixture was stirred at 20° C. for 1 h. The mixture was neutralized with 10M aq. KHSO4 solution and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude rac-tert-butyl 5-benzyl-2,4-dioxopiperidine-1-carboxylate (1.0 g) (used without further purification in subsequent transformations): m/z (ESI, +ve) 204.0 [(M+H)-100]+. the resulting mixture was stirred at 20° C. for 1 h extracted with EtOAc The organic extract was dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: A stirred mixture of 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (7.54 g, 32 mmol), 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 29.1 mmol) and sodium acetate (2.39 g, 29.1 mmol) in water (35 ml) and dioxane (35 ml) was heated to reflux for 2 hours. The mixture was cooled down to room temperature, and extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3), the combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents to give 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.8 g, 35%) as a yellow solid. was heated to reflux for 2 hours extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3) the combined organic phase was washed with saturated sodium chloride dried with anhydrous sodium sulfate filtered concentrated under reduced pressure the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents

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

Procedure: A stirred solution of [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxin-5-ylidene)-3-hydroxy-propyl]-carbamic acid tert-butyl ester (9.2 g, 29.2 mmol) obtained from Example 41 in 180 ml of dioxane was heated to reflux for 2 hours. The mixture was evaporated under reduced pressure to give the crude product 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.4 g) as a yellow oil which was used as such. to reflux for 2 hours The mixture was evaporated under reduced pressure

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

Procedure: To a suspension of Cs2CO3 (2.29 g, 7.03 mmol) in DMF (6 mL) at rt was added tert-butyl 2,4-dioxopiperidine-1-carboxylate (0.50 g, 2.35 mmol). The mixture was stirred at rt for 10 min. Carbon disulfide (0.21 mL, 3.5 mmol) was then added and the reaction mixture was stirred at rt for an additional 10 min. After cooling in an ice bath, a solution of chloroacetone (0.19 mL, 2.35 mmol) in DMF (6 mL) was added. After 1 h, a solution of Met (0.16 mL, 2.58 mmol) in DMF (3 mL) was added and the reaction mixture was warmed to rt and stirred overnight. The mixture was quenched with water (25 mL) and vigorously stirred for 10 h. The resulting mixture was concentrated in vacuo to remove DMF, partitioned between CH2Cl2 and water and filtered. The filtrate was washed with water, dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient elution, 0-30% EtOAc/hexanes) afforded the title compound. LRMS (ESI) m/z 342.0 [(M+H)+; calcd for C15H19NO4S2: 342], the reaction mixture was stirred at rt for an additional 10 min After cooling in an ice bath After 1 h the reaction mixture was warmed to rt stirred overnight The mixture was quenched with water (25 mL) vigorously stirred for 10 h The resulting mixture was concentrated in vacuo to remove DMF partitioned between CH2Cl2 and water filtered The filtrate was washed with water dried (Na2SO4) concentrated Purification by silica gel chromatography (gradient elution, 0-30% EtOAc/hexanes)

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

Procedure: To a suspension of Cs2CO3 (2.29 g, 7.03 mmol) in DMF (6 mL) at rt was added tert-butyl 2,4-dioxopiperidine-1-carboxylate (0.50 g, 2.35 mmol). The mixture was stirred at rt for 10 min. Carbon disulfide (0.21 mL, 3.5 mmol) was then added and the reaction mixture was stirred at rt for an additional 10 min. After cooling in an ice bath, a solution of chloroacetone (0.19 mL, 2.35 mmol) in DMF (6 mL) was added. After 1 h, a solution of Met (0.16 mL, 2.58 mmol) in DMF (3 mL) was added and the reaction mixture was warmed to rt and stirred overnight. The mixture was quenched with water (25 mL) and vigorously stirred for 10 h. The resulting mixture was concentrated in vacuo to remove DMF, partitioned between CH2Cl2 and water and filtered. The filtrate was washed with water, dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient elution, 0-30% EtOAc/hexanes) afforded the title compound. LRMS (ESI) m/z 342.0 [(M+H)+; calcd for C15H19NO4S2: 342], the reaction mixture was stirred at rt for an additional 10 min After cooling in an ice bath After 1 h the reaction mixture was warmed to rt stirred overnight The mixture was quenched with water (25 mL) vigorously stirred for 10 h The resulting mixture was concentrated in vacuo to remove DMF partitioned between CH2Cl2 and water filtered The filtrate was washed with water dried (Na2SO4) concentrated Purification by silica gel chromatography (gradient elution, 0-30% EtOAc/hexanes)

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

Procedure: A solution of tert-butyl[3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropyl]carbamate (8.3 g, 26.3 mmol) in EtOAc (130 mL) was heated at reflux for 4 h. The solution was concentrated to afford the title compound which was used without further purification. LRMS (ESI) m/z 214.2 [(M+H)+; calcd for C10H15NO4: 214]. at reflux for 4 h The solution was concentrated

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

Procedure: A stirred mixture of 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (7.54 g, 32 mmol), 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 29.1 mmol) and sodium acetate (2.39 g, 29.1 mmol) in water (35 ml) and dioxane (35 ml) was heated to reflux for 2 hours. The mixture was cooled down to room temperature, and extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3), the combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents to give 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.8 g, 35%) as a yellow solid. was heated to reflux for 2 hours extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3) the combined organic phase was washed with saturated sodium chloride dried with anhydrous sodium sulfate filtered concentrated under reduced pressure the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents

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

Procedure: A stirred mixture of 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (7.54 g, 32 mmol), 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 29.1 mmol) and sodium acetate (2.39 g, 29.1 mmol) in water (35 ml) and dioxane (35 ml) was heated to reflux for 2 hours. The mixture was cooled down to room temperature, and extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3), the combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents to give 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.8 g, 35%) as a yellow solid. was heated to reflux for 2 hours extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3) the combined organic phase was washed with saturated sodium chloride dried with anhydrous sodium sulfate filtered concentrated under reduced pressure the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents

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

Procedure: A stirred solution of [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxin-5-ylidene)-3-hydroxy-propyl]-carbamic acid tert-butyl ester (9.2 g, 29.2 mmol) obtained from Example 41 in 180 ml of dioxane was heated to reflux for 2 hours. The mixture was evaporated under reduced pressure to give the crude product 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.4 g) as a yellow oil which was used as such. to reflux for 2 hours The mixture was evaporated under reduced pressure

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropylcarbamate (I-59b: 50 g, 158.57 mmol) was dissolved in ethyl acetate (500 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was heated at 105° C. for 20 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mass was cooled to room temperature and concentrated under reduced pressure to afford the crude product. Purification by ether-wash afforded 28 g of the product (83% yield). the resulting reaction mass The reaction mass was cooled to room temperature concentrated under reduced pressure to afford the crude product Purification by ether- wash